Presented by Dr. Cimino-Mathews and prepared by Dr. Armen Khararjian
This case talks about: A 50 year-old male with a lung mass
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Week 626: Case 1
50 year-old male with a lung mass
Correct
Answer: E. Epithelioid Sarcoma
Histology:
The wedge resection of lung reveals a subpleural area of fibrosis with central necrosis surrounding by a peripheral rim atypical epithelioid cells. Cytologically, the individual cells are epithelioid with pale pink cytoplasm, high nuclear-to-cytplasmic ratios, prominent nucleoli and frequent mitotic figures. Architecturally, the atypical cells appear to be either making or lining slit-like and alveolar-like spaces, giving the impression of either vascular formation or an alveolar growth pattern. The patient has a history of a forearm epithelioid sarcoma. Immunostains on the lung lesion reveal it to be positive for AE1/AE3 and CD34, and negative for CD31, with loss of INI-1 labeling.
Discussion:
The wedge resection of lung reveals an atypical epithelioid proliferation that has a slit-like (pseudo-vascular) or alveolar-like growth pattern, mimicking a vascular neoplasm, lung adenocarcinoma in situ (bronchioalveolar carcinoma), or adenocarcinoma with lepidic growth. Indeed, without the clinical history of a known epithelioid sarcoma of soft tissue diagnosed six years prior, the diagnosis of metastatic epithelioid sarcoma a priori would be very difficult. As always, clinical history is key. Primary epithelioid sarcomas most commonly involve the distal extremities, characteristically display nodular growth with associated granulomatous inflammation, and are unique among sarcomas in that they can metastasize to lymph nodes and may develop late metastatic spread. The immunopanel performed in this case includes a cytokeratin (AE1/AE3), “vascular markers” CD31 and CD34, and INI-1, which are stains that cover the entities of carcinoma, angiosarcoma, and epithelioid sarcoma.
Carcinomas are immunoreactive for cytokeratin such as AE1/AE3, retain nuclear INI-1 labeling, and are usually negative for CD34 and CD31. Cytokeratin labeling is typically used to support a diagnosis of carcinoma; however cytokeratin labeling can be seen in some sarcomas—most notably epithelioid angiosarcoma and epithelioid sarcoma, but also leiomyosarcoma—and this is a potential diagnostic pitfall. Epithelioid angiosarcomas are typically immunoreactive for both CD34 and CD31 and retain nuclear INI-1 labeling, but may also display cytokeratin positivity. Epithelioid sarcomas are positive for cytokeratin and CD34, but are negative for CD31 and characteristically display loss of nuclear INI-1 labeling. INI-1 is a tumor suppressor gene, and loss of INI-1 labeling by immunohistochemistry is characteristically seen in epithelioid sarcoma, malignant rhabdoid tumor, renal medullary carcinoma, myoepithelial carcinomas, and extraskeletal myxoid chrondrosarcomas
References:
1. Hollmann TJ, Hornick JL. INI1-deficient tumors: diagnostic features and molecular genetics. Am J Surg Pathol. 2011 Oct;35(10):e47-63.
Incorrect
Answer: E. Epithelioid Sarcoma
Histology:
The wedge resection of lung reveals a subpleural area of fibrosis with central necrosis surrounding by a peripheral rim atypical epithelioid cells. Cytologically, the individual cells are epithelioid with pale pink cytoplasm, high nuclear-to-cytplasmic ratios, prominent nucleoli and frequent mitotic figures. Architecturally, the atypical cells appear to be either making or lining slit-like and alveolar-like spaces, giving the impression of either vascular formation or an alveolar growth pattern. The patient has a history of a forearm epithelioid sarcoma. Immunostains on the lung lesion reveal it to be positive for AE1/AE3 and CD34, and negative for CD31, with loss of INI-1 labeling.
Discussion:
The wedge resection of lung reveals an atypical epithelioid proliferation that has a slit-like (pseudo-vascular) or alveolar-like growth pattern, mimicking a vascular neoplasm, lung adenocarcinoma in situ (bronchioalveolar carcinoma), or adenocarcinoma with lepidic growth. Indeed, without the clinical history of a known epithelioid sarcoma of soft tissue diagnosed six years prior, the diagnosis of metastatic epithelioid sarcoma a priori would be very difficult. As always, clinical history is key. Primary epithelioid sarcomas most commonly involve the distal extremities, characteristically display nodular growth with associated granulomatous inflammation, and are unique among sarcomas in that they can metastasize to lymph nodes and may develop late metastatic spread. The immunopanel performed in this case includes a cytokeratin (AE1/AE3), “vascular markers” CD31 and CD34, and INI-1, which are stains that cover the entities of carcinoma, angiosarcoma, and epithelioid sarcoma.
Carcinomas are immunoreactive for cytokeratin such as AE1/AE3, retain nuclear INI-1 labeling, and are usually negative for CD34 and CD31. Cytokeratin labeling is typically used to support a diagnosis of carcinoma; however cytokeratin labeling can be seen in some sarcomas—most notably epithelioid angiosarcoma and epithelioid sarcoma, but also leiomyosarcoma—and this is a potential diagnostic pitfall. Epithelioid angiosarcomas are typically immunoreactive for both CD34 and CD31 and retain nuclear INI-1 labeling, but may also display cytokeratin positivity. Epithelioid sarcomas are positive for cytokeratin and CD34, but are negative for CD31 and characteristically display loss of nuclear INI-1 labeling. INI-1 is a tumor suppressor gene, and loss of INI-1 labeling by immunohistochemistry is characteristically seen in epithelioid sarcoma, malignant rhabdoid tumor, renal medullary carcinoma, myoepithelial carcinomas, and extraskeletal myxoid chrondrosarcomas
References:
1. Hollmann TJ, Hornick JL. INI1-deficient tumors: diagnostic features and molecular genetics. Am J Surg Pathol. 2011 Oct;35(10):e47-63.
Presented by Dr. Cimino-Mathews and prepared by Dr. Armen Khararjian.
This case talks about: A 25 year-old female with a lung mass.
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Week 626: Case 2
25 year-old female with a lung mass.
Correct
Answer: B. Granular Cell Tumor
Histology:
The lung lobectomy shows a peri-bronchial lesion centered in the submucosa, with polypoid projections into the bronchial lumen. The lesion consists of sheets and nests of round to polygonal cells with abundant eosinophilic, granular cytoplasm, round nuclei and prominent nucleoli. There is no necrosis, pleomorphism, or increased mitotic activity. Immunostains show the lesional cells to be positive for CD68 and S100, and to be negative for cytokeratin AE1/AE3.
Discussion:
Granular cell tumors are neoplasms arising from peripheral nerve Schwann cells and can occur throughout the body, although they characteristically involve the head and neck region. Granular cell tumors may be grossly well-circumscribed or infiltrative, and clinically can mimic a carcinoma. When occurring in submucosal regions, granular cell tumors can incite a prominent pseudoepitheliomatous hyperplasia in the overlying squamous epithelium, mimicking an in situ or invasive squamous cell carcinoma.
Histologically, granular cell tumors resemble histiocytes and the differential diagnosis includes xanthrogranulomatous inflammation or fat necrosis. In addition, when granular cell tumors infiltrate as cords of cells, they can resemble histiocytoid carcinoma (such as histiocytoid lobular carcinoma of the breast). Immunophenotypically, granular cell tumors are positive for inhibin, CD68, S100 protein, and NSE, and are negative for cytokeratin.
The majority of granular cell tumors are benign and are treated with complete excision, however malignant granular cell tumors that can metastasize do occur. The presence of three or more of the following features suggests malignancy in a granular cell tumor: the presence of necrosis, increased mitotic activity (>2 mitoses per 10 high power fields), vesicular nuclei with markedly prominent nucleoli, and pleomorphism.
References:
1. Fanburg-Smith JC, Meis-Kindblom JM, Fante R, Kindblom LG. Malignant granular cell tumor of soft tissue: diagnostic criteria and clinicopathologic correlation. Am J Surg Pathol. 1998;22(7):779-94.
2. Le BH, Boyer PJ, Lewis JE, Kapadia SB. Granular cell tumor: immunohistochemical assessment of inhibin-alpha, protein gene product 9.5, S100 protein, CD68, and Ki-67 proliferative index with clinical correlation. Archives Pathol Lab Med. 2004;128(7):771-5.
Incorrect
Answer: B. Granular Cell Tumor
Histology:
The lung lobectomy shows a peri-bronchial lesion centered in the submucosa, with polypoid projections into the bronchial lumen. The lesion consists of sheets and nests of round to polygonal cells with abundant eosinophilic, granular cytoplasm, round nuclei and prominent nucleoli. There is no necrosis, pleomorphism, or increased mitotic activity. Immunostains show the lesional cells to be positive for CD68 and S100, and to be negative for cytokeratin AE1/AE3.
Discussion:
Granular cell tumors are neoplasms arising from peripheral nerve Schwann cells and can occur throughout the body, although they characteristically involve the head and neck region. Granular cell tumors may be grossly well-circumscribed or infiltrative, and clinically can mimic a carcinoma. When occurring in submucosal regions, granular cell tumors can incite a prominent pseudoepitheliomatous hyperplasia in the overlying squamous epithelium, mimicking an in situ or invasive squamous cell carcinoma.
Histologically, granular cell tumors resemble histiocytes and the differential diagnosis includes xanthrogranulomatous inflammation or fat necrosis. In addition, when granular cell tumors infiltrate as cords of cells, they can resemble histiocytoid carcinoma (such as histiocytoid lobular carcinoma of the breast). Immunophenotypically, granular cell tumors are positive for inhibin, CD68, S100 protein, and NSE, and are negative for cytokeratin.
The majority of granular cell tumors are benign and are treated with complete excision, however malignant granular cell tumors that can metastasize do occur. The presence of three or more of the following features suggests malignancy in a granular cell tumor: the presence of necrosis, increased mitotic activity (>2 mitoses per 10 high power fields), vesicular nuclei with markedly prominent nucleoli, and pleomorphism.
References:
1. Fanburg-Smith JC, Meis-Kindblom JM, Fante R, Kindblom LG. Malignant granular cell tumor of soft tissue: diagnostic criteria and clinicopathologic correlation. Am J Surg Pathol. 1998;22(7):779-94.
2. Le BH, Boyer PJ, Lewis JE, Kapadia SB. Granular cell tumor: immunohistochemical assessment of inhibin-alpha, protein gene product 9.5, S100 protein, CD68, and Ki-67 proliferative index with clinical correlation. Archives Pathol Lab Med. 2004;128(7):771-5.
Presented by Dr. Cimino-Mathews and prepared by Dr. Armen Khararjian.
This case talks about: A 20 year-old female with a breast mass.
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Week 626: Case 3
A 20 year old female with a breast mass.
Correct
Answer: D. Lactating Adenoma
Histology:
The core needle biopsy of the breast reveals nodular arrangement of dilated, hyperplastic terminal ducts and lobules whose cells display prominent lactational (secretory) change, characterized by vacuolated cytoplasm, occasional hobnail appearance of the cells, and punctate nucleoli. Some of the dilated lobules contain pale pink secretions.
Discussion:
The patient is a pregnant female with a new firm, mobile breast mass. The core biopsy reveals characteristic features of a lactating adenoma (also termed “nodular lactational hyperplasia”), which occur during pregnancy and the post-partum period. These lesions are typically well circumscribed and clinically resemble fibroadenomas. The appearance of the nucleoli within the nuclei can initially appear alarming, however the nucleoli are punctate, the nuclei are fairly small and uniform and the associated secretions are reassuring. The differential diagnosis of benign lactational or secretory change is hypersecretory cystic hyperplasia, which contains dilated cystic spaces, and atypical hypersecretory cystic hyperplasia, which displays cytologic atypia such as nuclear enlargement and prominent nucleoli. Focal secretory or lactational-like change can also be seen in the benign breast tissue of non-pregnant or non-lactating patients as well.
References:
1. O’Hara MF, Page DL. Adenomas of the breast and ectopic breast under lactational influences. Hum Pathol. 1985 Jul;16(7):707-12.
Incorrect
Answer: D. Lactating Adenoma
Histology:
The core needle biopsy of the breast reveals nodular arrangement of dilated, hyperplastic terminal ducts and lobules whose cells display prominent lactational (secretory) change, characterized by vacuolated cytoplasm, occasional hobnail appearance of the cells, and punctate nucleoli. Some of the dilated lobules contain pale pink secretions.
Discussion:
The patient is a pregnant female with a new firm, mobile breast mass. The core biopsy reveals characteristic features of a lactating adenoma (also termed “nodular lactational hyperplasia”), which occur during pregnancy and the post-partum period. These lesions are typically well circumscribed and clinically resemble fibroadenomas. The appearance of the nucleoli within the nuclei can initially appear alarming, however the nucleoli are punctate, the nuclei are fairly small and uniform and the associated secretions are reassuring. The differential diagnosis of benign lactational or secretory change is hypersecretory cystic hyperplasia, which contains dilated cystic spaces, and atypical hypersecretory cystic hyperplasia, which displays cytologic atypia such as nuclear enlargement and prominent nucleoli. Focal secretory or lactational-like change can also be seen in the benign breast tissue of non-pregnant or non-lactating patients as well.
References:
1. O’Hara MF, Page DL. Adenomas of the breast and ectopic breast under lactational influences. Hum Pathol. 1985 Jul;16(7):707-12.
Presented by Justin Bishop, MD and prepared by Sarah Karram, MD
This case talks about a 47 year old woman with an anterior tongue mass.
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Week (625): Case 1
47 year old woman with an anterior tongue mass.
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Answer: PLACE Ectomesenchymal chondromyxoid tumor
The tumor is an unencapsulated but generally well circumscribed neoplasm within the tongue submucosa. At low power, it grows as lobules of cells separated by fibrous bands, with frequent slit-like clefts within the tumor. The tumor cells are round, fusiform, or spindled cells arranged in cords, sheets, or in a reticulated pattern within a myxoid or chondromyxoid stroma. Tumor cells have moderate amounts of eosinophilic to amphophilic cytoplasm, indistinct cell borders, and nuclei with irregular membranes including indentations or pseudoinclusions. Hyperchromatic nuclei and nuclear enlargement or multinucleation may be encountered. Mitotic figures are rare. Plasmacytoid cells and ductal structures are not encountered. The tumor is positive for GFAP and S100 protein (not shown) and negative for cytokeratins, EMA, actin, and p63.
Ectomesenchymal chondromyxoid tumor (ECT) is a benign mesenchymal neoplasm that arises almost exclusively in the tongue. Approximately 60 cases of ECT have been reported affecting a wide age range (7-78 years, mean 37) with no sex predilection. ECT arises almost exclusively in the dorsum of the anterior tongue. Rare cases have been reported in the posterior tongue and hard palate. ECT presents as a longstanding (months or even years), painless, submucosal tongue mass without ulceration. The histologic features described above are typical. It is consistently positive for GFAP, S100, and CD57, and variably positive for cytokeratins, actin, and p63.
ECT may arise from undifferentiated ectomesenchymal cells from the embryonic neural crest mesenchyme of the first branchial arch. While it bears some resemblance to myoepithelioma or benign mixed tumor, minor salivary gland origin is unlikely given the inconsistent cytokeratin immunostaining, the lack of any plamsacytoid cells or ducts, and the absence of minor salivary glands in the dorsal anterior tongue. The prognosis is excellent, with a low risk of recurrence.
Incorrect
Answer: PLACE Ectomesenchymal chondromyxoid tumor
The tumor is an unencapsulated but generally well circumscribed neoplasm within the tongue submucosa. At low power, it grows as lobules of cells separated by fibrous bands, with frequent slit-like clefts within the tumor. The tumor cells are round, fusiform, or spindled cells arranged in cords, sheets, or in a reticulated pattern within a myxoid or chondromyxoid stroma. Tumor cells have moderate amounts of eosinophilic to amphophilic cytoplasm, indistinct cell borders, and nuclei with irregular membranes including indentations or pseudoinclusions. Hyperchromatic nuclei and nuclear enlargement or multinucleation may be encountered. Mitotic figures are rare. Plasmacytoid cells and ductal structures are not encountered. The tumor is positive for GFAP and S100 protein (not shown) and negative for cytokeratins, EMA, actin, and p63.
Ectomesenchymal chondromyxoid tumor (ECT) is a benign mesenchymal neoplasm that arises almost exclusively in the tongue. Approximately 60 cases of ECT have been reported affecting a wide age range (7-78 years, mean 37) with no sex predilection. ECT arises almost exclusively in the dorsum of the anterior tongue. Rare cases have been reported in the posterior tongue and hard palate. ECT presents as a longstanding (months or even years), painless, submucosal tongue mass without ulceration. The histologic features described above are typical. It is consistently positive for GFAP, S100, and CD57, and variably positive for cytokeratins, actin, and p63.
ECT may arise from undifferentiated ectomesenchymal cells from the embryonic neural crest mesenchyme of the first branchial arch. While it bears some resemblance to myoepithelioma or benign mixed tumor, minor salivary gland origin is unlikely given the inconsistent cytokeratin immunostaining, the lack of any plamsacytoid cells or ducts, and the absence of minor salivary glands in the dorsal anterior tongue. The prognosis is excellent, with a low risk of recurrence.
The tumor consists of a polypod proliferation of cells growing as nests and sheets in the laryngeal submucosa. The tumor cells have abundant amphophilic cytoplasm and a vaguely plasmacytoid appearance. The tumor cells demonstrate nuclear pleomorphism, chromatin that varies from stippled to vesicular in quality, and variably prominent nucleoli. A few mitotic figures are identified, as are foci of single-cell necrosis. By immunohistochemistry the cells are positive for cytokeratin, synaptophysin, and calcitonin. There was no history of a thyroid tumor.
Moderately differentiated neuroendocrine carcinoma (NEC) (also known as atypical carcnioid tumor) is an epithelial neoplasm demonstrating neuroendocrine differentiation and histologic and prognostic features intermediate between well-differentiated and poorly-differentiated NEC. It is the most common NEC of the larynx, much more common than the rare well-differentiated NEC (carcnioid tumor). They occur most frequently in men in their 6th and 7th decades (mean, 63 years). Most affected patients are heavy cigarette smokers. More than 90% occur in the supgraglottic region. Patients present with hoarseness, dysphagia, sore throat, and occasionally hemoptysis. Patients rarely have a paraneoplastic syndrome due to aberrant hormone production by the tumor.
The histopathology of moderately differentiated neuroendocrine carcinoma is similar to that of well differentiated neuroendocrine carcinoma, with tumor cells growing as nests, cords, sheets, and trabeculae of round to slightly spindled cells with abundant amphophilic to eosinophilic granular cytoplasm. Gland-like structures or rosettes may be seen. The tumor nuclei may exhibit stippled, evenly dispersed chromatin or may show more nuclear atypia with prominent nucleoli. The defining features are necrosis and/or a mitotic rate of 2-10 mitoses per 2 mm2 of 10 high-power fields. Some examples demonstrate oncocytic cellular change or stromal amyloid deposition.
Moderately-differentiated NEC is positivite for cytokeratins and at least one neuroendocrine marker (i.e., synaptophysin, chromogranin, CD56). Ki-67 immunostaining is not used in the grading of ENC of the head and neck. These tumors are often positive for calcitonin, a potential pitfall particularly in a lymph node metastasis where it can be mistaken for medullary thyroid carcinoma. (serum calcitonin is the best way to distinguish these tumors – it is elevated in medullary carcinoma but not in laryngeal NEC).
Moderately-differentiated NEC is much more aggressive than its well-differentiated counterpart, with nearly 30% of patients presenting with advanced disease, a recurrence rate of approximately 60% and a 5-year survival of approximately 50%. Patients have been treated with surgery with adjuvant radiotherapy in some cases. Older studies reporting even more aggressive behavior included tumors now recognized as poorly differentiated NEC (especially large cell neuroendocrine carcinoma).
The tumor consists of a polypod proliferation of cells growing as nests and sheets in the laryngeal submucosa. The tumor cells have abundant amphophilic cytoplasm and a vaguely plasmacytoid appearance. The tumor cells demonstrate nuclear pleomorphism, chromatin that varies from stippled to vesicular in quality, and variably prominent nucleoli. A few mitotic figures are identified, as are foci of single-cell necrosis. By immunohistochemistry the cells are positive for cytokeratin, synaptophysin, and calcitonin. There was no history of a thyroid tumor.
Moderately differentiated neuroendocrine carcinoma (NEC) (also known as atypical carcnioid tumor) is an epithelial neoplasm demonstrating neuroendocrine differentiation and histologic and prognostic features intermediate between well-differentiated and poorly-differentiated NEC. It is the most common NEC of the larynx, much more common than the rare well-differentiated NEC (carcnioid tumor). They occur most frequently in men in their 6th and 7th decades (mean, 63 years). Most affected patients are heavy cigarette smokers. More than 90% occur in the supgraglottic region. Patients present with hoarseness, dysphagia, sore throat, and occasionally hemoptysis. Patients rarely have a paraneoplastic syndrome due to aberrant hormone production by the tumor.
The histopathology of moderately differentiated neuroendocrine carcinoma is similar to that of well differentiated neuroendocrine carcinoma, with tumor cells growing as nests, cords, sheets, and trabeculae of round to slightly spindled cells with abundant amphophilic to eosinophilic granular cytoplasm. Gland-like structures or rosettes may be seen. The tumor nuclei may exhibit stippled, evenly dispersed chromatin or may show more nuclear atypia with prominent nucleoli. The defining features are necrosis and/or a mitotic rate of 2-10 mitoses per 2 mm2 of 10 high-power fields. Some examples demonstrate oncocytic cellular change or stromal amyloid deposition.
Moderately-differentiated NEC is positivite for cytokeratins and at least one neuroendocrine marker (i.e., synaptophysin, chromogranin, CD56). Ki-67 immunostaining is not used in the grading of ENC of the head and neck. These tumors are often positive for calcitonin, a potential pitfall particularly in a lymph node metastasis where it can be mistaken for medullary thyroid carcinoma. (serum calcitonin is the best way to distinguish these tumors – it is elevated in medullary carcinoma but not in laryngeal NEC).
Moderately-differentiated NEC is much more aggressive than its well-differentiated counterpart, with nearly 30% of patients presenting with advanced disease, a recurrence rate of approximately 60% and a 5-year survival of approximately 50%. Patients have been treated with surgery with adjuvant radiotherapy in some cases. Older studies reporting even more aggressive behavior included tumors now recognized as poorly differentiated NEC (especially large cell neuroendocrine carcinoma).
Presented by Justin Bishop, MD and prepared by Sarah Karram, MD
This case talks about a 70 year old man with hoarseness and a laryngeal mass.
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Week (625): Case 3
70 year old man with hoarseness and a laryngeal mass.
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Answer: Large cell neuroendocrine carcinoma
The tumor grows as basaloid nests and trabeculae with peripheral palisading of tumor nuclei. There are numerous mitotic figures as well as necrosis. Focal rosette formation is seen. The tumor cells are large with abundant cytoplasm and tumor nuclei with open chromatin and prominent nucleoli. The tumor was positive for synapotphysin, cytokeratin, and CD56 and negative for CK5/6 and p63.
Laryngeal neuroendocrine carcinomas (NECs) are graded well-differentiated (i.e., carcinoid tumors), moderately differentiated (i.e., atypical carcinoid tumors), and poorly-differentiated. In the past, high-grade NECs that were not small cell carcinoma were classified as moderately differentiated, but now the poorly differentiated NECs are now subdivided into small cell carcinoma and large cell neuroendocrine carcinoma (LCNEC).
Laryngeal LCNECs tend to arise in older men (mean, 60 years). More than 90% of affected patients are cigarette smokers. LCNEC can arise virtually anywhere within the head and neck, but there is a predilection for the supraglottic larynx. Patients present with hoarseness and/or dysphagia. Many patients have regional or distant metastases at presentation.
LCNEC has a “neuroendocrine” architecture with organoid nesting, palisading, rosettes, and/or trabeculae; it is composed of medium-to-large sized cells with abundant cytoplasm. The nuclei of LCNEC have coarse chromatin, sometimes with a speckled, “salt and pepper” quality, and usually a single prominent nucleolus. LCNEC exhibits necrosis and >10 mitotic figures per 2 mm2 or 10 high-power fields. Rare examples of LCNEC harbor a component of squamous cell carcinoma either within the invasive tumor or within the overlying mucosa (i.e., squamous cell carcinoma-in-situ).
By immunohistochemistry, LCNEC is positive for cytokeratins. The neuroendocrine differentiation of these tumors is confirmed by staining with at least one neuroendocrine marker (i.e., synaptophysin, chromogranin, CD56). TTF-1 immunoexpression is variable. LCNEC is weakly positive or negative for p63, and are consistently negative for CK5/6. Ki67 immunolabeling is typically high (typically >50%) but is not used in the grading of neuroendocrine carcinomas.
Poorly differentiated NEC of the larynx (both small cell carcinoma and LCNEC) are aggressive malignancies with high rates of regional and distant metastasis. Almost 70% of patients present with advanced disease, and 5-year-survivals range from 5-20%. Patients are typically treated with a combined chemotherapy and external beam radiation.
Incorrect
Answer: Large cell neuroendocrine carcinoma
The tumor grows as basaloid nests and trabeculae with peripheral palisading of tumor nuclei. There are numerous mitotic figures as well as necrosis. Focal rosette formation is seen. The tumor cells are large with abundant cytoplasm and tumor nuclei with open chromatin and prominent nucleoli. The tumor was positive for synapotphysin, cytokeratin, and CD56 and negative for CK5/6 and p63.
Laryngeal neuroendocrine carcinomas (NECs) are graded well-differentiated (i.e., carcinoid tumors), moderately differentiated (i.e., atypical carcinoid tumors), and poorly-differentiated. In the past, high-grade NECs that were not small cell carcinoma were classified as moderately differentiated, but now the poorly differentiated NECs are now subdivided into small cell carcinoma and large cell neuroendocrine carcinoma (LCNEC).
Laryngeal LCNECs tend to arise in older men (mean, 60 years). More than 90% of affected patients are cigarette smokers. LCNEC can arise virtually anywhere within the head and neck, but there is a predilection for the supraglottic larynx. Patients present with hoarseness and/or dysphagia. Many patients have regional or distant metastases at presentation.
LCNEC has a “neuroendocrine” architecture with organoid nesting, palisading, rosettes, and/or trabeculae; it is composed of medium-to-large sized cells with abundant cytoplasm. The nuclei of LCNEC have coarse chromatin, sometimes with a speckled, “salt and pepper” quality, and usually a single prominent nucleolus. LCNEC exhibits necrosis and >10 mitotic figures per 2 mm2 or 10 high-power fields. Rare examples of LCNEC harbor a component of squamous cell carcinoma either within the invasive tumor or within the overlying mucosa (i.e., squamous cell carcinoma-in-situ).
By immunohistochemistry, LCNEC is positive for cytokeratins. The neuroendocrine differentiation of these tumors is confirmed by staining with at least one neuroendocrine marker (i.e., synaptophysin, chromogranin, CD56). TTF-1 immunoexpression is variable. LCNEC is weakly positive or negative for p63, and are consistently negative for CK5/6. Ki67 immunolabeling is typically high (typically >50%) but is not used in the grading of neuroendocrine carcinomas.
Poorly differentiated NEC of the larynx (both small cell carcinoma and LCNEC) are aggressive malignancies with high rates of regional and distant metastasis. Almost 70% of patients present with advanced disease, and 5-year-survivals range from 5-20%. Patients are typically treated with a combined chemotherapy and external beam radiation.
Presented by Dr. Jonathan Epstein and prepared by Dr. Jennifer Bynum
Case 1: A 51 year old man presented with a testicular nodule.
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Week (624): Case 1
A 51 year old man presented with a testicular nodule.
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Answer: Regressed germ cell tumor
Histology: There is a localized area of fibrosis with hemosiderin deposition. Focally there is an area of necrosis with at high magnification ghosts of cells with prominent nucleoli consistent with necrotic seminoma. The surrounding testis shows seminiferous tubules with germ cell aplasia but lacking germ cell neoplasia in-situ. There is no evidence of vasculitis.
Discussion: This case shows many of the classic findings associated with a regressed germ cell tumor. These include: 1) Discrete nodule of fibrous tissue at times stellate in configuration; 2) Surrounding testicular parenchyma often shows atrophy with impaired spermatogenesis and tubular atrophy; and 3) Scar with clusters of hemosiderin laden macrophages with lymphoplasmacytic inflammatory infiltrate. Other features of regression not seen in this case are: 1) Large coarse calcifications within adjacent scarred tubules; and 2) Residual germ cell neoplasia in-situ. This case also highlights the importance of carefully analyzing necrotic foci as there may be identifiable germ cell tumor. This author is aware of one such case misdiagnosed as torsion resulting in a delay in diagnosis and litigation. Despite the necrosis, immunohistochemistry with OCT3/4, CD117, and CD30 may still be useful in classifying the tumor. Torsion typically affects either neonates or teens or young adults and results in a totally necrotic testis from twisting of the cord. Localized infarcts in the testis most commonly result from a medium sized vessel vasculitis which is often restricted to the testis and only occasionally part of a systemic vasculitis.
Reference(s): Miller JS, Lee TK, Epstein JI, Ulbright TM. The utility of microscopic findings and immunohistochemistry in the classification of necrotic testicular tumors. A study of 11 cases. Am J Surg Pathol 2009;33:1293–1298.
Incorrect
Answer: Regressed germ cell tumor
Histology: There is a localized area of fibrosis with hemosiderin deposition. Focally there is an area of necrosis with at high magnification ghosts of cells with prominent nucleoli consistent with necrotic seminoma. The surrounding testis shows seminiferous tubules with germ cell aplasia but lacking germ cell neoplasia in-situ. There is no evidence of vasculitis.
Discussion: This case shows many of the classic findings associated with a regressed germ cell tumor. These include: 1) Discrete nodule of fibrous tissue at times stellate in configuration; 2) Surrounding testicular parenchyma often shows atrophy with impaired spermatogenesis and tubular atrophy; and 3) Scar with clusters of hemosiderin laden macrophages with lymphoplasmacytic inflammatory infiltrate. Other features of regression not seen in this case are: 1) Large coarse calcifications within adjacent scarred tubules; and 2) Residual germ cell neoplasia in-situ. This case also highlights the importance of carefully analyzing necrotic foci as there may be identifiable germ cell tumor. This author is aware of one such case misdiagnosed as torsion resulting in a delay in diagnosis and litigation. Despite the necrosis, immunohistochemistry with OCT3/4, CD117, and CD30 may still be useful in classifying the tumor. Torsion typically affects either neonates or teens or young adults and results in a totally necrotic testis from twisting of the cord. Localized infarcts in the testis most commonly result from a medium sized vessel vasculitis which is often restricted to the testis and only occasionally part of a systemic vasculitis.
Reference(s): Miller JS, Lee TK, Epstein JI, Ulbright TM. The utility of microscopic findings and immunohistochemistry in the classification of necrotic testicular tumors. A study of 11 cases. Am J Surg Pathol 2009;33:1293–1298.
Description/Discussion:
The tumor consists of a proliferation of papilla and villous structures, with foci of necrosis. The cytologic features of classic papillary thyroid carcinoma are not well developed. Rather, the nuclei are hyperchromatic and pseudostratified, highly reminiscent of colorectal carcinoma. Immunohistochemistry shows that the tumor is diffusely postiive for CDX-2, as well as TTF-1, PAX8, and thyroglobulin (not shown).
The columnar variant of papillary carcinoma occurs in adults, with a wide age range, as 1 or more thyroid nodules, often with evidence of regionally metastastic disease on presentation. While its cells are “tall,” it is distinguished from the tall cell variant of PTC by its characteristically hyperchromatic and pseudostratified tumor nuclei, closely resembling colorectal adenoma/carcinoma. Moreover, the columnar variant is sometimes positive for CDX-2 as seen here, which may result in mistaking it for a metastasis. Helpfully, this variant is consistently positive for the usual markers of PTC, PAX8, TTF-1, and thyroglobulin. The columnar variant of PTC appears to be more aggressive than conventional papillary carcinoma, with higher rates of extrathyroidal extension, metastatic disease, and death (although recent studies indicate that well encapsulated examples may be more indolent).
Description/Discussion:
The tumor consists of a proliferation of papilla and villous structures, with foci of necrosis. The cytologic features of classic papillary thyroid carcinoma are not well developed. Rather, the nuclei are hyperchromatic and pseudostratified, highly reminiscent of colorectal carcinoma. Immunohistochemistry shows that the tumor is diffusely postiive for CDX-2, as well as TTF-1, PAX8, and thyroglobulin (not shown).
The columnar variant of papillary carcinoma occurs in adults, with a wide age range, as 1 or more thyroid nodules, often with evidence of regionally metastastic disease on presentation. While its cells are “tall,” it is distinguished from the tall cell variant of PTC by its characteristically hyperchromatic and pseudostratified tumor nuclei, closely resembling colorectal adenoma/carcinoma. Moreover, the columnar variant is sometimes positive for CDX-2 as seen here, which may result in mistaking it for a metastasis. Helpfully, this variant is consistently positive for the usual markers of PTC, PAX8, TTF-1, and thyroglobulin. The columnar variant of PTC appears to be more aggressive than conventional papillary carcinoma, with higher rates of extrathyroidal extension, metastatic disease, and death (although recent studies indicate that well encapsulated examples may be more indolent).
Presented by Dr. Jonathan Epstein and prepared by Dr. Jennifer Bynum
Case 2: A 30 year old female with ureteropelvic junction obstruction underwent a nephrectomy for a nonfunctioning kidney.
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Week (624): Case 2
A 30 year old female with ureteropelvic junction obstruction underwent a nephrectomy for a nonfunctioning kidney.
Correct
Answer: Retention cysts with Mullerian stroma
Histology: Scattered in the kidney are cysts separated by uninvolved kidney. The tubules are lined by hobnail cells. Surrounding the cysts is cellular stroma resembling endometrial stroma cuffed by a circumferential layer of smooth muscle.
Discussion: Both AMLEC and MEST shares some features with this case in that they both often have cysts and Mullerian stroma. However, these lesions are neoplasms and form solitary masses without intervening stroma as seen in the current case. In contrast to endometriosis, the lining of the cysts in this case is hobnail consistent with flattened atrophic renal tubular epithelium. Immunohistochemistry could be misleading as the epithelium lining the cysts would be PAX8 positive and the stroma positive for ER and PR. It has been recognized that in addition to the tumors listed above, mullerian stroma may be seen associated with obstructive changes. It is frequently see around dilated renal pelvic epithelium or collecting ducts and is considered to represent a metaplastic phenomenon.
Reference(s): Tickoo SK, Gopolan A, Tu JJ, et al. Estrogen and progesterone-receptor-positive
stroma as a non-tumorous proliferation in kidneys: a possible metaplastic response
to obstruction. Modern Pathology 2008; 21, 60–65.
Incorrect
Answer: Retention cysts with Mullerian stroma
Histology: Scattered in the kidney are cysts separated by uninvolved kidney. The tubules are lined by hobnail cells. Surrounding the cysts is cellular stroma resembling endometrial stroma cuffed by a circumferential layer of smooth muscle.
Discussion: Both AMLEC and MEST shares some features with this case in that they both often have cysts and Mullerian stroma. However, these lesions are neoplasms and form solitary masses without intervening stroma as seen in the current case. In contrast to endometriosis, the lining of the cysts in this case is hobnail consistent with flattened atrophic renal tubular epithelium. Immunohistochemistry could be misleading as the epithelium lining the cysts would be PAX8 positive and the stroma positive for ER and PR. It has been recognized that in addition to the tumors listed above, mullerian stroma may be seen associated with obstructive changes. It is frequently see around dilated renal pelvic epithelium or collecting ducts and is considered to represent a metaplastic phenomenon.
Reference(s): Tickoo SK, Gopolan A, Tu JJ, et al. Estrogen and progesterone-receptor-positive
stroma as a non-tumorous proliferation in kidneys: a possible metaplastic response
to obstruction. Modern Pathology 2008; 21, 60–65.
Presented by Dr. Jonathan Epstein and prepared by Dr. Jennifer Bynum
Case 3: A 52 year old man underwent an orchiectomy for a 1.2 cm testicular mass.
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Week (624): Case 3
A 52 year old man underwent an orchiectomy for a 1.2 cm testicular mass.
Correct
Answer: Sertoli cell tumor of indeterminant malignant potential
Histology: The lesion in the testis is composed of nests and tubules which infiltrates between seminiferous tubules in the surrounding non-neoplastic testis. In areas the tumor cells demonstrate a spindled morphology. The nuclei are slightly variable in size and shape and have delicate euchromatin with a single small central nucleolus. Up to 7 mitoses per 10 HPF were identified. The lesion lacked necrosis and vascular invasion.
Discussion: In assessing a testicular neoplasm, one first considers could this be a germ cell tumor. After deciding that this lesion does not resemble any germ cell tumor, next one should evaluate whether it is consistent with a sex cord stromal tumor. The architecture in this case where tubules are formed lined by relatively bland cells with a central small nucleolus is consistent with Sertoli cell differentiation, recapitulating normal Sertoli cells. One could verify sex cord stromal differentiation with immunohistochemistry for inhibin and SF-1 with some cases also staining for calretinin, and synaptophysin. However, a minority of sex cord stromal tumors are negative for all these markers and must be diagnosed on the H&E morphology. Malignant Sertoli cell tumors are distinguished from benign tumors by lack of nuclear atypia, under 5 cm., less than 3 mitoses per 10HPF, no vascular invasion, more circumscribed, and lack of necrosis. In this case there is somewhat more atypia than benign lesions yet not overtly so. It has an elevated mitotic rate and is infiltrative. Given it has some but not a majority of atypical features it would be best considered as having borderline malignancy. Even if it was a malignant Sertoli cell tumor, there is no adjuvant therapy so either for malignant or borderline lesions patients are merely followed for the potential of metastatic disease, with a worse prognosis for malignant tumors.
Incorrect
Answer: Sertoli cell tumor of indeterminant malignant potential
Histology: The lesion in the testis is composed of nests and tubules which infiltrates between seminiferous tubules in the surrounding non-neoplastic testis. In areas the tumor cells demonstrate a spindled morphology. The nuclei are slightly variable in size and shape and have delicate euchromatin with a single small central nucleolus. Up to 7 mitoses per 10 HPF were identified. The lesion lacked necrosis and vascular invasion.
Discussion: In assessing a testicular neoplasm, one first considers could this be a germ cell tumor. After deciding that this lesion does not resemble any germ cell tumor, next one should evaluate whether it is consistent with a sex cord stromal tumor. The architecture in this case where tubules are formed lined by relatively bland cells with a central small nucleolus is consistent with Sertoli cell differentiation, recapitulating normal Sertoli cells. One could verify sex cord stromal differentiation with immunohistochemistry for inhibin and SF-1 with some cases also staining for calretinin, and synaptophysin. However, a minority of sex cord stromal tumors are negative for all these markers and must be diagnosed on the H&E morphology. Malignant Sertoli cell tumors are distinguished from benign tumors by lack of nuclear atypia, under 5 cm., less than 3 mitoses per 10HPF, no vascular invasion, more circumscribed, and lack of necrosis. In this case there is somewhat more atypia than benign lesions yet not overtly so. It has an elevated mitotic rate and is infiltrative. Given it has some but not a majority of atypical features it would be best considered as having borderline malignancy. Even if it was a malignant Sertoli cell tumor, there is no adjuvant therapy so either for malignant or borderline lesions patients are merely followed for the potential of metastatic disease, with a worse prognosis for malignant tumors.
Presented by Dr. Pedram Argani and prepared by Dr. Jennifer Bynum
Case 1: This is an 80 year old female with a pancreatic mass
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Week (623): Case 1
This is an 80 year old female with a pancreatic mass.
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Answer: Sarcomatoid carcinoma
Histology: This is a high grade malignant neoplasm with multiple morphologies. Some portions of the neoplasm are composed of malignant glands, consistent with the “large-gland” pattern of primary pancreatic adenocarcinoma. This pattern can mimic an intraductal papillary mucinous neoplasm. However, the majority of the neoplasm is sarcomatoid, and consists of malignant anaplastic and spindle cells which focally demonstrate osteoid formation (osteosarcomatous differentiation). Scattered within these anaplastic cells are bland, osteoclastic-like giant cells. The combination of these two morphologies is diagnostic of a sarcomatoid adenocarcinoma, clinically arising in the pancreas.
Discussion: Pancreatic adenocarcinoma may be associated with a highly cellular stroma which can raise the differential diagnosis of sarcomatoid carcinoma. However, this cellular stroma should not demonstrate the anaplasia and mitotic activity of a sarcomatoid carcinoma. Primary sarcomas of this organ are extremely rare, and the diagnosis of sarcomatoid carcinoma is much more likely. The additional malignant glandular component in this case establishes the diagnosis of sarcomatoid carcinoma. Mucinous cystic neoplasms are typically associated with ovarian type stroma, and may be associated with sarcomatoid change. The current lesion lacks the ovarian stroma and predominantly cystic appearance of the latter neoplasm.
Incorrect
Answer: Sarcomatoid carcinoma
Histology: This is a high grade malignant neoplasm with multiple morphologies. Some portions of the neoplasm are composed of malignant glands, consistent with the “large-gland” pattern of primary pancreatic adenocarcinoma. This pattern can mimic an intraductal papillary mucinous neoplasm. However, the majority of the neoplasm is sarcomatoid, and consists of malignant anaplastic and spindle cells which focally demonstrate osteoid formation (osteosarcomatous differentiation). Scattered within these anaplastic cells are bland, osteoclastic-like giant cells. The combination of these two morphologies is diagnostic of a sarcomatoid adenocarcinoma, clinically arising in the pancreas.
Discussion: Pancreatic adenocarcinoma may be associated with a highly cellular stroma which can raise the differential diagnosis of sarcomatoid carcinoma. However, this cellular stroma should not demonstrate the anaplasia and mitotic activity of a sarcomatoid carcinoma. Primary sarcomas of this organ are extremely rare, and the diagnosis of sarcomatoid carcinoma is much more likely. The additional malignant glandular component in this case establishes the diagnosis of sarcomatoid carcinoma. Mucinous cystic neoplasms are typically associated with ovarian type stroma, and may be associated with sarcomatoid change. The current lesion lacks the ovarian stroma and predominantly cystic appearance of the latter neoplasm.
Presented by Dr. Pedram Argani and prepared by Dr. Jennifer Bynum
Case 2: This is a lung nodule in a 49 year old female renal transplant patient.
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Week (623): Case 2
This is a lung nodule in a 49 year old female renal transplant patient.
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Answer: Angioinvasive fungal disease
Histology: The lung contains a well delineated nodule of necrotic, lung parenchyma. Surrounding the necrosis are areas of organizing pneumonia. Within the necrotic lung tissue, and emanating from necrotic blood vessels, one can appreciate fungal hyphae which radiate out from the vessels into the necrotic tissue. These hyphae are pauci-septate, and appear flimsy in that their walls are thin and appear to fold on each other. These features are typically seen with Zygomycetes, though definitive identification rests with cultures in the microbiology laboratory.
Discussion: CMV pneumonitis is infrequently associated with extensive necrosis, as it predominantly involves pneumocytes rather than the vasculature of the lung. One would appreciate markedly enlarged pneumocyte nuclei with prominent intranuclear and cytoplasmic inclusions. A fungus ball (mycetoma) typically occurs in cavities of a lung showing preexisting damage (cavitary change). One should not appreciate tissue necrosis in a setting in which the fungus is a colonizer. Infarction is seen in the current case; however, instead of being associated with merely hemorrhage as one would expect with vascular inclusion or trauma, the infarction here is associated with invasive fungus.
Angioinvasive fungal disease such as the current case is a medical emergency. One may need to report the margins of excision of a specimen such as this, as the goal of surgery is to completely remove the fungus which is notoriously resistant to antifungal chemotherapy.
Incorrect
Answer: Angioinvasive fungal disease
Histology: The lung contains a well delineated nodule of necrotic, lung parenchyma. Surrounding the necrosis are areas of organizing pneumonia. Within the necrotic lung tissue, and emanating from necrotic blood vessels, one can appreciate fungal hyphae which radiate out from the vessels into the necrotic tissue. These hyphae are pauci-septate, and appear flimsy in that their walls are thin and appear to fold on each other. These features are typically seen with Zygomycetes, though definitive identification rests with cultures in the microbiology laboratory.
Discussion: CMV pneumonitis is infrequently associated with extensive necrosis, as it predominantly involves pneumocytes rather than the vasculature of the lung. One would appreciate markedly enlarged pneumocyte nuclei with prominent intranuclear and cytoplasmic inclusions. A fungus ball (mycetoma) typically occurs in cavities of a lung showing preexisting damage (cavitary change). One should not appreciate tissue necrosis in a setting in which the fungus is a colonizer. Infarction is seen in the current case; however, instead of being associated with merely hemorrhage as one would expect with vascular inclusion or trauma, the infarction here is associated with invasive fungus.
Angioinvasive fungal disease such as the current case is a medical emergency. One may need to report the margins of excision of a specimen such as this, as the goal of surgery is to completely remove the fungus which is notoriously resistant to antifungal chemotherapy.
Presented by Dr. Pedram Argani and prepared by Dr. Jennifer Bynum
Case 3: This is a 34 year old female with a pancreas mass.
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Week (623): Case 3
This is a 34 year old female with a pancreas mass.
Correct
Answer: Solid pseudopapillary neoplasm
Histology: This is a solid cellular pancreatic neoplasm, and the differential includes the four choices provided. The nuclei in this case do not show the typical salt and pepper chromatin or the prominent nucleoli typical of pancreatic endocrine neoplasms or acinar cell carcinomas, respectively, and there are not squamoid morules typical of pancreatoblastoma. The cells are somewhat discohesive, and focal hyaline globules are present. The neoplasm is diffusely immunoreactive for beta catenin in a nuclear fashion, supporting the above diagnosis.
Discussion: Pancreatic endocrine neoplasms would demonstrate labeling for chromogranin and synaptophysin, but not for beta catenin. Acinar cell carcinomas label for BCL10, chymotrypsin, and trypsin, and do not show nuclear labeling for beta catenin. Pancreatoblastomas may show nuclear beta catenin labeling as they often harbor beta catenin mutations; however, these neoplasms typically have squamoid morules and areas of acinar differentiation.
Incorrect
Answer: Solid pseudopapillary neoplasm
Histology: This is a solid cellular pancreatic neoplasm, and the differential includes the four choices provided. The nuclei in this case do not show the typical salt and pepper chromatin or the prominent nucleoli typical of pancreatic endocrine neoplasms or acinar cell carcinomas, respectively, and there are not squamoid morules typical of pancreatoblastoma. The cells are somewhat discohesive, and focal hyaline globules are present. The neoplasm is diffusely immunoreactive for beta catenin in a nuclear fashion, supporting the above diagnosis.
Discussion: Pancreatic endocrine neoplasms would demonstrate labeling for chromogranin and synaptophysin, but not for beta catenin. Acinar cell carcinomas label for BCL10, chymotrypsin, and trypsin, and do not show nuclear labeling for beta catenin. Pancreatoblastomas may show nuclear beta catenin labeling as they often harbor beta catenin mutations; however, these neoplasms typically have squamoid morules and areas of acinar differentiation.
Presented by Dr. Jonathan Epstein and prepared by Dr. Jason Kern.
Case 1: A 59 year old female presented with hematuria and a urethral mass.
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A 59 year old female presented with hematuria and a urethral mass.
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Histological description: The lesion consists of a papillary tumor lined by pseudostratified columnar epithelium with apical cytoplasm. Focally, the nuclei are more pleomorphic and lose their orientation towards the basal layer consistent with focal high grade dysplasia. No definite invasive carcinoma is identified.
Discussion: The way to approach glandular lesions in the bladder is that they are entirely analogous to intestinal tumors ranging from intestinal metaplasia to intestinal metaplasia with high grade dysplasia to villous adenoma to villous adenoma with high grade dysplasia to infiltrating adenocarcinoma. The infiltrating carcinomas can be enteric, mucinous, or signet ring cell identical to intestinal carcinomas. If this lesion was primary in the urethra, which is most likely, it would a villous adenoma with focal high grade dysplasia. The recommended therapy is complete excision to rule out invasive carcinoma elsewhere as well as the potential for the progression to carcinoma if residual adenoma was left untreated. The only caveat is that adenocarcinoma of the colon can spread to the bladder histologically resembling a primary villous adenoma of the bladder. Consequently, I always state that while it is likely that this is a primary villous adenoma of the bladder, we cannot exclude spread from an intestinal primary mimicking a villous adenoma and clinical correlation is needed. Similar verbiage is used when an adenocarcinoma is diagnosed in the bladder with the need to exclude spread from an intestinal primary. Immunohistochemical stains are not that helpful in that CDX2 and Villin can be seen in both bladder and intestinal glandular neoplasms. Diffuse nuclear beta-catenin staining would favor a GI primary. However, it is easy and definitive for clinicians to rule out a large colorectal adenocarcinoma involving the bladder before treating the bladder tumor as primary at that site.
Incorrect
Histological description: The lesion consists of a papillary tumor lined by pseudostratified columnar epithelium with apical cytoplasm. Focally, the nuclei are more pleomorphic and lose their orientation towards the basal layer consistent with focal high grade dysplasia. No definite invasive carcinoma is identified.
Discussion: The way to approach glandular lesions in the bladder is that they are entirely analogous to intestinal tumors ranging from intestinal metaplasia to intestinal metaplasia with high grade dysplasia to villous adenoma to villous adenoma with high grade dysplasia to infiltrating adenocarcinoma. The infiltrating carcinomas can be enteric, mucinous, or signet ring cell identical to intestinal carcinomas. If this lesion was primary in the urethra, which is most likely, it would a villous adenoma with focal high grade dysplasia. The recommended therapy is complete excision to rule out invasive carcinoma elsewhere as well as the potential for the progression to carcinoma if residual adenoma was left untreated. The only caveat is that adenocarcinoma of the colon can spread to the bladder histologically resembling a primary villous adenoma of the bladder. Consequently, I always state that while it is likely that this is a primary villous adenoma of the bladder, we cannot exclude spread from an intestinal primary mimicking a villous adenoma and clinical correlation is needed. Similar verbiage is used when an adenocarcinoma is diagnosed in the bladder with the need to exclude spread from an intestinal primary. Immunohistochemical stains are not that helpful in that CDX2 and Villin can be seen in both bladder and intestinal glandular neoplasms. Diffuse nuclear beta-catenin staining would favor a GI primary. However, it is easy and definitive for clinicians to rule out a large colorectal adenocarcinoma involving the bladder before treating the bladder tumor as primary at that site.
Presented by Dr. Jonathan Epstein and prepared by Dr. Jason Kern
Case 2: An 86 year old female was diagnosed with a large bladder tumor and treated by transurethral resection.
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Week (622): Case 2
An 86 year old female was diagnosed with a large bladder tumor and treated by transurethral resection.
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Histological description: The tumor has both epithelial and mesenchymal differentiation. The epithelial component consists of predominantly low grade non-invasive papillary urothelial carcinoma. The mesenchymal component is composed of both nonspecific malignant spindle cells and osteogenic sarcoma.
Discussion. This lesion is a classic sarcomatoid carcinoma with biphasic epithelial and mesenchymal components. It is unusual in that typically the epithelial component, when present, is high grade. Nonetheless, primary osteogenic sarcomas of the bladder for the most part do not exist such that to propose a collision tumor with a low grade urothelial carcinoma would be incorrect. In the past, some experts would have used the term “carcinosarcoma” for this case and “sarcomatoid carcinoma” when the mesenchymal component was nonspecific malignant spindle cells. It is now accepted that both these terms should be used synonymously with the latter term preferred. As some urologists may not be familiar with both terms, I diagnose these cases as “sarcomatoid carcinoma (carcinosarcoma)”. I also list both the epithelial and mesenchymal components, although there is no prognostic significance to the different elements. If the patient develops metastases and the original material was not available for review, the pathology report would have detailed information on the various histological patterns present in the original tumor to compare to the more recent material. In the absence of an overt epithelial component, sarcomatoid carcinoma can be diagnosed when there is a nonspecific malignant spindle cell component that expresses epithelial markers immunohistochemically. The most sensitive and specific marker is high molecular weight cytokeratin.
Incorrect
Histological description: The tumor has both epithelial and mesenchymal differentiation. The epithelial component consists of predominantly low grade non-invasive papillary urothelial carcinoma. The mesenchymal component is composed of both nonspecific malignant spindle cells and osteogenic sarcoma.
Discussion. This lesion is a classic sarcomatoid carcinoma with biphasic epithelial and mesenchymal components. It is unusual in that typically the epithelial component, when present, is high grade. Nonetheless, primary osteogenic sarcomas of the bladder for the most part do not exist such that to propose a collision tumor with a low grade urothelial carcinoma would be incorrect. In the past, some experts would have used the term “carcinosarcoma” for this case and “sarcomatoid carcinoma” when the mesenchymal component was nonspecific malignant spindle cells. It is now accepted that both these terms should be used synonymously with the latter term preferred. As some urologists may not be familiar with both terms, I diagnose these cases as “sarcomatoid carcinoma (carcinosarcoma)”. I also list both the epithelial and mesenchymal components, although there is no prognostic significance to the different elements. If the patient develops metastases and the original material was not available for review, the pathology report would have detailed information on the various histological patterns present in the original tumor to compare to the more recent material. In the absence of an overt epithelial component, sarcomatoid carcinoma can be diagnosed when there is a nonspecific malignant spindle cell component that expresses epithelial markers immunohistochemically. The most sensitive and specific marker is high molecular weight cytokeratin.
Presented by Dr. Jonathan Epstein and prepared by Dr. Jason Kern.
A 71 year old male was noted to have a renal mass and underwent a nephrectomy.
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Week (622): Case 3
A 71 year old male was noted to have a renal mass and underwent a nephrectomy.
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Histological description:
The larger tumor nodule is composed of tubules and cribriform glands. The cells are a mixture with more eosinophilic cytoplasm alternating with cells with paler cytoplasm. Nuclei are crinkly and irregular with occasional perinuclear clearing (koilocytosis). Surrounding the larger mass are multiple small foci composed of cells with abundant eosinophilic cytoplasm and round nuclei.
Discussion: The findings in this slides are classic for oncocytosis where there are a multiple tumors with variable histology of oncocytoma, chromophobe RCC, and hybrid tumors where in the same tumor nodule there are both cells typical of oncocytoma and chromophobe RCC. The larger nodule in this case has typical features of chromophobe RCC with the smaller foci have the histology of cells seen in oncocytoma. While oncocytosis can be sporadic, it can also be seen in the autosomal dominant Birt Hogg Dube syndrome which is also characterized by fibrofolliculomas in the skin and pneumothoraces, as well as other types of renal cell carcinoma. Patients with oncocytosis often have bilateral disease and the goal is to remove large tumors while leaving smaller lesions intact so as to preserve renal function. Chromophobe RCC and hybrid tumors occurring in the setting of oncocytosis typically are benign in their behavior whereas bilateral nephrectomy followed by dialysis is associated with much greater morbidity and mortality.
Incorrect
Histological description:
The larger tumor nodule is composed of tubules and cribriform glands. The cells are a mixture with more eosinophilic cytoplasm alternating with cells with paler cytoplasm. Nuclei are crinkly and irregular with occasional perinuclear clearing (koilocytosis). Surrounding the larger mass are multiple small foci composed of cells with abundant eosinophilic cytoplasm and round nuclei.
Discussion: The findings in this slides are classic for oncocytosis where there are a multiple tumors with variable histology of oncocytoma, chromophobe RCC, and hybrid tumors where in the same tumor nodule there are both cells typical of oncocytoma and chromophobe RCC. The larger nodule in this case has typical features of chromophobe RCC with the smaller foci have the histology of cells seen in oncocytoma. While oncocytosis can be sporadic, it can also be seen in the autosomal dominant Birt Hogg Dube syndrome which is also characterized by fibrofolliculomas in the skin and pneumothoraces, as well as other types of renal cell carcinoma. Patients with oncocytosis often have bilateral disease and the goal is to remove large tumors while leaving smaller lesions intact so as to preserve renal function. Chromophobe RCC and hybrid tumors occurring in the setting of oncocytosis typically are benign in their behavior whereas bilateral nephrectomy followed by dialysis is associated with much greater morbidity and mortality.
Presented by Meredith Pittman, MD and prepared by Sarah Karram, MD
This case talks about a 64 year old man with new onset ascites.
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Week (621): Case 1
64 year old man with new onset ascites; the most likely cause of his symptoms based on this liver biopsy is:.
Correct
Answer: Congestive heart failure
Anything that reduces the venous outflow of the liver may cause the type of congestion seen in this biopsy. The underlying cause of congestive hepatopathy may vary: a mass causing localized obstruction, a thrombus occluding the hepatic veins or inferior vena cava (“Budd-Chiari syndrome”), or even congestive heart failure. Patients with often present with ascites.
When confronted with congestion in the sinusoids, the first step is to determine if the congestion is real. Liver biopsies sometimes have patchy congestion of the sinusoids that is artifactual rather than pathologic. Look to see where the congestion is occurring. In this case, the congestion is regularly spaced around the central veins of the biopsy (the zone you would expect to be impacted by venous outflow obstruction). Next, does the congestion appear to be injuring the hepatocytes? Look for thinning or atrophy of the hepatocyte cords, breakage of the cords, or hepatocyte dropout/ischemia (+/- fibrosis). Also, remember to check all 3 liver zones. In this biopsy the portal tract (zone 1) and the lobule (zone 3) appear relatively unremarkable. Just because a patient has congestion doesn’t mean that they couldn’t have a second liver process, as well.
The clinical record revealed that this man suffered from worsening congestive heart failure, and the biopsy was to rule out any other cause of his ascites. A diagnosis of congestive hepatopathy was made.
Incorrect
Answer: Congestive heart failure
Anything that reduces the venous outflow of the liver may cause the type of congestion seen in this biopsy. The underlying cause of congestive hepatopathy may vary: a mass causing localized obstruction, a thrombus occluding the hepatic veins or inferior vena cava (“Budd-Chiari syndrome”), or even congestive heart failure. Patients with often present with ascites.
When confronted with congestion in the sinusoids, the first step is to determine if the congestion is real. Liver biopsies sometimes have patchy congestion of the sinusoids that is artifactual rather than pathologic. Look to see where the congestion is occurring. In this case, the congestion is regularly spaced around the central veins of the biopsy (the zone you would expect to be impacted by venous outflow obstruction). Next, does the congestion appear to be injuring the hepatocytes? Look for thinning or atrophy of the hepatocyte cords, breakage of the cords, or hepatocyte dropout/ischemia (+/- fibrosis). Also, remember to check all 3 liver zones. In this biopsy the portal tract (zone 1) and the lobule (zone 3) appear relatively unremarkable. Just because a patient has congestion doesn’t mean that they couldn’t have a second liver process, as well.
The clinical record revealed that this man suffered from worsening congestive heart failure, and the biopsy was to rule out any other cause of his ascites. A diagnosis of congestive hepatopathy was made.
Presented by Meredith Pittman, MD and prepared by Sarah Karram, MD
This case talks about a 25 year old woman with upper right quadrant pain. She takes oral contraceptives.
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Week (621): Case 2
25 year old woman with upper right quadrant pain. She takes oral contraceptives.
Correct
Answer: Fibrolamellar carcinoma
Fibrolamellar carcinoma (FLC) is a type of hepatocellular carcinoma that arises in younger patients who do not have chronic liver disease. For this reason, it is taught that fibrolamellar carcinoma has a better prognosis than classic hepatocellular carcinoma. Do not be fooled into thinking that FLC is an indolent neoplasm, though. While these patients may live longer because of their relative health, they often present with bulky tumors and lymph node metastases, and they can require multiple operations over time to control their disease. If the tumor is unresectable, the 5-year survival is dismal (~10%).
The histologic diagnosis of FLC depends on architecture and cytology. The cells of FLC grow in sheets or pseudoglands separated by thick, eosinophilic collagen bundles that are usually oriented in parallel to one another. The cells themselves are large and polygonal with very eosinophilic cytoplasm due to increased mitochondria. The nuclei have a single prominent, often red, nucleolus. Some tumors have cytoplasmic inclusions, either “pale bodies” made up of fibrinogen that resemble Hepatitis B inclusions, or PAS-positive hyaline globules. If stained, these tumors will react with Hep-Par1, canalicular pCEA, and usually CK7.
Incorrect
Answer: Fibrolamellar carcinoma
Fibrolamellar carcinoma (FLC) is a type of hepatocellular carcinoma that arises in younger patients who do not have chronic liver disease. For this reason, it is taught that fibrolamellar carcinoma has a better prognosis than classic hepatocellular carcinoma. Do not be fooled into thinking that FLC is an indolent neoplasm, though. While these patients may live longer because of their relative health, they often present with bulky tumors and lymph node metastases, and they can require multiple operations over time to control their disease. If the tumor is unresectable, the 5-year survival is dismal (~10%).
The histologic diagnosis of FLC depends on architecture and cytology. The cells of FLC grow in sheets or pseudoglands separated by thick, eosinophilic collagen bundles that are usually oriented in parallel to one another. The cells themselves are large and polygonal with very eosinophilic cytoplasm due to increased mitochondria. The nuclei have a single prominent, often red, nucleolus. Some tumors have cytoplasmic inclusions, either “pale bodies” made up of fibrinogen that resemble Hepatitis B inclusions, or PAS-positive hyaline globules. If stained, these tumors will react with Hep-Par1, canalicular pCEA, and usually CK7.
Presented by Meredith Pittman, MD and prepared by Sarah Karram, MD
A 52 year old woman with itching and elevated liver enzymes.
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Week (621): Case 3
A 52 year old woman with itching and elevated liver enzymes.
Correct
Answer: Primary biliary cirrhosis
Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by anti-mitochondrial antibodies (M2 type) in the serum and destructive bile duct lesions histologically. Patients are classically middle aged women who present with itching; however, the age range of PBC is wide, and men are also affected.
The diagnosis of PBC can be difficult early in the disease process. Not only can the lesions of PBC be patchy, but the initial lesions involve medium to large size bile ducts that may not be sampled on liver biopsy. In our case, however, we have a classic florid duct lesion to assist in the diagnosis: a bile duct surrounded by lymphohistiocytic inflammation with ductal infiltration by lymphocytes and destruction of the biliary epithelium. At this stage in our patient’s disease, the lobule is relatively unremarkable, another clue that this is a bile-duct focused process.
Other clues to the diagnosis of PBC may be the presence of granulomas, which can be portal or lobular. These may range from small collections of epithelioid histiocytes to well-formed granulomas more typical of infectious processes. As the disease progresses, there will be duct loss with an increase in the ductular reaction surrounding portal tracts. Inflammation will begin to extend outside the portal tracts, as will fibrosis. Features of chronic cholestasis will be present, including swollen hepatocytes, hepatocyte rosette formation, and bile staining in the lobule.
Incorrect
Answer: Primary biliary cirrhosis
Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by anti-mitochondrial antibodies (M2 type) in the serum and destructive bile duct lesions histologically. Patients are classically middle aged women who present with itching; however, the age range of PBC is wide, and men are also affected.
The diagnosis of PBC can be difficult early in the disease process. Not only can the lesions of PBC be patchy, but the initial lesions involve medium to large size bile ducts that may not be sampled on liver biopsy. In our case, however, we have a classic florid duct lesion to assist in the diagnosis: a bile duct surrounded by lymphohistiocytic inflammation with ductal infiltration by lymphocytes and destruction of the biliary epithelium. At this stage in our patient’s disease, the lobule is relatively unremarkable, another clue that this is a bile-duct focused process.
Other clues to the diagnosis of PBC may be the presence of granulomas, which can be portal or lobular. These may range from small collections of epithelioid histiocytes to well-formed granulomas more typical of infectious processes. As the disease progresses, there will be duct loss with an increase in the ductular reaction surrounding portal tracts. Inflammation will begin to extend outside the portal tracts, as will fibrosis. Features of chronic cholestasis will be present, including swollen hepatocytes, hepatocyte rosette formation, and bile staining in the lobule.
Presented by Ashley Cimino-Mathews, MD and prepared by Armen Khararjian, MD
This case talks about:
A 40 year-old male with a gluteal mass.
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Week 620: Case 1
A 40 year-old male with a gluteal mass.
Correct
Answer: Hibernoma
Histology: The core biopsy shows lobules of adipocytes with polygonal, granular and variably eosinophilic cytoplasm containing multiple small vacuoles. The nuclei are small, bland and either peripherally or centrally located. These morphologic features are characteristic of brown fat.
Discussion: The cytologic features of these cells are those of brown fat, and this mass lesion is termed a “hibernoma.” Normal brown fat is seen primarily in children, but residual brown fat can also be seen in adults as incidental findings (such as focal brown fat in the adipose tissue associated with a lymph node dissection). The differential diagnosis of hibernoma includes residual brown fat (which does not form a mass), fat necrosis, other fatty tumors such as lipoma and atypical lipomatous tumor/liposarcoma, granular cell tumors, and histiocytoid carcinomas. The diagnosis of a hibernoma is made on the histologic features alone, but like other fatty tumors, hibernomas are immunoreactive for S-100 protein and negative for CD68. Classic lipomas lack the granular vacuoles seen in hibernomas, and atypical lipomatous tumors/liposarcomas have nuclear atypia and lipoblasts. Granular cell tumors also have granular, eosinophilic cytoplasm, but they are not vacuolated and are immunoreactive for both S-100 protein and CD68. Histiocytoid carcinomas display nuclear atypia and are immunoreactive for cytokeratin.
Reference:
Furlong MA, Fanburg-Smith JC, Miettinen M. The morphologic spectrum of hibernoma: a clinicopathologic study of 170 cases. The American journal of surgical pathology. 2001;25(6):809-14.
Incorrect
Answer: Hibernoma
Histology: The core biopsy shows lobules of adipocytes with polygonal, granular and variably eosinophilic cytoplasm containing multiple small vacuoles. The nuclei are small, bland and either peripherally or centrally located. These morphologic features are characteristic of brown fat.
Discussion: The cytologic features of these cells are those of brown fat, and this mass lesion is termed a “hibernoma.” Normal brown fat is seen primarily in children, but residual brown fat can also be seen in adults as incidental findings (such as focal brown fat in the adipose tissue associated with a lymph node dissection). The differential diagnosis of hibernoma includes residual brown fat (which does not form a mass), fat necrosis, other fatty tumors such as lipoma and atypical lipomatous tumor/liposarcoma, granular cell tumors, and histiocytoid carcinomas. The diagnosis of a hibernoma is made on the histologic features alone, but like other fatty tumors, hibernomas are immunoreactive for S-100 protein and negative for CD68. Classic lipomas lack the granular vacuoles seen in hibernomas, and atypical lipomatous tumors/liposarcomas have nuclear atypia and lipoblasts. Granular cell tumors also have granular, eosinophilic cytoplasm, but they are not vacuolated and are immunoreactive for both S-100 protein and CD68. Histiocytoid carcinomas display nuclear atypia and are immunoreactive for cytokeratin.
Reference:
Furlong MA, Fanburg-Smith JC, Miettinen M. The morphologic spectrum of hibernoma: a clinicopathologic study of 170 cases. The American journal of surgical pathology. 2001;25(6):809-14.
Presented by Ashley Cimino-Mathews, MD and prepared by Armen Khararjian, MD.
This case talks about:
A 33 year-old female with an abdominal wall mass.
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Week 620: Case 2
A 33 year-old female with an abdominal wall mass.
Correct
Answer: Endometriosis
Histology: The abdominal wall mass consists of irregularly shaped glandular spaces lined by columnar cells which are occasionally ciliated and do not show cytologic atypia. The glandular spaces appear to be filled with secretions. The glands have associated endometrial-type stroma, consisting of small, blue wavy cells as well as extravasated red blood cells, hemosiderin deposition and hemosiderin-laden macrophages. The background tissue shows evidence of scarring, suggesting previous surgery in this site
Discussion: This abdominal wall mass is endometriosis, characterized by the endometrial glands with associated endometrial stroma and evidence of “menstruation” (i.e., blood, hemosiderin deposition and hemosiderin laden macrophages). Endometriosis can occur as implants in the peritoneal cavity (including along the bowel wall) and on the ovaries, within the ovaries as cysts, or as solid masses adjacent to the rectum and vagina. Endometriosis can even form mass like projections into the lumen of the bowel. When endometriosis involves the bowel wall and serosa, it can mimic invasive carcinoma and can present a diagnostic pitfall in staging an actual invasive adenocarcinoma such as colorectal carcinoma. The key to avoiding misdiagnosis is to identify the bland epithelium and the endometrial-type stroma. The exact origin of endometriosis is unclear, but some theories include “retrograde flow” of menstruated epithelium, metaplasia of mesothelial cells into endometrial-like cells, and transit of endometrial cells via the blood system.
References:
1. Bulun SE. Endometriosis. N Engl J Med 2009; 360:268-279
2. Clement PB. The pathology of endometriosis: a survey of the many faces of a common disease emphasizing diagnostic pitfalls and unusual and newly appreciated aspects. Adv Anat Pathol. 2007 Jul;14(4):241-60.
Incorrect
Answer: Endometriosis
Histology: The abdominal wall mass consists of irregularly shaped glandular spaces lined by columnar cells which are occasionally ciliated and do not show cytologic atypia. The glandular spaces appear to be filled with secretions. The glands have associated endometrial-type stroma, consisting of small, blue wavy cells as well as extravasated red blood cells, hemosiderin deposition and hemosiderin-laden macrophages. The background tissue shows evidence of scarring, suggesting previous surgery in this site
Discussion: This abdominal wall mass is endometriosis, characterized by the endometrial glands with associated endometrial stroma and evidence of “menstruation” (i.e., blood, hemosiderin deposition and hemosiderin laden macrophages). Endometriosis can occur as implants in the peritoneal cavity (including along the bowel wall) and on the ovaries, within the ovaries as cysts, or as solid masses adjacent to the rectum and vagina. Endometriosis can even form mass like projections into the lumen of the bowel. When endometriosis involves the bowel wall and serosa, it can mimic invasive carcinoma and can present a diagnostic pitfall in staging an actual invasive adenocarcinoma such as colorectal carcinoma. The key to avoiding misdiagnosis is to identify the bland epithelium and the endometrial-type stroma. The exact origin of endometriosis is unclear, but some theories include “retrograde flow” of menstruated epithelium, metaplasia of mesothelial cells into endometrial-like cells, and transit of endometrial cells via the blood system.
References:
1. Bulun SE. Endometriosis. N Engl J Med 2009; 360:268-279
2. Clement PB. The pathology of endometriosis: a survey of the many faces of a common disease emphasizing diagnostic pitfalls and unusual and newly appreciated aspects. Adv Anat Pathol. 2007 Jul;14(4):241-60.
Presented by Ashley Cimino-Mathews, MD and prepared by Armen Khararjian, MD.
This case talks about:
A 55 year-old female with a scalp mass.
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Week 620: Case 3
A 55 year-old female with a scalp mass.
Correct
Answer: Malignant Peripheral Nerve Sheath Tumor
Histology: The resection of this scalp mass reveals highly atypical epithelioid cells with prominent nucleoli, nuclear hyperchromasia and abundant mitotic figures. There are regions of geographic necrosis and a low-power impression of “zonation” to the lesion, with some hypercellular and hypocellular regions. Adjacent to the malignant lesion is a background of bland spindled cells with wavy nuclei, delicate chromatin, and indistinct cellular borders. Numerous mast cells are present. The stromal collagen has a wavy, pink appearance resembling “shredded carrots.” These features are in keeping with a background of diffuse neurofibroma.
Discussion: This lesion is a malignant peripheral nerve sheath tumor (MPNST) arising in a pre-existing diffuse neurofibroma. This patient does not have a history of neurofibromatosis, but MPNST may arise de novo, in association with a sporadic neurofibroma, or in association with a neurofibroma as a part of neurofibromatosis. Syndromic neurofibromas have a greater likelihood of malignant transformation than sporadic neurofibromas. Diffuse neurofibromas, as seen here, are infiltrative, non-encapsulated lesions which entrap adnexal structures, skeletal muscle or adipose tissue, and they can arise sporadically or syndromically. Conventional MPST are cellular sarcomas comprised of spindled cells with wavy nuclei, tapering ends, and fascicular growth. The cells characteristically condense around hyalizined blood vessels within the neoplasm and may show geographic necrosis similar to that seen in glioblastoma. There are several morphologic varieties of MPNST, including epithelioid MPNST and Triton tumor (which skeletal muscle differentiation morphologically or immunophenotypically). The MPNST in this case displays abundant epithelioid features, with plump rather than spindled cells. The differential diagnosis of MPNST includes other sarcomas such as undifferentiated pleomorphic sarcoma (malignant fibrous histiocytoma, MFH), pleomorphic liposarcoma, leiomyosarcoma, fibrosarcoma, synovial sarcoma, as well as sarcomatoid carcinoma and melanoma. Conventional MPNST is only focally immunoreactive for S-100, but epithelioid MPNST can be diffusely positive. The presence of the associated neurofibroma supports classification as an MPNST.
References:
1. Cimino-Mathews A. Peripheral nerve sheath tumors. In Surgical Pathology Clinics: Current Concepts in Soft Tissue Pathology. Guest Editor, EA Montgomery. Consulting Editor, J Goldblum. 2011 (4); 761-782.
2. Evans DG, Baser ME, McGaughran J, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002 May;39(5):311-4.
3. Ferner RE. Neurofibromatosis 1 and neurofibromatosis 2: A twenty first century perspective. Lancet Neurol 2007;6(4):340-351.
4. McClatchey AI. Neurofibromatosis. Annu Rev Pathol 2007;2:191-216.
5. Wanebo JE, Malik JM, VandenBerg SR, et al. Malignant peripheral nerve sheath tumors. A clinicopathologic study of 28 cases. Cancer 1993;71(4):1247-1253.
Incorrect
Answer: Malignant Peripheral Nerve Sheath Tumor
Histology: The resection of this scalp mass reveals highly atypical epithelioid cells with prominent nucleoli, nuclear hyperchromasia and abundant mitotic figures. There are regions of geographic necrosis and a low-power impression of “zonation” to the lesion, with some hypercellular and hypocellular regions. Adjacent to the malignant lesion is a background of bland spindled cells with wavy nuclei, delicate chromatin, and indistinct cellular borders. Numerous mast cells are present. The stromal collagen has a wavy, pink appearance resembling “shredded carrots.” These features are in keeping with a background of diffuse neurofibroma.
Discussion: This lesion is a malignant peripheral nerve sheath tumor (MPNST) arising in a pre-existing diffuse neurofibroma. This patient does not have a history of neurofibromatosis, but MPNST may arise de novo, in association with a sporadic neurofibroma, or in association with a neurofibroma as a part of neurofibromatosis. Syndromic neurofibromas have a greater likelihood of malignant transformation than sporadic neurofibromas. Diffuse neurofibromas, as seen here, are infiltrative, non-encapsulated lesions which entrap adnexal structures, skeletal muscle or adipose tissue, and they can arise sporadically or syndromically. Conventional MPST are cellular sarcomas comprised of spindled cells with wavy nuclei, tapering ends, and fascicular growth. The cells characteristically condense around hyalizined blood vessels within the neoplasm and may show geographic necrosis similar to that seen in glioblastoma. There are several morphologic varieties of MPNST, including epithelioid MPNST and Triton tumor (which skeletal muscle differentiation morphologically or immunophenotypically). The MPNST in this case displays abundant epithelioid features, with plump rather than spindled cells. The differential diagnosis of MPNST includes other sarcomas such as undifferentiated pleomorphic sarcoma (malignant fibrous histiocytoma, MFH), pleomorphic liposarcoma, leiomyosarcoma, fibrosarcoma, synovial sarcoma, as well as sarcomatoid carcinoma and melanoma. Conventional MPNST is only focally immunoreactive for S-100, but epithelioid MPNST can be diffusely positive. The presence of the associated neurofibroma supports classification as an MPNST.
References:
1. Cimino-Mathews A. Peripheral nerve sheath tumors. In Surgical Pathology Clinics: Current Concepts in Soft Tissue Pathology. Guest Editor, EA Montgomery. Consulting Editor, J Goldblum. 2011 (4); 761-782.
2. Evans DG, Baser ME, McGaughran J, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002 May;39(5):311-4.
3. Ferner RE. Neurofibromatosis 1 and neurofibromatosis 2: A twenty first century perspective. Lancet Neurol 2007;6(4):340-351.
4. McClatchey AI. Neurofibromatosis. Annu Rev Pathol 2007;2:191-216.
5. Wanebo JE, Malik JM, VandenBerg SR, et al. Malignant peripheral nerve sheath tumors. A clinicopathologic study of 28 cases. Cancer 1993;71(4):1247-1253.
Presented by Dr. Pedram Argani and prepared by Dr. Jennifer Bynum
This is a 24 year old male with an axillary mass.
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Week (619): Case 1
This is a 24 year old male with an axillary mass.
Correct
Answer: Secretory carcinoma
Histology: The tumor is composed of solid nests of cells with high nucleus cytoplasm ratio and abundant mitotic activity. These cells are associated with prominent intracellular and extracellular eosinophilic secretions. The cells have vesicular chromatin and prominent nucleoli. The tumor demonstrates an ETV6 rearrangement by fluorescence in situ hybridization.
Discussion: None of the entities in the differential diagnosis would demonstrate the ETV6 gene rearrangement. The characteristic vacuolization and secretion separate secretory carcinoma from otherwise typical ductal carcinomas of breast or adnexal origin. Sebaceous carcinomas would demonstrate prominent cytoplasmic vacuoles which lack secretions and which indent the nucleus of the neoplastic cells.
Tumors associated with the ETV6/NTRK3 gene fusion include infantile fibrosarcoma/cellular congenital mesoblastic nephroma, secretory carcinoma of the breast (and now skin), mammary analog secretory carcinoma of salivary gland, and isolated case reports of leukemia.
Incorrect
Answer: Secretory carcinoma
Histology: The tumor is composed of solid nests of cells with high nucleus cytoplasm ratio and abundant mitotic activity. These cells are associated with prominent intracellular and extracellular eosinophilic secretions. The cells have vesicular chromatin and prominent nucleoli. The tumor demonstrates an ETV6 rearrangement by fluorescence in situ hybridization.
Discussion: None of the entities in the differential diagnosis would demonstrate the ETV6 gene rearrangement. The characteristic vacuolization and secretion separate secretory carcinoma from otherwise typical ductal carcinomas of breast or adnexal origin. Sebaceous carcinomas would demonstrate prominent cytoplasmic vacuoles which lack secretions and which indent the nucleus of the neoplastic cells.
Tumors associated with the ETV6/NTRK3 gene fusion include infantile fibrosarcoma/cellular congenital mesoblastic nephroma, secretory carcinoma of the breast (and now skin), mammary analog secretory carcinoma of salivary gland, and isolated case reports of leukemia.
Presented by Dr. Pedram Argani and prepared by Dr. Jennifer Bynum
This is a breast mass that is strongly immunoreactive for p63.
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Week (619): Case 2
This is a breast mass that is strongly immunoreactive for p63.
Correct
Answer: Malignant phyllodes tumor
Histology: This is a high grade malignant neoplasm featuring marked cytologic atypia and abundant mitotic activity. Much of the neoplasm consists of sheets of these malignant cells, without any associated epithelium. One can focally appreciate an underlying lower grade intracanalicular component which merges with the high grade malignant component. This component is highlighted on immunostains for cytokeratin, which highlight ghosts of necrotic protrusions of the intracanalicular pattern. These features allow a confident diagnosis of a malignant phyllodes tumor.
Discussion: Metaplastic carcinoma is suggested by the immunoreactivity for p63; however, it is now recognized that a subset of malignant phyllodes tumor express p63 and p40 (Am J Surg Pathol 2014; 38:1689-1696). The presence of a lower grade phyllodes component excludes the default diagnosis of sarcoma, not otherwise specified. Fibroadenoma could also have intracanalicular pattern; however, the malignant cytology of the current case excludes that diagnosis.
Incorrect
Answer: Malignant phyllodes tumor
Histology: This is a high grade malignant neoplasm featuring marked cytologic atypia and abundant mitotic activity. Much of the neoplasm consists of sheets of these malignant cells, without any associated epithelium. One can focally appreciate an underlying lower grade intracanalicular component which merges with the high grade malignant component. This component is highlighted on immunostains for cytokeratin, which highlight ghosts of necrotic protrusions of the intracanalicular pattern. These features allow a confident diagnosis of a malignant phyllodes tumor.
Discussion: Metaplastic carcinoma is suggested by the immunoreactivity for p63; however, it is now recognized that a subset of malignant phyllodes tumor express p63 and p40 (Am J Surg Pathol 2014; 38:1689-1696). The presence of a lower grade phyllodes component excludes the default diagnosis of sarcoma, not otherwise specified. Fibroadenoma could also have intracanalicular pattern; however, the malignant cytology of the current case excludes that diagnosis.
Presented by Dr. Pedram Argani and prepared by Dr. Jennifer Bynum
This is a retroperitoneal mass in a 42 year old female.
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Week (619): Case 3
This is a retroperitoneal mass in a 42 year old female.
Correct
Answer: Inflammatory liposarcoma
Histology: The major component of the lesion submitted is a nodule of spindle cells with myxoid stroma associated with prominent capillary vasculature and chronic inflammation. The appearances at low power suggest a lymph node. On higher power inspection, one can appreciate atypical cells within the nodule. Surrounding this nodule, in the associated fat, one can appreciate the atypical cells that are diagnostic of well differentiated liposarcoma. Therefore, the nodule represents a lymphocyte rich nodule within this well differentiated liposarcoma, which is termed inflammatory liposarcoma. Atypical cells in both the nodule and outside the nodule demonstrate strong nuclear labeling for MDM2, supporting the above diagnosis.
Discussion: Sclerosing mesenteritis would lack the prominent cytologic atypia of the current case, and would not label for MDM2. Myxoid liposarcoma is suggested by the myxoid stroma and prominent capillary vasculature within the lymphoid nodule of the current case; however, myxoid liposarcomas lack prominent cytologic atypia and would not demonstrate the well differentiated component seen at the periphery of the lesion. Dedifferentiated liposarcoma would be higher grade and lack lipogenic differentiation, which is not true of any of the components of the current lesion.
Reference(s):
– Am J Surg Pathol 1997; 21:884-895.
– Am J Surg Pathol 1997; 21:518-527.
Incorrect
Answer: Inflammatory liposarcoma
Histology: The major component of the lesion submitted is a nodule of spindle cells with myxoid stroma associated with prominent capillary vasculature and chronic inflammation. The appearances at low power suggest a lymph node. On higher power inspection, one can appreciate atypical cells within the nodule. Surrounding this nodule, in the associated fat, one can appreciate the atypical cells that are diagnostic of well differentiated liposarcoma. Therefore, the nodule represents a lymphocyte rich nodule within this well differentiated liposarcoma, which is termed inflammatory liposarcoma. Atypical cells in both the nodule and outside the nodule demonstrate strong nuclear labeling for MDM2, supporting the above diagnosis.
Discussion: Sclerosing mesenteritis would lack the prominent cytologic atypia of the current case, and would not label for MDM2. Myxoid liposarcoma is suggested by the myxoid stroma and prominent capillary vasculature within the lymphoid nodule of the current case; however, myxoid liposarcomas lack prominent cytologic atypia and would not demonstrate the well differentiated component seen at the periphery of the lesion. Dedifferentiated liposarcoma would be higher grade and lack lipogenic differentiation, which is not true of any of the components of the current lesion.
Reference(s):
– Am J Surg Pathol 1997; 21:884-895.
– Am J Surg Pathol 1997; 21:518-527.
Presented by Dr. Justin Bishop and prepared by Dr. Jason Kern
These cases talk about:
Case 1: 6 year old boy with chronic tonsillitis, who undergoes bilateral tonsillectomies.
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Week 618: Case 1
6 year old boy with chronic tonsillitis, who undergoes bilateral tonsillectomies.
Correct
Answer: Adenovirus Tonsillitis
Histologic Description: The specimen demonstrates the typical chronic inflammation and lymphoid hyperplasia of enlarged tonsils. In addition, the crypts are filled with purulent debris, consistent with an acute tonsillitis. Close inspection of the crypt epithlium reveals significantly atypical cells in the form of clusters of enlarged nuclei. Some of the nuclei contain large intranuclear inclusions, and some exhibit margination of the chromatin to the edge of the nucleus. A large panel of viral stains revealed that the cells were positive for adenovirus.
Discussion: Adenovirus is a non-enveloped double stranded DNA virus. The name adenovirus actually derives from the virus’s proclivity to infect the adenoids. Adenovirus is a common cause of mild infections of the upper and lower respiratory tracts as well as conjuncitivits and gastroenteritis. These infections are generally mild, except in patients with severe immunodeficiency. The adenovirus cytopathic effect consists of eosinophilic or basophilic inclusions and smudgy chromatin. It is rare to see adenoiral tonsillitis histologically simply because tonsillectomies are not often performed in the setting of acute tonsillitis.
Incorrect
Answer: Adenovirus Tonsillitis
Histologic Description: The specimen demonstrates the typical chronic inflammation and lymphoid hyperplasia of enlarged tonsils. In addition, the crypts are filled with purulent debris, consistent with an acute tonsillitis. Close inspection of the crypt epithlium reveals significantly atypical cells in the form of clusters of enlarged nuclei. Some of the nuclei contain large intranuclear inclusions, and some exhibit margination of the chromatin to the edge of the nucleus. A large panel of viral stains revealed that the cells were positive for adenovirus.
Discussion: Adenovirus is a non-enveloped double stranded DNA virus. The name adenovirus actually derives from the virus’s proclivity to infect the adenoids. Adenovirus is a common cause of mild infections of the upper and lower respiratory tracts as well as conjuncitivits and gastroenteritis. These infections are generally mild, except in patients with severe immunodeficiency. The adenovirus cytopathic effect consists of eosinophilic or basophilic inclusions and smudgy chromatin. It is rare to see adenoiral tonsillitis histologically simply because tonsillectomies are not often performed in the setting of acute tonsillitis.
Presented by Dr. Justin Bishop and prepared by Dr. Jason Kern.
Case 2: A 15 year old boy presents with a rapidly growing neck mass.
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Week 618: Case 2
A 15 year old boy presents with a rapidly growing neck mass.
Correct
Answer: Nodular Fasciitis
Histology: The lesion consists of a relatively well circumscribed proliferation of spindled cells. The lesional nuclei are elongated and hypochromatic. Extravasated red blood cells are prominent, and focal hyalinized, keloidal-like collagen is seen. Some mitotic figures are seen, but atypical mitoses are absent.
Discussion: Nodular fasciitis is a proliferation of fibroblasts and myofibroblasts that classically presents as a rapidly growing mass in the upper extremities or head and neck. A subset of cases have a history of preceding trauma. While classically thought of as a non-neoplastic, reactive proliferation, recent studies have shown a consistent fusion of the non-muscle myosin (MYH9) gene with the USP6 oncogene, suggesting that it is a benign self-limiting neoplasm. NF is benign; excision is curative and some cases resolve spontaneously.
Histologically nodular fasciitis is well circumscribed, and architecturally displays a haphazard, vaguely storiform, or “S-shaped” pattern of growth. NF consists of irregular, short fascicles of plump myofibroblasts with an appearance similar to those of granulation tissue (i.e., “tissue culture”-like). Cytologically, the myofibroblasts are bland and lack pleomorphism. The nuclei are hypochromatic and vesicular, with smooth nuclear contours and delicate nucleoli (Figure 11). The mitotic rate in NF is often high, a potentially alarming feature, but atypical mitoses are not seen. Lymphocytes, giant cells, and especially extravasated red blood cells are often intermixed with the spindled cells. Microcysts and microscopic areas of hemorrhage are common. Depending on the age of the lesion, NF varies from myxoid to fibrotic; the stages of evolution often coexist in the same lesion, imparting a “zoned” pattern.
In the differential diagnosis, sarcomas typically arise deeper in the soft tissue, and are often larger and more infiltrative than nodular fasciitsi. At the microscopic level, sarcomas usually have a more organized architectural pattern, and display overtly malignant cytologic features (e.g., nuclear pleomorphism, hyperchromasia, atypical mitotic figures, necrosis). A benign entity to consider in the differential diagnosis is fibromatosis. However, fibromatosis is more deep-seated and infiltrative, and grows in broad fascicles with prominent-appearing vessels. If there is doubt, nuclear expression of beta-catenin confirms the diagnosis of fibromatosis.
Incorrect
Answer: Nodular Fasciitis
Histology: The lesion consists of a relatively well circumscribed proliferation of spindled cells. The lesional nuclei are elongated and hypochromatic. Extravasated red blood cells are prominent, and focal hyalinized, keloidal-like collagen is seen. Some mitotic figures are seen, but atypical mitoses are absent.
Discussion: Nodular fasciitis is a proliferation of fibroblasts and myofibroblasts that classically presents as a rapidly growing mass in the upper extremities or head and neck. A subset of cases have a history of preceding trauma. While classically thought of as a non-neoplastic, reactive proliferation, recent studies have shown a consistent fusion of the non-muscle myosin (MYH9) gene with the USP6 oncogene, suggesting that it is a benign self-limiting neoplasm. NF is benign; excision is curative and some cases resolve spontaneously.
Histologically nodular fasciitis is well circumscribed, and architecturally displays a haphazard, vaguely storiform, or “S-shaped” pattern of growth. NF consists of irregular, short fascicles of plump myofibroblasts with an appearance similar to those of granulation tissue (i.e., “tissue culture”-like). Cytologically, the myofibroblasts are bland and lack pleomorphism. The nuclei are hypochromatic and vesicular, with smooth nuclear contours and delicate nucleoli (Figure 11). The mitotic rate in NF is often high, a potentially alarming feature, but atypical mitoses are not seen. Lymphocytes, giant cells, and especially extravasated red blood cells are often intermixed with the spindled cells. Microcysts and microscopic areas of hemorrhage are common. Depending on the age of the lesion, NF varies from myxoid to fibrotic; the stages of evolution often coexist in the same lesion, imparting a “zoned” pattern.
In the differential diagnosis, sarcomas typically arise deeper in the soft tissue, and are often larger and more infiltrative than nodular fasciitsi. At the microscopic level, sarcomas usually have a more organized architectural pattern, and display overtly malignant cytologic features (e.g., nuclear pleomorphism, hyperchromasia, atypical mitotic figures, necrosis). A benign entity to consider in the differential diagnosis is fibromatosis. However, fibromatosis is more deep-seated and infiltrative, and grows in broad fascicles with prominent-appearing vessels. If there is doubt, nuclear expression of beta-catenin confirms the diagnosis of fibromatosis.
Presented by Dr. Justin Bishop and prepared by Dr. Jason Kern.
Case 3 (No clinical history provided)
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Week 618: Case 3
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Answer: Biphenotypic Sinonasal Sarcoma
Histology: The tumor consists of a hypercellular proliferation of spindled cells that entraps submucosal glands. The tumor cells grow in a herringbone fascicular pattern. The tumor is focally positive for both S100 and actin.
Discussion: Lewis, et al. recently described a group of low-grade spindle cell sarcomas arising exclusively in the sinonasal tract and named them “low-grade sinonasal sarcoma with neural and myogenic differentiation.” The same group subsequently renamed the entity biphenotypic sinonasal sarcoma (BSNS). Thirty-six cases of BSNS have been reported. They typically arise in the superior aspects of the nasal cavity and ethmoid sinuses of women (M:F ratio is 1:3) ranging in age from 24 to 85 (mean, 52).
Histologically, BSNS is a poorly circumscribed and unencapsulated, uniformly hypercellular proliferation of intersecting fascicles. A “herringbone” fascicular pattern is commonly seen, and “staghorn” vessels are also common. The tumor cell nuclei are elongated, uniform, and hypochromatic. A feature that is diagnostically quite useful is the frequent presence of hyperplastic respiratory surface epithelium extending downward and entrapped by the spindle cell tumor. BSNS is histologically low-grade, lacking high mitotic rates and necrosis. By immunohistochemistry, BSNS characteristically expresses smooth muscle actin, calponin, and S100. BSNS is sometimes also focally positive for desmin, EMA, and cytokeratins. Almost all examples of BSNS harbor rearrangements of PAX3, and the most frequent translocation partner is MAML3. PAX3-MAML3 appears to be specific for BSNS. Huang, et al. recently described a subset of BSNS cases with the same PAX3-NCOA1 fusions that can be seen in alveolar rhabdomyosarcoma. Interestingly, these PAX3-NCOA1 tumors often harbor focal rhabdomyoblastic differentiation, with rare strap cells and myogenin immunoreactivity.
BSNS has only recently been recognized as a distinct entity, and it was likely misdiagnosed as several different neoplasms in the past. Its S100 positivity may suggest a nerve sheath tumor like schwannoma or malignant peripheral nerve sheath tumor. Certainly schwannomas of the sinonasal tract are unencapsulated and can be very hypercellular. However, while BSNS is S100 positive, it is generally not as diffusely immunoreactive as schwannoma, where essentially every cell is strongly positive. In addition, the presence of smooth muscle differentiation argues against schwannoma, and unlike schwannoma, BSNS has been consistently negative for SOX-10. Malignant peripheral nerve sheath tumor may, like BSNS, show aberrant muscle (i.e., malignant Triton tumor) or epithelial differentiation. However, malignant peripheral nerve sheath tumor is generally much higher grade than BSNS, with necrosis and considerable nuclear pleomorphism. It is likely that examples in the literature diagnosed as “low-grade” malignant Triton tumor are, in fact, BSNS. Given the focal cytokeratin immunostaining and uniform nuclear features, a monophasic synovial sarcoma is another diagnostic consideration. However, all cases of BSNS have been negative for synovial sarcoma fusion transcripts. Finally, the staghorn vasculature raises the possibility of glomangiopericytoma or solitary fibrous tumor. The spindled cells and S100 positivity of BSNS argues against glomangiopericytoma which is more epithelioid and S100 negative. In addition, BSNS lacks the characteristic ropey collagen and variable cellularity of solitary fibrous tumor, which is also S100-negative. Finally, the presence of the PAX3 rearrangement characteristic of BSNS is not found in any of the other diagnostic considerations.
Clinically, BSNS behaves relatively indolently. Almost half of patients with BSNS have experience local recurrences, but none of the tumors have metastasized, and none of the patients have died of their disease.
References
1. Lewis JT, Oliveira AM, Nascimento AG, et al. Low-grade sinonasal sarcoma with neural and myogenic features: a clinicopathologic analysis of 28 cases. Am J Surg Pathol. 2012;36:517-525.
2. Wang X, Bledsoe KL, Graham RP, et al. Recurrent PAX3-MAML3 fusion in biphenotypic sinonasal sarcoma. Nat Genet. 2014;46:666-668.
3. Huang SC, Ghossein RA, Bishop JA, et al. Novel PAX3-NCOA1 Fusions in Biphenotypic Sinonasal Sarcoma with Focal Rhabdomyoblastic Differentiation. American Journal of Surgical Pathology. 2015;In press.
Incorrect
Answer: Biphenotypic Sinonasal Sarcoma
Histology: The tumor consists of a hypercellular proliferation of spindled cells that entraps submucosal glands. The tumor cells grow in a herringbone fascicular pattern. The tumor is focally positive for both S100 and actin.
Discussion: Lewis, et al. recently described a group of low-grade spindle cell sarcomas arising exclusively in the sinonasal tract and named them “low-grade sinonasal sarcoma with neural and myogenic differentiation.” The same group subsequently renamed the entity biphenotypic sinonasal sarcoma (BSNS). Thirty-six cases of BSNS have been reported. They typically arise in the superior aspects of the nasal cavity and ethmoid sinuses of women (M:F ratio is 1:3) ranging in age from 24 to 85 (mean, 52).
Histologically, BSNS is a poorly circumscribed and unencapsulated, uniformly hypercellular proliferation of intersecting fascicles. A “herringbone” fascicular pattern is commonly seen, and “staghorn” vessels are also common. The tumor cell nuclei are elongated, uniform, and hypochromatic. A feature that is diagnostically quite useful is the frequent presence of hyperplastic respiratory surface epithelium extending downward and entrapped by the spindle cell tumor. BSNS is histologically low-grade, lacking high mitotic rates and necrosis. By immunohistochemistry, BSNS characteristically expresses smooth muscle actin, calponin, and S100. BSNS is sometimes also focally positive for desmin, EMA, and cytokeratins. Almost all examples of BSNS harbor rearrangements of PAX3, and the most frequent translocation partner is MAML3. PAX3-MAML3 appears to be specific for BSNS. Huang, et al. recently described a subset of BSNS cases with the same PAX3-NCOA1 fusions that can be seen in alveolar rhabdomyosarcoma. Interestingly, these PAX3-NCOA1 tumors often harbor focal rhabdomyoblastic differentiation, with rare strap cells and myogenin immunoreactivity.
BSNS has only recently been recognized as a distinct entity, and it was likely misdiagnosed as several different neoplasms in the past. Its S100 positivity may suggest a nerve sheath tumor like schwannoma or malignant peripheral nerve sheath tumor. Certainly schwannomas of the sinonasal tract are unencapsulated and can be very hypercellular. However, while BSNS is S100 positive, it is generally not as diffusely immunoreactive as schwannoma, where essentially every cell is strongly positive. In addition, the presence of smooth muscle differentiation argues against schwannoma, and unlike schwannoma, BSNS has been consistently negative for SOX-10. Malignant peripheral nerve sheath tumor may, like BSNS, show aberrant muscle (i.e., malignant Triton tumor) or epithelial differentiation. However, malignant peripheral nerve sheath tumor is generally much higher grade than BSNS, with necrosis and considerable nuclear pleomorphism. It is likely that examples in the literature diagnosed as “low-grade” malignant Triton tumor are, in fact, BSNS. Given the focal cytokeratin immunostaining and uniform nuclear features, a monophasic synovial sarcoma is another diagnostic consideration. However, all cases of BSNS have been negative for synovial sarcoma fusion transcripts. Finally, the staghorn vasculature raises the possibility of glomangiopericytoma or solitary fibrous tumor. The spindled cells and S100 positivity of BSNS argues against glomangiopericytoma which is more epithelioid and S100 negative. In addition, BSNS lacks the characteristic ropey collagen and variable cellularity of solitary fibrous tumor, which is also S100-negative. Finally, the presence of the PAX3 rearrangement characteristic of BSNS is not found in any of the other diagnostic considerations.
Clinically, BSNS behaves relatively indolently. Almost half of patients with BSNS have experience local recurrences, but none of the tumors have metastasized, and none of the patients have died of their disease.
References
1. Lewis JT, Oliveira AM, Nascimento AG, et al. Low-grade sinonasal sarcoma with neural and myogenic features: a clinicopathologic analysis of 28 cases. Am J Surg Pathol. 2012;36:517-525.
2. Wang X, Bledsoe KL, Graham RP, et al. Recurrent PAX3-MAML3 fusion in biphenotypic sinonasal sarcoma. Nat Genet. 2014;46:666-668.
3. Huang SC, Ghossein RA, Bishop JA, et al. Novel PAX3-NCOA1 Fusions in Biphenotypic Sinonasal Sarcoma with Focal Rhabdomyoblastic Differentiation. American Journal of Surgical Pathology. 2015;In press.
Presented by Jonathan Epstein, M.D. and prepared by Sarah Karram, M.D.
Clinical History: A 72 year old man underwent a resection of a scrotal mass.
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Week 617: Case 1
A 72 year old man underwent a resection of a scrotal mass.
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Answer: Metastatic prostate cancer
Histological Description: In the dermis is a tumor composed to nests and cords. The tumor cells have relatively uniform nuclei with prominent central nucleoli and amphophilic cytoplasm. A minority of the cells have clear cytoplasmic vacuoles.
Discussion: Although one might think given its proximity that testicular germ cell tumors would invade the scrotum, this typically does not occur. Even advanced testicular tumors extend up the spermatic cord and don’t invade through the tunica albuginea, tunica vaginalis, dartos muscle, and then to the dermis. Histologically, the tumor in this case lacked the larger nucleoli, clear cytoplasm, lymphocytic infiltrate and loosely arranged cells of a seminoma. Similarly the nesting and cording pattern rules out lymphoma. Melanoma primary to the scrotum would typically have an epidermal component. The histological features in the current case are typical of high grade prostate cancer which usually maintains uniform cytology without marked anaplasia even in advanced disease. The most common tumors to metastasize to the scrotum are prostate cancer and colorectal carcinoma and less likely from carcinomas originating in the lung, bladder, and kidney. In a minority of cases the scrotal tumor is the initial presentation of the carcinoma. The prognosis is grim with mean patient survival following scrotal resection of less than 4 months.
Incorrect
Answer: Metastatic prostate cancer
Histological Description: In the dermis is a tumor composed to nests and cords. The tumor cells have relatively uniform nuclei with prominent central nucleoli and amphophilic cytoplasm. A minority of the cells have clear cytoplasmic vacuoles.
Discussion: Although one might think given its proximity that testicular germ cell tumors would invade the scrotum, this typically does not occur. Even advanced testicular tumors extend up the spermatic cord and don’t invade through the tunica albuginea, tunica vaginalis, dartos muscle, and then to the dermis. Histologically, the tumor in this case lacked the larger nucleoli, clear cytoplasm, lymphocytic infiltrate and loosely arranged cells of a seminoma. Similarly the nesting and cording pattern rules out lymphoma. Melanoma primary to the scrotum would typically have an epidermal component. The histological features in the current case are typical of high grade prostate cancer which usually maintains uniform cytology without marked anaplasia even in advanced disease. The most common tumors to metastasize to the scrotum are prostate cancer and colorectal carcinoma and less likely from carcinomas originating in the lung, bladder, and kidney. In a minority of cases the scrotal tumor is the initial presentation of the carcinoma. The prognosis is grim with mean patient survival following scrotal resection of less than 4 months.
Presented by Jonathan Epstein, M.D. and prepared by Sarah Karram, M.D.
A 55 year old male had a well-circumscribed nodule in the groin.
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Week (617): Case 2
A 55 year old male had a well-circumscribed nodule in the groin.
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Answer: Cellular angiofibroma
Histology: A circumscribed nodule is present in the dermis. The lesion has Uniform, short spindle-shaped cells in fibrous stroma. Spindle cells are fairly cellular without a particular pattern. The stroma shows hyalinization with short bundles of densely eosinophilic collagen. Nuclei are ovoid to polygonal with inconspicuous nucleoli. Numerous small- to medium-sized thick walled vessels are seen with many of the larger vessels containing fibrin within their walls.
Discussion. The major differential diagnosis is aggressive angiomyxoma which overlaps in age and location and has some similar histological features. The cytology is the same and both lack atypia and have scant mitotic figures. A key difference is that typically aggressive angiomyxoma has a more infiltrative perimeter whereas angiofibroma is circumscribed. Angiomyxoma tends to be more myxoid with hypocelluarity with angiofibroma having a more collagenous appearance with increased cellularity. Characteristic findings are fibrin within vessels in angiofibroma and Small bundles of smooth muscle cells appear to spin off of blood vessels in aggressive angiomyxoma. It is important to correctly diagnose these lesions as angiofibroma does not recur whereas angiomyxoma requires aggressive surgery or else the lesion will recur. Immunohistochemistry is not helpful as both variably express ER, PR, desmin, muscle specific actin, and CD34.
Incorrect
Answer: Cellular angiofibroma
Histology: A circumscribed nodule is present in the dermis. The lesion has Uniform, short spindle-shaped cells in fibrous stroma. Spindle cells are fairly cellular without a particular pattern. The stroma shows hyalinization with short bundles of densely eosinophilic collagen. Nuclei are ovoid to polygonal with inconspicuous nucleoli. Numerous small- to medium-sized thick walled vessels are seen with many of the larger vessels containing fibrin within their walls.
Discussion. The major differential diagnosis is aggressive angiomyxoma which overlaps in age and location and has some similar histological features. The cytology is the same and both lack atypia and have scant mitotic figures. A key difference is that typically aggressive angiomyxoma has a more infiltrative perimeter whereas angiofibroma is circumscribed. Angiomyxoma tends to be more myxoid with hypocelluarity with angiofibroma having a more collagenous appearance with increased cellularity. Characteristic findings are fibrin within vessels in angiofibroma and Small bundles of smooth muscle cells appear to spin off of blood vessels in aggressive angiomyxoma. It is important to correctly diagnose these lesions as angiofibroma does not recur whereas angiomyxoma requires aggressive surgery or else the lesion will recur. Immunohistochemistry is not helpful as both variably express ER, PR, desmin, muscle specific actin, and CD34.
Histological Description: The tumor consists of small follicles that are back-to-back and in some areas there is the appearance more of solid foci. The cells are bland with small nuclei containing small nucleoli and the cytoplasm is eosinophilic. Scattered in the lesion are collections of foamy macrophages.
Discussion: Thyroid-like follicular RCC is a recently described rare variant of RCC. It bears close resemblance to follicular carcinoma of the thyroid but is negative for thyroglobulin and TTF-1. Tubulocystic carcinomas have large variably sized tubules. Oncocytomas may have some tubular differentiation but the tubules are larger and lack dense pink secretions and typically has areas with its more common nesting pattern. Although foamy macrophages are often seen in papillary renal cell carcinoma, they are not specific and can be seen in other renal tumors. Thyroid-like follicular RCC is a low grade neoplasm with no reports of metastases to date, but the number of cases reported is too limited to determine their malignant potential.
Histological Description: The tumor consists of small follicles that are back-to-back and in some areas there is the appearance more of solid foci. The cells are bland with small nuclei containing small nucleoli and the cytoplasm is eosinophilic. Scattered in the lesion are collections of foamy macrophages.
Discussion: Thyroid-like follicular RCC is a recently described rare variant of RCC. It bears close resemblance to follicular carcinoma of the thyroid but is negative for thyroglobulin and TTF-1. Tubulocystic carcinomas have large variably sized tubules. Oncocytomas may have some tubular differentiation but the tubules are larger and lack dense pink secretions and typically has areas with its more common nesting pattern. Although foamy macrophages are often seen in papillary renal cell carcinoma, they are not specific and can be seen in other renal tumors. Thyroid-like follicular RCC is a low grade neoplasm with no reports of metastases to date, but the number of cases reported is too limited to determine their malignant potential.
Presented by Justin Bishop, M.D. and prepared by Jennifer Bynum, M.D.
A 70 year old man with a parotid mass.
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Week 616: Case 1
70 year old man with a parotid mass.
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Answer: More than 1 of above
Histology: Most of the tumor has an appearance classic for pleomorphic adenoma. In one area, there is prominent hyalinizing sclerosis – a clue to the presence of a malignant component. In these areas, there is a proliferation of eosinophilic ducts with nuclear pleomorphism, elevated mitotic rate, and necrosis. There is focal cribriforming of these atypical glands, which were strongly positive for GCDFP, GATA-3, and androgen receptor. These findings are classic for salivary duct carcinoma, a form of high-grade salivary cancer. The carcinomatous component did not extend beyond the pleomorphic adenoma; in fact, the malignant glands were completely surrounded by the residual benign myoepithelial cells of the pleomorphic adenoma. The final diagnosis is non-invasive salivary duct carcinoma ex-pleomorphic adenoma.
Discussion: In the salivary glands carcinoma ex-pleomorphic adenoma represents malignant transformation of the epithelial component of a benign mixed tumor. Simply making a diagnosis of “carcinoma ex-pleomorphic adenoma” is not sufficient. You must also include the type and grade of the carcinomatous component (most commonly salivary duct carcinoma or high-grade adenocarcinoma not otherwise specified, but any salivary carcinoma can arise in a PA). In addition, you must specify the degree of invasion: non-invasive, minimally invasive (1.5 mm). The noninvasive and minimally invasive types have excellent prognoses, while the prognosis widely invasive form is dependent on the type of carcinoma.
Incorrect
Answer: More than 1 of above
Histology: Most of the tumor has an appearance classic for pleomorphic adenoma. In one area, there is prominent hyalinizing sclerosis – a clue to the presence of a malignant component. In these areas, there is a proliferation of eosinophilic ducts with nuclear pleomorphism, elevated mitotic rate, and necrosis. There is focal cribriforming of these atypical glands, which were strongly positive for GCDFP, GATA-3, and androgen receptor. These findings are classic for salivary duct carcinoma, a form of high-grade salivary cancer. The carcinomatous component did not extend beyond the pleomorphic adenoma; in fact, the malignant glands were completely surrounded by the residual benign myoepithelial cells of the pleomorphic adenoma. The final diagnosis is non-invasive salivary duct carcinoma ex-pleomorphic adenoma.
Discussion: In the salivary glands carcinoma ex-pleomorphic adenoma represents malignant transformation of the epithelial component of a benign mixed tumor. Simply making a diagnosis of “carcinoma ex-pleomorphic adenoma” is not sufficient. You must also include the type and grade of the carcinomatous component (most commonly salivary duct carcinoma or high-grade adenocarcinoma not otherwise specified, but any salivary carcinoma can arise in a PA). In addition, you must specify the degree of invasion: non-invasive, minimally invasive (1.5 mm). The noninvasive and minimally invasive types have excellent prognoses, while the prognosis widely invasive form is dependent on the type of carcinoma.
Presented by Justin Bishop, M.D. and prepared by Jennifer Bynum, M.D.
50 year old woman with a tumor in her mandible.
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Week 616: Case 2
50 year old woman with a tumor in her mandible.
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Answer: Ameloblastoma
Histology: The tumor consists of sheets and nests of cells with abundant granular eosinophilic cytoplasm. In areas, these granular cells appear to merge with nests and trabeculae of cells that exhibit peripheral palisading of columnar cells. These basal cells show reverse polarization with subnuclear vacuoles. In these areas, the center of the nests consists of loosely coheseive stellate cells. Taken together, the features are consistent with ameloblastoma, mixed type with granular cell and follicular patterns.
Discussion: Ameloblastoma is an epithelial neoplasm derived from the odontogenic apparatus that exhibits enamel organ differentiation. It is benign (though ameloblastic carcinomas do exist) but can behave in a locally aggressive manner. When its classic features (i.e., peripheral palisading, subnuclear vacuoles with reversely polarized nuclei, and the central stellate reticulum) are well developed, it is easily recognized, but several variant forms exist. These include plexiform, basaloid, acanthomatous, granular cell, and desmoplastic. The key to diagnosing these variants lies with recognizing more conventional areas of ameloblastoma; this can be difficult depending on how extensive the variant changes are. Fortunately, none of these variants seem to have any prognostic significance.
Incorrect
Answer: Ameloblastoma
Histology: The tumor consists of sheets and nests of cells with abundant granular eosinophilic cytoplasm. In areas, these granular cells appear to merge with nests and trabeculae of cells that exhibit peripheral palisading of columnar cells. These basal cells show reverse polarization with subnuclear vacuoles. In these areas, the center of the nests consists of loosely coheseive stellate cells. Taken together, the features are consistent with ameloblastoma, mixed type with granular cell and follicular patterns.
Discussion: Ameloblastoma is an epithelial neoplasm derived from the odontogenic apparatus that exhibits enamel organ differentiation. It is benign (though ameloblastic carcinomas do exist) but can behave in a locally aggressive manner. When its classic features (i.e., peripheral palisading, subnuclear vacuoles with reversely polarized nuclei, and the central stellate reticulum) are well developed, it is easily recognized, but several variant forms exist. These include plexiform, basaloid, acanthomatous, granular cell, and desmoplastic. The key to diagnosing these variants lies with recognizing more conventional areas of ameloblastoma; this can be difficult depending on how extensive the variant changes are. Fortunately, none of these variants seem to have any prognostic significance.
Presented by Justin Bishop, M.D. and prepared by Jennifer Bynum, M.D.
44 year old African American man who presented to his physician complaining of eye swelling and tearing as well as nasal obstruction. A CT scan revealed a 3.7 cm tumor centered in the left ethmoid sinus and extending into the nasal cavity.
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Week 616: Case 3
44 year old African American man who presented to his physician complaining of eye swelling and tearing as well as nasal obstruction. A CT scan revealed a 3.7 cm tumor centered in the left ethmoid sinus and extending into the nasal cavity.
Histology: The tumor consisted of expanding nests of cells in the sinonasal mucosa. No areas of dysplasia or carcinoma in situ were seen in the surface epithelium. The tumor was highly infiltrative, with areas of perineural and bone invasion. Tumor necrosis was evident, and the mitotic rate was high. The tumor nuclei were uniformly round, with open chromatin a single prominent nucleolus. The tumor cells contained abundant eosinophilic cytoplasm that was often eccentrically located, imparting a “rhabdoid” appearance to the cells. There were no areas of clear-cut squamous or glandular differentiation in the tumor. Immunohistochemical studies showed that the tumor was diffusely positive for pan-cytokeratin and p63, and negative for synaptophysin, chromogranin, NUT-1, actin, desmin, and S-100. Finally, SMARCB1 (INI-1) immunostaining revealed a complete lack of expression in the tumor cells; staining in the background stromal and inflammatory cells was intact. Taken together, the findings were consistent with what has recently been described as SMARCB1 (INI-1)-deficient carcinoma of the sinonasal tract.
Discussion: SMARCB1 (INI-1) is a tumor suppressor gene located on chromosome 22q11.2. Its gene product is ubiquitously expressed in nuclei of all normal tissues. SMARCB1 gene inactivation has been implicated in the pathogenesis of a diverse group of malignant neoplasms that tend to share “rhabdoid” cytomorphology. Recently, we and Agaimy, et al. independently introduced a new member of the SMARCB1 (INI-1) deficient tumor family: SMARCB1 (INI-1) deficient sinonasal carcinoma.
Twelve SMARCB1 (INI-1) deficient sinonasal carcinomas have been described to date. These carcinomas tend to grow as epithelioid nests in the sinonasal submucosa, architecturally mimicking the much more common squamous cell carcinoma. These tumors are usually highly infiltrative, with frequent bone invasion. At the cellular level, each SMARCB1 (INI-1) deficient sinonasal carcinoma contained some cells that are recognizable as rhabdoid or plasmacytoid, but the number of these cells is variable. In some cases, like the one presented here, they predominate and are very noticeable, while in other examples they are singly dispersed among more basaloid tumor cells. While the tumor cell cytoplasm is variable in quality, the tumor nuclei of these carcinomas tend to be uniformly round with open chromatin and a prominent nucleolus. Nuclear pleomorphism is not typical. None of the SMARCB1 (INI-1) deficient sinonasal carcinomas has shown overt squamous or glandular differentiation, but most of the cases we reported exhibited psuedovascular spaces that in one case led to a diagnosis of non-intestinal adenocarcinoma.
The consistent immunophenotypic features of SMARCB1 (INI-1) deficient carcinoma are strong, diffuse cytokeratin expression along with a complete absence of SMARCB1 (INI-1) immunostaining. Five of 11 cases were focally positive for synaptophysin, 4 of 9 were positive for p63 and p40 (with diffuse expression in 3 of 4 positive cases). In the 8 cases were SMARCB1 (INI-1) FISH was successfully performed, 6 showed SMARCB1 copy number alterations. Five cases showed homozygous deletion of SMARCB1, while an additional case showed a heterozygous deletion pattern. ).
SMARCB1 (INI-1) deficient sinonasal carcinomas present with non-specific signs and symptoms like pain, eye symptoms, and obstruction. Many cases have shown aggressive behavior in the form of local invasion into the brain and/or skull base. of 11 patients experienced local recurrence, 5 of 11 had regional or distant metastasis, and 5 of 11 patients up have died of their disease.
Reference(s):
– Bishop, et al. AJSP 2014; 38:1282-9.
– Agaimy, et al. AJSP 2014; 38: 1274-81.
Histology: The tumor consisted of expanding nests of cells in the sinonasal mucosa. No areas of dysplasia or carcinoma in situ were seen in the surface epithelium. The tumor was highly infiltrative, with areas of perineural and bone invasion. Tumor necrosis was evident, and the mitotic rate was high. The tumor nuclei were uniformly round, with open chromatin a single prominent nucleolus. The tumor cells contained abundant eosinophilic cytoplasm that was often eccentrically located, imparting a “rhabdoid” appearance to the cells. There were no areas of clear-cut squamous or glandular differentiation in the tumor. Immunohistochemical studies showed that the tumor was diffusely positive for pan-cytokeratin and p63, and negative for synaptophysin, chromogranin, NUT-1, actin, desmin, and S-100. Finally, SMARCB1 (INI-1) immunostaining revealed a complete lack of expression in the tumor cells; staining in the background stromal and inflammatory cells was intact. Taken together, the findings were consistent with what has recently been described as SMARCB1 (INI-1)-deficient carcinoma of the sinonasal tract.
Discussion: SMARCB1 (INI-1) is a tumor suppressor gene located on chromosome 22q11.2. Its gene product is ubiquitously expressed in nuclei of all normal tissues. SMARCB1 gene inactivation has been implicated in the pathogenesis of a diverse group of malignant neoplasms that tend to share “rhabdoid” cytomorphology. Recently, we and Agaimy, et al. independently introduced a new member of the SMARCB1 (INI-1) deficient tumor family: SMARCB1 (INI-1) deficient sinonasal carcinoma.
Twelve SMARCB1 (INI-1) deficient sinonasal carcinomas have been described to date. These carcinomas tend to grow as epithelioid nests in the sinonasal submucosa, architecturally mimicking the much more common squamous cell carcinoma. These tumors are usually highly infiltrative, with frequent bone invasion. At the cellular level, each SMARCB1 (INI-1) deficient sinonasal carcinoma contained some cells that are recognizable as rhabdoid or plasmacytoid, but the number of these cells is variable. In some cases, like the one presented here, they predominate and are very noticeable, while in other examples they are singly dispersed among more basaloid tumor cells. While the tumor cell cytoplasm is variable in quality, the tumor nuclei of these carcinomas tend to be uniformly round with open chromatin and a prominent nucleolus. Nuclear pleomorphism is not typical. None of the SMARCB1 (INI-1) deficient sinonasal carcinomas has shown overt squamous or glandular differentiation, but most of the cases we reported exhibited psuedovascular spaces that in one case led to a diagnosis of non-intestinal adenocarcinoma.
The consistent immunophenotypic features of SMARCB1 (INI-1) deficient carcinoma are strong, diffuse cytokeratin expression along with a complete absence of SMARCB1 (INI-1) immunostaining. Five of 11 cases were focally positive for synaptophysin, 4 of 9 were positive for p63 and p40 (with diffuse expression in 3 of 4 positive cases). In the 8 cases were SMARCB1 (INI-1) FISH was successfully performed, 6 showed SMARCB1 copy number alterations. Five cases showed homozygous deletion of SMARCB1, while an additional case showed a heterozygous deletion pattern. ).
SMARCB1 (INI-1) deficient sinonasal carcinomas present with non-specific signs and symptoms like pain, eye symptoms, and obstruction. Many cases have shown aggressive behavior in the form of local invasion into the brain and/or skull base. of 11 patients experienced local recurrence, 5 of 11 had regional or distant metastasis, and 5 of 11 patients up have died of their disease.
Reference(s):
– Bishop, et al. AJSP 2014; 38:1282-9.
– Agaimy, et al. AJSP 2014; 38: 1274-81.
Presented by Dr. Pedram Argani and prepared by Dr. Jason Kern
Case 1: This is a 67 year old female with a history of serous carcinoma of the ovary who has a cholecystectomy.
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Week 615: Case 1
This is a 67 year old female with a history of serous carcinoma of the ovary who has a cholecystectomy.
Correct
Answer: Metastatic serous carcinoma and primary gallbladder adenocarcinoma
Histologic Description: The specimen consists of a thickened gallbladder and an enlarged lymph node. The enlarged lymph node contains poorly differentiated metastatic carcinoma which is immunoreactive for PAX8 and not CDX2, consistent with the patient’s reported history of metastatic serous ovarian carcinoma. The thickened gallbladder contains adenocarcinoma, which initially could be written off as metastatic involvement from this patient’s serous ovarian carcinoma. However, on more careful examination, one can see a well-developed in situ carcinoma, evidence of intestinal differentiation, and a cytology which is similar to but slightly different from that of the serous carcinoma. By immunohistochemistry, the tumor in the gallbladder is positive for CDX2 but negative for PAX8, supporting the diagnosis of primary gallbladder adenocarcinoma.
Differential Diagnosis: The presence of an in situ gallbladder carcinoma component as well as the differing immunoprofiles of the two carcinomas supports that these are two distinctive cancers. The presence of an in situ component in the gallbladder excludes the possibility of metastatic pancreatic adenocarcinoma.
Incorrect
Answer: Metastatic serous carcinoma and primary gallbladder adenocarcinoma
Histologic Description: The specimen consists of a thickened gallbladder and an enlarged lymph node. The enlarged lymph node contains poorly differentiated metastatic carcinoma which is immunoreactive for PAX8 and not CDX2, consistent with the patient’s reported history of metastatic serous ovarian carcinoma. The thickened gallbladder contains adenocarcinoma, which initially could be written off as metastatic involvement from this patient’s serous ovarian carcinoma. However, on more careful examination, one can see a well-developed in situ carcinoma, evidence of intestinal differentiation, and a cytology which is similar to but slightly different from that of the serous carcinoma. By immunohistochemistry, the tumor in the gallbladder is positive for CDX2 but negative for PAX8, supporting the diagnosis of primary gallbladder adenocarcinoma.
Differential Diagnosis: The presence of an in situ gallbladder carcinoma component as well as the differing immunoprofiles of the two carcinomas supports that these are two distinctive cancers. The presence of an in situ component in the gallbladder excludes the possibility of metastatic pancreatic adenocarcinoma.
Presented by Dr. Pedram Argani and prepared by Dr. Jason Kern.
Case 2: This is a 21 year old male with a renal mass and a history of tuberous sclerosis
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Week 615: Case 2
This is a 21 year old male with a renal mass and a history of tuberous sclerosis
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Answer: Epithelioid Angiomyolipoma
Histologic Description: This is a malignant neoplasm composed of epithelioid cells with abundant eosinophilic cytoplasm, frequent tumor giant cells, atypical mitosis, and extensive necrosis. Some of the tumor giant cells have a wreath-like arrangement of nuclei, which is a typical finding in epithelioid angiomyolipoma (“ganglion-like cells”). By immunohistochemistry, this lesion was negative for PAX8 and S100 and immunoreactive for HMB45 and Melan A, supporting the diagnosis of epithelioid angiomyolipoma.
Differential Diagnosis: Renal cell carcinomas do occur in patients with tuberous sclerosis, and have several distinctive morphologies. However, these lesions are typically immunoreactive for PAX8 and not melanocytic markers. Xanthogranulomatous pyelonephritis would feature epithelioid histiocytes that simulate clear cell carcinoma. These cells would not label melanocytic markers, and would not demonstrate the features of malignancy (atypical mitosis) seen in the current lesion. Adrenal cortical carcinomas may extensively involve the kidney and simulate a primary renal neoplasm; however, while these may also label for melan A, they would be negative for HMB45.
The behavior of epithelioid angiomyolipomas is difficult to predict. Features that have been associated with malignancy include cytologic atypia, extensive epithelioid morphology, greater than two mitoses per high power field, atypical mitosis, necrosis, tumor size greater than 7cm, extrarenal extension, carcinoma-like growth, and association with tuberous sclerosis complex. While the incidence of malignant behavior in consultation material approaches 33%, single institution studies have demonstrated that lesions with the above worrisome features have a much lower rate (5%) of malignant behavior. Reference :American Journal of Surgical Pathology 2010; 34:715-722 and American Journal of Surgical Pathology 2011; 35:161-176 and Modern Pathology 2013; 26:1355-1364.
Incorrect
Answer: Epithelioid Angiomyolipoma
Histologic Description: This is a malignant neoplasm composed of epithelioid cells with abundant eosinophilic cytoplasm, frequent tumor giant cells, atypical mitosis, and extensive necrosis. Some of the tumor giant cells have a wreath-like arrangement of nuclei, which is a typical finding in epithelioid angiomyolipoma (“ganglion-like cells”). By immunohistochemistry, this lesion was negative for PAX8 and S100 and immunoreactive for HMB45 and Melan A, supporting the diagnosis of epithelioid angiomyolipoma.
Differential Diagnosis: Renal cell carcinomas do occur in patients with tuberous sclerosis, and have several distinctive morphologies. However, these lesions are typically immunoreactive for PAX8 and not melanocytic markers. Xanthogranulomatous pyelonephritis would feature epithelioid histiocytes that simulate clear cell carcinoma. These cells would not label melanocytic markers, and would not demonstrate the features of malignancy (atypical mitosis) seen in the current lesion. Adrenal cortical carcinomas may extensively involve the kidney and simulate a primary renal neoplasm; however, while these may also label for melan A, they would be negative for HMB45.
The behavior of epithelioid angiomyolipomas is difficult to predict. Features that have been associated with malignancy include cytologic atypia, extensive epithelioid morphology, greater than two mitoses per high power field, atypical mitosis, necrosis, tumor size greater than 7cm, extrarenal extension, carcinoma-like growth, and association with tuberous sclerosis complex. While the incidence of malignant behavior in consultation material approaches 33%, single institution studies have demonstrated that lesions with the above worrisome features have a much lower rate (5%) of malignant behavior. Reference :American Journal of Surgical Pathology 2010; 34:715-722 and American Journal of Surgical Pathology 2011; 35:161-176 and Modern Pathology 2013; 26:1355-1364.
Presented by Dr. Pedram Argani and prepared by Dr. Jason Kern
Case 3: This is a 2 year old female with a lesion on the forearm
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Week 615: Case 3
This is a 2 year old female with a lesion on the forearm
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Answer: Infantile fibromatosis
Histologic Description: This is a fairly bland but infiltrative spindle cell lesion. The spindle cells show minimal mitotic activity, and are associated with collagen production. The supporting capillary vasculature is prominent, as is typically seen in the fibromatosis.
Differential Diagnosis: Infantile fibrosarcoma may overlap in some cases with infantile fibromatosis, and most of these variant lesions appear to be cellular variants of infantile fibromatosis genetically. However, infantile fibrosarcoma typically demonstrates poorly formed fascicles of spindle cells, greater mitotic activity and necrosis. Low grade fibromyxoid sarcoma typically has focal nodules of myxoid areas associated arcade-like vasculature in the background of a more hyalinized fibroblastic proliferation showing nuclear hyperchromasia. Low grade fibromyxoid sarcoma labels for MUC4. Rhabdomyosarcoma typically demonstrates more coarse chromatin and eosinophilic cytoplasm, and would label for myogenic markers like myogenin.
Fibromatosis in infants often does not demonstrate nuclear beta-catenin expression.
Incorrect
Answer: Infantile fibromatosis
Histologic Description: This is a fairly bland but infiltrative spindle cell lesion. The spindle cells show minimal mitotic activity, and are associated with collagen production. The supporting capillary vasculature is prominent, as is typically seen in the fibromatosis.
Differential Diagnosis: Infantile fibrosarcoma may overlap in some cases with infantile fibromatosis, and most of these variant lesions appear to be cellular variants of infantile fibromatosis genetically. However, infantile fibrosarcoma typically demonstrates poorly formed fascicles of spindle cells, greater mitotic activity and necrosis. Low grade fibromyxoid sarcoma typically has focal nodules of myxoid areas associated arcade-like vasculature in the background of a more hyalinized fibroblastic proliferation showing nuclear hyperchromasia. Low grade fibromyxoid sarcoma labels for MUC4. Rhabdomyosarcoma typically demonstrates more coarse chromatin and eosinophilic cytoplasm, and would label for myogenic markers like myogenin.
Fibromatosis in infants often does not demonstrate nuclear beta-catenin expression.
Presented by Jonathan Epstein, MD and prepared by Armen Khararjian, MD
This case talks about:
A 30 year old female with hematuria underwent cystoscopy and was found to have the entire bladder filled with papillary lesions.
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Week 614: Case 1
A 30 year old female with hematuria underwent cystoscopy and was found to have the entire bladder filled with papillary lesions.
Correct
Answer: Condyloma
Histology: The lesion consists of a papillary squamous tumor that has a spiky surface. Overlying the lesion is hyperkeratosis with hypergranulosis and underlying squamous epithelium that is in general cytologically bland with occasional multinucleated cells with crinkly degenerative atypia. Some of the nuclei are associated with koilocytosis.
Discussion: The histological features in this case are typical of a condyloma occurring in an unusual site. This patient had a history of condylomas occurring on the external genitalia and now the lesions have extended up the urethra and into the bladder. In this case, they were so extensive that they could not be totally excised, fulgurated, or lasered and it was unclear how the patient was going to be managed as cystectomy in such a young person for benign tumors is not a good option. An additional concern is that condylomas in the bladder are associated with an increased risk of developing squamous cell carcinoma. In many cases the diagnosis of condylomas must be established on the H&E morphology as low risk HPV cannot always be identified using in-situ hybridization (ISH). Whereas all condylomas are associated with HPV even if they cannot be demonstrated with ISH, urothelial tumors are not related to HPV.
Incorrect
Answer: Condyloma
Histology: The lesion consists of a papillary squamous tumor that has a spiky surface. Overlying the lesion is hyperkeratosis with hypergranulosis and underlying squamous epithelium that is in general cytologically bland with occasional multinucleated cells with crinkly degenerative atypia. Some of the nuclei are associated with koilocytosis.
Discussion: The histological features in this case are typical of a condyloma occurring in an unusual site. This patient had a history of condylomas occurring on the external genitalia and now the lesions have extended up the urethra and into the bladder. In this case, they were so extensive that they could not be totally excised, fulgurated, or lasered and it was unclear how the patient was going to be managed as cystectomy in such a young person for benign tumors is not a good option. An additional concern is that condylomas in the bladder are associated with an increased risk of developing squamous cell carcinoma. In many cases the diagnosis of condylomas must be established on the H&E morphology as low risk HPV cannot always be identified using in-situ hybridization (ISH). Whereas all condylomas are associated with HPV even if they cannot be demonstrated with ISH, urothelial tumors are not related to HPV.
Presented by Jonathan Epstein, MD and prepared by Armen Khararjian, MD
This case talks about:
An 80 year old man underwent a simple prostatectomy for lower urinary tract symptoms.
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Week 614: Case 2
An 80 year old man underwent a simple prostatectomy for lower urinary tract symptoms.
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Answer: Adenoid cystic carcinoma of the prostate
Histology: The lesion consists of numerous basaloid cribriform glands populated by relatively bland cells with scant cytoplasm. The lumina within the cribriform glands contain dense pink secretions. In addition, there are foci composed of small solid nests with similar cells and peripheral palisading. Focally there is squamous differentiation with clear cytoplasm. The intervening stroma in areas is desmoplastic.
Discussion: There are several patterns of basal cell carcinoma of the prostate. The most distinctive is the adenoid cystic pattern as seen in this case. It bears striking resemblance to its salivary gland counterpart and we have recently demonstrated that a subset of these prostate tumors contain the same translocation as recently discovered in salivary gland adenoid cystic carcinoma. However, not all the tumors with an adenoid cystic pattern have the translocation and these tumors may also show other patterns that are typical for prostatic basal cell lesions, such that these tumors are considered variants of basal cell carcinoma as opposed to a distinct salivary gland-like entity. In this case the other pattern seen was solid nests with peripheral palisading. Other patterns include variably sized and shaped nests with central tubules lined by eosinophilic cytoplasm surrounded by basaloid cells. The last and most difficult pattern of basal cell carcinoma to diagnose resembles basal cell hyperplasia with the exception that the small basaloid nests and tubules are very infiltrative both within and outside the prostate. Features that favor basal cell carcinoma over basal cell hyperplasia are the presence of desmoplastic stroma, increased ki67 (>20%), and overexpression of Her2/Neu. Most prostatic basal cell carcinomas, with the exception of those composed of large nests with central necrosis, are locally infiltrative but typically do not metastasize to distant sites.
Incorrect
Answer: Adenoid cystic carcinoma of the prostate
Histology: The lesion consists of numerous basaloid cribriform glands populated by relatively bland cells with scant cytoplasm. The lumina within the cribriform glands contain dense pink secretions. In addition, there are foci composed of small solid nests with similar cells and peripheral palisading. Focally there is squamous differentiation with clear cytoplasm. The intervening stroma in areas is desmoplastic.
Discussion: There are several patterns of basal cell carcinoma of the prostate. The most distinctive is the adenoid cystic pattern as seen in this case. It bears striking resemblance to its salivary gland counterpart and we have recently demonstrated that a subset of these prostate tumors contain the same translocation as recently discovered in salivary gland adenoid cystic carcinoma. However, not all the tumors with an adenoid cystic pattern have the translocation and these tumors may also show other patterns that are typical for prostatic basal cell lesions, such that these tumors are considered variants of basal cell carcinoma as opposed to a distinct salivary gland-like entity. In this case the other pattern seen was solid nests with peripheral palisading. Other patterns include variably sized and shaped nests with central tubules lined by eosinophilic cytoplasm surrounded by basaloid cells. The last and most difficult pattern of basal cell carcinoma to diagnose resembles basal cell hyperplasia with the exception that the small basaloid nests and tubules are very infiltrative both within and outside the prostate. Features that favor basal cell carcinoma over basal cell hyperplasia are the presence of desmoplastic stroma, increased ki67 (>20%), and overexpression of Her2/Neu. Most prostatic basal cell carcinomas, with the exception of those composed of large nests with central necrosis, are locally infiltrative but typically do not metastasize to distant sites.
Presented by Jonathan Epstein, MD and prepared by Armen Khararjian, MD
This case talks about:
A 46 year old male was noted to have a lesion on the foreskin which was resected.
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Week 614: Case 3
A 46 year old male was noted to have a lesion on the foreskin which was resected.
Correct
Answer: Lichen sclerosis et atrophicus (LSA)
Histology: Areas of the skin show thinning of the squamous epithelium with superficial dermal pallor and underlying dense collagen with a sparse lymphocytic infiltrate.
Discussion: The findings are typical of LSA. The lesion lacks the acanthosis and interface dermatitis of lichen planus. Syphilis typically also has an interface dermatitis and numerous plasma cells. LSA is now recognized to be a precursor to usual squamous cell carcinoma of the penis and can be associated with PeIn. However, in the current case there is an absence of cytological atypia. LSA and usual squamous cell carcinoma is unrelated to HPV in contrast to basaloid PeIN and basaloid carcinoma which are strongly HPV driven.
Incorrect
Answer: Lichen sclerosis et atrophicus (LSA)
Histology: Areas of the skin show thinning of the squamous epithelium with superficial dermal pallor and underlying dense collagen with a sparse lymphocytic infiltrate.
Discussion: The findings are typical of LSA. The lesion lacks the acanthosis and interface dermatitis of lichen planus. Syphilis typically also has an interface dermatitis and numerous plasma cells. LSA is now recognized to be a precursor to usual squamous cell carcinoma of the penis and can be associated with PeIn. However, in the current case there is an absence of cytological atypia. LSA and usual squamous cell carcinoma is unrelated to HPV in contrast to basaloid PeIN and basaloid carcinoma which are strongly HPV driven.
Presented by Ashley Cimino-Mathews, M.D. and prepared by Sarah Karram, M.D.
10 year-old male with a suprasellar mass.
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Week (613): Case 1
10 year-old male with a suprasellar mass.
Correct
Answer: Germinoma
Histology: The lesion consists of sheets of loosely cohesive, round epithelioid cells with admixed chronic inflammatory cells. The individual cells have abundant, predominantly clear but variably granular cytoplasm and large round nuclei with prominent nucleoli as well as abundant mitotic figures. The morphology is identical to that of a testicular seminoma. By immunohistochemistry, this lesion is positive for ckit and OCT3/4, and negative for CD45, cytokeratin and EMA.
Discussion: Intracranial germ cell tumors are rare primary brain tumors that primarily affect children or adolescents, and most occur in the suprasellar/pineal/midline of the brain. Of the intracranial germ cell tumors, germinomas are most common and are identical to seminomas of the testis. In general germinomas, have better outcome than non-germinomatous germ cell tumors and respond well to radiation therapy, but since rarely there may be post-radiation sequela, combination lower dose radiation with chemotherapy may be used. Differential diagnosis based upon the lesional morphology and depending upon the anatomic site includes non-germinomatous germ cell tumors, glial neoplasms, lymphoma, pineal gland neoplasms, pituitary neoplasms, and metastases. Isochromosome 12p is seen in nearly all germ cell tumors and can aid in diagnosis if the histology and immunophenotype are ambiguous.
References:
1. Fujimaki T. Central nervous system germ cell tumors: classification, clinical features, and treatment with a historical overview. J Child Neurol. 2009 Nov;24(11):1439-45.
2. Packer RJ, Cohen BH, Cooney K. Intracranial germ cell tumors. Oncologist. 2000;5(4):312-20.
3. Ulbright TM. Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues. Mod Pathol. 2005 Feb;18 Suppl 2:S61-79.
Incorrect
Answer: Germinoma
Histology: The lesion consists of sheets of loosely cohesive, round epithelioid cells with admixed chronic inflammatory cells. The individual cells have abundant, predominantly clear but variably granular cytoplasm and large round nuclei with prominent nucleoli as well as abundant mitotic figures. The morphology is identical to that of a testicular seminoma. By immunohistochemistry, this lesion is positive for ckit and OCT3/4, and negative for CD45, cytokeratin and EMA.
Discussion: Intracranial germ cell tumors are rare primary brain tumors that primarily affect children or adolescents, and most occur in the suprasellar/pineal/midline of the brain. Of the intracranial germ cell tumors, germinomas are most common and are identical to seminomas of the testis. In general germinomas, have better outcome than non-germinomatous germ cell tumors and respond well to radiation therapy, but since rarely there may be post-radiation sequela, combination lower dose radiation with chemotherapy may be used. Differential diagnosis based upon the lesional morphology and depending upon the anatomic site includes non-germinomatous germ cell tumors, glial neoplasms, lymphoma, pineal gland neoplasms, pituitary neoplasms, and metastases. Isochromosome 12p is seen in nearly all germ cell tumors and can aid in diagnosis if the histology and immunophenotype are ambiguous.
References:
1. Fujimaki T. Central nervous system germ cell tumors: classification, clinical features, and treatment with a historical overview. J Child Neurol. 2009 Nov;24(11):1439-45.
2. Packer RJ, Cohen BH, Cooney K. Intracranial germ cell tumors. Oncologist. 2000;5(4):312-20.
3. Ulbright TM. Germ cell tumors of the gonads: a selective review emphasizing problems in differential diagnosis, newly appreciated, and controversial issues. Mod Pathol. 2005 Feb;18 Suppl 2:S61-79.
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