Presented by Ashley Cimino-Mathews, M.D. and prepared by Sarah Karram, M.D.
70 year-old male with a vocal cord mass
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Week (613): Case 2
70 year-old male with a vocal cord mass.
Correct
Answer: Vocal cord amyloidosis
Histology: The excision reveals fragments of benign respiratory and squamous mucosa with abundant extracellular proteinaceous debris characterized by acellular, pink amorphous material. A Congo red special stain is positive with apple-green birefringence, confirming a diagnosis of vocal cord amyloidosis.
Discussion: This patient actually had a decades-long history of amyloid deposition in the vocal cords. Laryngeal amyloidosis is a recognized clinical and pathologic entity, and it can either be a localized process or a manifestation of systemic amyloidosis. In one series, no patients with laryngeal amyloidosis had an associated myeloma or lymphoma. Histologically, the amyloid deposition may be confined to the blood vessels, or form an actual protuberant mass that can cause symptoms due to airway obstruction. On a small superficial biopsy, the amyloid may be overlooked or mistaken for submucosal fibrosis or scarring.
Reference:
1. Thompson LD, Derringer GA, Wenig BM. Amyloidosis of the larynx: a clinicopathologic study of 11 cases. Mod Pathol. 2000 May;13(5):528-35.
Incorrect
Answer: Vocal cord amyloidosis
Histology: The excision reveals fragments of benign respiratory and squamous mucosa with abundant extracellular proteinaceous debris characterized by acellular, pink amorphous material. A Congo red special stain is positive with apple-green birefringence, confirming a diagnosis of vocal cord amyloidosis.
Discussion: This patient actually had a decades-long history of amyloid deposition in the vocal cords. Laryngeal amyloidosis is a recognized clinical and pathologic entity, and it can either be a localized process or a manifestation of systemic amyloidosis. In one series, no patients with laryngeal amyloidosis had an associated myeloma or lymphoma. Histologically, the amyloid deposition may be confined to the blood vessels, or form an actual protuberant mass that can cause symptoms due to airway obstruction. On a small superficial biopsy, the amyloid may be overlooked or mistaken for submucosal fibrosis or scarring.
Reference:
1. Thompson LD, Derringer GA, Wenig BM. Amyloidosis of the larynx: a clinicopathologic study of 11 cases. Mod Pathol. 2000 May;13(5):528-35.
Presented by Ashley Cimino-Mathews, M.D. and prepared by Sarah Karram, M.D.
50 year-old male with a lung mass.
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Week (613): Case 3
50 year-old male with a lung mass.
Correct
Answer: Metastatic thymoma
Histology: The lung wedge resection shows benign alveolated lung parenchyma with a discrete, well circumscribed nodule consisting of lymphoid tissue. Careful examination reveals that this nodule lacks germinal centers, a distinct capsule and a subcapsular sinus, thus does not show definite features of lymph node architecture. Close examination reveals sheets of epithelioid cells dispersed throughout the lymphocytes in the nodule. There is minimal mitotic activity, no atypia, and no necrosis.
Discussion: This patient has a history of locally invasive thymoma (type B2) in the lateral neck, and this current lesion represents a metastatic thymoma. Thymomas may be seen in patients with myasthenia gravis, or sporadically as in this patient. The WHO classification of thymic epithelial neoplasms separates thymomas into various types depending upon the degree of the epithelial component (spindled versus epithelioid/cortical) and the degree of the admixed lymphocytes. In general type A contained spindled cells; type AB is mixed; type B1 is lymphocyte-rich; type B2 has admixed lymphocytes and epithelioid epithleial cells; and type B2 has a predominance of epithelial cells. “Type C” thymoma is actually thymic carcinoma and contains an overtly malignant epithelial component and are typically immunoreactive for CD5 and CKIT. Even though type B thymomas are not “carcinomas,” they still have the capacity to locally invade and even metastasize as seen in this case.
References:
1. Moran CA, Weissferdt A, Kalhor N, Solis LM, Behrens C, Wistuba II, Suster S. Thymomas I: a clinicopathologic correlation of 250 cases with emphasis on the World Health Organization schema. Am J Clin Pathol. 2012 Mar;137(3):444-50.
2. Moran CA, Walsh G, Suster S, Kaiser L. Thymomas II: a clinicopathologic correlation of 250 cases with a proposed staging system with emphasis on pathologic assessment. Am J Clin Pathol. 2012 Mar;137(3):451-61.
Incorrect
Answer: Metastatic thymoma
Histology: The lung wedge resection shows benign alveolated lung parenchyma with a discrete, well circumscribed nodule consisting of lymphoid tissue. Careful examination reveals that this nodule lacks germinal centers, a distinct capsule and a subcapsular sinus, thus does not show definite features of lymph node architecture. Close examination reveals sheets of epithelioid cells dispersed throughout the lymphocytes in the nodule. There is minimal mitotic activity, no atypia, and no necrosis.
Discussion: This patient has a history of locally invasive thymoma (type B2) in the lateral neck, and this current lesion represents a metastatic thymoma. Thymomas may be seen in patients with myasthenia gravis, or sporadically as in this patient. The WHO classification of thymic epithelial neoplasms separates thymomas into various types depending upon the degree of the epithelial component (spindled versus epithelioid/cortical) and the degree of the admixed lymphocytes. In general type A contained spindled cells; type AB is mixed; type B1 is lymphocyte-rich; type B2 has admixed lymphocytes and epithelioid epithleial cells; and type B2 has a predominance of epithelial cells. “Type C” thymoma is actually thymic carcinoma and contains an overtly malignant epithelial component and are typically immunoreactive for CD5 and CKIT. Even though type B thymomas are not “carcinomas,” they still have the capacity to locally invade and even metastasize as seen in this case.
References:
1. Moran CA, Weissferdt A, Kalhor N, Solis LM, Behrens C, Wistuba II, Suster S. Thymomas I: a clinicopathologic correlation of 250 cases with emphasis on the World Health Organization schema. Am J Clin Pathol. 2012 Mar;137(3):444-50.
2. Moran CA, Walsh G, Suster S, Kaiser L. Thymomas II: a clinicopathologic correlation of 250 cases with a proposed staging system with emphasis on pathologic assessment. Am J Clin Pathol. 2012 Mar;137(3):451-61.
Presented by Jonathan Epstein, M.D. and prepared by Sarah Karram, M.D.
This case talks about a 37 year old man underwent an orchiectomy for a palpable mass.
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Week (612): Case 1
A 37 year old man underwent an orchiectomy for a palpable mass.
Correct
Answer: Smooth muscle hyperplasia of testicular adnexa
Histology: Surrounding the vas deferens, cord vessels, and adjacent to the testis is a bland hypocellular proliferation of fibrous tissue.
Discussion: This condition is benign and of unknown etiology. It consists of fascicles of smooth muscle surrounding the vas and vessels of the distal spermatic cord, with interstitial growth between the structures of the spermatic cord. It lacks the circumscribed growth of a leiomyoma. A paratesticular fibrous pseudotumor is more fibrous and related to the tunica as opposed to the distal cord. The importance of recognizing the lesion as a specific entity is to correlate the histological findings with the clinical presence of a mass lesion, justifying the surgery.
Reference: Am J Surg Pathol 1999: 23: 903-9.
Incorrect
Answer: Smooth muscle hyperplasia of testicular adnexa
Histology: Surrounding the vas deferens, cord vessels, and adjacent to the testis is a bland hypocellular proliferation of fibrous tissue.
Discussion: This condition is benign and of unknown etiology. It consists of fascicles of smooth muscle surrounding the vas and vessels of the distal spermatic cord, with interstitial growth between the structures of the spermatic cord. It lacks the circumscribed growth of a leiomyoma. A paratesticular fibrous pseudotumor is more fibrous and related to the tunica as opposed to the distal cord. The importance of recognizing the lesion as a specific entity is to correlate the histological findings with the clinical presence of a mass lesion, justifying the surgery.
Presented by Jonathan Epstein, M.D. and prepared by Sarah Karram, M.D.
A 65 year old man with a history of a renal tumor underwent a bone biopsy for a presumed metastatic lesion.
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Week (612): Case 2
A 65 year old man with a history of a renal tumor underwent a bone biopsy for a presumed metastatic lesion.
Correct
Answer: Metastatic tubulocystic carcinoma
Histology: The needle biopsy contains dilated glands lined by cells with eosinophilic cytoplasm with enlarge nuclei with prominent nucleoli.
Discussion: This patient had a history of tubulocystic carcinoma of the kidney. This is an uncommon variant of renal cell carcinoma composed of variably sized cysts, some dilated, giving it a “swiss cheese” appearance. The cytology seen in this case is typical of this entity. Although initially considered a low grade collecting duct carcinoma, it is currently considered a distinct entity. In contrast to collecting duct carcinoma, tubulocystic carcinoma is circumscribed and lacks a desmoplastic stroma. Whereas collecting duct carcinoma is an aggressive tumor with frequent metastases, tubulocystic carcinoma has in general an excellent prognosis. However as seen in this case, metastases can rarely occur. One does not typically grade tubulocystic carcinomas as what would be considered grade 3 nuclei does not typically correlate with their indolent behavior.
Incorrect
Answer: Metastatic tubulocystic carcinoma
Histology: The needle biopsy contains dilated glands lined by cells with eosinophilic cytoplasm with enlarge nuclei with prominent nucleoli.
Discussion: This patient had a history of tubulocystic carcinoma of the kidney. This is an uncommon variant of renal cell carcinoma composed of variably sized cysts, some dilated, giving it a “swiss cheese” appearance. The cytology seen in this case is typical of this entity. Although initially considered a low grade collecting duct carcinoma, it is currently considered a distinct entity. In contrast to collecting duct carcinoma, tubulocystic carcinoma is circumscribed and lacks a desmoplastic stroma. Whereas collecting duct carcinoma is an aggressive tumor with frequent metastases, tubulocystic carcinoma has in general an excellent prognosis. However as seen in this case, metastases can rarely occur. One does not typically grade tubulocystic carcinomas as what would be considered grade 3 nuclei does not typically correlate with their indolent behavior.
Histology: The tumor is composed of cells with abundant eosinophilic cytoplasm arranged in a cribriform pattern. Oxylate crystals are present. The surrounding kidney shows end stage renal disease (ESRD).
Discussion: Patients with ESRD have an increased risk of developing renal cell carcinoma. While many different tumor variants can occur, the one tumor that exclusively occurs in this setting is acquired kidney disease (ACKD) associated RCC. The morphology of these tumors are consistent from one case to another, and identical to the current case. The cribriform pattern is also referred to as “sieve-like”. One can also see in the adjacent non-neoplastic kidney cysts that are lined by similar epithelium either as a single cell lining or with minimal cribriform growth, yet lacking the solid growth of ACRD associated RCC. These atypical cysts are thought to be precursor lesions to these distinctive carcinomas. Cribriform growth is uncommon in renal cell carcinoma and renal medullary carcinoma is the other variant with this morphology. Renal medullary carcinoma occurs in the setting of sickle cell trait and other than the cribriform growth pattern has a different morphology. ACKD associated RCC has an intermediate prognosis and is worse than clear cell papillary RCC, which is one of the other common tumors to arise in the setting of ESRD.
Histology: The tumor is composed of cells with abundant eosinophilic cytoplasm arranged in a cribriform pattern. Oxylate crystals are present. The surrounding kidney shows end stage renal disease (ESRD).
Discussion: Patients with ESRD have an increased risk of developing renal cell carcinoma. While many different tumor variants can occur, the one tumor that exclusively occurs in this setting is acquired kidney disease (ACKD) associated RCC. The morphology of these tumors are consistent from one case to another, and identical to the current case. The cribriform pattern is also referred to as “sieve-like”. One can also see in the adjacent non-neoplastic kidney cysts that are lined by similar epithelium either as a single cell lining or with minimal cribriform growth, yet lacking the solid growth of ACRD associated RCC. These atypical cysts are thought to be precursor lesions to these distinctive carcinomas. Cribriform growth is uncommon in renal cell carcinoma and renal medullary carcinoma is the other variant with this morphology. Renal medullary carcinoma occurs in the setting of sickle cell trait and other than the cribriform growth pattern has a different morphology. ACKD associated RCC has an intermediate prognosis and is worse than clear cell papillary RCC, which is one of the other common tumors to arise in the setting of ESRD.
Presented by Jonathan Epstein, MD and prepared by Jason Kern, MD
Case 1: A 40 year old man was noted to have a peri-anal polypoid mass. The most likely diagnosis is:
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Week 611: Case 1
A 40 year old man was noted to have a peri-anal polypoid mass. The most likely diagnosis is:
Correct
Answer: Syphillis
Syphillis IHC
Histology: The skin shows neutrophils within the superficial keratin layer. There is hyperplastic squamous epithelium with pseudoepitheliomatous hyperplasia. In the dermis is a prominent plasma cell infiltrate. An immunohistochemical stain against syphilis shows innumerable red filamentous organism consistent with Treponema Pallidum.
Discussion: The finding of psoriasiform hyperplasia with a dense plasma cell infiltrate in the genital regions should always prompt a differential diagnosis of syphilis. In the past, a Warthin-Starry stain was the preferred method to identify organisms histologically. However, it was often difficult to read this stain and distinguish organisms from non-specific background staining. Currently, the best method of finding the organisms is with immunohistochemistry which is very specific and also easier to read. In the current case, it is teeming with organisms consistent with secondary syphilis. In addition to plasma cells, it is common to have associated acute inflammation in the epidermis which, if not recognized as a component of syphilis, could be misconstrued to be suggestive of a fungal as opposed to a syphilitic infection.
Presented by Jonathan Epstein, MD and prepared by Jason Kern, MD
Case 1: A 64 year old man was found to have a renal mass.
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Week 611: Case 2
A 64 year old man was found to have a renal mass. Choose the correct diagnosis:
Correct
Answer: Renal-adrenal fusion with papillary renal cell carcinoma
Histology:
In addition to papillary renal cell carcinoma, there is associated adrenal tissue. Both adrenal cortical and medullary tissue is present. In areas the papillary carcinoma involves the adrenal tissue. Focally, the adrenal cortical tissue is thickened and composed of pale vacuolated cells.
Discussion:
Renal-adrenal fusion results from failure of retroperitoneal mesenchyme to stimulate adrenal capsule formation. Cells can irregularly extend into renal parenchymal in an infiltrative manner and can extend beyond the renal capsule into peri-renal adipose tissue without a surrounding fibrous capsule, mimicking a neoplastic process. In this case, the presence of medullary tissue rules out ectopic adrenal tissue, which is always exclusively cortical adrenal tissue. The pitfall in the current case is that seeing papillary renal cell carcinoma in adrenal tissue could be misdiagnosed as stage 4 renal cell carcinoma invading adrenal tissue. Also it is easy to overlook the adrenal cortical adenoma given the disorganized appearance of the adrenal-renal fusion. The presence of thickened monotonous sheets of clear cells of adrenal cortical tissue is consistent with an adenoma. The other pitfall with adrenal-renal fusion is misdiagnosing clear cell renal cell carcinoma. In contrast to the total empty clear cells which contain glycogen in clear cell renal cell carcinoma, the adrenal cortical tissue contains microvesicular clear cells which are full of lipid.
Incorrect
Answer: Renal-adrenal fusion with papillary renal cell carcinoma
Histology:
In addition to papillary renal cell carcinoma, there is associated adrenal tissue. Both adrenal cortical and medullary tissue is present. In areas the papillary carcinoma involves the adrenal tissue. Focally, the adrenal cortical tissue is thickened and composed of pale vacuolated cells.
Discussion:
Renal-adrenal fusion results from failure of retroperitoneal mesenchyme to stimulate adrenal capsule formation. Cells can irregularly extend into renal parenchymal in an infiltrative manner and can extend beyond the renal capsule into peri-renal adipose tissue without a surrounding fibrous capsule, mimicking a neoplastic process. In this case, the presence of medullary tissue rules out ectopic adrenal tissue, which is always exclusively cortical adrenal tissue. The pitfall in the current case is that seeing papillary renal cell carcinoma in adrenal tissue could be misdiagnosed as stage 4 renal cell carcinoma invading adrenal tissue. Also it is easy to overlook the adrenal cortical adenoma given the disorganized appearance of the adrenal-renal fusion. The presence of thickened monotonous sheets of clear cells of adrenal cortical tissue is consistent with an adenoma. The other pitfall with adrenal-renal fusion is misdiagnosing clear cell renal cell carcinoma. In contrast to the total empty clear cells which contain glycogen in clear cell renal cell carcinoma, the adrenal cortical tissue contains microvesicular clear cells which are full of lipid.
Presented by Jonathan Epstein, MD and prepared by Jason Kern, MD
Case 3: A 65 year old man underwent an orchiectomy for a testicular mass.
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Week (number): Case 1
A 65 year old man underwent an orchiectomy for a testicular mass. Choose the correct diagnosis:
Correct
Answer: Yolk sac tumor
Histology:
The tumor is composed of a uniform proliferation of glands with dense eosinophilic cytoplasm. Many of the glands have prominent subnuclear vacuoles.
Discussion:
Amongst germ cell tumors, yolk sac tumors are the most diverse histologically. The most common patterns are: Microcystic, solid, glandular, and endodermal sinus with the latter having characteristic Schiller-Duval bodies. Less common patterns are: myxomatous, hepatoid, papillary, sarcomatoid, parietal with eosinophilic basement membrane deposits, and polyvesicular vitelline which are dilated cysts with an hour glass configuration. The glandular, also known as alveolar, pattern must be distinguished from teratoma. In contrast to teratoma, there is the presence of subnuclear vacuoles and also the absence of smooth muscle cuffs around the glands. Verification of the diagnosis of yolk sac tumor can be made with immunohistochemistry using antibodies against AFP and Glypican 3. The latter antibody is specific for yolk sac differentiation and a more sensitive marker with less background staining than AFP.
Incorrect
Answer: Yolk sac tumor
Histology:
The tumor is composed of a uniform proliferation of glands with dense eosinophilic cytoplasm. Many of the glands have prominent subnuclear vacuoles.
Discussion:
Amongst germ cell tumors, yolk sac tumors are the most diverse histologically. The most common patterns are: Microcystic, solid, glandular, and endodermal sinus with the latter having characteristic Schiller-Duval bodies. Less common patterns are: myxomatous, hepatoid, papillary, sarcomatoid, parietal with eosinophilic basement membrane deposits, and polyvesicular vitelline which are dilated cysts with an hour glass configuration. The glandular, also known as alveolar, pattern must be distinguished from teratoma. In contrast to teratoma, there is the presence of subnuclear vacuoles and also the absence of smooth muscle cuffs around the glands. Verification of the diagnosis of yolk sac tumor can be made with immunohistochemistry using antibodies against AFP and Glypican 3. The latter antibody is specific for yolk sac differentiation and a more sensitive marker with less background staining than AFP.
Presented by Justin Bishop, MD and prepared by Sarah Karram, MD
Case 1: 50 year old woman with a parotid mass.
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Week 610: Case 1
50 year old woman with a parotid mass.
Correct
Answer: Acinic cell carcinoma, infarcted
Histology: This is a relatively well circumscribed tumor that is very “pink” on low power. On higher power it is evident that the vast majority of the tumor is infarcted, with the highly eosinophilic tumor “ghost cells” still visible. One microscopic focus of the tumor was viable, and exhibited the serous acinar differentiation that is diagnostic for acinic cell carcinoma. To confirm that the remaining infarcted tumor was also acinic cell carcinoma (and not a separate, unrelated tumor), DOG-1 immunohistochemistry was performed. Despite being dead, the infarcted tumor cells demonstrated the canalicular staining pattern for DOG-1 that is classic for acinic cell carcinoma.
Discussion: With the widespread use of fine needle aspiration to preoperatively diagnose salivary gland tumors, it is not uncommon to see FNA-related changes in the resection specimens. Often this takes the form of tumor infarction. The most commonly infarcted salivary gland tumors are pleomorphic adenoma and Warthin tumor, but any tumor can show these changes. The key to diagnosing and infarcted tumor (in any organ) lies in recognizing a residual, viable component; the viable cells will typically be in the most peripheral aspects of the neoplasm. If no tumor remains viable, a diagnosis can still be suggested by the FNA diagnosis, the architecture of the infarcted tumor (especially with Warthin tumor), and in occasional cases, immunohistochemistry on the ghost cells.
Incorrect
Answer: Acinic cell carcinoma, infarcted
Histology: This is a relatively well circumscribed tumor that is very “pink” on low power. On higher power it is evident that the vast majority of the tumor is infarcted, with the highly eosinophilic tumor “ghost cells” still visible. One microscopic focus of the tumor was viable, and exhibited the serous acinar differentiation that is diagnostic for acinic cell carcinoma. To confirm that the remaining infarcted tumor was also acinic cell carcinoma (and not a separate, unrelated tumor), DOG-1 immunohistochemistry was performed. Despite being dead, the infarcted tumor cells demonstrated the canalicular staining pattern for DOG-1 that is classic for acinic cell carcinoma.
Discussion: With the widespread use of fine needle aspiration to preoperatively diagnose salivary gland tumors, it is not uncommon to see FNA-related changes in the resection specimens. Often this takes the form of tumor infarction. The most commonly infarcted salivary gland tumors are pleomorphic adenoma and Warthin tumor, but any tumor can show these changes. The key to diagnosing and infarcted tumor (in any organ) lies in recognizing a residual, viable component; the viable cells will typically be in the most peripheral aspects of the neoplasm. If no tumor remains viable, a diagnosis can still be suggested by the FNA diagnosis, the architecture of the infarcted tumor (especially with Warthin tumor), and in occasional cases, immunohistochemistry on the ghost cells.
Presented by Justin Bishop, MD and prepared by Sarah Karram, MD
Case 2: 40 year old man with a nasal mass.
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Week (610): Case 2
40 year old man with a nasal mass.
Correct
Answer: Olfactory neuroblastoma
Histology: The tumor is a nested proliferation of small round cells growing in the sinonasal submucosa. It is positive for synaptophysin, chromogranin (not shown), and S100 in a sustentacular distribution. In addition, desmin (not shown) and myogenin highlight scattered tumor cells.
Discussion: Rhabdomyosarcoma (RMS) is a malignant mesenchymal neoplasm that exhibits skeletal muscle differentiation. About 40% of RMS affect the head and neck, in order of frequency: orbit, sinonasal tract, ear, and oral cavity, with other subsites rarely affected. Most forms of RMS are defined by the presence of rhabdomyoblasts – densely eosinophilic polygonal or spindled cells with hyperchromatic nuclei and occasional cytoplasmic cross-striations. Skeletal muscle differentiation is confirmed by nuclear immunohistochemical staining for myogenin and/or MyoD1. It must be remembered, however, that rhabdomyoblastic differentiation may be encountered in neoplasms other than RMS. This distinction is important because RMS is treated by specific chemotherapy protocols that may be different than those of other neoplasms in the differential diagnosis.
Olfactory neuroblastoma (ONB) is a malignant neoplasm that arises from the olfactory neuroepithelium of the superior nasal cavity and ethmoid sinus. By immunohistochemistry, ONB is positive for the neuroendocrine markers synaptophysin, chromogranin, and CD56 while S100 protein highlights the sustentacular supporting cells at the periphery of the tumor nests. Occasionally, ONB may exhibit unusual forms of differentiation that may obscure the diagnosis. Most common is epithelial differentiation, but rarely, ONB may exhibit melanocytic or rhabdomyoblastic differentiation.
It is important to distinguish ONB with rhabdomyoblastic differentiation from RMS, a problem compounded by both tumors being encountered in the sinonasal tract of young patients. Additionally, the alveolar subtype of RMS may express neuroendocrine markers, with nearly universal CD56 expression. An important key to this dilemma is recognizing the nature of the myogenin expression. Alveolar RMS, a nested, small round cell tumor, generally demonstrates diffuse myogenin expression, in contrast to the patchy distribution seen in ONB. Moreover, even in the face of patchy rhabdomyoblastic differentiation, classic areas of ONB should be recognizable in the background. Finally, in a very difficult case, molecular studies for the t(2;13) or t(1;13) translocations of alveolar RMS may be useful.
Reference:
– Bishop, et al. Rhabdomyoblastic differentiation in head and neck malignancies other than rhabdomyosarcoma. Head Neck Pathol. In press.
Incorrect
Answer: Olfactory neuroblastoma
Histology: The tumor is a nested proliferation of small round cells growing in the sinonasal submucosa. It is positive for synaptophysin, chromogranin (not shown), and S100 in a sustentacular distribution. In addition, desmin (not shown) and myogenin highlight scattered tumor cells.
Discussion: Rhabdomyosarcoma (RMS) is a malignant mesenchymal neoplasm that exhibits skeletal muscle differentiation. About 40% of RMS affect the head and neck, in order of frequency: orbit, sinonasal tract, ear, and oral cavity, with other subsites rarely affected. Most forms of RMS are defined by the presence of rhabdomyoblasts – densely eosinophilic polygonal or spindled cells with hyperchromatic nuclei and occasional cytoplasmic cross-striations. Skeletal muscle differentiation is confirmed by nuclear immunohistochemical staining for myogenin and/or MyoD1. It must be remembered, however, that rhabdomyoblastic differentiation may be encountered in neoplasms other than RMS. This distinction is important because RMS is treated by specific chemotherapy protocols that may be different than those of other neoplasms in the differential diagnosis.
Olfactory neuroblastoma (ONB) is a malignant neoplasm that arises from the olfactory neuroepithelium of the superior nasal cavity and ethmoid sinus. By immunohistochemistry, ONB is positive for the neuroendocrine markers synaptophysin, chromogranin, and CD56 while S100 protein highlights the sustentacular supporting cells at the periphery of the tumor nests. Occasionally, ONB may exhibit unusual forms of differentiation that may obscure the diagnosis. Most common is epithelial differentiation, but rarely, ONB may exhibit melanocytic or rhabdomyoblastic differentiation.
It is important to distinguish ONB with rhabdomyoblastic differentiation from RMS, a problem compounded by both tumors being encountered in the sinonasal tract of young patients. Additionally, the alveolar subtype of RMS may express neuroendocrine markers, with nearly universal CD56 expression. An important key to this dilemma is recognizing the nature of the myogenin expression. Alveolar RMS, a nested, small round cell tumor, generally demonstrates diffuse myogenin expression, in contrast to the patchy distribution seen in ONB. Moreover, even in the face of patchy rhabdomyoblastic differentiation, classic areas of ONB should be recognizable in the background. Finally, in a very difficult case, molecular studies for the t(2;13) or t(1;13) translocations of alveolar RMS may be useful.
Reference:
– Bishop, et al. Rhabdomyoblastic differentiation in head and neck malignancies other than rhabdomyosarcoma. Head Neck Pathol. In press.
Presented by Justin A. Bishop, MD and prepared by Sarah Karram, MD
This case talks about:
Case 3: 40 year old man with a tumor in his “pharynx.”
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Week (610): Case 3
40 year old man with a tumor in his “pharynx.”
Correct
Answer: Sclerosing rhabdomyosarcoma
Histology: This is a spindle cell tumor that has prominent hyaline matrix-like material. The tumor is mitotically active, but relatively uniform at the cellular level. Cytokeratins, p40, S100, and calponin were negative. Desmin is focally positive (in a dot-like manner), and myogenin was also focal.
Discussion: The most common forms of rhabdomyosarcoma (RMS) are alveolar and embryonal. Newer variants include pleomorphic, spindle cell, and sclerosing RMS. Sclerosing RMS is a newly-described variant that commonly affects the head and neck of adults. Unlike the more classic forms of RMS, sclerosing RMS has abundant hyaline stromal material that brings to mind other tumors such as myoepithelial carcinoma, chrondrosarcoma, and osteosarcoma. In addition, rhabdomyoblasts are only rarely identified in sclerosing RMS. The diagnosis must be confirmed by immunohistochemistry. Desmin is usually positive, but it is often focal and may show a peculiar dot-like staining pattern. Myogenin is typically focal or may even be negative; in contrast, MyoD1 is diffuse. While previously regarded as a variant of embryonal RMS, spindle cell and sclerosing variants of RMS were combined into a single, distinct entity in the latest WHO classification. Spindle cell/sclerosing RMS is a high-grade malignancy with a generally poor prognosis.
Incorrect
Answer: Sclerosing rhabdomyosarcoma
Histology: This is a spindle cell tumor that has prominent hyaline matrix-like material. The tumor is mitotically active, but relatively uniform at the cellular level. Cytokeratins, p40, S100, and calponin were negative. Desmin is focally positive (in a dot-like manner), and myogenin was also focal.
Discussion: The most common forms of rhabdomyosarcoma (RMS) are alveolar and embryonal. Newer variants include pleomorphic, spindle cell, and sclerosing RMS. Sclerosing RMS is a newly-described variant that commonly affects the head and neck of adults. Unlike the more classic forms of RMS, sclerosing RMS has abundant hyaline stromal material that brings to mind other tumors such as myoepithelial carcinoma, chrondrosarcoma, and osteosarcoma. In addition, rhabdomyoblasts are only rarely identified in sclerosing RMS. The diagnosis must be confirmed by immunohistochemistry. Desmin is usually positive, but it is often focal and may show a peculiar dot-like staining pattern. Myogenin is typically focal or may even be negative; in contrast, MyoD1 is diffuse. While previously regarded as a variant of embryonal RMS, spindle cell and sclerosing variants of RMS were combined into a single, distinct entity in the latest WHO classification. Spindle cell/sclerosing RMS is a high-grade malignancy with a generally poor prognosis.
Presented by Pedram Argani, MD and prepared by Armen Khararjian, MD
Case 1: This is a 75 year old female with a solitary lung mass.
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Week 609: Case 1
This is a 75 year old female with a solitary lung mass.
Correct
Answer: Hepatocellular Carcinoma
Histology:
This is a nested epithelioid proliferation with a sinusoidal capillary vasculature. The neoplastic cells have sharp crisp cell borders, which simulates that of a primary squamous cell carcinoma at the lung. However, there is no evidence of keratinization, and the sinusoidal vasculature pattern is not typical of squamous cell carcinoma. This patient had a prior history of hepatocellular carcinoma, and the current neoplasm labeled with arginase 1 and glypican 3, which supports the diagnosis of metastatic hepatocellular carcinoma.
Discussion:
Differential Diagnosis: Squamous cell carcinoma would demonstrate intercellular bridges, and would label for high molecular cytokeratin but not arginase 1. Pulmonary adenocarcinoma would typically label for TTF-1 and not arginase
1. Small cell carcinoma would feature small round blue cells with high nucleus to cytoplasm ratio, nuclear molding, high mitotic rate and necrosis.
Arginase 1 is likely the best marker hepatocellular carcinoma, in that it is more sensitive than specific than HepPar 1 or glypican 3. HepPar 1 has diminished sensitivity in that it misses poorly differentiated hepatocellular carcinomas, and also lacks specificity in that it frequently stains other carcinomas of foregut origin (such as gastric, colon, and pancreatobiliary adenocarcinomas). Glypican 3 can be negative in well differentiated hepatocellular carcinomas, also stains yolk sac tumors, and may stain other carcinomas and melanoma.
Incorrect
Answer: Hepatocellular Carcinoma
Histology:
This is a nested epithelioid proliferation with a sinusoidal capillary vasculature. The neoplastic cells have sharp crisp cell borders, which simulates that of a primary squamous cell carcinoma at the lung. However, there is no evidence of keratinization, and the sinusoidal vasculature pattern is not typical of squamous cell carcinoma. This patient had a prior history of hepatocellular carcinoma, and the current neoplasm labeled with arginase 1 and glypican 3, which supports the diagnosis of metastatic hepatocellular carcinoma.
Discussion:
Differential Diagnosis: Squamous cell carcinoma would demonstrate intercellular bridges, and would label for high molecular cytokeratin but not arginase 1. Pulmonary adenocarcinoma would typically label for TTF-1 and not arginase
1. Small cell carcinoma would feature small round blue cells with high nucleus to cytoplasm ratio, nuclear molding, high mitotic rate and necrosis.
Arginase 1 is likely the best marker hepatocellular carcinoma, in that it is more sensitive than specific than HepPar 1 or glypican 3. HepPar 1 has diminished sensitivity in that it misses poorly differentiated hepatocellular carcinomas, and also lacks specificity in that it frequently stains other carcinomas of foregut origin (such as gastric, colon, and pancreatobiliary adenocarcinomas). Glypican 3 can be negative in well differentiated hepatocellular carcinomas, also stains yolk sac tumors, and may stain other carcinomas and melanoma.
Presented by Pedram Argani, MD and prepared by Armen Khararjian, MD
Case 2: This is a 33 year old female with a cervical mass.
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Week 609: Case 2
This is a 33 year old female with a cervical mass.
Correct
Answer: Alveolar Soft Part Sarcoma
Histology: The biphasic “blue” spindle and glandular tissue in this specimen represents normal proliferative endometrium. The neoplasm is a nested proliferation of polygonal epithelioid cells with prominent nucleoli and abundant granular cytoplasm. The neoplastic cells label for cathepsin k, but are negative for HMB45, Melan A and S100 protein. They demonstrated TFE3 gene rearrangement by FISH. This supports the diagnosis of alveolar soft part sarcoma.
Discussion: Differential Diagnosis: Granular cell tumors frequently show nonspecific weak immunohistochemical labeling for TFE3, but lack TFE3 gene rearrangements. Most PEComas lack TFE3 gene rearrangement. A small subset of PEComas does demonstrate TFE3 gene rearrangements; however, these neoplasms typically have epithelioid clear cells and label for melanocytic markers like HMB45. Hence, the best diagnosis for this lesion is alveolar soft part sarcoma.
Alveolar soft part sarcomas contain a unbalanced derX t(X:17) (p11.2;q25) chromosome translocation, resulting in an ASPL-TFE3 gene fusion. This results in overexpression of TFE3 fusion proteins, and can be detected by break-apart TFE3 FISH assays.
Incorrect
Answer: Alveolar Soft Part Sarcoma
Histology: The biphasic “blue” spindle and glandular tissue in this specimen represents normal proliferative endometrium. The neoplasm is a nested proliferation of polygonal epithelioid cells with prominent nucleoli and abundant granular cytoplasm. The neoplastic cells label for cathepsin k, but are negative for HMB45, Melan A and S100 protein. They demonstrated TFE3 gene rearrangement by FISH. This supports the diagnosis of alveolar soft part sarcoma.
Discussion: Differential Diagnosis: Granular cell tumors frequently show nonspecific weak immunohistochemical labeling for TFE3, but lack TFE3 gene rearrangements. Most PEComas lack TFE3 gene rearrangement. A small subset of PEComas does demonstrate TFE3 gene rearrangements; however, these neoplasms typically have epithelioid clear cells and label for melanocytic markers like HMB45. Hence, the best diagnosis for this lesion is alveolar soft part sarcoma.
Alveolar soft part sarcomas contain a unbalanced derX t(X:17) (p11.2;q25) chromosome translocation, resulting in an ASPL-TFE3 gene fusion. This results in overexpression of TFE3 fusion proteins, and can be detected by break-apart TFE3 FISH assays.
Presented by Pedram Argani, MD and prepared by Armen Khararjian, MD
Case 3: This is a 56 year old female with lymphadenopathy.
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Week 609: Case 3
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Answer: Well Differentiated Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia
Histology: This lymph node is effaced, in that the sinusoids are obliterated and the node is composed of sheets of small monotonous lymphocytes. Among the sheets are paler rounded areas which are proliferation centers; these consist of enlarged prolymphocytes with more open chromatin and central nucleoli. The neoplastic cells label for CD20, CD5, and CD23, supporting the diagnosis of WDLL/CLL.
Discussion: Follicular small B-cell lymphoma could have a sheet-like and nodular architecture; however, the neoplastic small round cells would have more angulated nuclei, and the lesional cells typically label for CD10 but not for CD5. Mantle cell lymphoma typically lacks large transformed cells. Nuclei are typically only slightly angulated, more than those of WDLL/CLL but less than those of follicular lymphoma. Mantle cell lymphoma would label for cyclin D1, unlike WDLL/CLL or follicular lymphoma. Diffuse large cell lymphoma would be composed of sheets of atypical large lymphocytes with prominent nucleoli typically localized to the cell membrane.
Incorrect
Answer: Well Differentiated Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia
Histology: This lymph node is effaced, in that the sinusoids are obliterated and the node is composed of sheets of small monotonous lymphocytes. Among the sheets are paler rounded areas which are proliferation centers; these consist of enlarged prolymphocytes with more open chromatin and central nucleoli. The neoplastic cells label for CD20, CD5, and CD23, supporting the diagnosis of WDLL/CLL.
Discussion: Follicular small B-cell lymphoma could have a sheet-like and nodular architecture; however, the neoplastic small round cells would have more angulated nuclei, and the lesional cells typically label for CD10 but not for CD5. Mantle cell lymphoma typically lacks large transformed cells. Nuclei are typically only slightly angulated, more than those of WDLL/CLL but less than those of follicular lymphoma. Mantle cell lymphoma would label for cyclin D1, unlike WDLL/CLL or follicular lymphoma. Diffuse large cell lymphoma would be composed of sheets of atypical large lymphocytes with prominent nucleoli typically localized to the cell membrane.
Presented by Ashley Cimino-Mathews, MD. and prepared by Mohammed Lilo, MD.
Case 1: A 40 year-old male has a neck mass.
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Week 608: Case 1
A 40 year-old male has a neck mass
Correct
Answer:Triton tumor
Histology: The tumor consists of a high grade spindle cell lesion arranged in fascicular growth pattern with nuclear hyperchromasia and abundant mitotic figures. Many cells display overt evidence of skeletal muscle differentiation, with bright pink cytoplasm with cross striations. There are separate fragments of disc material (this is taken from the cervical spine), raising the possibility that this lesion arises from or involves the bone or cartilage. By immunohistochemistry, the lesion is positive for desmin and myogenin. Elsewhere in the lesion but not seen in this slide are regions of neurofibroma, which merge with the malignant neoplasm.
Discussion: This lesion is a malignant peripheral nerve sheath tumor (MPNST) with rhabdomyoblastic differentiation, a “Triton tumor.” The presence of an associated an known pre-existing neurofiboma aids in the diagnosis of this lesion. MPNST are the malignant counterpart to benign nerve sheath tumors and may arise de novo or in association with neurofibromas as a part of neurofibromatosis. 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 and Triton tumor. In the Triton tumor, the MPNSTS shows skeletal muscle differentiation as evidenced by the morphologic features of the cells as well as immunoreactivity for desmin and myogenin. The skeletal muscle differentiation may be focal, or as in this case, diffuse. 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.
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. Fisher C. Immunohistochemistry in diagnosis of soft tissue tumours. Histopathology 2011;58(7):1001-1012
4. 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:Triton tumor
Histology: The tumor consists of a high grade spindle cell lesion arranged in fascicular growth pattern with nuclear hyperchromasia and abundant mitotic figures. Many cells display overt evidence of skeletal muscle differentiation, with bright pink cytoplasm with cross striations. There are separate fragments of disc material (this is taken from the cervical spine), raising the possibility that this lesion arises from or involves the bone or cartilage. By immunohistochemistry, the lesion is positive for desmin and myogenin. Elsewhere in the lesion but not seen in this slide are regions of neurofibroma, which merge with the malignant neoplasm.
Discussion: This lesion is a malignant peripheral nerve sheath tumor (MPNST) with rhabdomyoblastic differentiation, a “Triton tumor.” The presence of an associated an known pre-existing neurofiboma aids in the diagnosis of this lesion. MPNST are the malignant counterpart to benign nerve sheath tumors and may arise de novo or in association with neurofibromas as a part of neurofibromatosis. 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 and Triton tumor. In the Triton tumor, the MPNSTS shows skeletal muscle differentiation as evidenced by the morphologic features of the cells as well as immunoreactivity for desmin and myogenin. The skeletal muscle differentiation may be focal, or as in this case, diffuse. 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.
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. Fisher C. Immunohistochemistry in diagnosis of soft tissue tumours. Histopathology 2011;58(7):1001-1012
4. 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 Ashley Cimino-Mathews, MD. and prepared by Mohammed Lilo, MD.
Case 2: A 60 year-old male has an enlarging thigh mass.
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Week 608: Case 2
A 60 year-old male has an enlarging thigh mass
Correct
Answer: Nodular fasciitis
Histology: The infiltrative lesion consists of a cellular proliferation of spindled cells with elongated, bipolar tapering ends. The cells display moderate nuclear atypia, with irregular nuclear contours and occasional prominent nucleoli. There are numerous mitotic figures, but no atypical mitoses. There are regions with extravasated red blood cells and a chronic inflammatory infiltrate.
Discussion: Nodular fasciitis is a benign fibroblastic/myofibroblastic proliferation that can occur anywhere in the body and can mimic a neoplastic process in both its clinical presentation of a rapidly growing mass, as well as in its histology of atypical and infiltrative spindled cells. It frequently involves the extremities or superficial trunk but can also involve deep organs. A subset of patients will have a history of trauma, which can be useful, but most patients do not. The classic histologic features are a “tissue culture-like” appearance of spindled fibroblasts/myofibroblasts with “feathery cytoplasm” in a loose matrix with associated chronic inflammation and extravasated red cells. The fibroblasts may display a hypercellular region at the periphery of the lesion, with a hypocellular center. However, the cellular phase of nodular fasciitis (i.e., in long standing lesions), the “tissue culture like appearance” is replaced by a more cellular and fibrotic proliferation. The spindled cells will label like fibroblasts/myofibroblasts and are typically immunoreactive for actin (characteristically in a “tram-track” pattern) as well as CD68, but are negative for desmin and S100. However, nodular fasciitis can show focal cytokeratin and p63 labeling, which is a potential diagnostic pitfall in the differential diagnosis of a sarcomatoid carcinoma. The differential diagnosis includes sarcoma and sarcomatoid carcinoma (which should display greater nuclear atypia and may show atypical mitotic figures); inflammatory myofibroblastic tumor (which display mixed inflammatory infiltrates and are commonly ALK positive); and fibromatosis (which displays nuclear beta-catenin reactivity).
References:
1. Barak S, Wang Z, Miettinen M. Immunoreactivity for calretinin and keratins in desmoid fibromatosis and other myofibroblastic tumors: a diagnostic pitfall. Am J Surg Pathol. 2012;36(9):1404-9.
2. Bishop JA, Montgomery EA, Westra WH. Use of p40 and p63 immunohistochemistry and human papillomavirus testing as ancillary tools for the recognition of head and neck sarcomatoid carcinoma and its distinction from benign and malignant mesenchymal processes. Am J Surg Pathol. 2014;38(2):257-64.
Incorrect
Answer: Nodular fasciitis
Histology: The infiltrative lesion consists of a cellular proliferation of spindled cells with elongated, bipolar tapering ends. The cells display moderate nuclear atypia, with irregular nuclear contours and occasional prominent nucleoli. There are numerous mitotic figures, but no atypical mitoses. There are regions with extravasated red blood cells and a chronic inflammatory infiltrate.
Discussion: Nodular fasciitis is a benign fibroblastic/myofibroblastic proliferation that can occur anywhere in the body and can mimic a neoplastic process in both its clinical presentation of a rapidly growing mass, as well as in its histology of atypical and infiltrative spindled cells. It frequently involves the extremities or superficial trunk but can also involve deep organs. A subset of patients will have a history of trauma, which can be useful, but most patients do not. The classic histologic features are a “tissue culture-like” appearance of spindled fibroblasts/myofibroblasts with “feathery cytoplasm” in a loose matrix with associated chronic inflammation and extravasated red cells. The fibroblasts may display a hypercellular region at the periphery of the lesion, with a hypocellular center. However, the cellular phase of nodular fasciitis (i.e., in long standing lesions), the “tissue culture like appearance” is replaced by a more cellular and fibrotic proliferation. The spindled cells will label like fibroblasts/myofibroblasts and are typically immunoreactive for actin (characteristically in a “tram-track” pattern) as well as CD68, but are negative for desmin and S100. However, nodular fasciitis can show focal cytokeratin and p63 labeling, which is a potential diagnostic pitfall in the differential diagnosis of a sarcomatoid carcinoma. The differential diagnosis includes sarcoma and sarcomatoid carcinoma (which should display greater nuclear atypia and may show atypical mitotic figures); inflammatory myofibroblastic tumor (which display mixed inflammatory infiltrates and are commonly ALK positive); and fibromatosis (which displays nuclear beta-catenin reactivity).
References:
1. Barak S, Wang Z, Miettinen M. Immunoreactivity for calretinin and keratins in desmoid fibromatosis and other myofibroblastic tumors: a diagnostic pitfall. Am J Surg Pathol. 2012;36(9):1404-9.
2. Bishop JA, Montgomery EA, Westra WH. Use of p40 and p63 immunohistochemistry and human papillomavirus testing as ancillary tools for the recognition of head and neck sarcomatoid carcinoma and its distinction from benign and malignant mesenchymal processes. Am J Surg Pathol. 2014;38(2):257-64.
Presented by Ashley Cimino-Mathews, MD. and prepared by Mohammed Lilo, MD.
Case 3: A 40 year-old female presents with a recurrent popliteal fossa mass.
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Week 608: Case 3
A 40 year-old female presents with a recurrent popliteal fossa mass
Correct
Answer:Clear cell sarcoma
Histology: The tumor consists of nests and sheets of cells with pale to amphophilic cytoplasm, atypical nuclei with irregular nuclear contours, mild pleomorphism, and prominent nucleoli. There are multiple mitotic figures. Immunostains show the neoplasm to be immunoreactive for HMB45 and melan A, and negative to AE1/AE3.
Discussion: Clear cell sarcoma (or “melanoma of soft parts”) is an aggressive soft tissue neoplasm that characteristically presents in the extremity deep tissues or in the trunk of adolescents/young adults. Although most sarcomas metastasize hematogenously to involve solid organs, clear cell sarcomas is one of the sarcomas which will metastasize lymphatically to involve lymph nodes. Clear cell sarcoma is morphologically and immunohistochemically indistinguishable from malignant melanoma. Like melanoma, clear cell sarcoma cells can have a varied appearance from spindled to epithelioid, and intracytoplasmic melanin may be present. A unique feature is the presence of floret-like giant cells. By immunohistochemistry, clear cell sarcomas are immunoreactive for melan A, MITF, HMB45 and Sox10 and can also label for EMA, bcl2 and neuroendocrine markers. Notably, clear cell sarcomas differ genetically from melanoma and have a characteristic translocation: t(12;22)(q13;q12), between ATF1 and EWS.
Epithelioid sarcoma is another aggressive sarcoma that affects the distal extremities (often the hand) of young adults and can metastatize to the lymph nodes; histologically, it is characterized by pleomorphic epithelioid cells with granuloma formation and cytokeratin immunoreactivity. Giant cell tumor of tendon sheath, or fibrous histiocytoma of tendon sheath, is comprised of mononuclear and multinucleated histiocytic cells. Paraganglioma is a typically benign neuroendocrine tumor comprised of nests of cells with clear to amphophilic cytoplasm with scattered neuroendocrine atypia. Pigmented villonodular synovitis is a reactive proliferation of synovial cells with papillary formation and hemosiderin laden macrophages.
Reference:
1. Hisaoka M, Ishida T, Kuo TT, et al. Clear cell sarcoma of soft tissue: a clinicopathologic, immunohistochemical, and molecular analysis of 33 cases. Am J Surg Pathol. 2008;32(3):452-60.
Incorrect
Answer:Clear cell sarcoma
Histology: The tumor consists of nests and sheets of cells with pale to amphophilic cytoplasm, atypical nuclei with irregular nuclear contours, mild pleomorphism, and prominent nucleoli. There are multiple mitotic figures. Immunostains show the neoplasm to be immunoreactive for HMB45 and melan A, and negative to AE1/AE3.
Discussion: Clear cell sarcoma (or “melanoma of soft parts”) is an aggressive soft tissue neoplasm that characteristically presents in the extremity deep tissues or in the trunk of adolescents/young adults. Although most sarcomas metastasize hematogenously to involve solid organs, clear cell sarcomas is one of the sarcomas which will metastasize lymphatically to involve lymph nodes. Clear cell sarcoma is morphologically and immunohistochemically indistinguishable from malignant melanoma. Like melanoma, clear cell sarcoma cells can have a varied appearance from spindled to epithelioid, and intracytoplasmic melanin may be present. A unique feature is the presence of floret-like giant cells. By immunohistochemistry, clear cell sarcomas are immunoreactive for melan A, MITF, HMB45 and Sox10 and can also label for EMA, bcl2 and neuroendocrine markers. Notably, clear cell sarcomas differ genetically from melanoma and have a characteristic translocation: t(12;22)(q13;q12), between ATF1 and EWS.
Epithelioid sarcoma is another aggressive sarcoma that affects the distal extremities (often the hand) of young adults and can metastatize to the lymph nodes; histologically, it is characterized by pleomorphic epithelioid cells with granuloma formation and cytokeratin immunoreactivity. Giant cell tumor of tendon sheath, or fibrous histiocytoma of tendon sheath, is comprised of mononuclear and multinucleated histiocytic cells. Paraganglioma is a typically benign neuroendocrine tumor comprised of nests of cells with clear to amphophilic cytoplasm with scattered neuroendocrine atypia. Pigmented villonodular synovitis is a reactive proliferation of synovial cells with papillary formation and hemosiderin laden macrophages.
Reference:
1. Hisaoka M, Ishida T, Kuo TT, et al. Clear cell sarcoma of soft tissue: a clinicopathologic, immunohistochemical, and molecular analysis of 33 cases. Am J Surg Pathol. 2008;32(3):452-60.
Presented by William Westra, M.D. and prepared by Doreen Nguyen, M.D.
Case 1: 50 year-old male with mass in the base of tongue.
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Week 607: Case 1
50 year-old male with mass in the base of tongue.
Correct
Answer: Cribriform adenocarcinoma of the tongue (CAT)
Histology: The tumor is covered by an intact squamous epithelium without dysplasia. It is unencapsulated. The tumor demonstrates a predominant cribriform to solid pattern of growth. Irregular solid tumor nodules are divided by fibrous septa. There is also an intermingled tubular pattern, and papillary/pseudopapillary structures are also encountered. The nuclei of the tumor cells are uniformly round to oval without significant pleomorphism. In areas, the nuclei overlap and demonstrate chromatin clearing.
Discussion: Cribriform adenocarcinoma of the tongue (CAT) is a tumor occurring mostly, but not exclusively, in the base of the tongue. In light of reports noting their location in other non-lingual sites of the oral cavity, the designation has been modified to cribriform adenocarcinoma of the tongue and minor salivary glands (CATMS). Histopathologically, CATMSG is sometimes confused with papillary carcinoma of the thyroid based on areas of papillary growth, nuclear overlapping and chromatin clearing, and (less commonly) the presence of psammomatous calcifications. Unlike papillary thyroid carcinomas, the tumor is negative for TTF-1 and thyroglobulin by immunohistochemistry. The tumor cells actually show differentiation along salivary gland secretory and myoepithelial lines. They tend to be positive for cytokeratin, cKit, p63, CK5/6 and S100. CATMSG differs from polymorphous low grade adenocarcinoma in terms of location (base of tongue vs palate) and architectural makeup.
CATMSG are often metastatic to regional lymph nodes at the time of presentation. Nonetheless, early metastatic disease seen in most cases of CATMSG is not associated with aggressive behavior as patients consistently follow an indolent course. Accordingly, CATMSG is regarded as a low grade salivary gland carcinoma.
Incorrect
Answer: Cribriform adenocarcinoma of the tongue (CAT)
Histology: The tumor is covered by an intact squamous epithelium without dysplasia. It is unencapsulated. The tumor demonstrates a predominant cribriform to solid pattern of growth. Irregular solid tumor nodules are divided by fibrous septa. There is also an intermingled tubular pattern, and papillary/pseudopapillary structures are also encountered. The nuclei of the tumor cells are uniformly round to oval without significant pleomorphism. In areas, the nuclei overlap and demonstrate chromatin clearing.
Discussion: Cribriform adenocarcinoma of the tongue (CAT) is a tumor occurring mostly, but not exclusively, in the base of the tongue. In light of reports noting their location in other non-lingual sites of the oral cavity, the designation has been modified to cribriform adenocarcinoma of the tongue and minor salivary glands (CATMS). Histopathologically, CATMSG is sometimes confused with papillary carcinoma of the thyroid based on areas of papillary growth, nuclear overlapping and chromatin clearing, and (less commonly) the presence of psammomatous calcifications. Unlike papillary thyroid carcinomas, the tumor is negative for TTF-1 and thyroglobulin by immunohistochemistry. The tumor cells actually show differentiation along salivary gland secretory and myoepithelial lines. They tend to be positive for cytokeratin, cKit, p63, CK5/6 and S100. CATMSG differs from polymorphous low grade adenocarcinoma in terms of location (base of tongue vs palate) and architectural makeup.
CATMSG are often metastatic to regional lymph nodes at the time of presentation. Nonetheless, early metastatic disease seen in most cases of CATMSG is not associated with aggressive behavior as patients consistently follow an indolent course. Accordingly, CATMSG is regarded as a low grade salivary gland carcinoma.
Histology: The tumor is present as a large (4 cm) pedunculated polyp of mostly fat and lined by unremarkable squamous epithelium. The lipomatous core is compartmentalized into lobules by thin fibrous bands. Within the fat and fibrous bands are cells with enlarged, hyperchromatic and sometimes multilobated nuclei. By immunohistochemistry, these atypical cells demonstrate nuclear expression of MDM2.
Discussion: Large stromal polyps with cores of fibroadipose tissue are sometimes encountered in the esophagus and hypopharynx. Those lesions that exhibit atypical cells have been problematic in terms of classification. Some have been reported these as well-differentiated liposarcomas or atypical lipomatous tumors; but unlike well differentiated liposarcomas of the deep soft tissues, they rarely recur and do not undergo dedifferentiation despite the fact that they are generally treated by polypectomy alone. Atypical lipomatous tumor/well-differentiated liposarcoma is characterized by the amplification of MDM2 and CDK4 genes on chromosome 12q15 and 12q14. The availability of immunohistochemical markers for MDM2 amplification now permits the sensitive and specific recognition of the MDM2 amplification, and the reliable distinction between atypical lipomatous tumor/well-differentiated liposarcomas and lipomas.
The finding of MDM2 in this and other cases provides strong support that the giant hypopharyngeal lipomatous tumor is in fact a liposarcoma rather than a giant fibrovascular polyp that simply displays atypical degenerated cells. The fact that these tumors do not undergo dedifferentiation likely reflects the fact that they typically come to medical attention and are removed as relatively small lesions (compared to their massive counterparts in the retroperitoneum). Accordingly, they are best regarded as giant pharyngeal atypical lipomatous tumors.
Histology: The tumor is present as a large (4 cm) pedunculated polyp of mostly fat and lined by unremarkable squamous epithelium. The lipomatous core is compartmentalized into lobules by thin fibrous bands. Within the fat and fibrous bands are cells with enlarged, hyperchromatic and sometimes multilobated nuclei. By immunohistochemistry, these atypical cells demonstrate nuclear expression of MDM2.
Discussion: Large stromal polyps with cores of fibroadipose tissue are sometimes encountered in the esophagus and hypopharynx. Those lesions that exhibit atypical cells have been problematic in terms of classification. Some have been reported these as well-differentiated liposarcomas or atypical lipomatous tumors; but unlike well differentiated liposarcomas of the deep soft tissues, they rarely recur and do not undergo dedifferentiation despite the fact that they are generally treated by polypectomy alone. Atypical lipomatous tumor/well-differentiated liposarcoma is characterized by the amplification of MDM2 and CDK4 genes on chromosome 12q15 and 12q14. The availability of immunohistochemical markers for MDM2 amplification now permits the sensitive and specific recognition of the MDM2 amplification, and the reliable distinction between atypical lipomatous tumor/well-differentiated liposarcomas and lipomas.
The finding of MDM2 in this and other cases provides strong support that the giant hypopharyngeal lipomatous tumor is in fact a liposarcoma rather than a giant fibrovascular polyp that simply displays atypical degenerated cells. The fact that these tumors do not undergo dedifferentiation likely reflects the fact that they typically come to medical attention and are removed as relatively small lesions (compared to their massive counterparts in the retroperitoneum). Accordingly, they are best regarded as giant pharyngeal atypical lipomatous tumors.
Presented by William Westra, M.D. and prepared by Doreen Nguyen, M.D.
Case 3: 60 year-old male with a parotid mass.
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Week 607: Case 3
60 year-old male with a parotid mass.
Correct
Answer: Basal cell adenocarcinoma
Histology: The tumor is characterized by a prominent nested pattern of growth. The rounded aggregates exhibit peripheral pallisading, and are separated by variably sized fibrous bands. The cellular composition is dominated by small basophilic cells with round nuclei and sparse cytoplasm. Within the nests, the cells form small tubules filled with an eosinophilic matrix. In areas, the mitotic rate is elevated to the point where several mitotic figures can be seen in a single high power field. At the periphery of the tumor, tumor nests grow in and around pre-existing acini in an invasive pattern.
Discussion: Basal cell adenocarcinoma is a low grade salivary gland malignancy that usually arises in the parotid. It is the malignant counterpart of basal cell adenoma. The distinction between the benign basal cell adenoma and the low grade basal cell adenocarcinoma is subtle and difficult. To diagnose malignancy, we generally require evidence of invasive tumor growth together with an elevated mitotic rate (usually 3 or more mitosis per 10 high power fields). The identification of invasive growth is not always straightforward since some basal cell adenomas (e.g. membraneous type) lack encapsulation and exhibit multinodular growth.
Incorrect
Answer: Basal cell adenocarcinoma
Histology: The tumor is characterized by a prominent nested pattern of growth. The rounded aggregates exhibit peripheral pallisading, and are separated by variably sized fibrous bands. The cellular composition is dominated by small basophilic cells with round nuclei and sparse cytoplasm. Within the nests, the cells form small tubules filled with an eosinophilic matrix. In areas, the mitotic rate is elevated to the point where several mitotic figures can be seen in a single high power field. At the periphery of the tumor, tumor nests grow in and around pre-existing acini in an invasive pattern.
Discussion: Basal cell adenocarcinoma is a low grade salivary gland malignancy that usually arises in the parotid. It is the malignant counterpart of basal cell adenoma. The distinction between the benign basal cell adenoma and the low grade basal cell adenocarcinoma is subtle and difficult. To diagnose malignancy, we generally require evidence of invasive tumor growth together with an elevated mitotic rate (usually 3 or more mitosis per 10 high power fields). The identification of invasive growth is not always straightforward since some basal cell adenomas (e.g. membraneous type) lack encapsulation and exhibit multinodular growth.
Presented by Pedram Argani, M.D. and prepared by Doreen Nguyen, M.D.
Case 1: This is a 57 year-old male with a peripheral lung mass.
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Week 605: Case 1
This is a 57 year-old male with a peripheral lung mass.
Correct
Answer: Metastatic adenoid cystic carcinoma
Histology: This is a basaloid neoplasm which involves peripheral lung and abuts the pleura. Cells are fairly uniform, and in some areas appear to colonize the existing alveolated septa, simulating a bronchioloalveolar adenocarcinoma (lepidic growth pattern). However, one can focally appreciate a dual cell population, with myoepithelial cells surrounding hyalinized basement membrane material. The lesion lacks marked nuclear atypia. This patient was subsequently discovered to have had prior surgery for an adenoid cystic carcinoma of the palate. Therefore, the current lesion represents a metastasis.
Discussion: Adenocarcinoma of the lung would demonstrate greater atypia, and would not show the biphasic pattern seen in this case. Carcinoid tumors may be somewhat similar cytologically, but would label for neuroendocrine markers and again would not demonstrate a dimorphic cell population. Basaloid squamous carcinoma would demonstrate greater cytologic atypia, and show overt areas of squamous differentiation.
Adenoid cystic carcinomas may recur late, long after the prior surgery has been remembered by the clinical team. Adenoid cystic carcinoma typically harbors t(6;9)(q22:p23) translocation which fusions the MYB and NFIB transcription factor genes.
Incorrect
Answer: Metastatic adenoid cystic carcinoma
Histology: This is a basaloid neoplasm which involves peripheral lung and abuts the pleura. Cells are fairly uniform, and in some areas appear to colonize the existing alveolated septa, simulating a bronchioloalveolar adenocarcinoma (lepidic growth pattern). However, one can focally appreciate a dual cell population, with myoepithelial cells surrounding hyalinized basement membrane material. The lesion lacks marked nuclear atypia. This patient was subsequently discovered to have had prior surgery for an adenoid cystic carcinoma of the palate. Therefore, the current lesion represents a metastasis.
Discussion: Adenocarcinoma of the lung would demonstrate greater atypia, and would not show the biphasic pattern seen in this case. Carcinoid tumors may be somewhat similar cytologically, but would label for neuroendocrine markers and again would not demonstrate a dimorphic cell population. Basaloid squamous carcinoma would demonstrate greater cytologic atypia, and show overt areas of squamous differentiation.
Adenoid cystic carcinomas may recur late, long after the prior surgery has been remembered by the clinical team. Adenoid cystic carcinoma typically harbors t(6;9)(q22:p23) translocation which fusions the MYB and NFIB transcription factor genes.
Presented by Pedram Argani, M.D. and prepared by Doreen Nguyen, M.D.
Case 2: This is a 35 year-old female with a large infiltrative ethmoid mass.
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Week 605: Case 2
This is a 35 year-old female with a large infiltrative ethmoid mass.
Correct
Answer: NUT midline carcinoma
Histology: This is highly cellular malignant small round blue cell tumor. Mitotic figures are readily evident. Focally, one sees the abrupt squamous differentiation with basaloid cells rapidly transforming into fairly well differentiated keratinized epithelium. These are the typical features of NUT midline carcinoma. The lesion was diffusely immunoreactive for cytokeratin and p63, and demonstrated diffuse nuclear labeling for NUT protein by immunohistochemistry.
Discussion: High grade olfactory neuroblastoma is essentially a high grade malignant small round cell tumor. It would not be expected to demonstrate squamous differentiation as the current lesion does. It would also label for neuroendocrine markers. Melanoma of the sinonasal tract may have a small cell appearance; however, it should not demonstrate focally squamous differentiation and would label for melanocytic markers, not epithelial markers. HPV-associated squamous cell carcinomas are frequently basaloid and demonstrate abrupt keratinization similar to that seen in the current case. However, the ethmoid is not a typical area for HPV-associated squamous cell carcinoma. The latter is excluded by absence of HPV DNA sequences by in situ hybridization, and by the labeling for NUT protein.
NUT midline carcinomas are highly aggressive lesions, with a mean survival in the range of 1 year. These tumors are all defined by chromosome translocation resulting in gene fusions involving the nuclear protein of testis (NUT) gene, which is located at chromosome 15q24.
Reference(s)
– Stelow E. Head and Neck Pathology 2011; 5:31-35.
Incorrect
Answer: NUT midline carcinoma
Histology: This is highly cellular malignant small round blue cell tumor. Mitotic figures are readily evident. Focally, one sees the abrupt squamous differentiation with basaloid cells rapidly transforming into fairly well differentiated keratinized epithelium. These are the typical features of NUT midline carcinoma. The lesion was diffusely immunoreactive for cytokeratin and p63, and demonstrated diffuse nuclear labeling for NUT protein by immunohistochemistry.
Discussion: High grade olfactory neuroblastoma is essentially a high grade malignant small round cell tumor. It would not be expected to demonstrate squamous differentiation as the current lesion does. It would also label for neuroendocrine markers. Melanoma of the sinonasal tract may have a small cell appearance; however, it should not demonstrate focally squamous differentiation and would label for melanocytic markers, not epithelial markers. HPV-associated squamous cell carcinomas are frequently basaloid and demonstrate abrupt keratinization similar to that seen in the current case. However, the ethmoid is not a typical area for HPV-associated squamous cell carcinoma. The latter is excluded by absence of HPV DNA sequences by in situ hybridization, and by the labeling for NUT protein.
NUT midline carcinomas are highly aggressive lesions, with a mean survival in the range of 1 year. These tumors are all defined by chromosome translocation resulting in gene fusions involving the nuclear protein of testis (NUT) gene, which is located at chromosome 15q24.
Reference(s)
– Stelow E. Head and Neck Pathology 2011; 5:31-35.
Presented by Pedram Argani, M.D. and prepared by Doreen Nguyen, M.D.
Case 3: This is a 27 year-old female with a parotid mass.
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Week 605: Case 3
This is a 27 year-old female with a parotid mass.
Correct
Answer: Solitary fibrous tumor
Histology: This is a bland spindle cell lesion associated with prominent sclerosis. The vessels have a hemangiopericytomatous pattern in many areas. The lesional cells demonstrate strong immunoreactivity for CD34, and strong nuclear labeling for STAT6.
These results support the diagnosis of solitary fibrous tumor.
Discussion: Synovial sarcoma has similar cytology to solitary fibrous tumor; however, it would not label for CD34, and most cases demonstrate greater mitotic activity and slightly more primitive chromatin. Sarcomatoid carcinomas would demonstrate greater nuclear atypia and a malignant epithelial component. Sclerosing epithelioid fibrosarcoma would demonstrate greater cytologic atypia, lack CD34 immunoreactivity, and is associated with gene fusions involving FUS or EWS genes.
Nuclear labeling for STAT6 is a highly specific marker for solitary fibrous tumors. This occurs as a result of NAB2-STAT6 gene fusion which is characteristic of solitary fibrous tumor.
Incorrect
Answer: Solitary fibrous tumor
Histology: This is a bland spindle cell lesion associated with prominent sclerosis. The vessels have a hemangiopericytomatous pattern in many areas. The lesional cells demonstrate strong immunoreactivity for CD34, and strong nuclear labeling for STAT6.
These results support the diagnosis of solitary fibrous tumor.
Discussion: Synovial sarcoma has similar cytology to solitary fibrous tumor; however, it would not label for CD34, and most cases demonstrate greater mitotic activity and slightly more primitive chromatin. Sarcomatoid carcinomas would demonstrate greater nuclear atypia and a malignant epithelial component. Sclerosing epithelioid fibrosarcoma would demonstrate greater cytologic atypia, lack CD34 immunoreactivity, and is associated with gene fusions involving FUS or EWS genes.
Nuclear labeling for STAT6 is a highly specific marker for solitary fibrous tumors. This occurs as a result of NAB2-STAT6 gene fusion which is characteristic of solitary fibrous tumor.
Histology: The lesion consists of a well-circumscribed nodule composed of well-formed tubules lined by abundant eosinophilic cytoplasm. Some of the tubules are cystically dilated. Cysts are lined by cells with hobnail appearance with vesicular nuclei and prominent nucleoli. Nuclei vary in shape and some have irregular shapes. The intervening stroma is paucicelluar.
Discussion: The leading differential in the diagnosis is oncocytomas, where one of the unusual patterns is with a predominance of tubules. In tubular oncocytomas, they lined by well-preserved nuclei have fine chromatin, and are uniformly round with variably sized nucleoli, Often abundant fibromyxoid stroma is present in onocytoma and typically there are nests of cells in addition to tubules. Collecting duct carcinoma is an infiltrative tumor with tubules in a dense desmoplastic stroma. Whereas the prognosis of oncocytoma is 100% benign, the prognosis with tubulocystic carcinoma is favorable with <10% rate of reported metastases.
Incorrect
Answer: Tubulocystic carcinoma
Histology: The lesion consists of a well-circumscribed nodule composed of well-formed tubules lined by abundant eosinophilic cytoplasm. Some of the tubules are cystically dilated. Cysts are lined by cells with hobnail appearance with vesicular nuclei and prominent nucleoli. Nuclei vary in shape and some have irregular shapes. The intervening stroma is paucicelluar.
Discussion: The leading differential in the diagnosis is oncocytomas, where one of the unusual patterns is with a predominance of tubules. In tubular oncocytomas, they lined by well-preserved nuclei have fine chromatin, and are uniformly round with variably sized nucleoli, Often abundant fibromyxoid stroma is present in onocytoma and typically there are nests of cells in addition to tubules. Collecting duct carcinoma is an infiltrative tumor with tubules in a dense desmoplastic stroma. Whereas the prognosis of oncocytoma is 100% benign, the prognosis with tubulocystic carcinoma is favorable with <10% rate of reported metastases.
Histology: The lesion consisted of a well-circumscribed mass measuring less than 2 cm. It consisted of a proliferation of eosinophilic focally vacuolated cells arranged in clusters, cords and tubules embedded in dense fibrous to smooth muscle stroma. There was a lacks of significant cytological atypia.
Discussion: The histology of this lesion is classic for an adenomatoid tumor. They can resemble metastatic carcinomas, yet the lack of any atypia should argue against that diagnosis. The characteristic presence of vacuoles suggests a vascular tumor, but the vacuoles are empty, lacking red blood cells. The typical location of this lesion is in the head of the epididymis. More unusual locations are paratubal and intra-adrenal. This is the first case to be noted within the spleen. Adenomatoid tumors are benign mesotheliomas and label immunohistochemically with mesothelial markers. They are entirely benign.
Incorrect
Answer: Adenomatoid tumor
Histology: The lesion consisted of a well-circumscribed mass measuring less than 2 cm. It consisted of a proliferation of eosinophilic focally vacuolated cells arranged in clusters, cords and tubules embedded in dense fibrous to smooth muscle stroma. There was a lacks of significant cytological atypia.
Discussion: The histology of this lesion is classic for an adenomatoid tumor. They can resemble metastatic carcinomas, yet the lack of any atypia should argue against that diagnosis. The characteristic presence of vacuoles suggests a vascular tumor, but the vacuoles are empty, lacking red blood cells. The typical location of this lesion is in the head of the epididymis. More unusual locations are paratubal and intra-adrenal. This is the first case to be noted within the spleen. Adenomatoid tumors are benign mesotheliomas and label immunohistochemically with mesothelial markers. They are entirely benign.
Presented by Jonathan Epstein, M.D. and prepared by Mohammed Lilo, M.D.
Case 3: An ill-defined lesion was removed from the posterior shoulder of a 65 year old female.
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Week 604: Case 3
An ill-defined lesion was removed from the posterior shoulder of a 65 year old female.
Histology: There is a non-circumscribed mass of fibrous tissue within the soft tissue. It consist of an admixture of heavy dense bands of collagenous tissue dissected by fat and abnormal elastic fibers. The elastic fibers are coarse, thick, and darkly eosinophilic, often fragmented into globules.
Discussion: This lesion is a classic example of elastofibroma both in histology and location. Although the characteristic elastic fibers can be seen on H&E sections, elastic stains (i.e. VVG) can highlight the abnormal elastic fibers where they have the appearance of “string of pearls” or “beads on a string”. These tumors are often related to hard manual labor, more common in women, and usually seen in individuals over 55 years of age. Simple resection is curative.
Incorrect
Answer: Elastofibroma
Histology: There is a non-circumscribed mass of fibrous tissue within the soft tissue. It consist of an admixture of heavy dense bands of collagenous tissue dissected by fat and abnormal elastic fibers. The elastic fibers are coarse, thick, and darkly eosinophilic, often fragmented into globules.
Discussion: This lesion is a classic example of elastofibroma both in histology and location. Although the characteristic elastic fibers can be seen on H&E sections, elastic stains (i.e. VVG) can highlight the abnormal elastic fibers where they have the appearance of “string of pearls” or “beads on a string”. These tumors are often related to hard manual labor, more common in women, and usually seen in individuals over 55 years of age. Simple resection is curative.
Histology: The lung demonstrates a well-defined nodular area, which features interstitial chronic inflammation along with plugs of granulation tissue which branch within air spaces. The septa show no evidence of acute injury such as fibrin deposition or highly reactive pneumocytes. No granulomas are seen. These are the typical features of bronchiolitis obliterans organizing pneumonia (BOOP).
Discussion: BOOP is a pattern of bronchiole-centered lung injury. It can be seen as a primary process (in which it can be either idiopathic or secondary to drug, infection, collagen vascular disease), adjacent to another process such as a neoplasm or infection, or as a component of another pulmonary process such hypersensitivity pneumonitis or eosinophilic pneumonia.
Diffuse alveolar damage will demonstrate interstitial edema and myxoid change, along with alveolar injury including hyaline membranes and reactive pneumocytes. Sarcoidosis is a granulomatous process that is unassociated with BOOP. Lymphocytic interstitial pneumonitis is a diffuse interstitial chronic inflammatory process which again lacks BOOP.
Histology: The lung demonstrates a well-defined nodular area, which features interstitial chronic inflammation along with plugs of granulation tissue which branch within air spaces. The septa show no evidence of acute injury such as fibrin deposition or highly reactive pneumocytes. No granulomas are seen. These are the typical features of bronchiolitis obliterans organizing pneumonia (BOOP).
Discussion: BOOP is a pattern of bronchiole-centered lung injury. It can be seen as a primary process (in which it can be either idiopathic or secondary to drug, infection, collagen vascular disease), adjacent to another process such as a neoplasm or infection, or as a component of another pulmonary process such hypersensitivity pneumonitis or eosinophilic pneumonia.
Diffuse alveolar damage will demonstrate interstitial edema and myxoid change, along with alveolar injury including hyaline membranes and reactive pneumocytes. Sarcoidosis is a granulomatous process that is unassociated with BOOP. Lymphocytic interstitial pneumonitis is a diffuse interstitial chronic inflammatory process which again lacks BOOP.
Presented by Pedram Argani, M.D. and prepared by Doreen Nguyen, M.D.
Case 2: a 68 year old male with a renal mass.
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Week 603: Case 2
This is a 68 year old male with a renal mass.
Correct
Answer: Papillary renal cell carcinoma
Histology: This is a largely solid lesion composed of epithelioid to focally spindled cells. The nuclear grade is low. In areas at the edge of the lesion, one can appreciate well developed papillae with macrophages within the fibrovascular cores. Mucinous stroma is not identified. These are the typical features of the solid variant of papillary renal cell carcinoma.
Discussion: Mucinous tubular and spindle cell carcinoma may overlap with papillary renal cell carcinoma, as the latter may in fact show bland spindle cell foci. The absence of myxoid stroma and well developed papillae in the current case favors papillary renal cell carcinoma. In difficult cases, FISH to detect trisomies of chromosome 7 and 17 supports the diagnosis of papillary renal cell carcinoma over mucinous tubular and spindle cell carcinoma. Sarcomatoid carcinoma would typically feature higher grade nuclei and areas of necrosis. Some of the cells in the current lesion have clear cytoplasm; however, they lack the water-clear cytoplasm of conventional (clear cell) renal cell carcinoma.
Reference(s):
– American Journal of Surgical Pathology 2008; 32:1353-1359.
Incorrect
Answer: Papillary renal cell carcinoma
Histology: This is a largely solid lesion composed of epithelioid to focally spindled cells. The nuclear grade is low. In areas at the edge of the lesion, one can appreciate well developed papillae with macrophages within the fibrovascular cores. Mucinous stroma is not identified. These are the typical features of the solid variant of papillary renal cell carcinoma.
Discussion: Mucinous tubular and spindle cell carcinoma may overlap with papillary renal cell carcinoma, as the latter may in fact show bland spindle cell foci. The absence of myxoid stroma and well developed papillae in the current case favors papillary renal cell carcinoma. In difficult cases, FISH to detect trisomies of chromosome 7 and 17 supports the diagnosis of papillary renal cell carcinoma over mucinous tubular and spindle cell carcinoma. Sarcomatoid carcinoma would typically feature higher grade nuclei and areas of necrosis. Some of the cells in the current lesion have clear cytoplasm; however, they lack the water-clear cytoplasm of conventional (clear cell) renal cell carcinoma.
Reference(s):
– American Journal of Surgical Pathology 2008; 32:1353-1359.
Presented by Pedram Argani, M.D. and prepared by Doreen Nguyen, M.D.
Case 3: a 17 month female with a scalp tumor.
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Week 603: Case 3
This is a 17 month female with a scalp tumor.
Correct
Answer: Fibromatosis
Histology: This is a bland but infiltrative spindle cell lesion. The spindle cells form in areas well-formed fascicles with abundant collagen deposition and there are associated capillaries which stand out from the spindle cell proliferation. Other areas of this lesion have more extravasated red blood cells and a less well developed vascular pattern. The lesion demonstrates nuclear labeling for beta-catenin, which supports the diagnosis of fibromatosis.
It is likely that cases such as this have been classified in the past as “cranial fasciitis”, which may account for the beta-catenin labeling reported in such lesions.
Discussion: Fasciitis would lack the well-developed fascicles of the current lesion, and would not infiltrate or demonstrate nuclear labeling for beta-catenin. Low grade fibromyxoid sarcoma has a more whorled, curvilinear pattern, and features nuclei that are hyperchromatic. Synovial sarcoma is typically more cellular than the current lesion, and features plump spindle cells with hyperchromatic nuclei forming short intersecting fascicles.
Incorrect
Answer: Fibromatosis
Histology: This is a bland but infiltrative spindle cell lesion. The spindle cells form in areas well-formed fascicles with abundant collagen deposition and there are associated capillaries which stand out from the spindle cell proliferation. Other areas of this lesion have more extravasated red blood cells and a less well developed vascular pattern. The lesion demonstrates nuclear labeling for beta-catenin, which supports the diagnosis of fibromatosis.
It is likely that cases such as this have been classified in the past as “cranial fasciitis”, which may account for the beta-catenin labeling reported in such lesions.
Discussion: Fasciitis would lack the well-developed fascicles of the current lesion, and would not infiltrate or demonstrate nuclear labeling for beta-catenin. Low grade fibromyxoid sarcoma has a more whorled, curvilinear pattern, and features nuclei that are hyperchromatic. Synovial sarcoma is typically more cellular than the current lesion, and features plump spindle cells with hyperchromatic nuclei forming short intersecting fascicles.
Histology: This is a sclerosing lesion with an overall lobular architecture. The central part of the lesion has a fibroelastic stroma and angulated entrapped tubules within. The rounded periphery of the lesion consists of dilated ducts, some of which are filled by usual duct hyperplasia. The cells filling these ducts are polymorphous in their appearance, have indistinct cell borders, have variably shaped nuclei, and have open chromatin. Overall, these are the typical features of a radial scar.
Discussion: Invasive well differentiated ductal carcinoma would have an infiltrative appearance at low power, and the small atypical glands would lack myoepithelial layer. The epithelial proliferation in the current lesion has features of usual duct hyperplasia described above. Ductal carcinoma in situ of low grade would consist of a monotonous population of epithelial cells with distinct cell borders and hyperchromatic nuclei. Microglandular adenosis would consist of an irregular, infiltrative proliferation of rounded tubules which contain dense eosinophilic secretions.
Incorrect
Answer: Radial scar
Histology: This is a sclerosing lesion with an overall lobular architecture. The central part of the lesion has a fibroelastic stroma and angulated entrapped tubules within. The rounded periphery of the lesion consists of dilated ducts, some of which are filled by usual duct hyperplasia. The cells filling these ducts are polymorphous in their appearance, have indistinct cell borders, have variably shaped nuclei, and have open chromatin. Overall, these are the typical features of a radial scar.
Discussion: Invasive well differentiated ductal carcinoma would have an infiltrative appearance at low power, and the small atypical glands would lack myoepithelial layer. The epithelial proliferation in the current lesion has features of usual duct hyperplasia described above. Ductal carcinoma in situ of low grade would consist of a monotonous population of epithelial cells with distinct cell borders and hyperchromatic nuclei. Microglandular adenosis would consist of an irregular, infiltrative proliferation of rounded tubules which contain dense eosinophilic secretions.
Histology: This is an irregular glandular proliferation which involves the dermis and subcutaneous tissue, and is associated with a stromal reaction. These are features which suggest adenocarcinoma. However, on closer inspection, one can appreciate that the epithelial cells in this proliferation are fairly uniform, and have round nuclei with open chromatin. Mitotic figures are difficult to find, and there is no significant cytologic atypia. Focally, one can appreciate a more cellular subepithelial stroma which resembles that of the endometrium. These are the atypical features of endometriosis.
Discussion: Metastatic adenocarcinoma would display greater cytologic atypia, mitotic activity, and infiltration. Metastatic adenocarcinoma would lack the endometrial stroma of the current lesion. Mesothelial inclusion cysts could occur secondary to prior surgery, as mesothelium from the peritoneal cavity is entrapped in the subcutaneous tissue. Mesothelial inclusion cysts would lack the endometrial stroma of the current case. Urachal remnants are typically associated with the umbilicus, and typically demonstrate urothelial lining.
Incorrect
Answer: Endometriosis
Histology: This is an irregular glandular proliferation which involves the dermis and subcutaneous tissue, and is associated with a stromal reaction. These are features which suggest adenocarcinoma. However, on closer inspection, one can appreciate that the epithelial cells in this proliferation are fairly uniform, and have round nuclei with open chromatin. Mitotic figures are difficult to find, and there is no significant cytologic atypia. Focally, one can appreciate a more cellular subepithelial stroma which resembles that of the endometrium. These are the atypical features of endometriosis.
Discussion: Metastatic adenocarcinoma would display greater cytologic atypia, mitotic activity, and infiltration. Metastatic adenocarcinoma would lack the endometrial stroma of the current lesion. Mesothelial inclusion cysts could occur secondary to prior surgery, as mesothelium from the peritoneal cavity is entrapped in the subcutaneous tissue. Mesothelial inclusion cysts would lack the endometrial stroma of the current case. Urachal remnants are typically associated with the umbilicus, and typically demonstrate urothelial lining.
Presented by Pedram Argani, M.D. and prepared by Doreen Nguyen, M.D.
Case 3: a 67-year-old male with a history of heart transplantation who has a cutaneous lesion.
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Week 602: Case 3
This is a 67-year-old male with a history of heart transplantation who has a cutaneous lesion.
Histology: This is an unusual lesion, in that there appears to be clones of malignant cells forming nests within the epidermis and demonstrating pagetoid growth upwards, similar to the pagetoid patterns seen in Paget’s disease or malignant melanoma. The atypical cells in the current lesion tend to spare the basal layer of the epidermis in their pagetoid pattern. Importantly, however, when one looks at the atypical cells in question, one can appreciate intercellular bridges between these cells, which are a hallmark of squamous differentiation. Therefore, the diagnosis for this lesion is squamous cell carcinoma in situ, with a pagetoid, intraepithelioma-like pattern.
Discussion: Basal cell carcinoma would be composed of basaloid cells with peripheral palisading and mucinous stroma. Melanoma typically demonstrates pagetoid growth; however, the malignant cells would lack intercellular bridges, and would involve the base of the epidermis. Paget’s disease atypically spares the basal layer of the epidermis; however, the malignant cells would demonstrate glandular features in lack intercellular bridges.
Incorrect
Answer: Squamous cell carcinoma in situ
Histology: This is an unusual lesion, in that there appears to be clones of malignant cells forming nests within the epidermis and demonstrating pagetoid growth upwards, similar to the pagetoid patterns seen in Paget’s disease or malignant melanoma. The atypical cells in the current lesion tend to spare the basal layer of the epidermis in their pagetoid pattern. Importantly, however, when one looks at the atypical cells in question, one can appreciate intercellular bridges between these cells, which are a hallmark of squamous differentiation. Therefore, the diagnosis for this lesion is squamous cell carcinoma in situ, with a pagetoid, intraepithelioma-like pattern.
Discussion: Basal cell carcinoma would be composed of basaloid cells with peripheral palisading and mucinous stroma. Melanoma typically demonstrates pagetoid growth; however, the malignant cells would lack intercellular bridges, and would involve the base of the epidermis. Paget’s disease atypically spares the basal layer of the epidermis; however, the malignant cells would demonstrate glandular features in lack intercellular bridges.
Histology: The lesion consists of nests of cells with abundant clear cytoplasm, small nuclei with punctate nucleoli, occasional mitotic figures, numerous capillaries, and pseudofollicular areas filled with blood. There is no necrosis. A rim of cortical brain tissue is evident at the periphery of the lesion. Immunostains confirm the lesion to have nuclear labeling for Pax8.
Discussion: This is a metastatic clear cell renal cell carcinoma (RCC) to the brain. The differential diagnosis includes other clear cell tumors, notably primary brain hemangioblastomas, primary brain clear cell meningiomas, and metastatic neuroendocrine tumors with clear cytoplasm (malignant paragangliomas, clear cell neuroendocrine tumors of the pancreas, parathyroid carcinomas, etc). The patient’s history and an immunopanel can help make the final diagnosis. Notably, clear cell RCC are positive for CAIX, Pax8, RCC, and CD10, while hemangioblastomas are positive for inhibin. However, wide range of clear cell tumors can occur in patients with the autosomal dominant von Hippel Lindau (VHL) syndrome, including clear cell renal cell carcinomas, brain hemangioblastomas, and clear cell neuroendocrine tumors of the pancreas. Thus, although a patient might have a clear cell RCC of the kidney, a new clear cell lesion in the brain might actually be a hemangioblastoma. Patients with VHL syndrome have mutations in the VHL gene on chromosome 3. The VHL protein regulates HIF1alpha (hypoxia inducible factor), so HIF1a is usually upregulated in hypoxic states to allow for angiogenesis. Of note, carbonic anhydrase IX (CAIX) is a downstream effector of the hypoxia inducible pathway, which is why CAIX immunohistochemistry is expressed in RCC.
Histology: The lesion consists of nests of cells with abundant clear cytoplasm, small nuclei with punctate nucleoli, occasional mitotic figures, numerous capillaries, and pseudofollicular areas filled with blood. There is no necrosis. A rim of cortical brain tissue is evident at the periphery of the lesion. Immunostains confirm the lesion to have nuclear labeling for Pax8.
Discussion: This is a metastatic clear cell renal cell carcinoma (RCC) to the brain. The differential diagnosis includes other clear cell tumors, notably primary brain hemangioblastomas, primary brain clear cell meningiomas, and metastatic neuroendocrine tumors with clear cytoplasm (malignant paragangliomas, clear cell neuroendocrine tumors of the pancreas, parathyroid carcinomas, etc). The patient’s history and an immunopanel can help make the final diagnosis. Notably, clear cell RCC are positive for CAIX, Pax8, RCC, and CD10, while hemangioblastomas are positive for inhibin. However, wide range of clear cell tumors can occur in patients with the autosomal dominant von Hippel Lindau (VHL) syndrome, including clear cell renal cell carcinomas, brain hemangioblastomas, and clear cell neuroendocrine tumors of the pancreas. Thus, although a patient might have a clear cell RCC of the kidney, a new clear cell lesion in the brain might actually be a hemangioblastoma. Patients with VHL syndrome have mutations in the VHL gene on chromosome 3. The VHL protein regulates HIF1alpha (hypoxia inducible factor), so HIF1a is usually upregulated in hypoxic states to allow for angiogenesis. Of note, carbonic anhydrase IX (CAIX) is a downstream effector of the hypoxia inducible pathway, which is why CAIX immunohistochemistry is expressed in RCC.
Histology: This wedge resection of lung shows alveolated lung parenchyma with organizing pneumonia, intra-alveolar fibroplasia and reactive pneumocyte hyperplasia. There are rare hyaline membranes. The pattern here is fairly homogeneous in this case (i.e., no patchy, honeycomb fibrosis). Bronchioles are present adjacent to arterioles, and the blood vessels are patent with normal thickness walls. No carcinoma, other neoplasms, acute pneumonia or granulomata are identified.
Discussion: This lung biopsy shows features of what has been traditionally called “bronchiolitis obliterans organizing pneumonia” (BOOP), although this is a confusing term because it is not the same this as “obliterans bronchiolitis” which is when the small bronchioles are obliterated adjacent to the small arteries. A perhaps preferred term for this BOOP pattern is “organizing pneumonia,” or “cryptogenic organizing pneumonia” (COP). In essence, these findings are a pathologic end result of a variety of clinical conditions, including infection, inhalants, medications, and collagen vascular disease. Thus, the pathologic diagnosis of “BOOP/COP” does not indicate the etiology. The “hallmark” of BOOP pattern are the “fibroblast plugs (Masson’s bodies),” which consist of spindled fibroblasts in a pale, bluish matrix (i.e., new collagen), also referred to as “intra-alveolar fibroplasia” because you may not be able to accurately tell if they are in the interstitium or airspace. You may also see some evidence of acute lung injury, i.e., the “diffuse alveolar damage” of hyaline membranes of fibrin deposition along the alveolar septae, as well as reactive pneumocyte hyperplasia.
Reference(s):
– Gordon IO1, Cipriani N, Arif Q, Mackinnon AC, Husain AN. Update in nonneoplastic lung diseases. Arch Pathol Lab Med. 2009 Jul;133(7):1096-105.
Histology: This wedge resection of lung shows alveolated lung parenchyma with organizing pneumonia, intra-alveolar fibroplasia and reactive pneumocyte hyperplasia. There are rare hyaline membranes. The pattern here is fairly homogeneous in this case (i.e., no patchy, honeycomb fibrosis). Bronchioles are present adjacent to arterioles, and the blood vessels are patent with normal thickness walls. No carcinoma, other neoplasms, acute pneumonia or granulomata are identified.
Discussion: This lung biopsy shows features of what has been traditionally called “bronchiolitis obliterans organizing pneumonia” (BOOP), although this is a confusing term because it is not the same this as “obliterans bronchiolitis” which is when the small bronchioles are obliterated adjacent to the small arteries. A perhaps preferred term for this BOOP pattern is “organizing pneumonia,” or “cryptogenic organizing pneumonia” (COP). In essence, these findings are a pathologic end result of a variety of clinical conditions, including infection, inhalants, medications, and collagen vascular disease. Thus, the pathologic diagnosis of “BOOP/COP” does not indicate the etiology. The “hallmark” of BOOP pattern are the “fibroblast plugs (Masson’s bodies),” which consist of spindled fibroblasts in a pale, bluish matrix (i.e., new collagen), also referred to as “intra-alveolar fibroplasia” because you may not be able to accurately tell if they are in the interstitium or airspace. You may also see some evidence of acute lung injury, i.e., the “diffuse alveolar damage” of hyaline membranes of fibrin deposition along the alveolar septae, as well as reactive pneumocyte hyperplasia.
Reference(s):
– Gordon IO1, Cipriani N, Arif Q, Mackinnon AC, Husain AN. Update in nonneoplastic lung diseases. Arch Pathol Lab Med. 2009 Jul;133(7):1096-105.
Histology: The biopsy reveals irregular nests of small round blue cells in a fibrous, sclerotic stroma with adjacent adipose tissue and ganglion. The individual cells have high nuclear-to-cytoplasmic ratio, abundant mitoses, some nuclear molding, no real cohesion, and no nucleoli. Immunostains are performed and show the lesional cells to be positive for cytokeratin, desmin and WT1.
Discussion:
Reference(s):
– Lae ME1, Roche PC, Jin L, Lloyd RV, Nascimento AG. Desmoplastic small round cell tumor: a clinicopathologic, immunohistochemical, and molecular study of 32 tumors. Am J Surg Pathol. 2002 Jul;26(7):823-35.
Incorrect
Answer: Desmoplastic small round cell tumor
Histology: The biopsy reveals irregular nests of small round blue cells in a fibrous, sclerotic stroma with adjacent adipose tissue and ganglion. The individual cells have high nuclear-to-cytoplasmic ratio, abundant mitoses, some nuclear molding, no real cohesion, and no nucleoli. Immunostains are performed and show the lesional cells to be positive for cytokeratin, desmin and WT1.
Discussion:
Reference(s):
– Lae ME1, Roche PC, Jin L, Lloyd RV, Nascimento AG. Desmoplastic small round cell tumor: a clinicopathologic, immunohistochemical, and molecular study of 32 tumors. Am J Surg Pathol. 2002 Jul;26(7):823-35.
Presented by Jonathan Epstein, M.D. and prepared by Sarah Karram, M.D.
Case 1: A 47 year old female underwent a nephrectomy for a 12.2 cm multicystic mass.
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Week 600: Case 1
A 47 year old female underwent a nephrectomy for a 12.2 cm multicystic mass. The cysts had thin walls and were filled with clear fluid. Cysts ranged from less than 1 cm to 4 cm.
Histology: The lesion is an encapsulated mass with predominantly cystic and focal solid areas. There are variably sized macroscopic cysts with very thin septae without solid foci. The cysts are lined by bland epithelial columnar/cuboidal to flat cells with occasional hobnail appearance. Stroma has areas of hypercellularity acquiring ovarian-like appearance in female patients. Other areas have a more fibrous appearance. Focally, there are thickened septae to more solid areas with focal cysts with focal proliferation of small tubules with thyroid-like secretions.
Discussion: Most experts consider that CN and MEST are the same lesion and show different ends of the spectrum with on one hand classic CN composed of a pure cystic lesion with thin septae and MEST mostly solid with cystic areas. However, there are numerous cases with hybrid features of both lesions, as in this case. They both occur in the same demographic population of middle aged women. If in men, there is often the history of endogenous or exogenous estrogenic treatment. Stromal cells are positive for ER, PR and occasionally CD10, smooth muscle actin and desmin. Cytokeratins, PAX8, PAX2 are positive in the epithelial cyst lining. The lesion is entirely benign. A peculiar feature of MEST is that in some cases there is herniation of a polypoid mass into the renal pelvis. Cystic renal cell carcinoma would have nodules of carcinoma, typically nests of clear cells, in the septae, which is lacking in CN/MEST. Also renal cell carcinoma lacks ovarian-type stroma.
Incorrect
Answer: Both A and B
Histology: The lesion is an encapsulated mass with predominantly cystic and focal solid areas. There are variably sized macroscopic cysts with very thin septae without solid foci. The cysts are lined by bland epithelial columnar/cuboidal to flat cells with occasional hobnail appearance. Stroma has areas of hypercellularity acquiring ovarian-like appearance in female patients. Other areas have a more fibrous appearance. Focally, there are thickened septae to more solid areas with focal cysts with focal proliferation of small tubules with thyroid-like secretions.
Discussion: Most experts consider that CN and MEST are the same lesion and show different ends of the spectrum with on one hand classic CN composed of a pure cystic lesion with thin septae and MEST mostly solid with cystic areas. However, there are numerous cases with hybrid features of both lesions, as in this case. They both occur in the same demographic population of middle aged women. If in men, there is often the history of endogenous or exogenous estrogenic treatment. Stromal cells are positive for ER, PR and occasionally CD10, smooth muscle actin and desmin. Cytokeratins, PAX8, PAX2 are positive in the epithelial cyst lining. The lesion is entirely benign. A peculiar feature of MEST is that in some cases there is herniation of a polypoid mass into the renal pelvis. Cystic renal cell carcinoma would have nodules of carcinoma, typically nests of clear cells, in the septae, which is lacking in CN/MEST. Also renal cell carcinoma lacks ovarian-type stroma.
Presented by Jonathan Epstein, M.D. and prepared by Sarah Karram, M.D.
Case 2: A 64 year old male with a history of biopsy showing keratinizing squamous metaplasia
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Week 600: Case 2
A 64 year old male with a history of biopsy showing keratinizing squamous metaplasia underwent a partial cystectomy.
Histology: There is a focal lesion with spiking or church spire-like squamous hyperplasia. In addition to the marked hyperkeratosis, there is parakeratosis and elongation of the rete pegs. The lesion lacks cytological atypia. Adjacent to the hyperplasia is keratinizing squamous metaplasia.
Discussion: Although warty carcinoma has a similar architectural pattern, there is overt cytological atypia and often a basaloid squamous appearance. In addition, warty carcinoma has hypergranulosis and koilocytosis. A condyloma would similarly have hypergranulosis and koilocytosis and would be composed of rounded papillary fronds which in some profiles appear to “float” surrounded by white space. The distinction between verrucous hyperplasia and verrucous carcinoma is solely based on invasion seen in the latter, since verrucous carcinoma also has no cytological atypia. Invasion is characterized by broad pushing papillae that irregularly extend into the underlying connective tissue. In the current case, the base of the lesion has a very regular flat non-infiltrative appearance. Verrucous hyperplasia and extensive keratinizing squamous metaplasia are both associated with an increased risk of subsequent squamous cell carcinoma of the bladder.
Reference(s):
– Am J Surg Pathol. 2006;30:883-91. Noninvasive squamous lesions in the urinary bladder: a clinicopathologic analysis of 29 cases. Guo CC, Fine SW, Epstein JI.
Incorrect
Answer: Verrucous hyperplasia
Histology: There is a focal lesion with spiking or church spire-like squamous hyperplasia. In addition to the marked hyperkeratosis, there is parakeratosis and elongation of the rete pegs. The lesion lacks cytological atypia. Adjacent to the hyperplasia is keratinizing squamous metaplasia.
Discussion: Although warty carcinoma has a similar architectural pattern, there is overt cytological atypia and often a basaloid squamous appearance. In addition, warty carcinoma has hypergranulosis and koilocytosis. A condyloma would similarly have hypergranulosis and koilocytosis and would be composed of rounded papillary fronds which in some profiles appear to “float” surrounded by white space. The distinction between verrucous hyperplasia and verrucous carcinoma is solely based on invasion seen in the latter, since verrucous carcinoma also has no cytological atypia. Invasion is characterized by broad pushing papillae that irregularly extend into the underlying connective tissue. In the current case, the base of the lesion has a very regular flat non-infiltrative appearance. Verrucous hyperplasia and extensive keratinizing squamous metaplasia are both associated with an increased risk of subsequent squamous cell carcinoma of the bladder.
Reference(s):
– Am J Surg Pathol. 2006;30:883-91. Noninvasive squamous lesions in the urinary bladder: a clinicopathologic analysis of 29 cases. Guo CC, Fine SW, Epstein JI.
Histology: Throughout all layers of the bladder and extending out of the bladder is an infiltrate of single loosely cohesive cells. Most of the cells are round with bland nuclei and a rim of eosinophilic cytoplasm. Some cells have clear vacuoles. These vacuoles lacked mucin on special stains.
Discussion: For these cases we add the following note: There is a group of urothelial carcinomas with the unifying feature being infiltrating, loosely cohesive relatively bland cells. The cytoplasm variably has rhabdoid, plasmacytoid or signet-ring cell features. These tumors often resemble infiltrating lobular cancer of the breast.
Tumors with rhabdoid and plasmacytoid features are a recognized variant of UC. Signet-ring cell cancer is a variant of adenocarcinoma. However, in some cases one has a tumor composed of individual cells which don’t have these cytoplasmic features yet have the same loosely cohesive widely infiltrative growth pattern. They are probably all part of the same spectrum of tumor and have a very poor prognosis. In the current case, there were metastases to 5/10 lymph nodes in keeping with the typical behavior of these lesions.
Incorrect
Answer: All of the above
Histology: Throughout all layers of the bladder and extending out of the bladder is an infiltrate of single loosely cohesive cells. Most of the cells are round with bland nuclei and a rim of eosinophilic cytoplasm. Some cells have clear vacuoles. These vacuoles lacked mucin on special stains.
Discussion: For these cases we add the following note: There is a group of urothelial carcinomas with the unifying feature being infiltrating, loosely cohesive relatively bland cells. The cytoplasm variably has rhabdoid, plasmacytoid or signet-ring cell features. These tumors often resemble infiltrating lobular cancer of the breast.
Tumors with rhabdoid and plasmacytoid features are a recognized variant of UC. Signet-ring cell cancer is a variant of adenocarcinoma. However, in some cases one has a tumor composed of individual cells which don’t have these cytoplasmic features yet have the same loosely cohesive widely infiltrative growth pattern. They are probably all part of the same spectrum of tumor and have a very poor prognosis. In the current case, there were metastases to 5/10 lymph nodes in keeping with the typical behavior of these lesions.
Presented by Jonathan Epstein, M.D. and prepared by Sarah Karram, M.D.
Case 1: A 74 year old male was noted to have bilateral renal masses.
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Week 599: Case 1
A 74 year old male was noted to have bilateral renal masses. A left radical nephrectomy was performed with multiple tan-brown renal masses noted ranging in size from 1.3 to 7.0 cm.
Histology: There are multiple nodules composed of oncocytic cells arranged variably in tubules or nests, some set in a fibromyxoid matrix. In most of the nodules, the cells have uniform round nuclei with variably sized nucleoli. In one of the nodules there are markedly enlarged pleomorphic nuclei with smudged indistinct chromatin detail, pseudonuclear inclusions, and lack of mitotic activity.
Discussion: With the exception of the nodule with atypical cells, the lesions are classic for oncocytoma. In contrast the eosinophilic variant of chromophobe renal cell carcinoma lacks fibromyxoid stroma and has some raisenoid nuclei with irregular, wrinkled, notched nuclear membrane and perinuclear halos. The presence in this case of multifocal and bilateral tumors is consistent with oncocytosis. Oncocytosis can be unrelated to an hereditary disease or can be seen in Birt-Hogg-Dubé Syndrome (BHD). The latter needs to be established based on other findings such as multiple fibrofolliculomas or by identifying FLCN germline mutation. In addition to oncocytomas, patients with BHD have chromophobe and hybrid oncocytoma/chromophobe RCCs. Even in patients with chromophobe RCC, the prognosis is excellent with rare metastases such that the goal is to preserve renal function and not to bilateral nephrectomies. Only the larger lesions are removed by partial nephrectomy to spare nephrons.
Incorrect
Answer: Oncocytosis
Histology: There are multiple nodules composed of oncocytic cells arranged variably in tubules or nests, some set in a fibromyxoid matrix. In most of the nodules, the cells have uniform round nuclei with variably sized nucleoli. In one of the nodules there are markedly enlarged pleomorphic nuclei with smudged indistinct chromatin detail, pseudonuclear inclusions, and lack of mitotic activity.
Discussion: With the exception of the nodule with atypical cells, the lesions are classic for oncocytoma. In contrast the eosinophilic variant of chromophobe renal cell carcinoma lacks fibromyxoid stroma and has some raisenoid nuclei with irregular, wrinkled, notched nuclear membrane and perinuclear halos. The presence in this case of multifocal and bilateral tumors is consistent with oncocytosis. Oncocytosis can be unrelated to an hereditary disease or can be seen in Birt-Hogg-Dubé Syndrome (BHD). The latter needs to be established based on other findings such as multiple fibrofolliculomas or by identifying FLCN germline mutation. In addition to oncocytomas, patients with BHD have chromophobe and hybrid oncocytoma/chromophobe RCCs. Even in patients with chromophobe RCC, the prognosis is excellent with rare metastases such that the goal is to preserve renal function and not to bilateral nephrectomies. Only the larger lesions are removed by partial nephrectomy to spare nephrons.
Presented by Jonathan Epstein, M.D. and prepared by Sarah Karram, M.D.
Case 2: A 51 year old man with a history of several TURBs over the last 1.5 years
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Week 599: Case 2
A 51 year old man with a history of several TURBs over the last 1.5 years underwent a radical cystectomy.
Histology: The lamina propria filled with large irregularly shaped nests. The nests have an irregular base with infiltrative nests extending to different depths. The nests are also crowded and irregularly spaced apart. The tumor invades muscularis propria and extends into perivesicular adipose tissue. There is no cytological atypia with nuclei even having nuclear grooves, as can be seen in normal urothelium. Mitotic figures are not seen.
Discussion: The large nested variant of urothelial carcinoma is a newly described entity. The classic nested carcinoma is composed of small nests. It can be very difficult to diagnose large nested cancer as it closely resembles von Brunn nests. In over 80% of cases, an overlying low grade papillary urothelial carcinoma may help establish the diagnosis. Regardless of bland the cytology, if nests of urothelium are seen in muscularis propria then it is diagnostic of malignancy as benign mimickers of urothelial carcinoma do not involve the muscularis propria. Even though nested carcinomas, either conventional or large nested, have an aggressive behavior equivalent stage for stage to usual high grade urothelial carcinoma, I do not grade nested cancer as high grade because of its low grade cytology. Rather, I diagnose them as “Invasive urothelial carcinoma with nested (or large nested) features” and do not give a grade. I add a note that they are aggressive despite their bland cytology. In cases where the large nested cancer is not in the muscularis propria the diagnosis is made because of the irregular shape, distribution, and infiltrative base of the lesion. In some cases, a desmoplastic reaction is also present and helps in the diagnosis. In contrast, von Brunn nests are round, regularly spaced, and has a flat non-invasive deep border.
Incorrect
Answer: Large nested urothelial carcinoma
Histology: The lamina propria filled with large irregularly shaped nests. The nests have an irregular base with infiltrative nests extending to different depths. The nests are also crowded and irregularly spaced apart. The tumor invades muscularis propria and extends into perivesicular adipose tissue. There is no cytological atypia with nuclei even having nuclear grooves, as can be seen in normal urothelium. Mitotic figures are not seen.
Discussion: The large nested variant of urothelial carcinoma is a newly described entity. The classic nested carcinoma is composed of small nests. It can be very difficult to diagnose large nested cancer as it closely resembles von Brunn nests. In over 80% of cases, an overlying low grade papillary urothelial carcinoma may help establish the diagnosis. Regardless of bland the cytology, if nests of urothelium are seen in muscularis propria then it is diagnostic of malignancy as benign mimickers of urothelial carcinoma do not involve the muscularis propria. Even though nested carcinomas, either conventional or large nested, have an aggressive behavior equivalent stage for stage to usual high grade urothelial carcinoma, I do not grade nested cancer as high grade because of its low grade cytology. Rather, I diagnose them as “Invasive urothelial carcinoma with nested (or large nested) features” and do not give a grade. I add a note that they are aggressive despite their bland cytology. In cases where the large nested cancer is not in the muscularis propria the diagnosis is made because of the irregular shape, distribution, and infiltrative base of the lesion. In some cases, a desmoplastic reaction is also present and helps in the diagnosis. In contrast, von Brunn nests are round, regularly spaced, and has a flat non-invasive deep border.
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