Correct: B

Histology: The tissue shows hyperplastic prostatic glands surrounded by hypercellular stroma with scattered pleomorphic cells with degenerative nuclear atypia.

Discussion: Stromal tumors of the specialized prostatic stroma are classified as STUMP and prostatic stromal sarcoma. STUMPS present at any age with a median age of 58 years. STUMP can be detected as an incidental finding in prostate needle biopsy performed for elevated PSA or due to obstructive urinary symptoms or rectal fullness in cases of large tumors (up to 19 cm in size). There are five histological patterns of STUMPs. The most common is the hypercellular stroma with scattered large pleomorphic stromal cells with degenerative nuclear atypia growing in between benign glands. The glands entrapped within the lesion frequently show hyperplasia and other changes including clear basal cell hyperplasia, clear cell cribriform hyperplasia, urothelial metaplasia, or PIN. The glandular complexity may mask the underlying stromal neoplasm, and in these cases STUMP may be undiagnosed. A second histologic pattern that is much less frequent than the previous is the phyllodes subtype, characterized by leaf-like stromal projections lined by benign prostatic epithelium. A third pattern is with sheets of myxoid stroma containing bland stromal cells usually without glands. The fourth pattern is hypercellular stroma with eosinophilic cytoplasm but without the classic degenerative nuclear atypia. The last pattern is very subtle and characterized by a cellular stroma with epithelioid or round stromal cells. Similar to the myxoid and the hypercellular types, the nuclei are bland and lack significant atypia, making the diagnosis more challenging. Mitotic figures or necrosis are typically absent and when these features are present, prostatic stromal sarcoma should be considered.
While the name of this tumor suggests that the malignant potential is “uncertain,” once completely excised and if the specimen does not show a prostatic stromal sarcoma, the tumor will have a benign behavior. However, low-grade or high-grade prostatic stromal sarcomas are identified in approximately 10% of the cases or may develop over time if unresected, where the term the uncertain malignant potential applies on needle biopsy. Tumors that compress the rectum often show a peritumoral fibrous reaction that should not be interpreted as rectal invasion. STUMPs are positive for CD34, and for progesterone receptor, and variable expression of smooth muscle markers including SMA or desmin. The differential diagnoses of STUMPs include stromal nodule of BPH, stromal sarcoma, solitary fibrous tumor, inflammatory myofibroblastic tumor, gastrointestinal stromal tumor (GIST), leiomyosarcoma, and synovial sarcoma. The myxoid pattern of STUMP is the subtype that more closely resembles a stromal nodule of BPH given the lack of associated glands or significant nuclear atypia. The presence of thick-walled blood vessels is a feature of stromal nodule of BPH and not of STUMP. Immunohistochemistry is usually not helpful in the differential diagnosis of STUMP and stromal nodule of BPH or prostatic stromal sarcoma. The other differential diagnoses are discussed below.

Reference:
1. Leong JY, Chandrasekar T, Sebastiano C, Rshaidat H, Steward JE, Trabulsi EJ. Prostatic Stromal Tumors of Uncertain Malignant Potential. Urology. 2019.
2. Nagar M, Epstein JI. Epithelial proliferations in prostatic stromal tumors of uncertain malignant potential (STUMP). Am J Surg Pathol. 2011;35(6):898-903.
3. Sadimin ET, Epstein JI. Round cell pattern of prostatic stromal tumor of uncertain malignant potential: a subtle newly recognized variant. Hum Pathol. 2016;52:68-73.
4. Herawi M, Epstein JI. Specialized stromal tumors of the prostate: a clinicopathologic study of 50 cases. Am J Surg Pathol. 2006;30(6):694-704.

Correct: D

Histology: This tumor is centered in the hilum of the testis and invades the epididymis and testicular parenchyma and is composed of large solid nests of tumor cells with central necrosis.

Discussion: Colon cancer usually metastasizes to regional lymph nodes, liver, lung, bone, and brain. Metastatic colorectal carcinoma to the testis is rare. In general, secondary malignancies of the testis are rare and the most common sites of origin include prostate, stomach, lung, malignant melanoma, pancreas and renal cell carcinoma. The key to arrive at the diagnosis is to recognize the absence of intratubular germ cell neoplasia in-situ in the surrounding testis and knowing the clinical history of previous malignancy. Most commonly, metastatic tumors are centered in the hilum of the testis in the junction of the testicular parenchyma and the epididymis.

References:
1. Hatoum HA, Abi Saad, GS, Otrock ZK, Barada KA, Shamseddine AI. Int J Clin Oncol (2011) 16:203-209

Correct: C

Histology: Prostate tissue with nodules of cribriform glands with clear cytoplasm, bland nuclei and foci of dark basal cell layer.

Discussion: Clear cell cribriform hyperplasia (CCCH) is a rare form of benign prostatic hyperplasia. When detected, it is most often on TURPs as it is located in the central and transition zone. It comprises of nodules of cribriform glands with clear cytoplasm, bland nuclei, and a prominent dark basal layer. It can be misconstrued as a Gleason score 4+4=8 (Grade Group 4) due to its cribriform morphology. The key to differentiating clear cell cribriform hyperplasia from high-grade PIN/Intraductal carcinoma is the lack of cytologic atypia (no prominent nucleoli). HMWK or p63 stains basal cells, although not every gland will be positive, differentiating it from a high-grade adenocarcinoma.

References
1. Frauenhoffer EE, Ro JY, el-Naggar AK, Ordonez NG, Ayala AG. Clear cell cribriform hyperplasia of the prostate. Immunohistochemical and DNA flow cytometric study. Am J Clin Pathol. 1991;95(4):446-453.
2. Ayala AG, Srigley JR, Ro JY, Abdul-Karim FW, Johnson DE. Clear cell cribriform hyperplasia of prostate. Report of 10 cases. Am J Surg Pathol. 1986;10(10):665-671.

Answer: D

Histologic Description: This is a pleomorphic spindle cell neoplasm that involves the dermis but also extends into the subcutaneous tissue and skeletal muscle. In some sections, perineural and vascular invasion were identified. The lesion is arising in chronically sun damaged skin; however, there is no evidence of in situ or invasive melanoma or squamous cell carcinoma. These are the typical features of pleomorphic dermal sarcoma.

Differential Diagnosis: Atypical fibroxanthoma (AFX) is on the spectrum of pleomorphic dermal sarcoma; however, by definition it does not involve subcutaneous tissues, does not show lymphovascular invasion or perineural invasion, and does not show necrosis. AFX generally has a benign outcome, reflecting its extremely superficial nature. Squamous cell carcinomas should demonstrate in situ component or labeling for cytokeratins, while melanoma would demonstrate either in situ or invasive component, and should demonstrate some labeling for S100 or HMB45. Unlike AFX, pleomorphic dermal sarcoma has significant potential for metastatic spread. Patients who do develop metastases have poor outcome.

Answer: B

Histologic Description: This clearly is a process that is centered on the airways, which should be paired with small arterioles in the lung. What is striking about the specimen is that the many of the small airways have been completely obliterated, such they appear as small fibrous nodules adjacent to medium sized arterioles. This is best demonstrated using the Movat stain, which demonstrates either obliteration or concentric narrowing of the airways by new fibrous tissue. These are the typical findings of constrictive bronchiolitis.

Differential Diagnosis: Respiratory bronchiolitis is typically associated with smoking, and would feature pigmented macrophages centered upon airways with extension into the adjacent alveolar spaces, frequently associated with interstitial fibrosis. Follicular bronchiolitis would demonstrate more prominent lymphoid follicles centered on the airways, without the narrowing seen in this case. Bronchiolitis obliterans organizing pneumonia would feature fibrous plugs which extend out of the bronchioles into the adjacent alveolar spaces. The concentric narrowing seen in constrictive bronchiolitis differs from the polypoid fibrosis seen in bronchiolitis obliterans organizing pneumonia.
Constrictive bronchiolitis is frequently idiopathic, but may be secondary to viral infections or other etiologies. In a lung transplant, constrictive bronchiolitis usually represents chronic rejection.

Answer: D

Histologic Description: This polypoid lesion is characterized by a lamina propria which has abundant fresh hemorrhage and hemosiderin, and has been replaced by bundles of smooth muscle. The crypts within tend to have a “diamond shaped appearance.” Superficially, the lesion is ulcerated, and the glands have a more hyperplastic appearance. These are the typical features of mucosal prolapse. Adjacent to diverticula, this constellation of findings has been referred to as “polypoid prolapsing mucosal fold.” The late Johns Hopkins pathologist Dr. Belur Bhagavan was one of the first to recognize this lesion.

Differential Diagnosis: Sessile serrated adenomas would typically demonstrate boat-shaped crypts at their base, and demonstrate greater serrations superficially. Adenomatous polyps would demonstrate nuclear stratification and hyperchromasia, typically at the top of the lesion. Neither a sessile serrated polyp nor adenomatous polyp would typically have the prominent smooth muscle replacement of lamina propria and hemosiderin seen in the current case. Peutz-Jeghers polyps typically have bands of smooth muscle which are well-formed and have a branching pattern, which is dissimilar to that seen in the current case.

Correct: D

Histology: The tumor is well circumscribed and surrounded by a thick fibrous capsule. Tumor cells have a primitive appearance and are columnar in areas of tubule formation. Mitoses are frequent.

Discussion: Wilms tumor, also known as nephroblastoma, is the most common kidney malignancy in children, occurring mainly in the first 5 years of life. Wilms tumor is very rare in adults with an incidence of about 0.2 per million per year. Histologically, the Wilms tumors are comprised of blastemal, stromal and epithelial elements, but cases can be monophasic or biphasic. The blastemal elements can be present in nodular fashion or have a syncytial pattern. Spindle cells are the most common form of stromal component but some tumors can show heterologous elements including skeletal muscle, smooth muscle, adipose tissue, cartilage, osteoid/bone, glial tissue, and squamous, ciliated, and glandular epithelium (teratoid Wilms tumors). Classical triphasic WT rarely presents diagnostic difficulty for pathologists, but when only one component is present, especially in a small biopsy specimen, the differential diagnosis may include renal cell carcinoma, metanephric adenoma and hyperplastic nephrogenic rest for epithelial elements, and clear cell sarcoma of the kidney, mesoblastic nephroma and synovial sarcoma for stromal elements. Pure blastemal-type WT may be difficult to distinguish from other embryonal small round blue cell tumors, including neuroblastoma, Ewing sarcoma, desmoplastic small round cell tumor and lymphoma. The presence of anaplasia defined as nuclear sized 3× tumor cells and tripolar mitosis is associated with high risk. All the three components, though usually blastema, can become anaplastic, leading to the diagnosis of either focal or diffuse anaplasia. WT with diffuse anaplasia and WT with blastemal predominance (after preoperative chemotherapy) are regarded as high-risk tumors and require more aggressive treatment. By immunohistochemistry, tumor cells are positive for WT1, PAX8 and CD56 and negative for CK7.

References:
Nat Rev Urol 2018 Nov;15(11):693-701
J Kidney Cancer VHL. 2021 Jul 20;8(2):40-48.
Pediatr Surg 2019 Mar;54(3):390-397.

Correct: B

Histology: This tumor is composed of large nests with papillary structures lines by clear cells with large nuclei. There are stromal septa composed of smooth muscle separating the tumor nests.

Discussion: This is translocation RCC involving region Xp11.2, resulting in fusion of the TFE3 gene. While they represent approximately 40% of pediatric RCCs, they can also develop in adults. Microscopically, the overall features are typically those of an RCC but are very heterogeneous. Papillary structures may be prominent, and the tumor cells can be either clear or have a markedly granular eosinophilic cytoplasm; however, some cases are more solid and clear cell predominant, closely mimicking clear cell RCC. Admixed psammoma bodies may be abundant (not present in the current case). The presence of large nests with prominent papillary structures lined by clear cells and separated by thick stromal septa could be a morphologic clue to the diagnosis. By immunohistochemistry, a proportion of these tumors express PAX8 and Cathepsin-K, and can be negative or weakly positive for cytokeratins.

References:
Am J Surg Pathol. 40:723-737 2016
Am J Clin Pathol. 126 (3):332-334 2006

Correct: C

Histology: Proliferation of nests and cords of urothelium with an endophytic growth and covered by normal or flattened urothelium.

Discussion: Inverted urothelial papillomas (IUP) are rare and account for approximately 1% of bladder tumors and can occur at any age (average age at presentation is 60). The most common location is the bladder neck and trigone. Painless gross hematuria is the most common presenting symptom. The majority of the tumors are smaller than 5 cm. Histologically, the tumor is composed of anastomosing nest and thin cords of urothelium growing endophytically from the superficial urothelium. An exophytic component should be absent. Tumor cells are bland and often streaming towards the center of the cords and with peripheral palisading. Some cases show focal squamous metaplasia. The main differential diagnosis is with low grade papillary urothelial carcinoma with inverted growth pattern, which is characterized by the presence of larger nests and/or cytologic atypia. Any stromal reaction/desmoplasia or involvement of the muscularis propria are not features of IUP and are suggestive of invasive carcinoma. Mitotic activity is usually low. The recurrence rate is ~5%.

References:
Can Urol Assoc J. 2017 Jan-Feb; 11(1-2): 66–69.

Answer: B

Histological description: Grossly, the tumor was well-circumscribed with minimally infiltrative borders. The tumor has a uniform appearance of bland epithelioid to slightly spindled cells with nuclei having delicate chromatin. The cytoplasm was lightly eosinophilic and in areas had a filamentous appearance. Focally, the stroma had thicker eosinophilic collagen bundles. The lesion lacked necrosis, increased mitoses, and atypical mitoses. In areas, epithelioid and spindle cells radiated off of vessel walls. The tumor lacked an adipose component.

Discussion: Angiomylipoma (AML) in the kidney are more often sporadic but can be seen in the setting of Tuberous Sclerosis where presentation is in younger individuals and the lesions are multifocal and bilateral. In contrast to leiomyomas that arise from vessels in the renal hilum, AMLs typically arise from the cortex and can extend out of the kidney or even be predominantly or exclusively in the perirenal fat. AMLs are most often spindled with smooth muscle cells having identical nuclei to low grade leiomyosarcomas, yet AMLs have cytoplasm that is looser and filamentous. The smooth muscle component in AML can be fascicular and indistinguishable from a smooth muscle tumor, and in other areas more haphazard. AMLs, including epithelioid cases that lack atypical features, are benign although they can involve lymph nodes. Some AMLs are associated with significant morbidity and even mortality due to massive retroperitoneal hemorrhage. There do exist atypical epithelioid AMLs where epithelioid cells have overall high N/C ratios with variable amount of pale clear to eosinophilic cytoplasm. There are populations of pleomorphic cells with multinucleation and abundant cytoplasm termed “amoeboid cells”. In these cases, malignant behavior correlates with the presence of 3 of the 4 following features: 1) >70% atypical epithelioid areas; 2) >2 mitoses per 10 HPF; 3) atypical mitotic figures; or 4) necrosis. AMLs are typically positive for HMB45, Melan A, and Cathepsin K. Cytokeratins and PAX8 are negative. The key features to recognize in the current case were the characteristic bland epithelioid to slightly spindled cells with lightly eosinophilic filamentous cytoplasm and the radiating cells coming off of some of the vessels. Also, for the diagnosis of AML, it is not necessary for the lesion to have an adipose tissue component, and typically lesions that come to resection are fat-poor AMLs as AMLs with a prominent fatty component can be recognized on imaging and unless symptomatic and not resected.

Answer: D

Histological Description: Within the lamina propria there is a proliferation of cells with amphophilic cytoplasm and overt pleomorphism. Although at a casual glance, the cells appear to grow in a diffuse sheet, upon closer inspection the cells are arranged in nests with a network of thin capillaries separating the nests. The tumor does not have prominent mitotic activity. The tumor invades muscularis propria.

Discussion: The mean age of paragangliomas in the bladder is 41 years with a broad range from 10-88 years. Although they often present with hematuria, patients may also have more specific symptoms of micturition attacks consisting of syncope, headache, hypertension, palpitation, blurred vision and/or sweating following straining when urinating. Two thirds of patients have hypertension. Most are exophytic with an intact smooth mucosa unless ulcerated. Tumors vary in size from several millimeters to 10 cm. Most are solitary. Usually, there are uniform sized and shaped nests delineated by delicate fibrovascular septae. Uncommonly, as in this case, paragangliomas can have foci of more diffuse growth where the nesting pattern is not as evident. The key to the correct diagnosis is recognizing the abundant amphophilic granular cytoplasm and also not having tunnel vision to only consider urothelial carcinoma when confronted with a nested tumor in the bladder. Another aspect of the current case that is diagnostically difficult is that in the typical case of paraganglioma involving the bladder, nuclei are typically uniform small and round with uniform chromatin. However, cases like our can have occasional scattered pleomorphic enlarged nuclei, most with a degenerative appearance consisting of smudgy indistinct chromatin. In contrast to a high grade pleomorphic urothelial carcinoma, mitotic figures are uncommon. In contrast to urothelial carcinoma, paragangliomas are cytokeratin negative and synaptophysin and chromogranin positive. In some cases, S100 highlights sustentacular cells surrounding tumor nests. An immunohistochemical pitfall is that both invasive urothelial carcinoma and paraganglioma are positive for GATA3. All paragangliomas should also be evaluated immunohistochemically for SDHB which can be lost as a result of a sporadic mutation but could also represent a germline mutation associated with the hereditary paraganglioma syndrome. Paragangliomas which show loss of SDHB have a higher risk of malignant behavior. Depending on the location and size of the tumor, final treatment could be only the initial TUR, repeat TUR, or partial or radical cystectomy. Paragangliomas can invade the muscularis propria, as seen in the current case. 10% of bladder paragangliomas are malignant, which cannot be predicted based on the morphology.

Answer: A

Histological Description: At the interface of more dense fibrous and more reactive inflammatory fibrous tissue there is a linear proliferation of tubules with focal papillary formation. Cytologically, the tubules are lined by bland cuboidal epithelium.

Discussion. Hydroceles which are fluid-filled mesothelial-lined sacs surrounding the testis that in adults usually does not communicate with the peritoneal cavity. The fluid accumulates as a reaction to injury, most often as a reaction to infection (i.e. epididymitis). In this setting, the hydrocele sac may have an associated florid reactive mesothelial proliferation, mimicking malignant mesothelioma. Further compounding the diagnostic difficulty, is that hydroceles can also arise as a reaction to malignancy in this site, such as malignant mesothelioma. The key to recognizing that the process is not malignant is that the reactive proliferation remains confined to a sharply demarcated zone immediately underlying the luminal surface. Proliferating mesothelial cells typically form lines that parallel the surface of hydrocele and fail to penetrate beyond the associated superficial zone of inflammation and fibrosis. Tubules do not invade adipose tissue. Architecturally, simple papillary structures, tubules and nests can be present, but solid areas and broad arborizing complex papillary structures with hyalinized fibrous cores are not identified. Reactive cells maintain abundant cytoplasm and may contain enlarged vesicular nuclei and brisk mitotic activity in inflamed areas. Cytologically, malignant mesothelioma in this region can also have relatively uniform bland cuboidal cells with only modest amount of eosinophilic cytoplasm, although occasionally, frank anaplasia may be demonstrated. Architecturally, malignant mesothelioma has broad arborizing complex papillary and tubular structures and nests with occasional solid areas. Although at times predominantly involving surface as exophytic papillary growth, at least focally, a haphazard infiltrative tubular or nested component exists. Malignant mesotheliomas often invades adipose tissue. In general, immunohistochemistry is often not helpful in the differential diagnosis, although malignant mesothelioma can show loss of MTAP and BAP1 in 50% of malignant mesotheliomas and not reactive mesothelial proliferations.

Answer: C
Histologic Description: This is a post-therapy specimen, so there are large areas of regression consisting of macrophages and scarring. There are also areas of differentiated epithelium at the periphery of the tumor. Other areas show the usual proliferating blastemal elements that are non-anaplastic. However, there is well-defined nodule of blastemal cells with markedly enlarged nuclei showing hyperchromasia, along with atypical mitotic figures. This focus was well delineated and confined to the kidney, which justifies the diagnosis of focal anaplasia.
Differential Diagnosis: The presence of enlarged hyperchromatic nuclei demonstrating atypical mitotic figures supports the diagnosis of anaplasia (unfavorable histology). Focal anaplasia must be well delineated and confined to the kidney, as seen in the current case. If not, anaplasia is considered diffuse by default. Desmoplastic small round cell tumor is immunoreactive for WT1, desmin and keratin like the current Wilms tumor; however, it typically demonstrates desmoplastic stroma and nuclei that have coarser chromatin than the delicate chromatin of a blastemal Wilms tumor nucleus.

Answer: B
Histologic Description: The neoplasm is separated by fibrous septa which have a hyalinized appearance. The neoplastic cells have well defined cell borders and irregular nuclei with perinuclear halos. There is abundant psammomatous calcification present. The latter suggests the possibility of Xp11 translocation RCC, but can be seen in chromophobe RCC. The neoplasm demonstrated diffuse membranous labeling for CD117, supporting the diagnosis of chromophobe RCC.
Differential Diagnosis: Xp11 translocation RCC does not usually show diffuse membranous labeling for CD117, and would label for TFE3. Clear cell RCC would have more vascularized septa, and lack the prominent perinuclear halos and nuclear irregularities of this case. t(6;11) renal cell carcinomas typically have a biphasic large cell /small cell morphology, and label for melanocytic markers like Melan A.

Correct Answer: C

Histology: This prostate tumor shows a proliferation of spindle stroma cells with small nuclei and variable amount of eosinophilic cytoplasm arranged in a whorled of haphazard pattern. The tumor is characterized by having thick walled vessels.

Discussion: One of the most common stromal proliferations identified in prostate needle biopsies are stromal nodules of benign prostatic hyperplasia (BPH). BPH is common among middle age and elder men and it affects up to 80% of men. BPH refers to the proliferation and enlargement of both the stromal and the glandular components but there is evidence that suggests that it is the stroma the one that leads to more pronounced enlargement and obstructive symptoms. By immunohistochemistry, the spindle cells are most commonly positive for vimentin and some cases with more prominent fibromuscular differentiation show positive staining for smooth muscle actin and desmin. The immunohistochemistry profile is not specific and of limited utility in the differential diagnosis. The main differential diagnoses include stromal tumor of uncertain malignant potential (STUMP) which, in contrast to stromal nodule of BPH, has more pronounced nuclear pleomorphism, often infiltrates around glands, and lacks the characteristic thick-walled blood vessels.

References:
J Urol. 1984;132(3):474-479.
J Urol. 1992;147(5):1293-1297.
Prostate. 2014;74(14):1433-1443.