D. Succinate dehydrogenase deficient renal cell carcinoma

Histologic Description: This is a difficult to classify oncocytic neoplasm. There are focal areas of calcification suggestive of the MiT family translocation carcinoma. Well-developed cell vacuolization is not present, and neither are cytoplasmic inclusions. By immunohistochemistry, this neoplasm demonstrates loss of SDHB, supporting the diagnosis of SDH-deficient RCC. Fumarate hydratase immunostaining was intact, and no evidence of TFE3 rearrangement was identified by break-apart FISH.

Differential Diagnosis: Oncocytoma would have a more nested pattern, edematous stroma, and round nuclei throughout. Xp11 translocation RCC would almost always demonstrate rearrangement of TFE3 by FISH. Fumarate hydratase deficient RCC shows loss of fumarate hydratase protein by immunohistochemistry, and typically shows more prominent nucleoli.

This case illustrates the phenomenon which we have recently reported; specifically, that SDH-deficient RCC in young patients frequently do not demonstrate the characteristic morphologic features that have been described such as cytoplasmic vacuolization and inclusions. We have a low threshold for ordering SDHB and fumarate hydratase immunostains in this setting (Li Y et al. Histopathology 2018; 72:588-60).

D. Malignant phyllodes tumor

Histologic Description: Most of the sections of this case demonstrate a highly pleomorphic, mitotically active, malignant spindle cell neoplasm. There is no epithelial component. The clue to the diagnosis comes from additional sections, demonstrating an associated lower grade phyllodes tumor component with associated epithelium demonstrating an intracanalicular pattern. By immunohistochemistry, this neoplasm was negative for high molecular cytokeratin, and demonstrated focal immunoreactivity for CD34.
Differential Diagnosis: Sarcomatoid carcinoma would label for cytokeratins, and frequently would demonstrate an associated epithelial component. Fibromatosis would lack the pleomorphism and mitotic activity of the current case. Malignant melanoma would demonstrate diffuse immunoreactivity for S100, along with immunoreactivity for melanocytic markers.
This case highlights the importance of thorough sectioning in establishing at the diagnosis of a malignant spindle cell breast tumor.

C. Malignant Leydig cell tumor

Histological description: The testis is involved by a multinodular lesion composed of solid sheets of cells with abundant eosinophilic cytoplasm. Nuclei are relatively uniform with a central prominent nucleus and readily identifiable mitotic figures. The lesion invades the rete testis. Focally, the tumor has a dimorphic pattern with the additional finding of cells with scant cytoplasm and nuclei with prominent grooves.

Discussion: One can have massive Leydig cell hyperplasia mimicking a Leydig cell tumor, especially in adrenogenital syndrome. The difference is that with hyperplasia, the Leydig nodules have intervening uninvolved testicular parenchyma as opposed to a solid Leydig cell tumor and are often bilateral. Also Leydig cell hyperplasia would lack any atypical features. Features seen more frequently in malignant as opposed to benign Leydig cell tumors are: 1) size >5 cm.; 2) >3 mitosis per 10 HPF; 3) necrosis; 4) vascular invasion; 5) widespread infiltration (minimal infiltration into the adjacent testis can be seen in benign Leydig cell tumors); and 6) pleomorphism (not very pleomorphic but more hyperchromatic nuclei with some variation in shape). Most malignant tumors have 3 or more of these atypical features. The current case with large size, necrosis, numerous mitotic figures, and infiltration warrants the diagnosis of a malignant Leydig cell tumor. In cases with only 1-2 atypical features, the diagnosis of an “atypical Leydig cell tumor” is rendered with the recommendation for close follow-up. This case is very rare as there is also the component of a Granulosa cell tumor, which when present in the testis is usually seen as a pure Granulosa cell tumor. In this case, the Granulosa cell component would not affect the prognosis. Immunohistochemically, Leydig cell tumors most frequently express inhibin and Steroid Factor 1 (SF1), although their close resemblance to normal Leydig cells usually obviates the need for special stains.

B. Spindle cell rhabdomyosarcoma

Histological Description: The tumor is a polypoid spindle cell tumor covered by a simple bland cuboidal lining. In areas, there is condensation of the spindle cells beneath the lining. The spindle cells are arranged in short fascicles with scant cytoplasm. The nuclei are uniform without a lot of pleomorphism, yet have frequent mitotic figures.

Discussion: Synovial sarcoma does not occur in this site. The epithelial lining over the spindle cell tumor is the mesothelial lining of the tunica albuginea. In biphasic synovial sarcoma, the epithelial component is cytologically malignant as opposed to the benign appearing epithelium overlying the tumor in this case. The most common paratesticular soft tissue tumors in adults are well-differentiated liposarcoma, which not infrequently can have de-differentiation, followed by leiomyosarcoma. De-differentiated liposarcoma consists of typically high grade spindle cells arranged in a haphazard growth pattern associated with a well-differentiated lipoma-like liposarcoma component. Paratesticular leiomyosarcoma, as with leiomyosarcomas elsewhere, are composed of intersecting long fascicles of spindle cells with abundant eosinophilic cytoplasm, different from what is seen in this case. Another paratesticular spindle cell tumor that must be considered is rhabdomyosarcoma. Rhabdomyosarcoma is the most common paratesticular mesenchymal tumor in children, but also can rarely be seen in adults. The majority of paratesticular rhabdomyosarcomas are embryonal subtype where one can often see overt skeletal muscle differentiation with cells having eccentric eosinophilic tails and even well-developed cross striations on occasion. Paratesticular spindle cell rhabdomyosarcoma usually seen in children is less common. The finding of a paratesticular spindle cell rhabdomyosarcoma in an adult is very rare, only described in a few cases. The prognosis of spindle cell rhabdomyosarcoma is excellent, with over a cure rate over 90%. Paratesticular rhabdomyosarcomas in general also have an excellent prognosis, better than in other anatomical sites. A pitfall with the diagnosis of spindle cell rhabdomyosarcoma, as was present in the current case, is that myogenin may be only focally positive.

D. Infiltrating plasmacytoid urothelial carcinoma

Histological Description: The tumor consists of infiltrating cells with variable cytology. Many of the cells have eccentric cytoplasm which is amphophilic, resembling plasma cells. However, the nuclei have a single small central nucleolus as opposed to the more stippled chromatin in plasma cells. Some cells have clear cytoplasmic vacuoles with a signet-ring cell appearance. Other cells have central uniform nuclei with a scant ring of amphophilic cytoplasm similar to the cells in lobular carcinoma of the breast. No in situ urothelial carcinoma component is noted.

Discussion: This tumor is typical of plasmacytoid urothelial carcinoma. Other cases, in addition to cells with plasmacytoid morphology, may have signet-ring cells, cells resembling lobular carcinoma of the breast, and cells with a rhabdoid appearance. The unifying feature in plasmacytoid urothelial carcinoma is the dyscohesive nature of the cells which is also manifested by loss of e-cadherin immunohistochemically similar to what is seen with lobular carcinoma of the breast and signet-ring cell adenocarcinoma from the gastrointestinal tract. In a woman, plasmacytoid urothelial carcinoma must be differentiated from metastatic lobular carcinoma of the breast and metastatic signet ring cell adenocarcinoma from the gastrointestinal tract, if there is no associated more definitive urothelial component (ie CIS or papillary urothelial carcinoma). We have recently shown the plasmacytoid urothelial carcinoma can express GCDFP and PR, mimicking lobular carcinoma. GATA3 is not helpful in this differential as it is positive in both breast and urothelial carcinoma. The two useful immunohistochemical stains for this differential diagnosis are ER, which is negative in plasmacytoid urothelial carcinoma and almost uniformly positive in lobular carcinoma, as well as uroplakin II, which is positive in 50% of plasmacytoid urothelial carcinomas and negative in lobular carcinoma. GATA3 positivity, present in almost all plasmacytoid urothelial carcinomas, is negative in signet-ring cell adenocarcinoma from the stomach. Plasmacytoid urothelial carcinoma is a very aggressive variant of urothelial carcinoma with a predilection for spreading within the peritoneal cavity.

(C) Sinonasal glomangiopericytoma

Histology: The surface epithelium is intact with squamous metaplasia. The underlying tumor consists of a hypercellular proliferation of spindled to epithelioid cells in short fascicles and whorls. The nuclei are oval to elongated with uniform chromatin and only rare mitotic figures. The tumor contains prominent blood vessels with marked hyalinization of the vessel walls. Immunostains show that the tumor cells are positive for nuclear b-catenin, SMA and Factor XIIIa and negative for CD34, supporting a diagnosis of sinonasal glomangiopericytoma.

Discussion: Sinonasal glomangiopericytoma was previously known as sinonasal hemangiopericytoma and hemangiopericytoma-like tumor of the sinonasal tract. However, these names are misleading because glomangiopericytomas are not truly part of the solitary fibrous tumor/ hemangiopericytoma spectrum of tumors, and lack their characteristic CD34 positivity, NAB2-STAT6 translocations, and unpredictable behavior. Instead, glomangiopericytoma is thought to originate from pericytic cells, as is evidenced by its positivity for SMA and Factor XIIIa. Recently, glomangiopericytoma has been shown to have consistent CTNNB1 gene mutations, leading to its characteristic diffuse nuclear positivity for b-catenin by immunohistochemistry (Lasota et. al, Mod Pathol 2015). Glomangiopericytoma generally behaves in an indolent fashion.

(B) Calcifying Odontogenic Cyst

Histology: The lesion is cystic and is lined by a proliferation of epithelial cells with ameloblastic features, including a basal layer of palisaded columnar cells and an associated area of stellate-reticulum-like spindled cells with intracellular edema. Interspersed throughout the epithelium are large epithelioid cells with abundant eosinophilic cytoplasm and loss of nuclear basophilia, consistent with ghost cells. There are also coarse calcifications. This appearance is diagnostic of a calcifying odontogenic cyst.

Discussion: A wide range of developmental, reactive, and neoplastic odontogenic cysts can arise within the jaw. In general, odontogenic keratocysts (OKCs) and ameloblastomas are the most important types of odontogenic cyst to recognize because they carry a high risk of recurrence. OKCs have an epithelium 5-7 cells thick with basal palisading and a surface layer of corrugated parakeratin- features that are not seen in calcifying odontogenic cyst. Ameloblastomas share the ameloblastic epithelium of calcifying odontogenic cyst but should entirely lack ghost cell formation. Calcifying odontogenic cysts are relatively uncommon, comprising <1% of jaw cysts. They are generally cured with complete excision although they can recur.

(A) Well-differentiated liposarcoma

Histology: The tumor consists of a largely bland proliferation of adipocytes with intermixed fibrous septae. The tumor underlies benign squamous mucosa and entraps benign skeletal muscle cells. Scattered throughout the fibrous septae are spindled cells with nuclear hyperchromasia and irregular nuclear membranes. An immunostain for MDM2 is positive in these spindled cells. Fluorescence in-situ hybridization also confirms the presence of MDM2 amplification. These findings support a diagnosis of well-differentiated liposarcoma.

Discussion: Fatty lesions of the pharynx and upper esophagus have traditionally been referred to as lipomas or giant fibrovascular polyps. However, there have been persistent reports of well-differentiated liposarcomas arising in association with these lesions. Recently, molecular analysis has highlighted the presence of MDM2 amplification in the vast majority of fatty tumors at this site regardless of previous classification (Graham et. al, Mod Pathol 2018), suggesting that most might be better classified as well-differentiated liposarcomas. In the absence of de-differentiation, the vast majority of patients with these tumors do well if they are excised completely.

Answer: B

Histology: This is a bland spindle cell lesion centered in the muscularis propria. The neoplastic cells form fascicles, have generally rectangular nuclei, and have pink cytoplasm, all features which suggest smooth muscle differentiation. There are intervening areas of hyalinization and cells with pale cytoplasm. The spindle cells do not show significant atypia or mitotic activity. The lesional cells are diffusely immunoreactive for desmin and caldesmon, which support smooth muscle differentiation. There is abundant staining for CD117 (c-kit) in the tumor. These represent hyperplastic entrapped interstitial cells of Cajal, which has been reported in deep leiomyoma of the esophagus and stomach (Am J Surg Pathol 2014; 38:72-77).

Differential Diagnosis: GIST would feature cells with more angulated nuclei and more diffuse CD117 immunoreactivity. GIST typically do not stain desmin and caldesmon. Leiomyosarcoma would demonstrate greater nuclear atypia and mitotic activity. Schwannomas would not label for desmin, and would feature more angulated nuclei and Verocay bodies.