Answer: A. Adrenocortical carcinoma

Histology: The resection specimen contains sheets of atypical cells with abundant and predominantly eosinophilic cytoplasm, focal cytoplasmic vacuolization, and prominent nucleoli. There is minimal mitotic activity. The adjacent liver does not show evidence of cirrhosis or marked inflammation. There is no necrosis. There is no appreciable bile pigment or melanin pigment. The patient also has a separate morphologically identical mass in the adrenal gland; immunohistochemistry shows the tumors to be positive for inhibin and melan A, and negative for HEPPAR1, S100 and Pax8.

Discussion: The clinical presentation, tumor morphology and immunoprofile support classification as a metastatic adrenocortical carcinoma involving the liver. The differential diagnosis of malignant “pink cell tumors” must always include melanoma, melanoma, melanoma (which can have variable morphology and cytology), followed by adrenocortical carcinoma, hepatocellular carcinoma, and renal cell carcinoma, as well as rarer tumors such as alveolar soft parts sarcoma, clear cell sarcoma, oncocytic neoplasms of the thyroid (Hurthle cell) and parathyroid, and granular cell tumors. Although the tumor in this case shows marked atypical, adrenocortical carcinomas can be deceptively bland. The only definitive criteria for malignancy is the presence of local invasion or metastatic spread. The Wiess and Modified Weiss criteria provide a scoring system for assessing malignancy in primary adrenocortical neoplasms (i.e., predicting which primary lesions have metastatic potential). Briefly, in the Modified Weiss Criteria, the presence of the following features are scored: mitotic rate >5/50 HPF (2 points), abnormal mitoses (1 point), eosinophilic cytoplasm in >75% of tumor (2 points), necrosis (1 point), and capsular invasion (1 point). A total score of 3 or more is suggestive of malignancy. The original Weiss criteria also incorporates nuclear grade, a diffuse architectural pattern, and venous or sinusoidal invasion.

In regards to immunohistochemistry and other characteristic features of neoplasms in the differential diagnosis, adrenocortical neoplasms label for melanA/Mart1, inhibin and calretinin but are negative for most cytokeratin markers (they may label for Cam5.2, but are typically negative for AE1/AE3, CK7 and CK20). Note that adrenocortical neoplasms may contain melanin pigment and are immunoreactive for melanA/Mart1, thus can mimic melanoma. Alveolar soft part sarcomas show nests of loosely cohesive cells with abundant eosinophilic cytoplasm, and they are immunoreactive for cathepsin K; alveolar soft part sarcomas are characterized by a specific translocation of der(17)t(X:17) that results in the fusion of TFE3 with ASPSCR1 (alveolar soft part sarcoma critical region 1). Hepatocellular neoplasms typically label for HePAR1, arginase, glypican 3, CK8/18 (Cam5.2) and polyclonal CEA (pericannalicular pattern). Hepatocellular neoplasms may contain intracytoplasmic bile pigment. Melanomas typically label for HMB45, melanA/Mart1, S100, Sox10 and MITF and are negative for cytokeratin; melanomas may contain melanin pigment. Renal cell carcinomas typically label for Pax8 and RCC, and variably for CK7 or CAIX depending upon the subtype.

References:
1. Aubert S, Wacrenier A, Leroy X, et al. Weiss system revisited: a clinicopathologic and immunohistochemical study of 49 adrenocortical tumors. Am J Surg Pathol. 2002 Dec;26(12):1612-9.
2. Weiss LM. Comparative histologic study of 43 metastasizing and nonmetastasizing adrenocortical tumors. Am J Surg Pathol. 1984 Mar;8(3):163-9.

Answer: C. Secretory Carcioma

Histology: The excisional specimen reveals a tumor mass comprised of polygonal cells with eosinophilic cytoplasm, arranged in variably microcystic, solid, and tubular patterns. The individual cells have fairly uniform nuclei with punctate nucleoli. Mitotic figures are rare. There is no necrosis. There is prominent secretory material that is PAS positive. Immunostains for ER, PR and HER2 are negative. FISH analysis reveals a t(12;15) translocation resulting in the ETV6-NTRK3 gene fusion.

Discussion: The histologic features are characteristic of secretory carcinoma of the breast, which is characterized by the ETV6-NTRK3 gene fusion product also seen in the mammary analogue secretory carcinoma (MASC) of the salivary glands. (Parenthetically, this translocation is also seen in non-epithelial neoplasms, specifically cellular mesoblastic nephroma and infantile fibrosarcoma). Secretory carcinomas of the breast are rare, accounting for far less than 1% of all breast carcinomas, but they are the most common primary breast carcinoma seen in children and adolescents. Despite being “triple negative” for ER, PR and HER2, the overall prognosis if secretory carcinoma is relatively favorable, with nearly 100% survival in children; however, a more aggressive course has been described in adults. Although sometimes appearing as solid or circumscribed nests, secretory carcinomas are invasive and lack myoepithelial cells. (distinguishing them from in situ carcinomas with secretory features). Benign lobules with secretory/lactactional-type changes display vacuolated cytoplasm often with prominent cytoplasm and intraluminal pale pink secretions.

References:
1. Del Castillo M, Chibon F, Arnould L, et al. Secretory Breast Carcinoma: A Histopathologic and Genomic Spectrum Characterized by a Joint Specific ETV6-NTRK3 Gene Fusion. Am J Surg Pathol. 2015 Nov;39(11):1458-67.
2. Ito Y, Ishibashi K, Masaki A, et al. Mammary analogue secretory carcinoma of salivary glands: a clinicopathologic and molecular study including 2 cases harboring ETV6-X fusion. Am J Surg Pathol. 2015 May;39(5):602-10.
3. Tognon CE, Somasiri AM, Evdokimova VE, et al.. ETV6-NTRK3-mediated breast epithelial cell transformation is blocked by targeting the IGF1R signaling pathway. Cancer Res. 2011;71:1060–1070.

Answer: A. Fibromatosis

Histology: The resection specimen shows a bland spindle cell neoplasm characterized by fascicles of spindled cells with euchromatic nuclei, blunt-ended to tapering ends, minimal cytologic atypia, and pale pink cytoplasm. From low power, the blood vessels appear to “stand out” from the surrounding spindled cells, as the lesional cells are hypochromatic relative to the lesional spindled cells. In areas, there is a space between the capillaries and the adjacent lesional cells. Mitotic figures are scarce. There is no necrosis. There is no significant inflammation or extravasation of red blood cells.

Discussion: The histologic features are characteristic of deep fibromatosis (desmoid tumor), a lesion which shows identical morphology when occurring in either intra- and extra-abdominal locations. Fibromatoses classically occurs in the abdominal wall of young adult women often after pregnancy or surgery. Extra-abdominal desmoid tumors classically occur in the shoulder girdle, but can occur throughout the body. One primary histologic and clinical differential diagnosis is of scar, but fibromatoses tend to be more infiltrative, more cellular and have the characteristic vascular pattern described above. Although not necessary for diagnosis in morphologically classic cases, immunohistochemistry for beta-catenin typically shows nuclear reactivity and would confirm the diagnosis in this setting and can be very helpful in differentiating fibromatosis from scar.

Regarding the other entities in the answer choices, gastrointestinal stromal tumors can directly involve or metastasize to the abdominal wall and are characterized by epithelioid to spindled nuclei with peri-nuclear vacuoles and immunoreactivity for c-kit/CD117, DOG1 and SMA. Inflammatory myofibroblastic tumors display elongated spindled cells with a mixed acute and chronic infiltrate and immunoreactivity for ALK. Nodular fasciitis can display varying histologic appearances ranging from stellate spindled cells resembling tissue culture fibroblasts to more cellular fibrotic areas, as well as associated extravasated red blood cells, a chronic inflammatory infiltrate, and a “tram track” labeling pattern with actin.

References:
1. Wu JM, Montgomery E. Soft tissue tumors: Classification and pathology. Surg Clin North Am. 2008 Jun;88(3):483-520, v-vi.