Case of the Month: Ovary

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2016, case 12, and is an adenocarcinoma ex goblet cell carcinoid.

The slides show ovarian stroma infiltrated by clusters, trabeculae, and cords of plump neoplastic cells with abundant pale, sometimes vacuolated, cytoplasm. The nuclei are eccentrically located due to distension by intracytoplasmic material and display variable pleomorphism. Microscopic examination of the concurrently resected appendix shows a similar, although less prominent, proliferation of signet ring cells involving the full thickness of the appendiceal wall, as well as a component of more classic neuroendocrine tumor. The overall findings are characteristic of primary appendiceal adenocarcinoma ex goblet cell carcinoid (GCC) with metastasis to bilateral ovaries.

GCCs have a mixed phenotype with partial neuroendocrine differentiation and intestinal-type goblet cell morphology. Adenocarcinoma ex GCC has been defined as a subset with a more diffuse irregular architecture, cytologic atypia, and worse prognosis; these have been further subcategorized into two types, defined by histologic features present in the primary lesion. The signet ring cell type shows goblet or signet ring cells in irregular large clusters, discohesive single file or single cell infiltrating pattern, significant cytologic atypia, and desmoplasia with associated destruction of the appendiceal wall. The poorly differentiated type shows at least focal evidence of goblet cell morphology, but also contains a component that is not otherwise distinguishable from poorly differentiated adenocarcinoma, which may appear as gland forming, confluent sheets of signet ring cells, or undifferentiated. Under the current World Health Organization terminology, these tumors fall within the category of mixed adenoneuroendocrine carcinoma (MANEC). GCCs demonstrate at least focal immunoreactivity with neuroendocrine markers synaptophysin and chromogranin (differing from the diffuse staining pattern seen in most classic carcinoid tumors). However, it should be noted that focal neuroendocrine immunoreactivity alone, without a component of typical morphology, does not qualify a tumor as a MANEC; immunohistochemically detectable neuroendocrine cells may be found in gastrointestinal adenocarcinomas that have no morphological features of a discrete neuroendocrine component. Adenocarcinoma ex GCC typically expresses CK7 and CK20. Studies have shown the poorly-differentiated type displays p53 and MUC1 immunoexpression, with a loss of MUC2. Despite the presence of intestinal-type goblet or signet ring cells, these lesions do not appear to arise from an adenoma-carcinoma sequence as seen in conventional colonic/appendiceal adenocarcinomas. Additionally, studies have demonstrated genetic alterations in GCCs are more compatible with neuroendocrine origin and are different from appendiceal adenocarcinomas. Although these histogenetic differences exist, GCCs display a biological behavior intermediate between classic carcinoid and conventional adenocarcinoma, or closer to that of adenocarcinoma, with reported 5-year survival rates of 60 to 84%.

Metastatic adenocarcinomas presenting in the ovary may mimic primary ovarian neoplasms histologically; however, there are some gross and microscopic features that may help to distinguish the diagnosis. Gross features that favor metastases include bilaterality, nodularity, smaller size (often less than 12.0 cm), and the presence of extraovarian disease. However, while primary ovarian mucinous tumors are more likely unilateral and larger, metastatic tumors may also present this way forming a cystic ovary and mimicking primary disease. Eliciting clinical history, including past and concurrent associated abnormalities, is always helpful when the differential diagnosis includes metastasis.

Histologically, the presence of signet ring cells almost always points to a diagnosis of metastatic carcinoma. Exceptions are rare and include the diagnosis of signet ring stromal tumor (SRST)—an extremely rare tumor of the ovary characterized by a proliferation of signet ring cells admixed with spindled, fibroblastic cells in broad sheets or short fascicles. The diffuse growth pattern of the signet ring cells may resemble that seen in metastatic adenocarcinoma ex GCC. However, in addition to the gross features described above, SRST may also be distinguished by the presence of intra- and extracellular hyaline globules in some cases, and special stains that show the cytoplasmic vacuoles lack mucin, glycogen, or lipid. SRST will display no evidence of epithelial differentiation in the form of tubular glands, nests, or cords of cells, which may be present at least focally in metastatic adenocarcinoma ex GCC. More common origins of signet ring cells in the ovary include metastasis from the breast or gastrointestinal tract. Metastatic lobular breast carcinoma in the ovary typically displays single-file linear cords, trabeculae, or diffuse patterns; however, signet ring cell differentiation may be seen. Immunohistochemistry is useful as these tumors often express GATA-3, estrogen and progesterone receptor, mammaglobin, and GCDFP-15, distinguishing them from primary ovarian neoplasms as well as metastatic gastrointestinal carcinomas. Metastatic gastric carcinoma, the prototypical Krukenberg tumor, is usually predominantly composed of signet ring cells and often displays associated stromal fibrosis or edema, as well as stromal luteinization. While immunohistochemistry may be helpful, knowledge of the patient’s clinical history is crucial in distinguishing this tumor from metastatic adenocarcinoma ex GCC.

Clear cell carcinoma of the ovary may display a diffuse growth pattern and rarely intracytoplasmic mucin mimicking signet ring cells; however, thorough sampling should identify regions with more typical morphology including tubulocystic or papillary growth and hobnail cells with hyperchromatic apical nuclei projecting into glandular lumens. Unlike metastatic adenocarcinoma ex GCC, clear cell carcinomas will express PAX8 and napsin by immunohistochemistry.

Adenomatoid tumors involving the ovary are usually identified incidentally but may also present with symptoms associated with a pelvic mass. These tumors are of mesothelial origin and are typically composed of anastomosing gland-like spaces and tubules with cytoplasmic vacuoles. These spaces may be dilated or smaller, mimicking signet ring cells. Unlike metastatic adenocarcinoma ex GCC, these benign tumors express mesothelial cell markers such as calretinin and CK 5/6 by immunohistochemistry.

Ovarian steroid cell tumors, not otherwise specified, are unilateral in most cases and associated with androgenic symptoms in about half of cases. At first glance the diffuse growth pattern of pale vacuolated cells may resemble adenocarcinoma ex GCC, however close examination will identify round central nuclei rather than the eccentric nuclei of signet ring cells. Variable amounts of lipochrome pigment may also be seen in these tumors, which have benign clinical behavior in two-thirds of the cases. Additionally, steroid cell tumors can be distinguished from metastatic adenocarcinoma ex GCC by immunohistochemistry, as the former is positive for sex cord-stromal markers such as inhibin, calretinin, steroidogenic factor-1 and melan-A.

1. In which of the following ways is adenocarcinoma ex GCC similar to conventional colonic adenocarcinoma?
   1. They are both unlikely to metastasize to the ovaries.
   2. They both arise from an adenoma-carcinoma sequence.
   3. They both display less aggressive clinical behavior than classic low-grade neuroendocrine (carcinoid) tumors.
   4. They have similar molecular pathways including KRAS mutations.
   5. They may have a prominent signet ring cell component.
2. An ovarian tumor with signet ring cells also containing a component of hobnail cells in tubulocystic growth pattern is most characteristic of which of the following neoplasms?
   1. Adenocarcinoma ex goblet cell carcinoid
   2. Clear cell carcinoma
   3. Metastatic breast carcinoma
   4. Signet ring stromal tumor
   5. Steroid cell tumor
3. An ovarian tumor with a diffuse growth pattern of cells with clear cytoplasm, central nuclei, and immunoreactivity with inhibin is most characteristic of which of the following neoplasms?
   1. Adenocarcinoma ex goblet cell carcinoid
   2. Clear cell carcinoma
   3. Metastatic breast carcinoma
   4. Signet ring stromal tumor
   5. Steroid cell tumor

1. Tang LH, Shia J, Soslow RA, et al. Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of the appendix. Am J Surg Pathol. 2008;32:1429-1442.
2. Crum CP, Nucci MR, Lee KR, eds. Diagnostic Gynecologic and Obstetric Pathology. 2nd ed. Philadelphia, PA: Elsevier Saunders; 2011:625-628.
3. Bosman FT, Carneiro F, Hruban RH, Theise ND (eds). World Health Organization Classification of Tumours of the Digestive System. Lyon, FR: IARC Press; 2010;122-128.
4. Vang R, Bague S, Tavassoli FA, Prat J. Signet-ring stromal tumor of the ovary: clinicopathologic analysis and comparison with Krukenberg tumor. Int J Gynecol Pathol. 2003;23:45-51.
5. Kurman RJ, Carcangiu ML, Herrington CS, Young RH (eds). World Health Organization Classification of Tumours of Female Reproductive Organs. Lyon, FR: IARC Press; 2014;83-86.

2016
Rochelle A. Simon, MD
Surgical Pathology Committee
Pacific Pathology Partners
Seattle, WA

1. They may have a prominent signet ring cell component. (e)
2. Clear cell carcinoma (b)
3. Steroid cell tumor (e)