Case of the Month: Peritoneum

This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2015, case 09, and is a serous carcinoma.

The slides show omental adipose tissue containing neoplastic cells embedded within reactive fibrous desmoplastic stroma. The cells have a high nuclear to cytoplasmic ratio and display marked nuclear atypia with the presence of scattered large, bizarre nuclei. Prominent nucleoli, including macronucleoli, are present and numerous mitotic figures are readily identified, including atypical forms. The neoplastic cells form solid nests and some glandular structures. Some slides show intraluminal proliferations with hierarchical branching. Areas of slit-like spaces within the neoplastic proliferation are seen. Scattered associated calcifications are present, predominantly appearing psammomatous with a concentric, lamellate configuration. The findings are diagnostic of serous carcinoma.

Extrauterine pelvic serous tumors may involve any combination of the fallopian tubes, ovaries, and peritoneum. While the majority of low grade serous carcinomas (defined as tumors with uniform nuclei and less than 12 mitoses per 10 high power fields) are associated with BRAF or KRAS mutations, high grade serous carcinomas (with marked cytological atypia or 12 or more mitoses per 10 high power fields) are more commonly associated with mutations in the TP53 gene. There has been much interest, research, and debate in recent years regarding the origin of these high grade serous carcinomas. Patients with BRCA1 or BRCA2 mutations are at significant risk for developing ovarian and breast cancer, therefore it was anticipated that thorough examination of the prophylactic, risk-reducing bilateral salpingo-oophorectomy specimens would identify some early or precursor pelvic serous carcinomas in these cases. Early fallopian tube intramucosal lesions were indeed identified in such patients. Subsequent detailed microscopic examination of the fallopian tube utilizing the SEE-FIM protocol (Sectioning and Extensively Examining the FIMbria) has led to increased frequency of detection of these serous tubal intraepithelial carcinomas (STICs), which are predominantly located in the distal fimbriated segment. As these lesions share the cytologic features, aberrant p53 protein overexpression, and genomic instability of high grade serous carcinoma, it was therefore hypothesized that the fallopian tube was also the origin of some sporadic high grade serous carcinomas. Subsequent studies have shown that STICs are present in 40-60% of female patients with high grade serous carcinomas that would otherwise be classified as ovarian or peritoneal. While there is mounting evidence to support the theory that a significant proportion of pelvic high grade serous carcinomas originate in the fallopian tube, research continues to explore alternate hypotheses for the pathogenesis of those cases in which a fallopian tube lesion is not identified.

It may be challenging to determine definitively the site of tumor origin in the setting of diffuse serous carcinoma within the pelvis. In this case, the presence of a fallopian tube mucosal lesion warrants classification as tubal origin, according to current recommendations. In the absence of a STIC, pelvic serous carcinoma may be classified as ovarian if there is prominent ovarian parenchymal involvement, or peritoneal if there is predominant peritoneal disease with minimal ovarian surface involvement. Fortunately, these classifications are of more academic than practical significance, as pelvic serous carcinomas have similar staging criteria and are treated with similar cytoreductive debulking surgery and platinum-based chemotherapy regimens regardless of origin. Due to the difficulty diagnosing pelvic serous carcinoma at an early stage, the overall prognosis is poor (despite aggressive therapy), with 5-year survival rates of 32-38% for patients with peritoneal lesions greater than 2.0 cm (pathologic stage T3c).

Metastatic adenocarcinoma in the peritoneal cavity may be of gynecologic or gastrointestinal origin, among others. In the setting of primary colonic adenocarcinoma with transmural invasion, the peritoneal cavity is at risk for seeding with metastatic disease. The anatomic nature of the ovaries and fallopian tubes gives tumors of these organs easy access to spread through the peritoneum. While these tumors may have some overlapping histologic features, metastatic colon adenocarcinoma more closely resembles endometrioid or mucinous tumors, rather than serous. Factors that would favor a diagnosis of metastatic colon cancer include garland and cribriform architecture of the glandular structures and epithelial necrosis with intraluminal debris. The immunoprofile is typically cytokeratin (CK) 7-negative, CK20-positive, CDX-2-positive, CA125-negative and PAX-8-negative. The lack of an identified mucosal intestinal lesion and the presence of ovarian and tubal (particularly mucosal) involvement argue against metastatic colon cancer in this case. As the slides show some glandular spaces with tall columnar neoplastic cells without a prominent papillary architecture, the diagnosis of endometrioid adenocarcinoma may be considered. However, the marked nuclear pleomorphism and presence of psammomatous calcifications are not typical features of endometrioid adenocarcinoma. Identification of areas of squamous metaplasia or background endometrioid proliferation such as endometriosis would support a diagnosis of endometrioid adenocarcinoma; however, those features were not present in this case. Serous carcinoma may show a prominent papillary architecture and cytoplasmic clearing, resembling clear cell carcinoma. A panel of immunohistochemical stains is useful in such cases as high grade serous carcinoma is typically positive for WT-1, diffusely, strongly positive for p53, variably positive for estrogen receptor (ER), and negative for hepatocyte nuclear factor (HNF)-1β, while clear cell carcinoma shows the opposite immunoprofile. Although more common in males, malignant mesothelioma may involve the female peritoneal cavity, displaying numerous growth patterns including solid, papillary, and tubular. Its cytologic features may be similar to those of serous carcinoma, even displaying psammoma bodies; however immunohistochemistry is useful to differentiate malignant mesothelioma and serous carcinoma. While WT-1 may be positive in both lesions, serous carcinoma is characteristically ER-positive, PAX-8-positive, and calretinin-negative, while the reverse is typical of malignant mesothelioma. In this case, the presence of a mucosal fallopian tube lesion indicates a gynecologic origin.

1. A 72-year-old woman presents with abdominal fullness. Imaging and exploratory laparotomy with debulking reveal pelvic tumor with diffuse omental caking. Microscopic examination of randomly submitted sections of the grossly normal ovaries and fallopian tubes (lumenal cross sections) reveals multiple small foci of high-grade serous carcinoma on the surface of bilateral ovaries and the serosa of both tubes. Which of the following is the most appropriate course of action?
   
   1. Report as primary fallopian tube serous carcinoma.
   2. Report as primary ovarian serous carcinoma.
   3. Report as primary peritoneal serous carcinoma.
   4. Report that the primary site cannot be determined.
   5. Submit the fallopian tube fimbria for histologic evaluation for an intramucosal lesion.
2. Which of the following is the most typical immunoprofile of pelvic serous carcinoma?
   
   1. Calretinin-negative, ER-positive, PAX-8-positive, WT-1-positive
   2. Calretinin-positive, ER-negative, PAX-8-negative, WT-1-positive
   3. CDX-2-positive, CK7-negative, CK20-positive, WT-1-negative
   4. CK7-positive, p53-positive, PAX-8-negative, WT-1-negative
   5. ER-negative, HNF-1β-positive, p53-negative, WT-1-positive
3.  Which of the following statements regarding high-grade serous carcinoma of the fallopian tube is true?
   
   1. It is associated with BRAF mutations.
   2. It is typically diagnosed at an early pathological stage (T1).
   3. It occurs exclusively in patients with BRCA1 or BRCA2 mutations.
   4. It originates predominantly in the isthmic region of the tube.
   5. It typically displays aberrant p53 protein overexpression.

1. Crum CP, Nucci MR, Lee KR, eds. Diagnostic Gynecologic and Obstetric Pathology. 2^nd ed. Philadelphia: Elsevier Saunders; 2011: 668-672,818-895.
2. DeLair D, Soslow RA. Key features of extrauterine pelvic serous tumours (fallopian tube, ovary, and peritoneum). Histopathology 2012; 61:329-339.
3. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti III A, eds. AJCC Cancer Staging Manual. 7^th ed. New York, NY: Springer/American Joint Committee on Cancer; 2010.
4. Lee S, Nelson G, Duan W, Magliocco AM, Duggan MA. Precursor lesions and prognostic factors in primary peritoneal serous carcinoma. Int J Gynecol Pathol. 2013; 32:547-555.
5. Royal RE, Pingpank Jr JF. Diagnosis and management of peritoneal carcinomatosis arising from adenocarcinoma of the colon and rectum. Semin Oncol. 2008; 35:183-191.

Rochelle A. Simon, MD
Surgical Pathology Committee
Women & Infants Hospital of Rhode Island
Providence, RI

1. Submit the fallopian tube fimbria for histologic evaluation for an intramucosal lesion. (e)
2. Calretinin-negative, ER-positive, PAX-8-positive, WT-1-positive. (a)
3. It typically displays aberrant p53 protein overexpression. (e)