Lynch syndrome (LS) is an autosomal dominant disease caused by a germline mutation in DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, PMS2, and EPCAM. Acquired damages in the other allele induce MMR deficiency resulting in a high frequency of microsatellite instability and accumulation of mutations in oncogenes and/or tumor suppressor genes 1.
LS increases the risk of several cancers such as endometrial cancer (EC) and colorectal cancer (CRC). The lifetime risk of EC and CRC for a woman with LS is 14% to 54% and 22% to 74%, respectively 1. Other LS-related cancers include gastric (risk: 0.2%–13%), ovarian (4%–20%), small intestine (4%–12%), bile duct (0.2%–4%), pancreatic (0.4%–4%), and ureteral (0.2%–25%) 1. Sebaceous adenomas and keratoacanthomas are also classified as LS-related neoplasms according to the revised Bethesda diagnostic criteria 1. However, there are only a few reports on peritoneal tumors including high-grade serous carcinomas and malignant mesotheliomas in patients with LS 2–5.
Here for the first time, we report a case of primary peritoneal low-grade serous carcinoma (PPLSC) in a woman with LS, who had a total hysterectomy and bilateral salpingo-oophorectomy (BSO) for endometrial carcinoma 14 yr ago. Furthermore, we discuss the pathologic differences between PPLSC and peritoneal malignant mesothelioma (PMM) which have some histologic similarities but require quite different treatments.
The patient is a 72-yr-old gravid 2 para 2 Japanese woman with LS, and a germline mutation in the MLH1 gene (c.676C>T, p.Arg226Thr). Besides a family history of colon cancer, she herself had CRC and EC in the past. Having undergone right semi-colectomy for early stage CRC at the age of 38, she was receiving colonoscopic evaluations every second year. She also underwent endoscopic mucosal resections of colonic tubular adenomas and intramucosal tubular adenocarcinomas, 15 and 2 times, respectively. For EC and uterine leiomyoma, she underwent total hysterectomy and BSO at the age of 58. Pathologic examination revealed an exophytic 10×8×1 mm tumor at the uterine fundus and a grade 1 endometrioid carcinoma invading 1 mm of the myometrium without lympho-vascular invasion. There were no malignant findings in the BSO specimens. Immunohistochemistry (IHC) revealed that the CRC and EC were negative for PMS2 and MLH1 but positive for MSH6 and MSH2 (Supplementary Fig. 1, Supplemental Digital Content 1, http://links.lww.com/IJGP/A97). At the age of 58, a cystic pancreatic lesion was detected by abdominal computed tomography (CT) which was being followed annually.
Fourteen years later, an abdominal CT revealed localized small nodules in the omentum and peritoneum. The cystic pancreatic lesion remained unchanged with no evidence of a solid component or pancreatic duct dilatation. Positron emission tomography/magnetic resonance images showed abnormal uptake in the peritoneal nodules, but not in the pancreatic cyst. Upper gastrointestinal endoscopy and colonoscopy revealed no tumors in the alimentary tract. CT-guided biopsy of a peritoneal nodule revealed a low-grade serous carcinoma. Upon surgical exploration for total resection of the peritoneal lesions, diffused miliary nodules were found in the peritoneum (Fig. 1A), and intraoperative peritoneal cytology revealed adenocarcinoma cells. We performed a partial resection of the nodular peritoneum to confirm the histologic diagnosis, following which she was scheduled to receive systemic chemotherapy for the residual tumors.
Macroscopically, we observed tumors of varying sizes (measuring up to 1.5×1×0.5 cm) on the resected peritoneum (7.5×5×3 cm). These gray-white solid tumors with irregular margins invaded the surrounding peritoneal adipose tissue (Fig. 1B). Microscopically, the tumor presented papillary structures on the surface and solid nests at the invasive front with numerous psammoma bodies (Fig. 1C). Destructive invasion of the surrounding adipose tissue by the tumor accompanied by lymphoid follicles with germinal centers (Fig. 1D) was also seen. The tumor was composed of monomorphous atypical cells with cuboidal to columnar cytoplasm and enlarged nuclei without pleomorphism (Figs. 1E, F). The tumor also included a region with a classic morphology of low-grade serous carcinoma (Figs. 1G, H). The mitotic count was 0 to 2/10 high-power fields, and necrosis was not observed. Endosalpingiosis was not detected in the peritoneal tissue.
IHC revealed that the tumor cells were positive for calretinin, D2-40, MOC31, BerEP4, WT-1, BRAFV600E, CEA, CA19-9 and negative for PAX8, HNF4-alfa, CDX2, BAP1, and HER2 (Fig. 2). For PAX8, this analysis was performed in 6 different blocks of the tumor; however, no PAX8-positive cells were observed (Supplementary Fig. 3, Supplemental Digital Content 1, http://links.lww.com/IJGP/A97). Focal positivities were observed for claudin 4 and estrogen receptor. While MMR proteins, including PMS2 and MLH1, were lost, MSH6 and MSH2 were retained (Fig. 2). Peritoneal cytology revealed adenocarcinoma which was positive for BerEP4 and CEA with psammoma bodies (Supplementary Fig. 2, Supplemental Digital Content 1, http://links.lww.com/IJGP/A97). The detailed information regarding all the antibodies used for IHC is provided in the Supplementary Table 1 (Supplemental Digital Content 2, http://links.lww.com/IJGP/A98).
On the basis of these findings, the final pathologic diagnosis was PPLSC, though there were no malignant findings in the BSO specimens obtained 14 yr ago.
We here report the first case of PPLSC in a woman with LS. We have focused on the pathologic differential diagnosis of PMM and peritoneal dissemination of other LS-related cancers. Furthermore, we provide a literature review of the previously reported primary peritoneal malignancies in patients with LS.
Our patient had a history of CRC and EC. However, as these tumors were removed at the earliest stage, the risk of metastases was extremely low. Furthermore, the histologic features and immunohistochemical findings for peritoneal cancer (negative for both CDX2 and PAX8) were quite different from those for her previous cancers (Supplementary Fig. 1, Supplemental Digital Content 1, http://links.lww.com/IJGP/A97). Moreover, as there was no evidence of a primary lesion following the chest and abdominopelvic CT and positron emission tomography/magnetic resonance images and gastrointestinal endoscopy, peritoneal metastasis of another LS-related cancer seemed to be unlikely. Besides, there were no malignant findings such as serous tubal intraepithelial carcinoma in the bilateral adnexa and uterus resected 14 yr ago. Collectively, the tumor was thought to be of peritoneal origin and its pathologic features, lack of nuclear pleomorphism, lower mitotic counts, and wild-type p53 status, support the diagnosis of PPLSC 6.
Notably, this tumor showed some overlapping immunohistochemical features with PMM. It was diagnosed as an adenocarcinoma based on the expression of epithelial markers (MOC31, BerEP4, and claudin 4) and adenocarcinoma specific markers (CEA and CA19-9). In addition, MOC31 (5%), BerEP4 (9%–13%), claudin 4 (0%), CEA (0%), and CA19-9 (0%) are rarely positive in PMM 7–9. However, the structure (papillary and solid) and positivity of mesothelial markers such as calretinin, D2-40, and WT-1 were reminiscent of epithelioid PMM. Only a small fraction of the peritoneal serous carcinomas reportedly are positive for D2-40 and calretinin 7. Furthermore, this tumor exhibited a loss of nuclear BAP1 and PAX8, which is uncommon in PPLSC. BAP1 is a tumor suppressor gene which is reportedly mutated in some malignant mesotheliomas and uveal melanomas 10. Loss of BAP1 expression has been reported in 67% of the PMMs and 2.5% of the peritoneal serous carcinomas 11. PAX8 is a transcriptional factor expressed in tumors of the Müllerian duct and in 93% of the peritoneal serous carcinomas 9. These ambiguous features of PPLSC are a diagnostic pitfall and highlight the need to use multiple IHC markers for differential diagnosis. The results of IHC, in this case, have been summarized in Supplementary Table 2 (Supplemental Digital Content 2, http://links.lww.com/IJGP/A98) 7–9,11.
To date, only 5 cases of primary peritoneal malignancies have been reported in patients with LS (Table 1) 2–5. These included 2 patients with PMM, 2 with high-grade serous carcinomas and 1 with a moderately differentiated carcinoma diagnosed by a small biopsy specimen, and all of them had LS-associated cancer such as endometrial or colon cancer. Tumors were both MMR deficient and proficient, indicating that not all these peritoneal neoplasms are LS-associated. These cases point to the difficulty in differentiating between PMM and PPC. Although expression of cytokeratin 7 or pan-cytokeratin (AE1/AE3) is indicative of a carcinoma, these markers could be positive in PMM also 7. Detailed histologic and IHC findings including more specific epithelial markers such as BerEP4 and MOC31 were not provided except in 1 PMM case 5. Therefore, it was difficult to differentiate between PMM and PPC in all the reported cases.
The PPLSC in the present case showed loss of PMS2 and MLH1 protein expression as well as aggregates of prominent lymphoid cells. Methylation of the MLH1 promoter, which is known to be a major cause of loss in MLH1 protein expression in CRC and EC 12, has not been reported in the sporadic cases of PPLSC. Thus, in our patient, the loss of MMR proteins was probably associated with the germline mutation in MLH1, while the tumor was LS-related. CRCs related to LS often show an increased number of infiltrating lymphocytes, mucinous carcinoma or signet-ring cell carcinoma like features and medullary growth 1. However, LS-related EC has prominent infiltration of lymphocytes around the tumor or histologic heterogeneity with a dedifferentiated component 1. The prominent lymphocyte aggregates, in this case, might also reflect MMR deficiency.
In summary, we report a case of PPLSC in a patient with LS. Since LS-related cancers usually precede primary peritoneal malignancies, clinicians and pathologists should add this rare entity to the list of differential diagnosis of PPLSC. Given the ambiguous pathological features resembling PMM, use of several IHC markers is recommended for a correct diagnosis and appropriate treatment.
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