Mesothelial Neoplasms Presenting as, and Mimicking, Ovarian Cancer

Summary:

Mesotheliomas of the abdominal cavity are rare tumors that primarily involve the peritoneum, mesentery, and omentum. The involvement of the viscera is usually secondary to bulky and extensive serosal disease. We describe 7 cases of mesothelioma in which the initial manifestation was that of an ovarian mass. All patients underwent surgery with a primary diagnosis of ovarian cancer. Clinical histories, gross features, and histology slides were reviewed. Immunostains were performed on all cases and electron microscopy was performed in 2 cases. The patients ranged in age from 22 to 52 years and the lesions ranged in size from 3.8 to 9 cm. Of the 7 cases, 4 were predominantly cystic and 3 were solid. Histologically, all cystic tumors were multicystic mesothelioma, whereas the 3 solid tumors were diffuse malignant mesotheliomas. One patient had a borderline mucinous tumor with the mesothelioma occurring as a mural nodule, an association not described earlier. The oldest patient in this series had a diffuse malignant mesothelioma of the peritoneum with predominant ovarian surface involvement. Mesothelial neoplasms can present as ovarian masses in young women. Awareness of this presentation is important to establish appropriate management.

Mesotheliomas of the abdominal cavity are rare tumors that primarily involve the peritoneum, mesentery, and omentum, with an incidence of between 0.2 and 2 cases per million in women (1,2). The clinical presentation, diagnostic imaging, and operative findings of peritoneal mesothelioma are often similar to those of ovarian carcinomas. However, recent advances in management of mesotheliomas have improved outcomes in these patients (3–5), underscoring the importance of a precise diagnosis. Mesotheliomas have bulky serosal involvement with minimal visceral invasion (6), and a dominant ovarian mass is unusual. We describe 7 cases of mesothelioma in which the initial manifestation was that of an ovarian mass.

METHODS

We reviewed our files for patients who had been accepted for the consideration of treatment in ovarian cancer protocols, but were reclassified as having mesothelial neoplasms after pathology evaluation. Available clinical histories were obtained and histologic slides/blocks were retrieved. One consultation case had a single representative section (slide and block), whereas the other cases were represented by 10 to 62 (mean 33) slides. Immunostains were variably performed for cytokeratins (CK) (pancytokeratin AE1/AE3, CK5/6, CK7, and CK20), mesothelin, calretinin, HBME-1, Ber-EP4, MOC-31, carcinoembryonic antigen (CEA), CA-125, CD15, estrogen receptor (ER), CD31, and CD34 (Dako, Carpinteria, CA). Electron microscopy was performed in 2 cases.

RESULTS

Seven cases presenting with ovarian masses were reclassified as mesothelioma, over an 8-year period (1999 to 2007). All patients had undergone surgery with a clinical diagnosis of ovarian cancer. Patients ranged in age from 22 to 52 years (mean 32.7 y, median 33 y). By imaging, the lesions were described as complex masses with variable solid and cystic components. On gross examination, the ovarian masses were predominantly solid in 3 cases and predominantly cystic in 4 cases. The lesions varied from 3.8 to 9 cm (mean 5.76 cm) in dimension. Six patients had peritoneal and/or omental involvement; 1 case (number 4) was seen in consultation and detailed information on extraovarian involvement was not available. Clinicopathologic features are summarized in Table 1.

TABLE 1.

Clinicopathologic features

Case number	Age (y)	Imaging/gross	Sites	Size (cm)	Diagnosis
1	22	Predominantly solid	Ovary, colon, omentum	5	Malignant mesothelioma
2	22	Predominantly solid	Ovary, peritoneum	9	Mucinous tumor; mesothelioma
3	30	Predominantly cystic	Ovary, peritoneum	Multiple, 4	Multicystic mesothelioma
4	33	Predominantly cystic	Ovary	Not known	Multicystic mesothelioma
5	34	Predominantly cystic	Ovary, pelvis, colon	Multiple, 7	Multicystic mesothelioma
6	36	Predominantly cystic	Ovary, pelvis	3.8	Multicystic mesothelioma
7	52	Predominantly solid	Ovary, peritoneum	5	Malignant mesothelioma

Four cases (case numbers 3 to 6) had features of multicystic mesothelioma (Fig. 1). All 4 patients with multicystic mesothelioma were in the fourth decade of life. However, the 4 patients showed variable extent of disease. Case number 3 had multiple ovarian cysts measuring up to 4 cm in diameter. In addition, there was a multilocular peritoneal cyst measuring 4.3 cm, with individual locules ranging from 0.2 to 1 cm and containing serous fluid. Case number 5 presented with pelvic pain and imaging identified a right adnexal mass. Multiple cystic lesions were found involving predominantly the right ovary, and also the peritoneal surfaces of the left fallopian tube, pelvic side walls, cul-de-sac, urinary bladder, and rectosigmoid colon. The individual lesions contained clear fluid and ranged in size from 0.3 to 4.5 cm. Case number 6 was a 36-year-old woman with sickle cell disease, who presented with chronic pelvic pain. A multi-cystic, complex right ovarian mass was seen on imaging studies. Intraoperatively, the ovarian mass was densely adherent to the posterior cul-de-sac. The ovarian mass measured 3.8 cm and showed multiple cysts containing clear and hemorrhagic fluid. A separate pelvic cyst (1.2 cm) was also excised. Case number 4 was seen in consultation and no operative details were available. All tumors in these 4 patients showed similar morphology and comprised multiple variably sized cysts separated by fibrous/adipose septa. The cysts were lined with a single layer of flattened-to-cuboidal/hobnailed cells with no or little atypia. Immunohistochemically, the lining cells were positive for pancytokeratin, calretinin, and CK5/6, and negative for CEA consistent with mesothelial lineage. CD31 and CD34 stains were negative and helped to exclude lymphangiomatosis.

FIG. 1.

Multicystic mesothelioma was comprised of multiple variably sized cysts separated by fibrous/adipose septa; cysts were lined by a single layer of flattened-to-cuboidal/hobnailed mesothelial cells with no or little atypia [(A) hematoxylin and eosin, 200 ×]. Lining cells were uniformly positive for calretinin [(B) 200 ×] and cytokeratin5/6 [(C) 200 ×].

Case number 1 presented with a right tuboovarian mass. Intraoperatively, there was apparent involvement of the serosal surfaces of the small and large intestines and the omentum. The tuboovarian mass (5 cm) was solid and cystic, the cyst being multilocular. Histopathologic evaluation showed epithelioid tumor cells in sheets and glandular formations, many showing papillary proliferation (Fig. 2). The cells were large with ample eosinophilic to clear cytoplasm, and had central nuclei with prominent nucleoli. However, unlike a typical serous carcinoma, there was no significant nuclear pleomorphism and only occasional scattered mitotic figures were seen. The omental and peritoneal components showed invasion of underlying fat. Immunostains were positive for calretinin, CK5/6, CK7, and CA125, and were negative for BER-EP4, ER, CK20, and CEA, consistent with mesothelioma. Case number 2 presented with a predominantly solid left ovarian mass (9 cm), which, on gross examination, was seen to have a gray white-to-red glistening cut surface. Histologically, there were 2 components: a borderline mucinous tumor, intestinal type, and a malignant spindle and epithelioid neoplasm (Fig. 3). The borderline mucinous tumor component was characterized by an arborizing villous architecture lined by pseudostratified and focally stratified gastric-type mucinous epithelium without intraepithelial carcinoma or stromal invasion. This component was positive for pancytokeratin (AE1/AE3), CK20, polyclonal CEA, focally positive for CD15, and negative for calretinin, CA125, and CK5/6. The adjacent malignant spindle and epithelioid neoplasm was initially considered to be either a focus of anaplastic carcinoma or a sarcomatoid mural nodule occurring in a mucinous ovarian tumor. However, this malignant component involved peritoneal surfaces and omentum, with invasion into fat, and had the immunoprofile of a mesothelioma, staining positive for CK7 and calretinin, and negative for CK20, BER-EP4, MOC31, CD15, and CK5/6. Electron microscopy was performed to further resolve the differential diagnosis and showed long, slender microvilli, supporting a diagnosis of mesothelioma.

FIG. 2.

The tumor in case number 1 showed cells in papillary and tubular formations (hematoxylin and eosin, 100 ×), that were positive for calretinin and cytokeratin5/6 (not shown).

FIG. 3.

Case number 2 showed features of a borderline mucinous tumor [(A) H&E, 100 ×]. A mural nodule was identified, comprised of a malignant sarcomatoid [(B) H&E, 100 ×] and epithelioid neoplasm [(C) H&E, 200 ×], positive for calretinin [(D) 200 ×]. H&E indicates hematoxylin and eosin.

The oldest patient in our study (case number 7) presented with vaginal bleeding and an adnexal mass. An endometrial biopsy revealed atypical epithelioid cells positive for calretinin and the patient was taken up for surgery. Intraoperatively, there was disseminated abdominal tumor involving the uterus, left ovary, peritoneal surfaces, and the diaphragm. Histologically, the tumor had a papillary and glandular architecture. The ovarian involvement was predominantly confined to the surface and superficial parenchyma, whereas the uterus showed focal transmural involvement reaching the endometrial surface. The tumor cells were positive for pancytokeratin, calretinin, CA125, and HBME-1, and were negative for BER-EP4, CD15, CK5/6, and ER. Electron microscopy showed tumor cells with abundant vacuoles, rough endoplasmic reticulum, and prominent slender microvilli projecting into intercellular lumina, consistent with a malignant mesothelioma.

DISCUSSION

Ovarian involvement with mesothelioma is distinctly uncommon. Ovarian mesotheliomas comprised 0.03% of the mesothelioma-related deaths in the United Kingdom registry, over a 24-year period (7). Although diffuse peritoneal mesothelioma may secondarily involve the ovaries, these patients present with abdominal disease rather than with ovarian masses (6,8). Goldblum and Hart (9) found secondary ovarian disease in 10 cases with diffuse peritoneal mesothelioma; the average age of the cohort was 52 years and all the patients predominantly had surface or superficial stromal involvement. Clement et al (10) reported a series of 9 cases of malignant mesothelioma presenting as ovarian masses. The average age of the patients was 52 years; 7 of 9 had an extensive extraovarian peritoneal tumor, whereas the tumors were confined to the ovaries in 2 cases. Attanoos and Gibbs (7) found only 4 cases (average age 60 y) with predominant ovarian involvement among 11,629 malignant mesothelioma deaths in the United Kingdom. Our study is different from the above series in many respects. The patients in the present series are younger (average 33 y age). All patients presented with ovarian masses and extraovarian disease was only discovered at surgery. Further, all but 1 had predominant ovarian involvement. Only case number 7 had more extensive peritoneal disease with secondary involvement of ovarian surface and superficial parenchyma.

Four of our cases had the features of multicystic mesothelioma, a lesion that was specifically excluded in the study by Goldblum and Hart (9). The origin and pathogenesis of multicystic mesothelioma remain uncertain. Some investigators consider multicystic mesothelioma to be benign or indolent lesions and label them as multiloculated peritoneal inclusion cysts (11–13). However, others have described these as neoplasms with a slow but progressive growth of untreated lesions, a marked tendency to recur after surgical resection, malignant transformation, and high disease-related mortality (14–16). The uncertain pathogenesis, coupled with the potential for transformation into a potentially lethal process has resulted in a more aggressive approach to manage these neoplasms, with definitive tumor eradication by cytoreduction and hyperemic intraperitoneal chemotherapy. Multimodality therapy confers significantly better overall survival than conventional debulking procedures in these patients (5). Multicystic mesotheliomas occur most frequently in young to middle-aged premenopausal women, most often in the pelvic peritoneum, growing along the surfaces of the cul-de-sac, uterus, and rectum (17). Three of our 4 cases of multicystic mesothelioma had extraovarian involvement and, in the fourth case (case number 4, seen in consultation), no further information regarding extraovarian pathology was known. Given the young age at occurrence, the presence of extraovarian disease and the potential (however small) for malignant transformation, it is important to recognize this entity to triage patients for further management. These patients may need close follow-up to identify recurrence or extension of peritoneal disease.

Mural nodules are rare lesions seen in the walls of mucinous cystic tumors of the ovary. These mural nodules may be benign, "sarcoma-like" nodules (18,19) or may represent true malignancies including sarcomas (20,21), anaplastic carcinomas (22,23), and carcinosarcoma (24). Sarcoma-like mural nodules are well-delimited lesions restricted to the ovary, comprising a cellular heterogeneous population of inflammatory cells, fibroblastic cells, and/or giant cells, and are considered to be reactive in nature with favorable prognosis. In contrast, the presence of a true sarcoma or carcinoma is associated with a poor outcome, especially if the malignancy extends beyond the ovary. Our case showed a histologically malignant neoplasm with extraovarian involvement in association with a borderline mucinous tumor. The biphasic morphology with spindle and epithelioid cells raised a differential diagnosis of anaplastic carcinoma and carcinosarcoma. Anaplastic carcinomas associated with mucinous tumors have been described to have varied morphology including rhabdoid, sarcomatoid, and pleomorphic patterns (23). Carcinosarcomas are also biphasic neoplasms, but usually contain heterologous elements (chondrosarcoma or rhabdomyosarcoma). Although our case showed mixed epithelioid and spindled morphology, the absence of heterologous elements, the immunostaining profile, and the long slender villi seen on electron microscopy favor a diagnosis of malignant mesothelioma. Alternatively, the presence of 2 distinct components does raise a differential diagnosis of a diffuse mesothelioma secondarily involving an ovary with a preexisting borderline mucinous tumor. To the best of our knowledge, ours is the first case with a combined mesothelioma and mucinous tumor. However, many of the so-called sarcoma-like mural nodules reported in literature have not been extensively evaluated by immunostains and electron microscopy; it is conceivable that some of these sarcoma-like nodules could in fact represent spindle cell mesotheliomas.

In the ovary, mesotheliomas need to be differentiated from other neoplasms. The differential diagnosis of multicystic mesotheliomas includes benign lesions such as cystic lymphangioma, cystic forms of endosalpingiosis, endometriosis, and cystic adenomatoid tumors (25). Cystic lymphangiomas are lined with endothelial cells that are positive for CD31, CD34, and D2–40 immunostains, although the latter stain by itself is not helpful in differentiation as it is also positive in mesotheliomas. Endometriosis and endosalpingiosis can be separated by adequate sampling, identification of the lining epithelium and stroma, and positive staining for epithelial markers. Adenomatoid tumors consist of epithelioid cells that form vacuoles and tubular spaces within a fibrous stroma. However, they are immunopositive for keratin and mesothelial markers, similar to multicystic mesotheliomas. Composite tumors with both multicystic mesothelioma and adenomatoid tumors have also been reported, suggesting that they may be different morphologic manifestations of the same process (26). Diffuse malignant mesotheliomas need to be differentiated from primary ovarian carcinomas. Use of immunohistochemistry and electron microscopy are helpful in this regard (27–30). At the same time, one must remember that the florid-reactive mesothelial proliferations may be seen in association with other neoplastic processes and could be a diagnostic pitfall (31). The presence of extraovarian mesothelial proliferation by itself is not sufficient to make a diagnosis of mesothelioma and unequivocal stromal invasion, as seen in our cases, is a prerequisite for this diagnosis.

In conclusion, mesothelial tumors can present as ovarian masses in both young and older women. A high index of suspicion and ancillary studies are necessary for correct diagnosis. Awareness of this presentation is important to establish appropriate surgical and adjuvant therapies.