Primary Peritoneal Serous Carcinoma Detected by Abnormal Cervical Smear: a Case Report

Primary peritoneal serous carcinoma (PPSC) is a rare malignancy, the clinical characteristics of which resemble ovarian serous carcinoma. We present a rare case of PPSC detected by an abnormal cervical smear, the first one with an absence of ovarian tissue at the time of the initial diagnosis. A 59-year-old asymptomatic woman presented with glandular atypia on routine Papanicolaou smear. Endocervical and endometrial curettage showed an adenocarcinoma with focal squamous differentiation and uncertain further classification. The patient had a past surgical history of bilateral salpingoophorectomy due to endometriosis. Abdominal MRI depicted omental multinodularity, great amount of ascites and possible endometrial tumor. The patient underwent total hysterectomy, omentectomy and biopsies of implants on Douglass pouch. Surgical and histological findings were consistent with primary peritoneal serous carcinoma. Abnormal pap smear could rarely be suggestive of extrauterine malignancies, such as peritoneal cancer.


INTRODUCTION
Primary peritoneal carcinoma is a relatively uncommon neoplasm arising from peritoneal epithelium which was first described by Swerdlow in 1959. Among primary peritoneal malignancies, primary peritoneal serous carcinoma (PPSC) is the most common histologic subtype affecting approximately 0.62/100000 women in US population. 1 Clinical symptoms of PPSC derive predominantly from massive ascites, usually in advanced stage of the disease. Typical preoperative findings indicating PPSC can be elevated Ca-125 levels and depiction of diffuse peritoneal disease, with or without omental involvement, and absence of an ovarian mass.
Only a few cases with atypical presentation of the disease have been described in the literature. The aim of the present study was to report a case of PPSC diagnosed by a glandular atypia on routine Pap smear, the first one with an absence of ovarian tissue at the time of initial diagnosis.

CASE REPORT
A 59-year-old asymptomatic woman, with previous gynecologic history of bilateral salpingo-oophorectomy due to endometriosis (15 years previously)  Abdominal MRI detected omental thickness, free peritoneal fluid and relatively thin endometrium, given the previously performed D&C. The imaging characteristics of the latter indicated a possible endometrial tumor without myometrial and parametrial involvement. Colonoscopy was also performed because of a referred change of bowel habits during the last month; however, the only pathology found was diverticulosis of sigmoid colon.
With a potential diagnosis of endometrial adenocarcinoma, the patient underwent exploratory laparotomy which revealed free peritoneal fluid, extensive omental involvement, multiple adhesions between the small intestine loops, and small implants of the tumor on the pouch of Douglass, as well as the uterine and the bladder serosa. Ovaries and fallopian tubes were not recognized. Perioperative assessment of the upper abdomen did not reveal any further pathology. Total hysterectomy, omentectomy and biopsies of the greater implants on Douglass pouch were performed, resulting in extensive debulking to R1 disease. Small implants < 1 cm in diameter remained in the pouch of Douglass and the bladder serosa.
Histological and immunohistochemical analysis of the specimens revealed no uterine disease. However, extended infiltration of the great omentum consistent with primary peritoneal serous carcinoma was found. Specifically, the neoplasm stained positive for tumor-associated glycoprotein 72 (TAG72), cancer antigen 125 (Ca 125), e-cadherin, HBME, keratin 7 (Ker 7) and negative for keratin 20 (Ker20), Wilms tumor 1(WT1) and cluster of differentiation antigen 15 (CD15), indicating a serous carcinoma. Microscopic lesions of the same tumor were also found in the external cervical surface. Pelvic washings showed metastatic adenocarcinoma. Based on the above findings, the diagnosis was PPSC (Fig. 1).
The patient was discharged uneventfully on the seventh postoperative day. Given the diagnosis of primary peritoneal serous carcinoma st IIIc, adjuvant chemotherapy with carboplatin-paclitaxel was scheduled.
Supplementary immunochemistry markers were applied to confirm the diagnosis. D2-40 was negative, so in comparison with the negative expression of the marker WT1 peritoneal mesothelioma was excluded (Fig. 2).

DISCUSSION
Primary peritoneal serous carcinoma (PPSC) affects predominantly elderly and postmenopausal women. Although early stages of the disease may be asymptomatic, most patients in advanced stages complain of abdominal distension, abdominal lump, diffuse nonspecific abdominal pain, vomiting, weight gaining and dyspnoea secondary to massive ascites. Elevated Ca-125 levels and scan findings consistent with ascites, omental involvement, and parietal peritoneal nodules without ovarian pathology may indicate PPSC. Given that PPSC shares the same clinical presentation with primary ovarian serous carcinoma and the two entities are indistinguishable immunohistochemically, the Gynaecology Oncology Group has set specific criteria in order to set the diagnosis of PPSC. Apart from ovarian serous carcino-

C.
ma, PPSC is crucial to be distinguished from other primary peritoneal cancer subtypes, such as malignant mesothelioma, pseudomyxoma peritonei and clear cell carcinoma of peritoneum, as well as from secondary peritoneal carcinomatosis or inflammatory peritoneal diseases such as actinomycosis. Standard management includes cytoreductive surgery combined with pre/postoperative platinum-based chemotherapy. Hyperthermic intraperitoneal chemotherapy (HIPEC) is also suggested. Given the diffuse spread of the carcinoma in omental, peritoneal and serosal surfaces, an optimal debulking is not always possible to be achieved. 2 Apart from the typical presentations mentioned above, some uncommon presentations have also been reported in the literature. An asymptomatic, abdominal skin lesion that led to the diagnosis of PPSC was described by Cowan et al. in 1995. 3 Another patient was diagnosed as having PPSC by a video-assisted thoracoscopic surgery due to bilateral pleural masses 4 , while three cases of PPSC 5-7 and one of serous peritoneal psammocarcinoma 8 were diagnosed by abnormal cytology ( Table 1). We report the fourth case of PPSC detected by abnormal cervical cytology, which is the first one with an absence of ovarian and tubal tissue at the time of the diagnosis.
Concerning the pathogenesis of PPSC, accumulating evidence suggests that most extrauterine high-grade serous carcinomas originate from the fimbriated end of the fallo-   7 49 Asymptomatic High grade adenocarcinoma PPSC pian tubes. Serous tubal intraepithelial carcinoma is a precursor lesion of the fallopian tubes that has been found in many cases of both primary ovarian and peritoneal serous carcinomas and is considered to be the source of a significant proportion of these diseases. Based on the latter theory, it is of great interest that our patients had a history of bilateral salpingo-oophorectomy 15 years before the diagnosis of PPSC. Possible illustrations have been reported in the literature in order to explain the development of PPSC in the absence of fallopian tubes, predominantly in BRCA mutation carriers with a history of a prophylactic bilateral salpingo-oophorectomy and they include: i) the presence and the metastasis of the precursor lesion in the peritoneum before the salpingo-oophorectomy, ii) remnant ovarian or tubal tissue postoperatively, and iii) primary origin of peritoneal cancer. 9 Pap smear is typically used to detect either pre-invasive or invasive cervical disease. Schnatz PF et al. performed a metanalysis of 24 studies including 2389206 Pap smears, 0.29% of which revealed glandular cells of undetermined significance (AGUS). Out of these AGUS revealing smear tests, 5.2% were proved to be consistent with malignancy. The most common malignancies were endometrial adenocarcinoma (57.6%), cervical adenocarcinoma (23.6%), ovarian and fallopian tube carcinoma (6.4%), squamous cell carcinoma of the cervix (5.4%), and other (6.9%), indicating thus that an abnormal test pap could also be suggestive of extra-uterine malignancies. 10 Specifically, ovarian, fallopian tube, gastrointestinal and breast tumors seems to be the most common of the carcinomas detected by an abnormal test pap 11 , while less common primary tumors such as melanoma 12 , renal cell and urothelial carcinoma 13 have also been reported. Six cases of serous borderline carcinoma of the ovary with abnormal glandular cells and/or psammoma bodies on the smear test have also been discussed in the literature. 14 The first case of extrauterine malignancy detected by an abnormal smear test was reported by Frech in 1946, when malignant glandular cells were found in the Pap smear test of a patient with serous papillary carcinoma of the ovary. 15 Efflux of the neoplasmatic peritoneal cells through the genital track, secondary cervical metastasis and the possible origin of PPSC from serous tubal intraepithelial carcinoma could explain the presence of malignant cells in a pap smear. Cervical metastasis, although, occurs rarely because of the limited blood flow and lymphatic drainage of the cervix, as well as its high content of fibrous tissue.
To sum up, abnormal cytology could rarely be suggestive of an extrauterine malignancy, such as PPCS. We raise the awareness of such a rare entity.