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 carci - noma. 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 endometri - al 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.

cervical smear, extrauterine malignancies, glandular atypia, primary peritoneal serous carcinoma,

Primary peritoneal carcinoma is a relatively uncommon neoplasm arising from peritoneal epithelium which was first described by Swerdlow in 1959. Among primary peri- toneal 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 ele - vated Ca-125 levels and depiction of diffuse peritoneal dis- ease, with or without omental involvement, and absence of an ovarian mass. Only a few cases with atypical presentation of the dis - ease 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 gyneco- logic history of bilateral salpingo-oophorectomy due to en - dometriosis (15 years previously) and two dilatations and curettages (D&C) due to endometrial hyperplasia (1 and 2 years ago, respectively), presented in our outpatient clin - ic with nuclear atypia of glandular cells found on routine Papanicolaou smear. Previous cervical screening had not detected any pathology. Transvaginal ultrasound depicted an endometrial thickness of 8 mm and free peritoneal fluid, Case Report 196 N. Blontzos et al Folia Medica I 2020 I Vol. 62 I No. 1 while mammography was normal. Ca-125 was measured up to 119 U/ml. Endocervical and endometrial curettage was scheduled and pathologic report revealed an adenocarcinoma on the grounds of an endometrial polyp, with focal squamous differentiation. However, the primary origin of the tumor could not be identified. Abdominal MRI detected omental thickness, free peritone- al fluid and relatively thin endometrium, given the previous- ly performed D&C. The imaging characteristics of the latter indicated a possible endometrial tumor without myometrial and parametrial involvement. Colonoscopy was also per - formed because of a referred change of bowel habits during the last month; however, the only pathology found was diver- ticulosis of sigmoid colon. With a potential diagnosis of endometrial adenocarcino - ma, the patient underwent exploratory laparotomy which revealed free peritoneal fluid, extensive omental involve - ment, 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 great - er 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 neo- plasm 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 carbo- platin-paclitaxel was scheduled. Supplementary immunochemistry markers were applied to confirm the diagnosis. D2-40 was negative, so in compar- ison with the negative expression of the marker WT1 perito- neal mesothelioma was excluded (Fig. 2).

Primary peritoneal serous carcinoma (PPSC) affects pre - dominantly elderly and postmenopausal women. Although early stages of the disease may be asymptomatic, most pa - tients in advanced stages complain of abdominal distension, abdominal lump, diffuse nonspecific abdominal pain, vom- iting, weight gaining and dyspnoea secondary to massive ascites. Elevated Ca-125 levels and scan findings consistent with ascites, omental involvement, and parietal peritone - al 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 Gynaecolo- gy Oncology Group has set specific criteria in order to set the diagnosis of PPSC. Apart from ovarian serous carcino- Figure 1. Microscopic findings (×50). Tumor cells characteristic of adenocarcinoma. A. HE ×2.5; B. HE ×5; C. HE ×10. A. B. C. Peritoneal Carcinoma Found by Pap Smear 197 Folia Medica I 2020 I Vol. 62 I No. 1 ma, PPSC is crucial to be distinguished from other primary peritoneal cancer subtypes, such as malignant mesothelio- ma, pseudomyxoma peritonei and clear cell carcinoma of peritoneum, as well as from secondary peritoneal carcino - matosis or inflammatory peritoneal diseases such as acti - nomycosis. Standard management includes cytoreductive surgery combined with pre/postoperative platinum-based chemotherapy. Hyperthermic intraperitoneal chemothera- py (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 ev- idence suggests that most extrauterine high-grade serous carcinomas originate from the fimbriated end of the fallo - Figure 2. Adenocarcinoma markers. A. Marker TAG72: positive; B. marker CK7: positive; C. marker CEA: positive; D. marker WT1: negative. A. B. C. D. Table 1. Clinical and laboratory findings Age Symptoms Pap smear findings Final histological report Olsen TG, et al.5 76 Asymptomatic Severe glandular dysplasia Primary peritoneal carcinoma Wright JD, et al.6 Postmenopausal Vaginal bleeding Adenocarcinoma cells Primary peritoneal carcinoma Riboni F , et al.8 70 Asymptomatic Neoplastic cells with psammoma bodies Peritoneal serous psammocarcinoma Wang H, et al.7 49 Asymptomatic High grade adenocarcinoma PPSC 198 N. Blontzos et al Folia Medica I 2020 I Vol. 62 I No. 1 pian tubes. Serous tubal intraepithelial carcinoma is a pre- cursor 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 signifi - cant proportion of these diseases. Based on the latter the - ory, it is of great interest that our patients had a history of bilateral salpingo-oophorectomy 15 years before the diag - nosis 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 peritone - um 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 ade - nocarcinoma (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%), indi- cating thus that an abnormal test pap could also be sugges- tive of extra-uterine malignancies.10 Specifically, ovarian, fallopian tube, gastrointestinal and breast tumors seems to be the most common of the carci - nomas detected by an abnormal test pap11, while less com- mon primary tumors such as melanoma 12, renal cell and urothelial carcinoma13 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 possi - ble origin of PPSC from serous tubal intraepithelial carci - noma 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 cer- vix, 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.

1. Liao Cl, Chow S, Chen LM, et al. Trends in the incidence of serous fal- lopian tube, ovarian, and peritoneal cancer in the US. Gynecol Oncol 2018; 149(2): 318-23. 2. Iavazzo C, Vorgias G, et al. Primary peritoneal serous papillary car - cinoma: clinical and laboratory characteristics. Arch Gynecol Obstet 2008; 278(1): 53-6. 3. Cowan LJ, Roller JI, Connelly PJ, et al. Extraovarian stage IV perito - neal serous papillary carcinoma presenting as an asymptomatic skin lesion – a case report and literature review. Gynecol Oncol 1995; (3): 433-5. 4. Suh JH, Kim YH, Chang ED. Primary papillary serous carcinoma of the peritoneum diagnosed by video-assisted thoracoscopic surgery: report of a case. Surg Today 2008; 38(8): 743-6. 5. Olsen TG, Nycum LR, Graham RL, et al. Primary peritoneal carcino- ma presenting on routine Papanicolaou smear. Gynecol Oncol 2000; 78(1):71-3. 6. Wright JD, Horowitz NS, Rader JS. Primary peritoneal carcinoma presenting as adenocarcinoma on a Pap smear. A case report. J Re - prod Med 2002; 47(11): 933-5. 7. Wang H, Chen PC. Primary serous peritoneal carcinoma present - ing first on a routine Papanicolaou smear: a case report. Acta Cytol 20120; 54(4): 623-6. 8. Riboni F , Giana M, Piantanida P , et al. Peritoneal psammocarcinoma diagnosed by a Papanicolaou smear; a case report. Acta Cytol 2010; 54(3): 311-3. 9. Iavazzo C, Gkegkes I, Vrachnis N. Primary peritoneal cancer in BRCA carriers after prophylactic bilateral salpingo-oophorectomy. J Turk Ger Gynecol Assoc 2016; 17(2): 73-6. 10. Schnatz PF , Guile M, O’Sullivan DM, et al. Clinical significance of atypical glandular cells on cervical cytology. Obstet Gynecol 2006; 107(3): 701-8. 11. Grupta D, Balsara G. Extrauterine malignancies. Role of Pap smears in diagnosis and management. Acta Cytol 1999; 43(5): 806-13. 12. Giordano G, Gnetti L, Pilato FP , et al. The role of cervical smear in the diagnosis and management of extrauterine malignancies metastatic to the cervix: three case reports. Diagn Cytopathol 2010; 38(1): 41-5. 13. Allison DB, Olson MT, Maleki Z, et al. Metastatic urinary tract can - cers in pap test: Cytomorphological findings and differential diagno- sis. Diagn Cytopathol 2016; 44(12): 1078-81. 14. Tepeoğlu M, Ozen O, Ayhan A. Ovarian serous borderline tumor de- tected by conventional Papanicolaou smear: a case report. Acta Cytol 2013; 57(1): 96-9. 15. Frech HC. Adenocarcinoma of the ovary diagnosed by vaginal smear. Am J Obstet Gynecol 1949; 57(4): 802-4. Peritoneal Carcinoma Found by Pap Smear 199 Folia Medica I 2020 I Vol. 62 I No. 1 Первичная перитонеальная серозная карцинома, обнаруженная в аномальном цитологическом мазке: клинический случай Николаос Блонтзос, Кристос Иавазо, Эйрини Джованопулу, Джордж Г ланопулос, Виктория Псомиаду, Джордж Воргиас, Отделение гинекологии, Мемориальная онкологическая больница „Метакса”, Пирей, Греция Адрес для корреспонденции: Николаос Блонтзос, Отделение гинекологии, Мемаксическая онкологическая больница, Пирей, Ксенофон - тос 103, Каллифея, 17674 Афины, Г реция; Электронная почта: [email protected]; Тел .: +306949239752 Дата получения: 21 апреля 2019 ♦ Дата приемки: 30 июля 2019 ♦ Дата публикации: 31 марта 2020 Образец цитирования: Blontzos N, Iavazzo C, Giovannopoulou E, Galanopoulos G, Psomiadou V , Vorgias G. Primary peritoneal se- rous carcinoma detected by abnormal cervical smear: a case report. Folia Med (Plovdiv) 2020;62(1):195-9. doi: 10.3897/folmed.62.e47875. Абстракт Первичная перитонеальная серозная карцинома (ППСК) представляет собой редкое злокачественное новообразование, кли - нические характеристики которого аналогичны таковым у серозной карциномы яичников. Мы представляем редкий случай ППСК с дефицитом ткани яичника во время первоначального диагноза аномального цитологического мазка. 59-летняя бессимптомная женщина с железистой атипией при рутинном цитологическом мазке. Эндоцервикальный и эндо - метриальный кюретаж выявил аденокарциному с очаговой плоскоклеточной дифференцировкой и неопределённой класси - фикацией. Больная в прошлом имела в хирургическом анамнезе двустороннюю сальпингоофоректомию вследствие эндоме - триоза. МРТ брюшной полости показала мультинодулярность предсердий, большое количество асцитической жидкости и возможную опухоль эндометрия. Больная подверглась тотальной гистерэктомии, оментэктомии и биопсии Дугласова про - странства. Хирургические и гистологические данные соответствуют первичной перитонеальной серозной карциноме. Аномальный цитологический мазок редко может указывать на внематочные злокачественные новообразования, такие как рак брюшины. Ключевые слова первичная перитонеальная серозная карцинома, цитологический мазок, железистая атипия, внематочные злокачественные новообразования.