A New Case of Primary Signet Ring Cell Carcinoma of the Uterine Cervix: A Case Report and Review of the Literature

Primary signet-ring cell carcinoma of cervix is extremely rare in the literature. Usually Signet-Ring Cell Carcinomas (SRCCs) of the cervix are metastatic from a primary gastric, colonic, ovarian, or breast carcinoma. A 48-year-old woman was referred to our Department due to persistent abnormal vaginal bleeding during the last two months. Gynecologic examination revealed cervical tumor. Biopsy revealed a signet ring cell type of mucinous adenocarcinoma. Extensive systemic examination reveals liver metastases biopsies confirmed. The patient was treated with palliative chemotherapy. The prognosis of primary signet ring cell adenocarcinoma of the uterine cervix is still unclear because of the rare incidence of cases. In this report we reviewed the literature to identify the clinical, pathological and immunohistochemical features of this rare malignancy. Figure 1: Microscopic examination shows cells with eccentric hyperchromatic nuclei and large mucin filled cytoplasmic vacuoles growing in clusters and in nests or columns within pools of extracellular mucin (signet-ring cells) (×400). Figure 2: Immunohistochemical analysis showed positivity to p16 (× 200). Citation: Doghri R, Tounsi N, Slimane M, Boujelbene N, Driss M, et al. (2017) A New Case of Primary Signet Ring Cell Carcinoma of the Uterine Cervix: A Case Report and Review of the Literature. J Cancer Sci Ther 9: 713-716. doi:10.4172/1948-5956.1000496 J Cancer Sci Ther, an open access journal ISSN: 1948-5956 Volume 9(10) 713-716 (2017) 714 total, oral endoscopy and mammography, failed to show any other primary tumor. We practiced an abdominal pelvic scanner which revealed lombo-aortic adenopathy as well as hepatic metastasis biopsyconfirmed. All these results were consistent with a primary PSRCC FIGO (2009) cervical tumor stage IVB. The patient was referred to medical oncology for palliative treatment. Cisplatin has been indicated at doses 50 mg/m2 once every 3 weeks. But, his health condition had severely and rapidly deteriorated, therefore she doesn’t receive chemotherapy. She was deceased three months later. Discussion The most common adenocarcinoma of the uterine cervix is the usual endocervical type [1]. Mucinous adenocarcinoma of signet-ring cell type is very rare [4,5]. Usually, signet-ring cell differentiation found in cervical carcinoma strongly suggests a metastatic carcinoma usually from a gastro-intestinal, appendicular, mammary or ovarian origin Figure 3: Abdominopelvic magnetic resonance imaging (MRI): the tumor measured 53 mm × 36 mm size in the endocervical canal. Induration extended to the parametria. Authors, years Age (yrs) Presenting symptoms FIGO stage Immunohistochemical studies other than ER and PR ER, PR HPV Treatment Outcome Moll et al. [9] 50 Post-coital vaginal bleeding, III NA NA NA Sx ,RT DOD 10 mo menometrorrhagia Mayorga et al. [6] Post-coital bleeding Ib NA NA NA Pre-chemo, Sx NED 35 Mo case (1) 68 case (2) 74 Post-menopausal bleeding Ib NA NA NA Sx NED 25 Mo Haswani et al. [5] Post-coital vaginal bleeding In both cases III NA ER: − HPV type 18: + Palliative RT and chemo DOD 10 mo case (1) 33 case (2) 38 Ib NA ER: −, R: − NA Sx and RT NED 18 Mo Cardosi et al. [10] 53 Perimenopausal bleeding Ib NA ER+ PR + NA Sx RT Chemo NED 6 Mo Moritani et al. [14] 29 Persistent abnormal genital Bleeding III Positive for CK, MUC5AC Negative for vimentin, MUC2, MUC6 ER: −, PR: − − Chemo NED 6 Mo Insabato et al. [8] 46 Vaginal bleeding in cervical polypoid lesion Ib NA NA NA Sx,RT,Chemo NED 8 Yrs Suárez et al. [7] 80 Vaginal discharge IIIb Positive for CK AE1-AE3, CK 20, CEA, chromogranin A, synaptophysin NA NA Rx Chemo DOD 18 Mo Negative for vimentin, S-100 protein, HMB-45, adrenocorticotropic hormone, prolactin, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, growth hormone, GCDFP 15 Mc Cluggage et al. [17] NA Two cases NA NA Positive for CK 7 and CK 16 NA NA NA NA (2 cases) Negative for CK 20 and CDX2 Versas et al. [13] Thromboembolic events (Trousseau Syndrome) IV Positive for p16 and CK 7 Negative for CK 20, CDX2 and Dpc4. ER: −, PR: − + Chemo DOD 7 wks (2009) [3] 36 Case (2) 43 Metastases of lung and lymph nodes IV positive for p16 and CK negative for CK 20, CDX2 and mammoglobin Chemo DOD 2 Lowery et al. [15] 60 Post-menopausal bleeding Ib1 NA NA NA RT brachytherapy Sx DOD>10 years Balci et al. [2] 53 Post-menopausal bleeding IIb Positive for CK, p16, CEA, MUC1, and MUC5. Negative for CK 20, GCDFP15, MUC2, chromogranine, synaptophysin, PGP 9.5, CD56, vimentin, CDX-2, TTF-1, and mammaglobin ER: −, PR. − HPV type 18: + Sx NR Citation: Doghri R, Tounsi N, Slimane M, Boujelbene N, Driss M, et al. (2017) A New Case of Primary Signet Ring Cell Carcinoma of the Uterine Cervix: A Case Report and Review of the Literature. J Cancer Sci Ther 9: 713-716. doi:10.4172/1948-5956.1000496 J Cancer Sci Ther, an open access journal ISSN: 1948-5956 Volume 9(10) 713-716 (2017) 715 [1,6]. To the best of our knowledge, only 20 cases (included our case) of primary cervical carcinoma containing signet-ring cell morphology have been reported in the literature (Table 1). In most cases of previous reports, the signet-ring cell component is included in a part of histological types [6]. All cases were admitted as primary only after a careful combined clinical, endoscopic and radiological investigation to rule out the presence of an occult primary site. Immunohistochemical and molecular studies have often provided important information for differential diagnosis. Several immunohistochemical markers have been used in the literature to support the primary origin of cervical cancer, although their usefulness is debatable. Indeed, primary cervical carcinoma can express colorectal antigens such as ACE, caudal-related homeoboxn (CDX-2) and cytokeratin 20 (CK20) [7,8]. Moreover, simultaneous positivity to ACE and keratin 7 do not differentiate between PCSRCC and gastric or mammary metastatic malignancy [5]. However, positivity for mammoglobin favors a mammary origin. No positive case of PCSRCC was reported [5]. Oestrogen and progesterone receptors have been tested in only 4 previous cases [2,3,9] and these were present only in one example [10]. Neuroendocrine differentiations have been demonstrated in two cases [7,10] but these markers were negative in our case. Positivity of Human Papillomavirus (HPV) DNA using molecular analysis provides diagnostic evidence of primary signetring cell carcinoma of the cervix [4,5]. The presence of HPV 18 has been determined in five cases of primary signet-ring cell carcinoma of the cervix [4,7,11-13]. No case was reported with negative p16 immunohistochemical staining [13]. In our case, as well as in some previous published examples of the PCSRCC, the primary cervical origin was supported by the presence of P16 Immunoreactivity [12,13], which may be considered a surrogate marker for HPV infection [4]. The absence of extra genital pathology, demonstrated by investigations at the moment of the diagnosis and later in the course of the disease, also supports this opinion [7]. The prognosis of primary signet-ring cell carcinoma of the cervix is not well known [1]. Ten patients had localized disease to the cervix and eight patients had advanced tumors Yoon et al (2011) [1] 47 post-coital bleeding Ib Positive for p53 and Rb NA NA Sx NED 6 mo Giordano et al. [4] 45 Vaginal discharge IIb Positive for CK 7, CA-125, CEA and p16 Negative for vimentin, NA HPV type 18: + Sx NA O. Kaidar-Person [16] 37 post-coital bleeding IIb2 Negative for chromogranin , synaptosin, CEA. NA NA concomitant chemo radiotherapy NED 4 mo brachytherapy Sx Washimi et al. [11] 31 Abnormal vaginal bleeding. IIa Positive for MUC2, CDX2, CEA, CK7. ER: −, PR: − HPV type 18: + Sx and chemo Disease-free at 41 mo Negative for MUC1, MUC5AC, MUC6, p53, CK20, TTF-1, GCDFP-1, mammoglobin, chromogranin-1, p16, HIK1083. Cracchiolo et al. [12] 64 Abdominal fullness. IVB Cytokeratin 7, (CEA) ER: +, PR: + Palliative ± 3 mo P16 positive (GCDFP), S-100 protein synaptophysin, (SMA) CDX-2, colon carcinoma and Cytokeratin 20 negative. Sal et al. [13] 48 Postcoital vaginal bleeding Ib Positivity for p16, CDX-2, ER: -, PR: HPV type 18: + Sx Disease-free at 18 mo MUC1, MUC2 and MUC5AC. Negativity for synaptophysin, chromogranin A and CK–20 CKCK: Cytokeratin; MUC: Mucin; TTF: Thyroid Transcripton Factor; GCDFP: Gross Cystic Disease Fluid Protein; ER: Estrogen Receptor; PR: Progesteron Receptor; NA: Not Available; Sx: Surgery; Rx: Radiation Therapy; DOD: Died of Disease; NED: Not Evidence of Disease; Mo: Months; Yrs: Years; Wks: Weeks; Chemo: Chemotherapy; CEA: Carcinoembryonic Antigen; CDX-2: Caudal-Type Homeobox 2; SMA: Smooth Muscle Actin; PGP: Protein Gene Product; TTF: Thyroid Transcripton Factor 1; PreChemo: Preoperative Chemotherapy Table 1: Previous reported cases of primary cervical carcinoma containing signet-ring cell morphology. [2,4,5,7,10-14], in one cases with stage IV, was expired shortly after 3 months [12]. However, extended survival in a low-stage tumor was reported in two cases [8,15]. We have not a clear consensus; the treatment of this rare tumor joins the treatment recommendations for uterine cervix adenocarcinoma [16]. A resistance to radiotherapy and/ or chemotherapy was reported [3-5,7,9]. But it has been suggested that advanced stage disease is particularly aggressive [4,7,12,14]. Conclusion Primary signet-ring cell carcinomas of the cervix are rare and associated with a poor outcome [17]. Prognosis seems to be related to the clinical stage [4,10]. Awareness of this entity is important as it simulate metastatic signet-ring cell carcinoma. Clinical investigations and immunohistological studies are essentials for differential diagnosis [4,8]. Competing Interests The authors declare that they have no competing interests.


Introduction
Carcinoma of the uterine cervix is the most common malignancy in female genital tract in developing countries [1]. The current frequency of cervical adenocarcinoma is 10% to 25% of all the cervical carcinomas in developed countries and most of them are endocervical type [1].
Mucinous adenocarcinoma of the cervix was subdivided into 5 subtypes: endocervical, intestinal, signet-ring cell, minimal deviation, and villoglandular [2]. Adenocarcinomas with signet ring cell are mostly metastatic from gastric, breast, colonic or ovarian carcinomas and primary tumor is extremely rare [1][2][3]. The prognosis of primary signet-ring cell carcinoma (PSRCCs) of the cervix is not well known as a result of the small number of case reports.
We describe a case of primary adenocarcinoma of the uterine cervix, signet-cell type. In addition, we reviewed all reported cases in the literature, to the best of our knowledge.

Case Report
A 48-year-old woman, gravida seven, para five, aborta 2, married at the age of 18 not yet menopause and her medical and family history was unremarkable. She was a heavy smoker (tow pack/day) for 10 years, no alcohol, and used oral contraceptives on and off for about 10 years. She was admitted to our hospital for spontaneous and intermittent abnormal vaginal bleeding which had been present during the last two months. Gynecological examination revealed diffuse enlargement of the cervix which had been replaced by an exophytic ulcerated, reddish lesion with distal parametrial infiltration. We performed a cervical biopsy and endocervical curettage. Microscopic examination shows cells with eccentric hyperchromatic nuclei and large mucin filled cytoplasmic vacuoles growing in clusters and in nests or columns within pools of extracellular mucin (signet-ring cells) (Figures 1-3). An extensive immunohistochemical evaluation of the biopsies was performed. The neoplastic cells were diffusely positive for p16, Cytokeratin 7 and carcinoembryonic antigen, whereas cytokeratin 20, chromogranin A, synaptophysin, vimentin and hormonal (estrogens and progesterone) receptors were negative. Abdominal pelvic magnetic resonance imaging (MRI) demonstrated about 53 mm × 36 mm size mass in the endocervical canal. Chest X-ray, gastroscopy, colonoscopy total, oral endoscopy and mammography, failed to show any other primary tumor. We practiced an abdominal pelvic scanner which revealed lombo-aortic adenopathy as well as hepatic metastasis biopsyconfirmed. All these results were consistent with a primary PSRCC FIGO (2009) cervical tumor stage IVB. The patient was referred to medical oncology for palliative treatment. Cisplatin has been indicated at doses 50 mg/m 2 once every 3 weeks. But, his health condition had severely and rapidly deteriorated, therefore she doesn't receive chemotherapy. She was deceased three months later.

Discussion
The most common adenocarcinoma of the uterine cervix is the usual endocervical type [1]. Mucinous adenocarcinoma of signet-ring cell type is very rare [4,5]. Usually, signet-ring cell differentiation found in cervical carcinoma strongly suggests a metastatic carcinoma usually from a gastro-intestinal, appendicular, mammary or ovarian origin   [1,6]. To the best of our knowledge, only 20 cases (included our case) of primary cervical carcinoma containing signet-ring cell morphology have been reported in the literature (Table 1). In most cases of previous reports, the signet-ring cell component is included in a part of histological types [6]. All cases were admitted as primary only after a careful combined clinical, endoscopic and radiological investigation to rule out the presence of an occult primary site. Immunohistochemical and molecular studies have often provided important information for differential diagnosis. Several immunohistochemical markers have been used in the literature to support the primary origin of cervical cancer, although their usefulness is debatable. Indeed, primary cervical carcinoma can express colorectal antigens such as ACE, caudal-related homeoboxn (CDX-2) and cytokeratin 20 (CK20) [7,8]. Moreover, simultaneous positivity to ACE and keratin 7 do not differentiate between PCSRCC and gastric or mammary metastatic malignancy [5]. However, positivity for mammoglobin favors a mammary origin. No positive case of PCSRCC was reported [5]. Oestrogen and progesterone receptors have been tested in only 4 previous cases [2,3,9] and these were present only in one example [10]. Neuroendocrine differentiations have been demonstrated in two cases [7,10] but these markers were negative in our case. Positivity of Human Papillomavirus (HPV) DNA using molecular analysis provides diagnostic evidence of primary signet-ring cell carcinoma of the cervix [4,5]. The presence of HPV 18 has been determined in five cases of primary signet-ring cell carcinoma of the cervix [4,7,[11][12][13]. No case was reported with negative p16 immunohistochemical staining [13]. In our case, as well as in some previous published examples of the PCSRCC, the primary cervical origin was supported by the presence of P16 Immunoreactivity [12,13], which may be considered a surrogate marker for HPV infection [4]. The absence of extra genital pathology, demonstrated by investigations at the moment of the diagnosis and later in the course of the disease, also supports this opinion [7]. The prognosis of primary signet-ring cell carcinoma of the cervix is not well known [1]. Ten patients had localized disease to the cervix and eight patients had advanced tumors   [2,4,5,7,[10][11][12][13][14], in one cases with stage IV, was expired shortly after 3 months [12]. However, extended survival in a low-stage tumor was reported in two cases [8,15]. We have not a clear consensus; the treatment of this rare tumor joins the treatment recommendations for uterine cervix adenocarcinoma [16]. A resistance to radiotherapy and/ or chemotherapy was reported [3][4][5]7,9]. But it has been suggested that advanced stage disease is particularly aggressive [4,7,12,14].

Conclusion
Primary signet-ring cell carcinomas of the cervix are rare and associated with a poor outcome [17]. Prognosis seems to be related to the clinical stage [4,10]. Awareness of this entity is important as it simulate metastatic signet-ring cell carcinoma. Clinical investigations and immunohistological studies are essentials for differential diagnosis [4,8].