bs_bs_banner
Pathology International 2015; 65: 393–395
doi:10.1111/pin.12275
Letter to the Editor Diagnosis of primary pure signet-ring cell carcinoma of the cervix To the Editor: Primary signet-ring cell carcinoma of the cervix is extremely rare in the literature.1 We report a case of primary signet-ring cell carcinoma of the cervix, and discuss its cytology, immunohistochemical profile, HPV DNA results obtained with in situ hybridization (ISH) and polymerase chain reaction (PCR), and clinical course. The patient was a 31-year-old Japanese woman, gravida 4 para 2, without history of malignancy who visited a hospital for abnormal vaginal bleeding. Cytologic examination of cervical smears revealed agglomeration of atypical cells with intracellular mucinous vacuoles. Clusters of cells with a signet-ring appearance were observed in the mucus (Fig. 1a). It was categorized as atypical glandular cells. A 15-mm tumor was observed on the dorsal wall of the uterine cervix with magnetic resonance imaging; therefore, conization was performed. The histological diagnosis was signet-ring cell carcinoma. The tumor marker levels (carbohydrate antigen [CA] 125, 18.9 U/mL; CA 19-9, 12.2 U/mL; squamous cell carcinoma-related antigen, 0.7 ng/mL; carcinoembryonic antigen [CEA], 2.2 ng/mL) were not elevated. No other lesion was identified via a gastrointestinal endoscopic examination. An abnormal accumulation of fluorodeoxyglucose was observed only at the uterine cervix with positron emission tomography-computed tomography. Because no other tumor was identified, it was diagnosed with cervical cancer (International Federation of Gynecologic Oncologists [FIGO] stage IB1). A radical hysterectomy with pelvic lymphadenectomy and bilateral salpingooophorectomy was performed. No macroscopic lesions were identified during the radical hysterectomy except those in the conization scar. Microscopically, signet-ring cells infiltrated the superficial to the muscular layers of the cervix, and extended to less than one-third from the bottom of the vaginal wall, but not to the pelvic wall or parametrium. The tumor invaded the deeper part of the cervical wall (invasion depth, 20 mm). Total tumor size was 60 × 30 × 20 mm. There was lymphatic involvement (1/29, external iliac nodes). No histological type other than proliferating signet-ring cells was observed (Fig. 1b). Signet-ring cells were stained blue with alcian blue stain and periodic acid-Schiff reaction (Fig. 1c). Immunohistologically, the signet-ring cells tested positive for mucin 2 (MUC2), CDX2, CEA, and cytokeratin 7 (CK7), and negative for MUC1, MUC5AC, MUC6, p53, CK20, thyroid transcription factor 1 (TTF-1), gross cystic disease fluid protein-15 (GCDFP-15), mammaglobin, estrogen
receptor (ER), progesterone receptor (PgR), chromogranin A, p16, and HIK1083. ISH showed the presence of HPV DNA (Human Papillomavirus Type 16/18 Biotinylated DNA probe [Y1412]; Dako, Japan) in the nuclei of Signet-ring cells (Fig. 1d). The nonneoplastic cervical glandular epithelium tested positive for HPV. DNA samples from the tumor lesions were selectively captured from 10-μm dewaxed sections with a laser capture microdissection (LCM) system (LM200; Olympus Co. Ltd, Tokyo, Japan). DNA isolation from LCM specimens was performed with a PicoPure DNA Extraction kit (Arcturus Engineering, Mountain View, CA, USA) according to the manufacturer’s protocol. PCR was performed according to the manufacturer’s protocol with HPV16 (E6 forward, 5′-CTGCGACGTGAGGTATATGACTTT-3′; E6 reverse, 5′-ACATACAGCATATGGATTCCCATCT-3′) and HPV18 (E6 forward, 5′-AAACCGTTGAATCCAGCAGAA-3′; E6 reverse, 5′-GTCGTTCCTGTCGTGCTCG-3′). DNA of our sample was HPV18-positive on agarose gel electrophoresis. The histological diagnosis was primary signet-ring cell carcinoma of the cervix; the pathological stage was FIGO stage IIA (TNM category, pathological T2aN1M0). Postoperative chemotherapy consisting of six courses of paclitaxel and carboplatin was administered. The patient is currently alive with no evidence of disease 41 months after the surgery. Sixteen cases of primary cervical carcinoma containing signet-ring cells were reported in the English literature1–3 (Table 1). In most cases of previous reports, the signet-ring cell components is included in a part of histological types. The occurrence of the pure form of primary signet-ring cell carcinoma, a subtype of mucinous adenocarcinoma of the cervix, is extremely rare.1 Signet-ring cell carcinoma of the cervix commonly represents a metastasis, usually from the stomach but less frequently from the colon, breast, lungs, appendix, gallbladder, bladder, or ovary.4–6 Therefore, it is necessary to combine clinical, imaging, and endoscopic findings to identify other primary sites. Immunohistochemical and molecular studies have often provided critical information for the origin of a tumor. Six previous cases were tested for immunohistochemical expression of ER and PgR; only one case was positive for ER and PgR. Three cases reported positive reaction for CK7 as well as negative reaction for CK20, TTF-1, GCDFP-15, mammaglobin, vimentin, and MUC5AC. The previous two cases were negative for CDX2; however, our case was positive. Negative CDX2 expression is not sufficient to reject the diagnosis of primary cervical cancer.
© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
394
Letter to the Editor
a
b
c
d Figure 1 Histological and cytological examination of the uterine cervix. (a) Signet-ring cells with eccentric nuclei can be observed (papanicolaou stain). (b) Signet-ring cells invading the muscle layer (hematoxylin-eosin staining). (c) Signetring cells stained blue with alcian blue and periodic acid-Schiff. (d) In situ hybridization (ISH) showing the presence of human papillomavirus 18 (HPV18) DNA in the nuclei of signet-ring cells.
Table 1 Comparison of this case and the previous cases This case Age (y) FIGO stage
Previous cases (16 cases)
31 2a
Average 49.6 (29–80) 1a-1b: 6 cases 2b: 1 case 3: 4 cases Histological pure AIS: 2 cases features Adenocarcinoma: 7 cases except Adenocarcinoma with neuroendocrine Signet-ring diff.: 2 cases cell Adenosquamous carcinoma: 1 case Glassy cell component: 1 case HPV HPV18+ ISH HPV 18 + ISH: 2 cases and PCR HPV 18 + PCR: 3 cases HPV 18- IHC: 1 case ER/PgR ER−/PgR− ER−/PgR−: 5 cases ER+/PgR+: 1 case Outcome NED 41mo DOD: Median 8mo (7wks–18mo) NED: Median 26.5mo (6mo–96mo) AIS, adenocarcinoma in situ; diff, differentiation; DOD, dead of disease; ER, estrogen receptor; HPV, human papilloma virus; IHC, immunohistochemistry; ISH, in situ hybridization; mo, month; PCR, polymerase chain reaction amplification; PgR, progesterone receptor; y, years; wks, weeks.
Mammaglobin and GCDFP-15 are highly specific markers for breast cancer, while TTF-1 is specific for lung cancer. Therefore, these organ specific markers are considered useful for the differential diagnosis of cervical adenocarcinoma.7,8 Differential diagnosis of cervical adenocarcinoma and gastric adenocarcinoma is difficult immunohistochemically. Therefore, identify gastric cancer with endoscopic examinations is important.
The presence of HPV has been determined in seven cases of primary signet-ring cell carcinoma of the cervix, including this case. Immunohistochemically, our case is negative for p16, and other one case was negative for HPV18. In all cases, HPV gene was observed by ISH or PCR. Apart from cervical cancer, HPV infection is well known to be involved in head and neck tumors, but it is also rarely associated with other tumors. HPV positivity provides diagnostic evidence of primary signet- ring cell carcinoma of the cervix. HPV18 is a risk factor for the development of adenocarcinoma.9 Primary Signet-ring cell carcinoma of the cervix tested positive for only HPV18 in the current and previous cases. There is possibility that HPV18 is a risk factor for the signet-ring cell carcinoma of the cervix. This case was a stage IIA primary lesion of the cervix; if it had been a metastatic lesion from an extra organ, it would have been stage IV. An accurate diagnosis is critical to the choice of therapeutic strategy and prognosis. Therefore, thorough consideration of immunohistochemical and clinical information, for example by eliminating the diagnosis of gastric cancer via endoscopy is important for diagnosing primary signet-ring cell carcinoma of the cervix. In particular, if discrimination is difficult, positive proof of HPV DNA via ISH or PCR can impart a clue of diagnosis.
DISCLOSURE None declared.
© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
Letter to the Editor
ACKNOWLEDGMENTS We thank Ms. S Osanai, Ms. M Yoshihara, and Mr. Y Nakamura for their excellent technical assistance. Kota Washimi,1 Tomoyuki Yokose,1 Akira Noguchi,1 Kyoko Ono,1 Kae Kawachi,1 Yasuyo Maruyama,2 Rieko Kawase,3 Hisamori Kato4 and Yoichi Kameda1
Departments of 1Pathology and 4Gynecology, Kanagawa Cancer Center Hospital, 2Department of Obstetrics and Gynecology, Yokohama City University, Yokohama and 3 Department of Obstetrics and Gynecology, Nippon Medical School Hospital, Tokyo, Japan REFERENCES 1 Insabato L, Simonetti S, De Cecio R, Di Tuoro S, Bifulco G, Di Spiezio Sardo A. Primary signet-ring cell carcinoma of the uterine cervix with long term follow-up: Case report. Eur J Gynaecol Oncol 2007; 28: 411–4. 2 Yoon A, Kim S-H, Kim H-J, Bae D-S, Lee J-W. Primary signetring cell carcinoma of the uterine cervix: A case report. Korean J Obstet Gynecol 2011; 54: 570–73.
395
3 Giordano G, Pizzi S, Berretta R, D’Adda T. A new case of primary signet-ring cell carcinoma of the cervix with prominent endometrial and myometrial involvement: Immunohistochemical and molecular studies and review of the literature. World J Surg Oncol 2012; 10: 7. doi: 10.1186/1477-7819-10-7. 4 el-Zimaity HM, Itani K, Graham DY. Early diagnosis of signet-ring cell carcinoma of the stmach: Role of the Genta stain. J Clin Pathol 1997; 50: 867–8. 5 Pudasainin S, Subedi N, Prasad KB et al. Signet-ring cell carcinoma of the gallbladder: A case report. Nepal Med Coll J 2011; 13: 308–10. 6 El-Safadi S, Stahl U, Tinneberg HR, Hackethal A, Muenstedt K. Primary signet-ring cell mucinous ovarian carcinoma: A case report and literature review. Case Rep Oncol 2010; 3: 451–7. doi:10.1159/0003230003. 7 Bhargava R, Beriwal S, Dabbs DJ. Mammaglobin vs GCDFP-15: An immunohistologic validation survey for sensitivity and specificity. Am J Clin Pathol 2007; 127: 103–13. 8 Matoso A, Singh K, Jacob R et al. Comparison of thyroid transcription factor-1 expression by 2 monoclonal antibodies in pulmonary and nonpulmonary primary tumors. Appl Immunohistochem Mol Morphol 2010; 18: 142–9. doi: 10.1097/ PAI.0b013e3181bdf4e7. 9 Bulk S, Berkhof J, Bulkmans NW et al. Preferential risk of HPV16 for squamous cell carcinoma and of HPV18 for adenocarcinoma of the cervix compared to women with normal cytology in The Netherlands. Br J Cancer 2006; 94: 171–5.
© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
Pathology International 2015; 65: 393–395
doi:10.1111/pin.12275
Letter to the Editor Diagnosis of primary pure signet-ring cell carcinoma of the cervix To the Editor: Primary signet-ring cell carcinoma of the cervix is extremely rare in the literature.1 We report a case of primary signet-ring cell carcinoma of the cervix, and discuss its cytology, immunohistochemical profile, HPV DNA results obtained with in situ hybridization (ISH) and polymerase chain reaction (PCR), and clinical course. The patient was a 31-year-old Japanese woman, gravida 4 para 2, without history of malignancy who visited a hospital for abnormal vaginal bleeding. Cytologic examination of cervical smears revealed agglomeration of atypical cells with intracellular mucinous vacuoles. Clusters of cells with a signet-ring appearance were observed in the mucus (Fig. 1a). It was categorized as atypical glandular cells. A 15-mm tumor was observed on the dorsal wall of the uterine cervix with magnetic resonance imaging; therefore, conization was performed. The histological diagnosis was signet-ring cell carcinoma. The tumor marker levels (carbohydrate antigen [CA] 125, 18.9 U/mL; CA 19-9, 12.2 U/mL; squamous cell carcinoma-related antigen, 0.7 ng/mL; carcinoembryonic antigen [CEA], 2.2 ng/mL) were not elevated. No other lesion was identified via a gastrointestinal endoscopic examination. An abnormal accumulation of fluorodeoxyglucose was observed only at the uterine cervix with positron emission tomography-computed tomography. Because no other tumor was identified, it was diagnosed with cervical cancer (International Federation of Gynecologic Oncologists [FIGO] stage IB1). A radical hysterectomy with pelvic lymphadenectomy and bilateral salpingooophorectomy was performed. No macroscopic lesions were identified during the radical hysterectomy except those in the conization scar. Microscopically, signet-ring cells infiltrated the superficial to the muscular layers of the cervix, and extended to less than one-third from the bottom of the vaginal wall, but not to the pelvic wall or parametrium. The tumor invaded the deeper part of the cervical wall (invasion depth, 20 mm). Total tumor size was 60 × 30 × 20 mm. There was lymphatic involvement (1/29, external iliac nodes). No histological type other than proliferating signet-ring cells was observed (Fig. 1b). Signet-ring cells were stained blue with alcian blue stain and periodic acid-Schiff reaction (Fig. 1c). Immunohistologically, the signet-ring cells tested positive for mucin 2 (MUC2), CDX2, CEA, and cytokeratin 7 (CK7), and negative for MUC1, MUC5AC, MUC6, p53, CK20, thyroid transcription factor 1 (TTF-1), gross cystic disease fluid protein-15 (GCDFP-15), mammaglobin, estrogen
receptor (ER), progesterone receptor (PgR), chromogranin A, p16, and HIK1083. ISH showed the presence of HPV DNA (Human Papillomavirus Type 16/18 Biotinylated DNA probe [Y1412]; Dako, Japan) in the nuclei of Signet-ring cells (Fig. 1d). The nonneoplastic cervical glandular epithelium tested positive for HPV. DNA samples from the tumor lesions were selectively captured from 10-μm dewaxed sections with a laser capture microdissection (LCM) system (LM200; Olympus Co. Ltd, Tokyo, Japan). DNA isolation from LCM specimens was performed with a PicoPure DNA Extraction kit (Arcturus Engineering, Mountain View, CA, USA) according to the manufacturer’s protocol. PCR was performed according to the manufacturer’s protocol with HPV16 (E6 forward, 5′-CTGCGACGTGAGGTATATGACTTT-3′; E6 reverse, 5′-ACATACAGCATATGGATTCCCATCT-3′) and HPV18 (E6 forward, 5′-AAACCGTTGAATCCAGCAGAA-3′; E6 reverse, 5′-GTCGTTCCTGTCGTGCTCG-3′). DNA of our sample was HPV18-positive on agarose gel electrophoresis. The histological diagnosis was primary signet-ring cell carcinoma of the cervix; the pathological stage was FIGO stage IIA (TNM category, pathological T2aN1M0). Postoperative chemotherapy consisting of six courses of paclitaxel and carboplatin was administered. The patient is currently alive with no evidence of disease 41 months after the surgery. Sixteen cases of primary cervical carcinoma containing signet-ring cells were reported in the English literature1–3 (Table 1). In most cases of previous reports, the signet-ring cell components is included in a part of histological types. The occurrence of the pure form of primary signet-ring cell carcinoma, a subtype of mucinous adenocarcinoma of the cervix, is extremely rare.1 Signet-ring cell carcinoma of the cervix commonly represents a metastasis, usually from the stomach but less frequently from the colon, breast, lungs, appendix, gallbladder, bladder, or ovary.4–6 Therefore, it is necessary to combine clinical, imaging, and endoscopic findings to identify other primary sites. Immunohistochemical and molecular studies have often provided critical information for the origin of a tumor. Six previous cases were tested for immunohistochemical expression of ER and PgR; only one case was positive for ER and PgR. Three cases reported positive reaction for CK7 as well as negative reaction for CK20, TTF-1, GCDFP-15, mammaglobin, vimentin, and MUC5AC. The previous two cases were negative for CDX2; however, our case was positive. Negative CDX2 expression is not sufficient to reject the diagnosis of primary cervical cancer.
© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
394
Letter to the Editor
a
b
c
d Figure 1 Histological and cytological examination of the uterine cervix. (a) Signet-ring cells with eccentric nuclei can be observed (papanicolaou stain). (b) Signet-ring cells invading the muscle layer (hematoxylin-eosin staining). (c) Signetring cells stained blue with alcian blue and periodic acid-Schiff. (d) In situ hybridization (ISH) showing the presence of human papillomavirus 18 (HPV18) DNA in the nuclei of signet-ring cells.
Table 1 Comparison of this case and the previous cases This case Age (y) FIGO stage
Previous cases (16 cases)
31 2a
Average 49.6 (29–80) 1a-1b: 6 cases 2b: 1 case 3: 4 cases Histological pure AIS: 2 cases features Adenocarcinoma: 7 cases except Adenocarcinoma with neuroendocrine Signet-ring diff.: 2 cases cell Adenosquamous carcinoma: 1 case Glassy cell component: 1 case HPV HPV18+ ISH HPV 18 + ISH: 2 cases and PCR HPV 18 + PCR: 3 cases HPV 18- IHC: 1 case ER/PgR ER−/PgR− ER−/PgR−: 5 cases ER+/PgR+: 1 case Outcome NED 41mo DOD: Median 8mo (7wks–18mo) NED: Median 26.5mo (6mo–96mo) AIS, adenocarcinoma in situ; diff, differentiation; DOD, dead of disease; ER, estrogen receptor; HPV, human papilloma virus; IHC, immunohistochemistry; ISH, in situ hybridization; mo, month; PCR, polymerase chain reaction amplification; PgR, progesterone receptor; y, years; wks, weeks.
Mammaglobin and GCDFP-15 are highly specific markers for breast cancer, while TTF-1 is specific for lung cancer. Therefore, these organ specific markers are considered useful for the differential diagnosis of cervical adenocarcinoma.7,8 Differential diagnosis of cervical adenocarcinoma and gastric adenocarcinoma is difficult immunohistochemically. Therefore, identify gastric cancer with endoscopic examinations is important.
The presence of HPV has been determined in seven cases of primary signet-ring cell carcinoma of the cervix, including this case. Immunohistochemically, our case is negative for p16, and other one case was negative for HPV18. In all cases, HPV gene was observed by ISH or PCR. Apart from cervical cancer, HPV infection is well known to be involved in head and neck tumors, but it is also rarely associated with other tumors. HPV positivity provides diagnostic evidence of primary signet- ring cell carcinoma of the cervix. HPV18 is a risk factor for the development of adenocarcinoma.9 Primary Signet-ring cell carcinoma of the cervix tested positive for only HPV18 in the current and previous cases. There is possibility that HPV18 is a risk factor for the signet-ring cell carcinoma of the cervix. This case was a stage IIA primary lesion of the cervix; if it had been a metastatic lesion from an extra organ, it would have been stage IV. An accurate diagnosis is critical to the choice of therapeutic strategy and prognosis. Therefore, thorough consideration of immunohistochemical and clinical information, for example by eliminating the diagnosis of gastric cancer via endoscopy is important for diagnosing primary signet-ring cell carcinoma of the cervix. In particular, if discrimination is difficult, positive proof of HPV DNA via ISH or PCR can impart a clue of diagnosis.
DISCLOSURE None declared.
© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
Letter to the Editor
ACKNOWLEDGMENTS We thank Ms. S Osanai, Ms. M Yoshihara, and Mr. Y Nakamura for their excellent technical assistance. Kota Washimi,1 Tomoyuki Yokose,1 Akira Noguchi,1 Kyoko Ono,1 Kae Kawachi,1 Yasuyo Maruyama,2 Rieko Kawase,3 Hisamori Kato4 and Yoichi Kameda1
Departments of 1Pathology and 4Gynecology, Kanagawa Cancer Center Hospital, 2Department of Obstetrics and Gynecology, Yokohama City University, Yokohama and 3 Department of Obstetrics and Gynecology, Nippon Medical School Hospital, Tokyo, Japan REFERENCES 1 Insabato L, Simonetti S, De Cecio R, Di Tuoro S, Bifulco G, Di Spiezio Sardo A. Primary signet-ring cell carcinoma of the uterine cervix with long term follow-up: Case report. Eur J Gynaecol Oncol 2007; 28: 411–4. 2 Yoon A, Kim S-H, Kim H-J, Bae D-S, Lee J-W. Primary signetring cell carcinoma of the uterine cervix: A case report. Korean J Obstet Gynecol 2011; 54: 570–73.
395
3 Giordano G, Pizzi S, Berretta R, D’Adda T. A new case of primary signet-ring cell carcinoma of the cervix with prominent endometrial and myometrial involvement: Immunohistochemical and molecular studies and review of the literature. World J Surg Oncol 2012; 10: 7. doi: 10.1186/1477-7819-10-7. 4 el-Zimaity HM, Itani K, Graham DY. Early diagnosis of signet-ring cell carcinoma of the stmach: Role of the Genta stain. J Clin Pathol 1997; 50: 867–8. 5 Pudasainin S, Subedi N, Prasad KB et al. Signet-ring cell carcinoma of the gallbladder: A case report. Nepal Med Coll J 2011; 13: 308–10. 6 El-Safadi S, Stahl U, Tinneberg HR, Hackethal A, Muenstedt K. Primary signet-ring cell mucinous ovarian carcinoma: A case report and literature review. Case Rep Oncol 2010; 3: 451–7. doi:10.1159/0003230003. 7 Bhargava R, Beriwal S, Dabbs DJ. Mammaglobin vs GCDFP-15: An immunohistologic validation survey for sensitivity and specificity. Am J Clin Pathol 2007; 127: 103–13. 8 Matoso A, Singh K, Jacob R et al. Comparison of thyroid transcription factor-1 expression by 2 monoclonal antibodies in pulmonary and nonpulmonary primary tumors. Appl Immunohistochem Mol Morphol 2010; 18: 142–9. doi: 10.1097/ PAI.0b013e3181bdf4e7. 9 Bulk S, Berkhof J, Bulkmans NW et al. Preferential risk of HPV16 for squamous cell carcinoma and of HPV18 for adenocarcinoma of the cervix compared to women with normal cytology in The Netherlands. Br J Cancer 2006; 94: 171–5.
© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
