Small cell neuroendocrine carcinoma of the cervix
- Mario M Leitao, Jr, MD
Mario M Leitao, Jr, MD
- Assistant Member
- Division of Gynecology
- Department of Surgery
- Memorial Sloan-Kettering Cancer Center
- Oliver Zivanovic, MD
Oliver Zivanovic, MD
- Attending Surgeon
- Memorial Sloan Kettering Cancer Center
- Assistant Professor
- Cornell Weill Medical College
- Section Editors
- Barbara Goff, MD
Barbara Goff, MD
- Section Editor — Gynecologic Oncology
- Professor of Gynecologic Oncology
- University of Washington
- Don S Dizon, MD, FACP
Don S Dizon, MD, FACP
- Section Editor – Gynecologic Oncology
- Clinical Co-Director, Gynecologic Oncology
- Founder and Director, The Oncology Sexual Health Clinic
- Massachusetts General Hospital Cancer Center
- Associate Professor of Medicine
- Harvard Medical School
Cervical cancer encompasses several histologic types, of which the most common is squamous cell (70 percent) (table 1) [1,2]. Adenocarcinoma and its variants account for about 25 percent of cases, while other histologic subtypes are uncommon. Cervical neuroendocrine (mainly small cell) tumors represent only about 2 percent of all cervical malignancies [3-7]. Small cell neuroendocrine carcinoma represents an extrapulmonary variant of small cell lung cancer. (See "Neuroendocrine neoplasms of unknown primary site" and "Extrapulmonary small cell cancer".)
This topic review will cover the epidemiology, clinical presentation, staging, and treatment of small cell neuroendocrine carcinoma of the cervix. Because of the rarity of other neuroendocrine tumors of the cervix, they will not be discussed further.
The management of squamous cell cervical cancer and adenocarcinoma arising in the uterine cervix, as well as the management of other extrapulmonary sites of small cell cancer, are addressed elsewhere. (See "Management of early-stage cervical cancer" and "Management of locally advanced cervical cancer" and "Invasive cervical adenocarcinoma" and "Extrapulmonary small cell cancer".)
EPIDEMIOLOGY AND RISK FACTORS
Small cell neuroendocrine carcinoma of the cervix is a rare disease, accounting for only up to 2 percent of all invasive cervical cancers [3-8]. In a series from the Surveillance, Epidemiology and End Results (SEER) database, the mean annual incidence in the United States from 1977 to 2003 was 0.06 per 100,000 women, compared with 6.6 and 1.2 for squamous cell carcinoma and adenocarcinoma, respectively . Although the disease has been described in women from 22 to 87 years of age, the mean age at diagnosis of small cell neuroendocrine carcinoma of the cervix is about 45 years [10,11]. An association with high risk human papillomavirus (HPV) infection (HPV 18 more than HPV 16) has been described for both small and large cell neuroendocrine cancers [11-15].
In contrast to small cell carcinoma of the lung, smoking has not been established as a risk factor for small cell carcinoma of the cervix. However, it has been associated with a poorer prognosis . (See "Overview of the risk factors, pathology, and clinical manifestations of lung cancer", section on 'Smoking' and "Pathobiology and staging of small cell carcinoma of the lung", section on 'Epidemiology'.)
- SEER data for 2003-2007: http://seer.cancer.gov/ (Accessed on November 02, 2010).
- Alfsen GC, Thoresen SO, Kristensen GB, et al. Histopathologic subtyping of cervical adenocarcinoma reveals increasing incidence rates of endometrioid tumors in all age groups: a population based study with review of all nonsquamous cervical carcinomas in Norway from 1966 to 1970, 1976 to 1980, and 1986 to 1990. Cancer 2000; 89:1291.
- Albores-Saavedra J, Larraza O, Poucell S, Rodríguez Martínez HA. Carcinoid of the uterine cervix: additional observations on a new tumor entity. Cancer 1976; 38:2328.
- Scully RE, Aguirre P, DeLellis RA. Argyrophilia, serotonin, and peptide hormones in the female genital tract and its tumors. Int J Gynecol Pathol 1984; 3:51.
- Miller B, Dockter M, el Torky M, Photopulos G. Small cell carcinoma of the cervix: a clinical and flow-cytometric study. Gynecol Oncol 1991; 42:27.
- Van Nagell JR Jr, Donaldson ES, Wood EG, et al. Small cell cancer of the uterine cervix. Cancer 1977; 40:2243.
- Albores-Saavedra J, Gersell D, Gilks CB, et al. Terminology of endocrine tumors of the uterine cervix: results of a workshop sponsored by the College of American Pathologists and the National Cancer Institute. Arch Pathol Lab Med 1997; 121:34.
- McCusker ME, Coté TR, Clegg LX, Tavassoli FJ. Endocrine tumors of the uterine cervix: incidence, demographics, and survival with comparison to squamous cell carcinoma. Gynecol Oncol 2003; 88:333.
- Chen J, Macdonald OK, Gaffney DK. Incidence, mortality, and prognostic factors of small cell carcinoma of the cervix. Obstet Gynecol 2008; 111:1394.
- Viswanathan AN, Deavers MT, Jhingran A, et al. Small cell neuroendocrine carcinoma of the cervix: outcome and patterns of recurrence. Gynecol Oncol 2004; 93:27.
- Abeler VM, Holm R, Nesland JM, Kjørstad KE. Small cell carcinoma of the cervix. A clinicopathologic study of 26 patients. Cancer 1994; 73:672.
- Mannion C, Park WS, Man YG, et al. Endocrine tumors of the cervix: morphologic assessment, expression of human papillomavirus, and evaluation for loss of heterozygosity on 1p,3p, 11q, and 17p. Cancer 1998; 83:1391.
- Ambros RA, Park JS, Shah KV, Kurman RJ. Evaluation of histologic, morphometric, and immunohistochemical criteria in the differential diagnosis of small cell carcinomas of the cervix with particular reference to human papillomavirus types 16 and 18. Mod Pathol 1991; 4:586.
- Stoler MH, Mills SE, Gersell DJ, Walker AN. Small-cell neuroendocrine carcinoma of the cervix. A human papillomavirus type 18-associated cancer. Am J Surg Pathol 1991; 15:28.
- Wang KL, Yang YC, Wang TY, et al. Neuroendocrine carcinoma of the uterine cervix: A clinicopathologic retrospective study of 31 cases with prognostic implications. J Chemother 2006; 18:209.
- Lee JM, Lee KB, Nam JH, et al. Prognostic factors in FIGO stage IB-IIA small cell neuroendocrine carcinoma of the uterine cervix treated surgically: results of a multi-center retrospective Korean study. Ann Oncol 2008; 19:321.
- REAGAN JW, HAMONIC MJ, WENTZ WB. Analytical study of the cells in cervical squamous-cell cancer. Lab Invest 1957; 6:241.
- Cohen JG, Kapp DS, Shin JY, et al. Small cell carcinoma of the cervix: treatment and survival outcomes of 188 patients. Am J Obstet Gynecol 2010; 203:347.e1.
- Masuda K, Banno K, Yanokura M, et al. Carcinoma of the Lower Uterine Segment (LUS): Clinicopathological Characteristics and Association with Lynch Syndrome. Curr Genomics 2011; 12:25.
- Upanal N, Enjeti A. Primary lymphoma of the uterus and cervix: two case reports and review of the literature. Aust N Z J Obstet Gynaecol 2011; 51:559.
- Dyer MJ, Ye H, Isaacson PG. Primary lymphoma-like lesions of the uterine cervix; sheep in wolves' clothing. Br J Haematol 2011; 153:791.
- Conner MG, Richter H, Moran CA, et al. Small cell carcinoma of the cervix: a clinicopathologic and immunohistochemical study of 23 cases. Ann Diagn Pathol 2002; 6:345.
- Ishida GM, Kato N, Hayasaka T, et al. Small cell neuroendocrine carcinomas of the uterine cervix: a histological, immunohistochemical, and molecular genetic study. Int J Gynecol Pathol 2004; 23:366.
- Straughn JM Jr, Richter HE, Conner MG, et al. Predictors of outcome in small cell carcinoma of the cervix--a case series. Gynecol Oncol 2001; 83:216.
- McCluggage WG, Kennedy K, Busam KJ. An immunohistochemical study of cervical neuroendocrine carcinomas: Neoplasms that are commonly TTF1 positive and which may express CK20 and P63. Am J Surg Pathol 2010; 34:525.
- Gilks CB, Young RH, Gersell DJ, Clement PB. Large cell neuroendocrine [corrected] carcinoma of the uterine cervix: a clinicopathologic study of 12 cases. Am J Surg Pathol 1997; 21:905.
- Krivak TC, McBroom JW, Sundborg MJ, et al. Large cell neuroendocrine cervical carcinoma: a report of two cases and review of the literature. Gynecol Oncol 2001; 82:187.
- Sato Y, Shimamoto T, Amada S, et al. Large cell neuroendocrine carcinoma of the uterine cervix: a clinicopathological study of six cases. Int J Gynecol Pathol 2003; 22:226.
- Gardner GJ, Reidy-Lagunes D, Gehrig PA. Neuroendocrine tumors of the gynecologic tract: A Society of Gynecologic Oncology (SGO) clinical document. Gynecol Oncol 2011; 122:190.
- Hoskins PJ, Swenerton KD, Pike JA, et al. Small-cell carcinoma of the cervix: fourteen years of experience at a single institution using a combined-modality regimen of involved-field irradiation and platinum-based combination chemotherapy. J Clin Oncol 2003; 21:3495.
- Chan JK, Loizzi V, Burger RA, et al. Prognostic factors in neuroendocrine small cell cervical carcinoma: a multivariate analysis. Cancer 2003; 97:568.
- Sevin BU, Method MW, Nadji M, et al. Efficacy of radical hysterectomy as treatment for patients with small cell carcinoma of the cervix. Cancer 1996; 77:1489.
- Boruta DM 2nd, Schorge JO, Duska LA, et al. Multimodality therapy in early-stage neuroendocrine carcinoma of the uterine cervix. Gynecol Oncol 2001; 81:82.
- Collinet P, Lanvin D, Declerck D, et al. Neuroendocrine tumors of the uterine cervix. Clinicopathologic study of five patients. Eur J Obstet Gynecol Reprod Biol 2000; 91:51.
- Chang TC, Hsueh S, Lai CH, et al. Phase II trial of neoadjuvant chemotherapy in early-stage small cell cervical cancer. Anticancer Drugs 1999; 10:641.
- Sykes AJ, Shanks JH, Davidson SE. Small cell carcinoma of the uterine cervix: a clinicopathological review. Int J Oncol 1999; 14:381.
- Chang TC, Lai CH, Tseng CJ, et al. Prognostic factors in surgically treated small cell cervical carcinoma followed by adjuvant chemotherapy. Cancer 1998; 83:712.
- Randall ME, Kim JA, Mills SE, et al. Uncommon variants of cervical carcinoma treated with radical irradiation. A clinicopathologic study of 66 cases. Cancer 1986; 57:816.
- Zivanovic O, Leitao MM Jr, Park KJ, et al. Small cell neuroendocrine carcinoma of the cervix: Analysis of outcome, recurrence pattern and the impact of platinum-based combination chemotherapy. Gynecol Oncol 2009; 112:590.
- Hirahatake K, Hareyama H, Kure R, et al. Cytologic and hormonal findings in a carcinoid tumor of the uterine cervix. Acta Cytol 1990; 34:119.
- Videtic GM, Stitt LW, Dar AR, et al. Continued cigarette smoking by patients receiving concurrent chemoradiotherapy for limited-stage small-cell lung cancer is associated with decreased survival. J Clin Oncol 2003; 21:1544.
- Sevin BU, Lu Y, Bloch DA, et al. Surgically defined prognostic parameters in patients with early cervical carcinoma. A multivariate survival tree analysis. Cancer 1996; 78:1438.
- Sheets EE, Berman ML, Hrountas CK, et al. Surgically treated, early-stage neuroendocrine small-cell cervical carcinoma. Obstet Gynecol 1988; 71:10.
- EPIDEMIOLOGY AND RISK FACTORS
- CLINICAL PRESENTATION
- DIFFERENTIAL DIAGNOSIS
- Squamous cell carcinoma
- Undifferentiated carcinomas of lower uterine segment
- Embryonal rhabdomyosarcoma
- Metastatic disease
- POST-DIAGNOSIS EVALUATION
- Staging system
- Role of surgery
- - Fertility sparing surgery
- - Benefit of chemotherapy
- - Chemotherapy alone versus chemoradiotherapy
- Role of prophylactic cranial irradiation
- POSTTREATMENT SURVEILLANCE
- APPROACH TO RECURRENT OR METASTATIC DISEASE
- SUMMARY AND RECOMMENDATIONS