A 22-year-old woman carrying twin gestations at 30 weeks presented with preterm labor and a prolapsing cervical mass. Following Cesarean section birth, she was treated with multiagent chemotherapy followed by pelvic radiotherapy for a Stage IIA small cell cancer of the uterine cervix. She is without evidence of disease 5.5 years after diagnosis and is the first reported long-term survivor of a small cell cervical carcinoma diagnosed during pregnancy

Balderston, KD

Berman, ML

Gregory, WT

Kucera, PR

Tewari, K

Balderston, Keith D

Tewari, Krishnansu

Gregory, W Thomas

Berman, Michael L

Kucera, Paul R

eScholarship - University of California

UC IrvineUC Irvine Previously Published WorksTitleNeuroendocrine Small Cell Uterine Cervix Cancer in Pregnancy: Long-Term Survival Following Combined TherapyPermalinkhttps://escholarship.org/uc/item/13n5s0b9JournalGynecologic Oncology, 71(1)ISSN0090-8258AuthorsBalderston, Keith DTewari, KrishnansuGregory, W Thomaset al.Publication Date1998-10-01DOI10.1006/gyno.1998.5104Copyright InformationThis work is made available under the terms of a Creative Commons Attribution License, availalbe at https://creativecommons.org/licenses/by/4.0/ Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaCASE REPORTNeuroendocrine Small Cell Uterine Cervix Cancer in Pregnancy:Long-Term Survival Following Combined TherapyKeith D. Balderston, M.D.,* Krishnansu Tewari, M.D.,* W. Thomas Gregory, M.D.,†Michael L. Berman, M.D.,* and Paul R. Kucera, M.D.†*Divisions of Maternal–Fetal Medicine & Gynecologic Oncology, Department of Obstetrics & Gynecology, University of California, Irvine–Medical Center,Orange, California; and†Division of Gynecologic Oncology, Department of Obstetrics & Gynecology,Oregon Health Sciences University, Portland, OregonReceived February 23, 1998A 22-year-old woman carrying twin gestations at 30 weekspresented with preterm labor and a prolapsing cervical mass.Following Cesarean section birth, she was treated with multiagentchemotherapy followed by pelvic radiotherapy for a Stage IIAsmall cell cancer of the uterine cervix. She is without evidence ofdisease 5.5 years after diagnosis and is the first reported long-termsurvivor of a small cell cervical carcinoma diagnosed duringpregnancy. © 1998 Academic PressINTRODUCTIONEndocrine tumors account for only 1–2% of all uterinecervix cancers. A variety of descriptive terms have been usedto account for the broad morphologic spectrum encountered,including neuroendocrine tumor, small cell carcinoma, oat cellcarcinoma, carcinoid tumor, argyrophil cell carcinoma, andapudoma. In an effort to facilitate comparisons of the clinico-pathologic characteristics and biologic behavior of these raretumors, a workshop was sponsored by the College of AmericanPathologists and the National Cancer Institute to construct auniform terminology system for the endocrine tumors of theuterine cervix [1]. The classification scheme developed issimilar to that of the neuroendocrine tumors of the lung andincludes the classical carcinoid tumor, the atypical carcinoid,the large cell neuroendocrine carcinoma, and the small (oat)cell carcinoma.The small cell carcinomas are histologically indistinguish-able from oat cell pulmonary cancer and portend a graveprognosis. More than half of patients with apparent early-stagedisease have nodal involvement and most patients treated byradical surgery and radiotherapy succumb to widespread me-tastases [2]. Because of its poor prognosis and propensity forhematogenous spread, systemic chemotherapy is a mainstay oftreatment of small cell carcinoma of the cervix, with manypatients experiencing prolonged disease-free survival. We re-port the first known survivor of a small cell cervical carcinomadiagnosed during pregnancy.CASE HISTORYIn July 1992, a 22-year-old Caucasian woman, gravida 5,para 3, presented with preterm labor and a prolapsing cervicalmass. She was carrying a twin gestation at 30 2/7 weeks. Hermost recent Papanicolaou test had been performed 6 monthspreviously at an outside facility and reportedly was withinnormal limits. A pelvic examination revealed an 8-cm, pedun-culated, tan, friable mass arising from the anterior cervix,assumed to be a myoma. She was admitted and underwentintravenous tocolysis with magnesium sulfate. A course ofintramuscular corticosteroids was administered. Ultrasonogra-phy demonstrated concordant twins with no anomalies, both invertex presentation. The patient was kept at bedrest and thec rvical mass was reduced. Several pessaries were fitted, butthe mass continued to prolapse.On the ninth hospital day, the patient was taken to theoperating room for an examination under anesthesia whichrevealed an 8-cm friable, necrotic cervical mass extending intothe upper vagina wall (Fig. 1). An acute hemorrhage promptedan emergency Cesarean section with delivery of viable twinfemale infants with birth weights of 1,625 and 1,800 g. Thelower uterine segment was palpably normal and there was nogross disease in the abdomen or pelvis. A portion of thec rvical mass was sent for pathologic analysis. Hemostaticsutures and a vaginal pack were placed to control bleeding.The specimen was composed entirely of malignant cellswithout cystic spaces, papillary structures, or normal cervicalmucosa. Small round cells with hyperchromatic nuclei andscant cytoplasm, characteristic of a small cell carcinoma of theuterine cervix, were observed (Fig. 2). Neurosecretory granuleswere present on electron microscopy. ImmunohistochemistryGYNECOLOGIC ONCOLOGY71, 128–132 (1998)ARTICLE NO. GO9851041280090-8258/98 $25.00Copyright © 1998 by Academic PressAll rights of reproduction in any form reserved.studies demonstrated tumor cells which stained positively withantibodies to cytokeratin and focally with antibodies to chro-mogranin. The tumor cells failed to stain with antibodies tosynaptophysin. The placenta was without evidence of meta-static disease. Pelvic washings retrieved at the time of Cesar-ean section did not contain malignant cells.Examination 3 weeks postpartum revealed an 83 10 cmfriable fleshy cervical mass extending to the left vaginal fornix.There was no parametrial thickening or nodularity. A meta-static workup included a normal chest roentgenogram, bonescan, and cranial computed tomography. Abdominal and pelviccomputed tomography showed no retroperitoneal or liver in-volvement.From August to December 1992, the patient received threecourses of cisplatin (80 mg/m2) and etoposide (400 mg/m2)alternating with two courses of VAC: vincristine (1.2 mg/m2wk 3 3 weeks), dactinomycin (300mg/m2/day3 5 days), andcyclophosphamide (150 mg/m2/day3 5 days) (Table 1). Treat-ment was interrupted once due to neutropenic sepsis which wasmanaged with antimicrobial therapy and granulocyte colony-stimulating factor. The tumor regressed to 4-cm diameter.Consolidation pelvic radiotherapy was administered to 45Gy followed by two tandem and ovoid implants, bringing thepoint A dose to 90.2 Gy and the point B dose to 64.1 Gy. Shereceived four additional courses of cisplatin (80 mg/m2) andetoposide (400 mg/m2) administered from April to July 1993,during which time she had no evidence of disease.All pelvic examinations, Papanicolaou tests, endocervicalcurretage specimens, and chest roentgenograms have beenwithin normal limits since completion of therapy. She is alive,5 years after diagnosis, with no evidence of recurrent disease orsignificant complications of therapy.DISCUSSIONSheets and colleagues reported 14 patients with Stage IB orIIA small cell cervical cancer treated either by radical surgeryalone or by surgery and postoperative radiotherapy at theUniversity of California, Irvine [2]. Twelve patients were deadof disease within 3 years of diagnosis and the 2 survivors hadrecurred. Abeler and co-workers reported a 5-year survival rateof 14% among 26 patients with small cell cervical cancertreated at the Norwegian Radium Hospital [3]. Fifteen of thesep tients had Stage I disease, and of these, 11 had died withdisease. These two studies suggest that traditional nonsystemicmodes of cervical cancer treatment were not efficacious in themanagement of small cell tumors.In light of similar histologic appearances and clinical behav-ior, Pazdur recommended that the bronchogenic neuroendo-crine tumors serve as a model to guide the therapy of endocrineFIG. 1. Photograph of the cervical mass prior to excisional biopsy.129CASE REPORTcancers arising from the cervix [4]. He treated three patientswith advanced disease with chemotherapeutic agents known tobe active in the management of pulmonary oat cell carcinoma.One patient experienced tumor regression in the pelvis andsupraclavicular nodal regions of 11 months duration, prior todeveloping brain metastases. Utilizing a bronchogenic neu-roendocrine protocol, Sutton and colleagues documented apartial response of nodal metastases to VAC chemotherapy [5].The first sustained remission following administration ofVAC chemotherapy was reported by Sheets at the Universityof California, Irvine [2]. The patient underwent radical hyster-ectomy, bilateral pelvic and para-aortic lymphadenectomies,and postoperative whole pelvis radiotherapy for a 9-cm diam-eter exophytic small cell cervical cancer which had metasta-sized to numerous pelvic and para-aortic lymph nodes. Thepatient received four courses of VAC chemotherapy and sur-vived without evidence of disease for a minimum of 3 years.O’Hanlan and colleagues have reported an additional twoFIG. 2. Hematoxylin–eosin stained section demonstrating small cell carcinoma of the uterine cervix with hyperchromatic nuclei and scant cytoplasm.TABLE 1Multiagent Intravenous Chemotherapy Regimen and RadiotherapyInductiona Consolidation MaintenancecAugust–December 1992 January–March 1993 April–July 1993Cisplatin (80 mg/m2) External beam radiotherapy 4,500 cGy Cisplatin (80 mg/m2)Etoposide (400 mg/m2) Cesium137 intracavitary implant 2,345 cGyb Etoposide (400 mg/m2)Alternating with Cesium137 intracavitary implant 2,176 cGyVincristine (1.2 mg/m2/week3 3 weeks)Dactinomycin (300mg/m2/day 3 5 days)Cyclophosphamide (150 mg/m2/day 3 5 days)a Three courses of cisplatin–etoposide alternating with two courses of VAC.b Brachytherapy dosages to left point A.c Total of four courses.130 BALDERSTON ET AL.patients with small cell cervical cancer who have experiencedcomplete responses with systemic therapy lasting 2 to 4 years[6]. Finally, at 21 to 60 months follow-up, Morris and co-workers noted disease-free survival in three patients with StageIB disease who had received cisplatin, doxorubicin, and eto-poside [7].The model for the induction phase of treatment for ourpatient was based on protocols used in the treatment of bron-chogenic oat cell carcinoma of the lung. Turrisi and colleaguesdemonstrated a 93% complete response rate in patients withsmall cell lung cancer treated with chemoirradiation [8]. Al-ternating etoposide–cisplatin with VAC was tested in severalrandomized trials which demonstrated efficacy of this regimenin the treatment of small cell lung cancers [9]. The completeresponse to chemotherapy and radiotherapy experienced by ourpatient has subsequently translated into long-term survival.We were able to find six other case reports of small cellcarcinoma of the cervix complicating pregnancy [10–15]. Intheir clinicopathologic study of 26 patients with small cellcervical cancer, Abeler and colleagues cite a pregnant patientwith Stage IB disease who was alive 54 months followingdefinitive surgical treatment and adjunctive chemotherapy [2].A personal communication from Professor Abeler revealed thatthis patient did not have a neuroendocrine small cell cervicalcarcinoma. Rather the patient had the intermediate cell varietyof small cell cervical cancer. Thus, we have not included thispatient in our review.Table 2 summarizes the outcomes of the six cases and thecurrent case.(1) Pregnancy outcome.Cesarean delivery was carried outfor the five women who were at least 25 weeks pregnant at thetime of diagnosis. Five had favorable neonatal outcomes andone neonate who delivered at 26 weeks gestation died ofprematurity. The one case diagnosed during the first trimesterwas treated before fetal maturity could be achieved, resultingin a spontaneous abortion.(2) Nodal status.Four of six patients who underwent pelviclymphadenectomies had nodal metastases; all four of thesepatients had Stage IB disease [10, 12–14].(3) Survival. With the exception of the current report, allpatients have died of widespread metastatic disease within 3years of diagnosis of Stage IB (n 5 4) or Stage IIA (n 5 2)disease. Four patients survived only 2, 6, and 9 months. Thesefour had been treated initially by radical surgery and eitherpostoperative radiotherapy [14] or adjunctive chemotherapy[10, 12, 15]. The other two patients died 24 and 32 monthsafter diagnosis. One had been treated with a single course ofcisplatin preoperatively, followed by radical surgery and post-operative radiotherapy [13], while the other received radiother-apy for a Stage IIA lesion [11].(4) Systemic therapy.Turner and colleagues describe treat-ment of a Stage IB cervical cancer with a chemotherapyregimen similar to ours [10]. Their patient began systemictreatment 10 days after having undergone radical hysterectomyand pelvic lymph node dissection. Metastatic disease had beenfound in one hypogastric node. The patient experienced anupper abdominal recurrence and died 9 months after diagnosis.TABLE 2Literature Review—Small Cell Cervical Carcinoma Complicating PregnancyaAuthor Age E.G.A.FIGOstage Treatment Nodes StatusTurner [10] 26 26 weeks IB C/S; RH, PLNDadj. chemotherapyPositive DOD 9 months,widespread metastasesKodousek [12] 29 28 weeks IB C/S; RH, PLNDadj. chemotherapyPositive DOD 6 months,widespread metastasesJacobs [13] 25 10 weeks IB Neoadjuvant chemotherapy;RH, PLND radiotherapyPositive DOD 24 months,widespread metastasesLojek [11] 28 25 weeks IIA C/S; PLND; radiotherapyadj. chemotherapybNegative DOD 32 months,widespread metastasesChang [14] 27 36 weeks IB C/S; RH, PLNDradiotherapyPositive DOD 2 months,widespread metastasesPerrin [15] 23 25 weeksc IIA C/S; RH, PLNDadj. chemotherapyPositived DOD 6 months,widespread metastasesPresent 22 30 weeks IIA C/S; chemotherapyradiotherapyNot sampled NED 5.5 yrNote. E.G.A., estimated gestational age at diagnosis; C/S, Cesarean section; RH, radical hysterectomy; PLND, pelvic lymphadenectomy; DOD, dead ofdisease; NED, no evidence of disease.a Modified after Turner and colleagues [10]b Chemotherapy administered for recurrent disease onlyc Patient presented at 25, 28, 33 & 36 weeks with a cervical mass and vaginal bleeding; actual diagnosis made 6 weeks postpartumd Clinically positive; pathological analysis of lymph nodes not stated in manuscript131CASE REPORTAlthough a modest treatment delay to allow fetal maturityfor some patients with Stage Isquamouscell carcinomas of thecervix has not been found to impact negatively on maternalsurvival [16], such a delay is contraindicated in pregnanciescomplicated by theneuroendocrinecervical cancer. Given theaggressive nature of this tumor type, we advise that therapy beinstituted immediately without delay following diagnosis. Aviable fetus should be delivered by classical Cesarean sectionto avoid the lower uterine segment. Induction of systemictherapy followed by radiotherapy should begin in the immedi-ate postpartum period. Patients who insist on treatment delaysin order to permit gestational advancement in early pregnancymay be candidates for antepartum systemic therapy and fetalsurveillance. Once fetal viability is attained, delivery should beaccomplished by Cesarean section with surgical assessment ofthe para-aortic lymph nodes and debulking of enlarged pelviclymph nodes. Postoperatively, continued systemic therapy fol-lowed by radiotherapy to ports which encompass the extent ofdisease found on exam and lymph node assessment is required.REFERENCES1. Albores-Saavedra J, Gersell D, Gilks B, Henson DE, Lindberg G, SantiagoH, Scully RE, Silva E, Sobin LH, Tavassoli FJ, Travis WD, Woodruff JM:Terminology of endocrine tumors of the uterine cervix: results of aworkshop sponsored by the College of American Pathologists and theNational Cancer Institute. Arch Pathol Lab Med 121:34–39, 19972. Sheets EE, Berman ML, Hrountas CK, Liao SY, DiSaia PJ: Surgicallytreated, early-stage neuroendocrine small cell cervical carcinoma. ObstetGynecol 71:10–14, 19883. Abeler VM, Holm R, Nesland JM, Kjørstad KE: Small cell carcinoma ofthe cervix: a clinicopathologic study of 26 patients. Cancer 73:672–677,19944. Pazdur R, Bonomi P, Slayton R, Gould VE, Miller A, Jao W, Dolan T,Wilbanks G: Neuroendocrine carcinoma of the cervix: implications forstaging and therapy. Gynecol Oncol 12:120–128, 19815. Sutton GP, Siemers E, Stehman FB, Ehrlich CE: Eaton-Lambert syndromeas a harbinger of recurrent small-cell carcinoma of the cervix with im-provement after combination chemotherapy. Obstet Gynecol 72:516–518,19886. O’Hanlan KA, Goldberg GL, Jones JG, Runowicz CD, Ehrlich L, Ro-driguez-Rodriguez L: Adjuvant therapy for neuroendocrine small cellcarcinoma of the cervix: case report and review of the literature. GynecolOncol 43:167–172, 19917. Morris M, Gershenson DM, Eifel P, Silva EG, Mitchell MF, Burke TW,Wharton JT: Treatment of small cell carcinoma of the cervix with cispla-tin, doxorubicin, and etoposide. Gynecol Oncol 47:62–65, 19928. Turrisi AT, Glover DJ, Mason BA: Concurrent twice-daily radiotherapyplus platinum-etoposide chemotherapy for the treatment of limited smallcell lung cancer: a preliminary report. Antibiot Chemother 41:109–114,19889. Bunn PA Jr, Carney DN: Overview of chemotherapy for small cell lungcancer. Semin Oncol 24 (suppl 7) S769–S774, 199710. Turner WA, Gallup DG, Talledo OE, Otken LB Jr, Guthrie TH: Neuroen-docrine carcinoma of the uterine cervix complicated by pregnancy: casereport and review of the literature. Obstet Gynecol 67:80S–83S, 198611. Lojek MA, Fer MF, Kasselberg AG, Glick AD, Burnett LS, Julian CG,Greco FA, Oldham RK: Cushing’s syndrome with small cell carcinoma ofthe uterine cervix. Am J Med 69:140–144, 198012. Kodousek R, Gazarek F, Dusek J, Dostal S: Malignant “apudoma” (argy-rophil cell cancer) of the uterine cervix in a 24-year-old woman inpregnancy. Cesk Pathol 12:37–44, 197613. Jacobs AJ, Marchevsky A, Gordon RE, Deppe G, Cohen CJ: Oat cellcarcinoma of the uterine cervix in a pregnant woman treated withcis-diamminedichloroplatinum: case report. Gynecol Oncol 9:405–410, 198014. Chang DH-C, Hsueh S, Soong Y-K: Small cell carcinoma of the uterinecervix with neurosecretory granules associated with pregnancy: a casereport. J Reprod Med 39:537–540, 199415. Perrin L, Bell J, Ward B: Small cell carcinoma of the cervix of neuroen-docrine origin causing obstructed labor. Aust NZ J Obstet Gynaecol36:85–87, 199616. Duggan B, Muderspach LI, Roman LD, Curtin JP, d’Ablaing III G,Morrow CP: Cervical cancer in pregnancy: reporting on planned delay oftherapy. Obstet Gynecol 82:598–602, 1993132 BALDERSTON ET AL.

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Neuroendocrine Small Cell Uterine Cervix Cancer in Pregnancy: Long-Term Survival Following Combined Therapy

Neuroendocrine small cell uterine cervix cancer in pregnancy: long-term survival following combined therapy.

Neuroendocrine small cell uterine cervix cancer in pregnancy: long-term survival following combined therapy.

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