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CASE REPORT – OPEN ACCESSInternational Journal of Surgery Case Reports 4 (2013) 651– 655

Contents lists available at SciVerse ScienceDirect

International Journal of Surgery Case Reports

journa l h om epage: www.elsev ier .com/ locate / i j scr

are large cell neuroendocrine tumor of the endometrium: case report and review of the literature

y-Linh T. Nguyena,∗, Liying Hanb, Anjoinette M. Minorsa, Stuart Bentley-Hibbertc,ana S. Pradhana,d, Tara L. Puaa,d, Sean S. Tedjarati a,d

Department of Obstetrics and Gyencology, New York Medical College, United StatesDepartment of Pathology, New York Medical College, United StatesDepartment of Radiology, New York Medical College, United StatesDivision of Gynecologic Oncology, New York Medical College, United States

a r t i c l e i n f o

rticle history:eceived 11 April 2013ccepted 15 April 2013vailable online 3 May 2013

eywords:arge celleuroendocrine tumorndometrial cancerynaptophysinhromogranin

a b s t r a c t

INTRODUCTION: Large cell neuroendocrine carcinoma (LCNEC) of the endometrium is a rare malignancywith an aggressive course. Although data is limited to case reports, the prognosis appears to be poor,similar to other type II uterine cancers. A total of 12 cases of LCNEC of the uterus have been published todate.PRESENTATION OF CASE: A 71 year-old woman presented with postmenopausal vaginal bleeding. Endome-trial biopsy was non-diagnostic for LCNEC. She underwent surgical debulking and staging of a 22 cmendometrial tumor with omental metastasis and positive lymph nodes. Her final FIGO stage was IVB.DISCUSSION: We summarize all prior case reports of LCNEC of the endometrium and discuss the defini-tion, presentation, imaging and surgical management. The pathology with immunohistochemical review,adjuvant therapy and prognosis of LCNEC of the endometrium are also reviewed.

D56 CONCLUSION: Pathologic findings and immunohistochemistry are essential in making a diagnosis ofLCNEC of the endometrium. Primary debulking and surgical staging is typically performed, but if adiagnosis of LCNEC can be made preoperatively with immunohistochemistry, surgeons should considerneoadjuvant chemotherapy due to its high grade histology and aggressive course. Otherwise adjuvantchemotherapy is usually given. Even with early stage disease, the prognosis seems poor. Due to the rarityof this aggressive malignancy, more data is needed to establish incidence.

gical

© 2013 Sur

. Introduction

Large cell neuroendocrine carcinoma (LCNEC) of thendometrium is a rare malignancy with an aggressive course.lthough data is limited to case reports, the prognosis appears

o be poor, similar to other type II uterine cancers. A total of2 cases of LCNEC of the uterus, not including ours, have beenublished in the English literature (Table 1).1–7 Here we discusshe clinical course of a 71 year-old woman with widely metastaticisease.

. Case presentation

A 71 year-old Caucasian female, with a BMI of 44, presentedith her first episode of postmenopausal vaginal bleeding. She

∗ Corresponding author at: Department of Obstetrics & Gynecology, New Yorkedical College, Munger Pavilion, Room 617, Valhalla, NY 10595, United States.

el.: +1 408 202 1927; fax: +1 914 594 4775.E-mail addresses: Miminguyen17@gmail.com, dr.miminguyen@gmail.com

M.-L.T. Nguyen).

210-2612 © 2013 Surgical Associates Ltd. Published by Elsevier Ltd. ttp://dx.doi.org/10.1016/j.ijscr.2013.04.027

Open access under CC BY

Associates Ltd. Published by Elsevier Ltd.

underwent an endometrial biopsy which revealed extensive necro-sis and apoptosis. Tumor cells were diffusely positive for vimentin,desmin, and Ki67, while negative for AE1/AE3, CD10 and SMA. Thedifferential diagnosis from biopsy included undifferentiated sar-coma, poorly differentiated adenocarcinoma and malignant mixedmullerian tumor.

MRI revealed a uterus measuring 19.5 cm × 13.1 cm × 12.3 cmwith complete loss of usual myometrial architecture with increasedT2 signal at the infiltrative lesion (Fig. 1A–D). The mass appeared toinvolve the entire myometrium and appeared to extend along theright fallopian tube surrounding a 7.4 cm myoma lying in the broadligament. The endometrial echo was thickened to 3.5 cm contain-ing heterogeneous debris. No definite extension to parametria wasseen on MRI. A 3.1 cm × 2.5 cm left external iliac lymph node wasenlarged along with a 1.9 cm × 2.4 cm paraaortic node, which bothappeared concerning for metastasis.

Two weeks later, the patient underwent an exploratory laparo-tomy, radical hysterectomy, debulking of a retroperitoneal tumor,

Open access under CC BY-NC-ND license.

bilateral salpingo-oophorectomy, pelvic and para-aortic lymphnode dissection, bilateral ureterolysis, omenectomy, and resectionof the posterior bladder wall with repair. Intraoperatively, a largeprimary tumor approximately 25 cm in size extruded from the

-NC-ND license.

CASE REPORT – OPEN ACCESS652 M.-L.T. Nguyen et al. / International Journal of Surgery Case Reports 4 (2013) 651– 655

Table 1Large cell neuroendocrine tumor of the endometrium.

Case Year Author Age Surgery Stage Histology Treatment Immunoprofilepositivity

Outcome(months)

1 2004 Erhan 52 TAH, BSO ICa Pure LCNEC RT, Cis, Eto NSE SNP DOD 32 2007 Mulvany 50 TAH, BSO,

OMY, LNIIIC Pure LCNEC RT, Cis, Eto NSE SNP AWD 12

3 2007 Mulvany 80 TAH, BSO, LN ICa LCNEC + endometrioid NFT NSE CGA DOD 54 2007 Mulvany 77 TAH, BSO IIBa LCNEC + endometrioid RT NSE SNP CGA CD56 DOD 235 2007 Mulvany 79 TAH, BSO,

omental bx,peritoneum

IIIA LCNEC + endometrioid RT NSE CGA CD56 AWD 2

6 2007 Mulvany 88 TAH, BSO, LN IIIC LCNEC + SCNEC+ endometrioid

RT NSE CGA CD56 AWD 1

7 2008 Albores-Saavedra 42 RH ICa Pure LCNEC Cis, Eto SNP CGA CD56 AWD 98 2010 Terada 40 TAH, BSO,

PLND, OMYIB LCNEC + sarcomatoid None SNP CD56 AWD 16

9 2011 Deodhar 70 TAH, BSO, OMY 1B Pure LCNEC Cis, Eto SNP CGA CD56 AWD 610 2011 Shahibi 59 TAH, BSO, OMY,

PPALND, APPYIIIC2 Pure LCNEC Carbo, Taxol,

RT.Doxil.Cis, Eto, Oct

NSE SNP CGA CD56 DOD 12

11 2012 Makihara 73 None IVB Pure LCNEC NFT NSE SNP CGA DOD 112 2012 Makihara 73 TAH, BSO,

OMY, PPALNDIIIC1 Pure LCNEC Cis, Iri SNP CGA CD56 AWD 13

13 2013 Present case 71 RH, BSO, OMY,PPALND

IVB Pure LCNEC Planned Cis,Eto, Oct

SNP CGA CD56 DOD 1

TAH = Total abdominal hysterectomy, BSO = Bilateral salpingoophorectomy, OMY = Omentectomy, RH = Radical hysterectomy, PLND = Pelvic lymph node dissec-tion, PPALND = Pelvic and paraaortic lymph node dissection, APPY = Appendectomy, RT = Radiotherapy, NFT = No further treatment, Cis = Cisplatin, Eto = Etoposide,Carbo = Carboplatin, Oct = Octreotide, Doxil = Pegelated doxorubicin, Iri = Irinotecan, NSE = Neural-specific enolase, SNP = Synaptophysin, CGA = Chromogranin A, DOD = Deadof disease, AWD = Alive with disease

a 1998 FIGO staging.

Fig. 1. Sagittal (A) and coronal (B) T2 weighted images without fat saturationthrough the pelvis demonstrates abnormal diffusely infiltrative high T2 signalthroughout the myometrium with loss of the normal architecture. Rounded masslesions with decreased T2 signal within the myometrium represent leiomyomas.Heterogeneous signal within the endometrial canal is likely debris. Axial diffusionweighted images (C) and axial T2-weighted images with fat saturation (D) redemon-strated diffusely infiltrative process with increased signal one restricted diffusioniTa

unt

s

and C). Immunohistochemical stains confirmed the diagnosisof a large cell neuroendocrine carcinoma of the endometrium(Table 2). Synaptophysin, chromogranin A (CGA), and CD56 werediffusely and strongly positive neuroendocrine markers. P53 and

Table 2IHC profile of present case.

Antibody Marker for Results

CK7 Cytokeratin 7 NegativeAE1/3 Cytokeratin AE-1/AE-3 cocktail NegativeEMA Epithelial membrane antigen NegativeCK8/18 CAM 5.2 Ck, LMW NegativeVIMENTIN Vimentin Focal positiveCD10 CD10 NegativeSYN Synaptophysin Diffuse strongly positiveCHRO Chromogranin Diffuse positiveCD56 CD56 Diffuse strongly positiveP53 Oncoprotein 70%; 3+P16 Dysplastic epithelial cell 90%; 3+ER Estrogen receptor NegativePR Progesterone receptor 70%; 2+S100 S100 NegativeHMB45 Human melanoma Focal positiveMYOGENIN Myogenin NegativeDESMIN Desmin Negative

mages suggestive of a hypercellular state restricting the motion of water molecules.he process can be seen to extend along the broad ligament on the left surrounding

broad ligament leiomyoma.

terus and involved the small bowel mesentery with bulky lymph

odes measuring up to 4 cm No gross residual disease was noted athe end of the procedure.

On gross pathologic exam, the uterus weighed 2120 g and mea-ured 22 cm in widest diameter. The endometrial cavity was filled

with necrotic-hemorrhagic material and showed a friable, polypoidmass attached to the anterior fundus (Fig. 2A). The tumor involvedthe full thickness of the myometrium as well as the cervix, bilat-eral ovaries and tubes. The upper vagina and bilateral parametriawere also infiltrated by tumor and lymphovascular space invasionwas present. One of 18 pelvic lymph nodes and one of 13 paraaor-tic lymph nodes were positive for metastasis. The omentum wasdiffusely infiltrated by tumor. Her final FIGO stage was IVB due toomental involvement.

Microscopically, the tumor was poorly differentiated (Fig. 2B

CD45 CD45 NegativeCD3 T cell NegativeCD20 B cell NegativeCD138 Plasma cell Negative

CASE REPORT – OPEN ACCESSM.-L.T. Nguyen et al. / International Journal of Surgery Case Reports 4 (2013) 651– 655 653

Fig. 2. (A) Uterus and cervix shows marked thickened, yellow-tan, fleshy walls and a subserosal, calcified nodule on the upper side. The endometrial cavity is filled withnecrotic and hemorrhagic debris. (B) Sheets of the tumor cells. H&E 100×. (C) Tumor cehigh nuclear/cytoplasmic ratios, prominent nucleoli, and amphophillic cytoplasm. Numerareas of necrosis. H&E 400×.

FP

Pt(

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ig. 3. Positive immunohistochemical stains (Synaptophysin, Chromogranin, CD56,53, P16 and PR).

16 revealed 70–90% staining with 3+ intensity, estrogen recep-or (ER) was negative, progesterone receptor (PR) was positiveFig. 3).

Postoperatively, the patient’s course was complicated by auperficial wound infection and separation. She was treated withntibiotics, discharged home, and was planned to receive com-

ination chemotherapy with etoposide, cisplatin and octreotide.n the 32nd post-operative day, she expired due to recurrentalignant ascites and acute renal failure secondary to her malig-

ancy.

lls are arranged in sheets without a defined border. Individual cells are large withous mitotic figures and apoptotic bodies are seen, as well as multiple, interspersed

3. Discussion

3.1. Definition

LCNEC is an extremely rare malignancy of the uterus, most oftenfound in the cervix and/or ovaries and more commonly of the smallcell neuroendocrine type. The WHO defines small-cell carcinoma asan undifferentiated carcinoma with cellular and nuclear featureswhich include small-sized cells, scant cytoplasm, hyperchromatic,finely granular and molded nuclei and inconspicuous nuclei.4 Incontrast, large cell carcinoma is defined as undifferentiated largecells that lack cytologic and architectural features of small cell car-cinoma and glandular or squamous differentiation.4 More simply,LCNEC are defined as malignant tumors composed of large cellsthat show neuroendocrine differentiation.6 All reported large cellcarcinomas of the uterus have contained neuroendocrine features.

3.2. Presentation

The median age at diagnosis for all cases of endometrial LCNECis 71 years (range 40–88 years). In the current case, the 71-yearold patient presented with postmenopausal vaginal bleeding aswas common among all prior reports. On endometrial sampling,the biopsy was not suggestive of a neuroendocrine carcinoma;

the usual differential diagnosis for such a specimen includes type2 tumors such as undifferentiated carcinoma or mesenchymaltumors such as sarcoma or mixed mullerian tumor based onimmunohistochemical staining.

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CASE REPORT54 M.-L.T. Nguyen et al. / International Jou

.3. Imaging

Preoperatively, imaging was obtained to evaluate for metastaticisease. Preoperative MRI, performed without intravenous gadolin-

um secondary to the patient’s renal function, demonstrated diffusebnormal infiltrative myometrial signal throughout the uterus withoss of the normal uterine architecture. This diffusely infiltrativerocess extended along the broad ligament to the left adnexand demonstrated restricted diffusion suggestive of a hypercel-ular process. Conglomerate right external iliac lymphadenopathynd paraaortic lymphadenopathy also with restricted diffusion wasresent. These findings were suggestive of a uterine sarcoma.

In another report by Makihara et al., the MRI findings of LCNECeem to mimic MRI findings found in other poorly differentiatedndometrial adenocarcinomas and uterine sarcomas.7 A gyneco-ogic exam, endometrial sampling and MRI should be included inhe initial workup of a suspected uterine LCNEC.

.4. Surgical management

The most common initial management of LCNEC is cytore-uctive surgery, based on prior published reports. Typically, aysterectomy and bilateral salpingo-ophorectomy are performedt minimum. In one reported case where a biopsy confirmed widelyetastatic disease, the patient did not undergo surgery and died.7

post-mortem autopsy then confirmed LCNEC of the uterus.7

lthough several case reports have noted an early stage at the timef surgery, many of these patients went on to have distant metasta-is and/or rapid recurrence. In cases where only TAH and BSO wereerformed without lymph node dissection, stage III disease mayave been missed. Though there is no surgical standard for thisare histology, most patients will undergo hysterectomy presumedigh grade sarcoma or carcinoma that is in fact LCNEC. If a LCNECan feasibly be diagnosed on a preoperative endometrial biopsy orurettage specimen, providers may want to consider neoadjuvantherapy versus primary surgery as is done in advanced cases ofvarian cancer. Although complete surgical staging with omentec-omy and pelvic and paraaortic lymphadenectomy is required forccurate staging of uterine cancer, treating physicians may wanto asses the patient’s response to chemotherapy first, since surgeryas not been proven to be entirely beneficial in most cases.

.5. Pathology

Because LCNEC can sometimes be mixed with other histolog-cal types, they can be easily dismissed as poorly differentiatedndometrioid carcinomas and are likely underreported. Histogeni-ally, LCNEC of the uterus most likely arises from neuroendocrineells of the endometrium.1 Grossly, the typical finding is a polypoidass confined to the endometrium in stage 1 disease.1–5 The patho-

ogic features typically include high grade scant stroma, ulceration,xtensive tumor necrosis, and a trabecular, organoid, palisadingr rosette-like growth pattern.1–3,5 In the majority of cases, theollowing cellular features of abundant cytoplasm with a granularosinophilic or basophilic appearance, large nuclei, small but fre-uent nucleoli and mitotic rates > 10 per 10 HPF were observed.1–7

.6. Immunoprofile

The most useful tool for diagnosing uterine LCNEC is themmunohistochemical profile. Neuroendocrine differentiation inCNEC of the uterus can be confirmed by staining for synapto-

hysin, chromogranin and CD56. A summary of previous reportsuggests that two of the three tumor markers may confirm

diagnosis of LCNEC. Cervical LCNEC may express neuroen-ocrine markers with approximately 25 to 38% of cases expressing

PEN ACCESS Surgery Case Reports 4 (2013) 651– 655

chromogranin and synpatophysin.9–12 In the present case, thetumor was diffusely strongly positive for all three markers. Ear-lier case reports suggest that neuron-specific enolase (NSE) may bea sensitive marker but may not be as useful for diagnosis.1,2,7

3.7. Adjuvant therapy

In previous reports on uterine LCNEC, adjuvantchemotherapy1–3,5–7 and/or radiation1,2,6 was either performed orplanned. There is limited data to guide treatment for LCNEC of theuterus or cervix. No prospective trials exist for uterine LCNEC oreven for SCNEC of the cervix. Currently there is no consensus as tothe optimal management of these tumors. Like LCNEC of the cervix,LCNEC of the endometrium requires a multi-modality approach.Most physicians will favor surgery, followed by chemother-apy, radiation or both. The patient in this report was optimallydebulked to no gross residual disease, but she still recurred withinone month of surgery and succumbed to her disease. Octreotide,a synthetic somatostatin analog, was planned for the patient inthe present case. Two other case reports have reported its use forneuroendocrine tumors, one case demonstrating a partial responseand the other with progression of disease.6,13 Given this aggressivecourse and poor prognosis, perhaps surgeons who are able topreoperatively diagnose LCNEC of the endometrium should con-sider neoadjuvant chemotherapy and/or therapy with octreotideprior to surgery. Platinum and Etoposide based chemotherapyis generally used as adjuvant therapy, and this data is largelyextrapolated from SCNEC of the lung since data for cervical anduterine neuroendocrine tumors is limited.14

3.8. Prognosis

Even for early stages, LCNEC of the endometrium appears to havean aggressive course with a strong propensity for distant metastasisand rapid recurrence. No prognostic data is available for LCNEC ofthe uterus or cervix. The best available survival data is from smallcell neuroendocrine carcinoma (SCNEC) of the cervix. One small,retrospective study showed that the estimated 3-year progressionfree survival (PFS) and overall survival (OS) rates for cervical SCNECwere 22% and 30%, respectively8. The median time to progressionwas 9.1 months and the extent of disease was the only signifi-cant prognostic factor.8 In the same study, patients who receivedplatinum-based chemotherapy had both a 3-year recurrence-freesurvival (RFS) and a 3-year overall survival (OS) of 83%.8 In patientswho did not receive chemotherapy, the RFS and OS were 0% and20%, respectively.8 In our review of all reported cases of uterineLCNEC, six out of 13 patients died of their disease. Of these six,only two received chemotherapy and four were dead of diseaseby five months, two of whom were early stage (IC) at diagnosis(Table 1). Of the seven patients who are reported to be alive withLCNEC, four received platinum-based chemotherapy, two receivedradiotherapy only, and one received no further treatment (Table 1).Of all 13 reported cases, eight patients presented with advancedFIGO stage III or IV disease. Based upon these reported cases, theremay be some benefit to chemotherapy in LCNEC. Again, providersmay consider administering neoadjuvant chemotherapy when apreoperative diagnosis of uterine LCNEC is possible, given the poorprognosis of the disease even after surgical debulking.

3.9. Classification

Endometrial LCNEC is a rare entity which is often likelyunder-reported and misdiagnosed. When LCNEC of the uterusis diagnosed, whether treatment should proceed as suggestedin earlier reports is questionable. Although the data on LCNEC

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CASE REPORTM.-L.T. Nguyen et al. / International Jour

s limited, endometrial LCNEC appears to behave very aggres-ively, akin to type II uterine cancers. In brief, type II cancers ofhe endometrium typically present in older-aged, postmenopausalomen, are unrelated to unopposed estrogen, have P53 muta-

ions, have poorly-differentiated and non-endometrioid histology,resent with stage 3 or 4 disease, and have an unfavorablerognosis.15,16 All of the above were true of the patient in theresent case. Most, if not all, of these same elements were alsoound in the 12 other cases of endometrial LCNEC listed in thiseview (Table 1).

. Conclusion

The presentation of endometrial LCNEC can mimic uterinearcoma with postmenopausal or abnormal uterine bleeding. Pre-perative imaging with MRI can be useful in assessing the extentf disease. Cytoreductive debulking and surgical staging is typ-cally performed for diagnostic and staging accuracy. Commonathological findings and a typical immunohistochemistry profilesynptophysin, chromogranin and CD56) are paramount in mak-ng a diagnosis of uterine LCNEC. In theory, a diagnosis of LCNEC

ay be made preoperatively with immunohistochemistry. If thiss the case, surgeons may consider neoadjuvant chemotherapy

ith etoposide and a platinum agent followed by surgical cytore-uction. Adjuvant therapy should consist of a similar regimen,lthough prognosis even with early stage disease and adjuvantherapy appears to be poor. LCNEC of the endometrium behavesimilarly to other type II uterine cancers and should be classifieds such. Due to the rarity of this aggressive malignancy, more datas needed to establish incidence. Clinicians are urged to report anyew cases and may need to rely on case reports and reviews touide treatment.

onflict of interest statement

The authors have no conflicts of interest to declare.

unding

None.

thical approval

Written informed consent was obtained from the patient forublication of this case report and accompanying images. A copyf the written consent is available for review by the Editor-in-Chieff this journal on request.

uthor contributions

My-Linh Nguyen is the primary author of manuscript, data col-ection, drafting of full article, final approval. Liying Han involved

n drafting of the following manuscript sections: case presentation,athology, immunoprofile, concession of images and final approval.njoinette Minors involved in data collection, drafting of the fol-

owing manuscript sections: Introduction, Definition, editing of full

1

PEN ACCESS Surgery Case Reports 4 (2013) 651– 655 655

article. Stuart Bentley-Hibbert involved in drafting of the follow-ing manuscript sections: Case presentation, Imaging; concessionof images and final approval. Tana Pradhan involved in draftingof the following manuscript sections: Case presentation, Surgicalmanagement, Adjuvant treatment; classification and final review.Tarah Pua and Tana Pradhan involved in drafting of the follow-ing manuscript sections: Case presentation, Surgical management,Adjuvant treatment; classification and final review. Sean Tedjaratiis primary surgeon for present case and involved in drafting of thefollowing manuscript sections: Case presentation, Surgical man-agement, Adjuvant treatment; classification and final approval.

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