Case Report

Small-Cell Carcinoma in Association With aMature Cystic Teratoma of the Ovary:A Case Report With Literature ReviewKarina E. Hew,1 Kimberley Studeman,2 Panayotis Ledakis,3

Arvind Bakhru,4 Neil B. Rosenshein1

Clinical Practice Points

� Malignant transformation of mature cystic teratoma(MCT) is a rare event, occurring in 1% to 2% of cases.Small-cell carcinoma arising from an MCT is particu-larly rare, with only 3 other cases described in theEnglish literature.

� We report a case of a 54-year-old para 1 female whowas found to have advanced-stage small-cell carci-noma of the ovary in association with a MCT. Theclinicopathological features, treatment regimen, andoutcome of this patient were compared with the other

cases described in the literature to evaluate theprognostic significance of this unusual subtype ofovarian cancer.

� Small-cell carcinoma of the ovary arising from amature cystic teratoma is a rare form of ovariancancer. It is usually of the pulmonary subtype andis treated with the same chemotherapeutic regimenas small-cell lung cancer. The prognostic signifi-cance of this unusual cancer subtype remainsuncertain.

Clinical Ovarian and Other Gynecologic Cancer, Vol. 6, No. 1/2, 53-7 ª 2014 Elsevier Inc. All rights reserved.Keywords: Dermoid cyst, Malignant transformation, Mature cystic teratoma, Ovarian cancer, Small cell cancer of the ovary

IntroductionMalignant transformation of a mature cystic teratoma (MCT)

is a well-documented event that occurs in 1% to 2% of cases ofMCTs undergo malignant transformation.1-3 The most commonmalignancies arising from MCTs are squamous cell carcinomas,accounting for 80% to 90% of cases.4,5 Malignant transformationinvolving small-cell carcinoma of the ovary is particularly rare, withonly 3 cases reported in the English literature.6-8 Primary small-cellcarcinoma of the ovary can be divided into a pulmonary and ahypercalcemic type.9 The hypercalcemic type is thought to bepresent in two-thirds of cases.10 They demonstrate aggressive bio-logic behavior and high rates of local and distant recurrence. Theseneuroendocrine carcinomas are thought to have poor prognoses.11,12

1Department of Obstetrics and Gynecology, The Gynecologic Oncology Center2Department of Pathology3Department of Medical Oncology and HematologyMercy Medical Center, Baltimore, MD4Department of Obstetrics and Gynecology, University of Michigan ComprehensiveCancer Center, Ann Arbor, MI

Submitted: Mar 18, 2013; Revised: Sep 8, 2013; Accepted: Dec 18, 2013; Epub:Dec 27, 2013

Address for correspondence: Karina E. Hew, MD, The Gynecologic Oncology Center,Weinberg Building, 6th Floor, Mercy Medical Center, 301 St Paul Place, Baltimore,Maryland 21202E-mail contact: karinahew04@hotmail.com

2212-9553/$ - see frontmatter ª 2014 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.cogc.2013.12.006

It has also been put forward that malignant transformation of anMCT, particularly to squamous cell carcinoma, carries a worseprognosis than primary squamous cell carcinoma of the ovary.13,14

However, little is known about the natural history, optimal treat-ment regimens, or prognosis when an MCT undergoes trans-formation to a small-cell carcinoma of the ovary.

Case DescriptionThe patient is a 54-year-old gravida 1 para 1 married white

female who originally presented in February 2010. She presentedwith a 1-month history of abdominal pain and increased abdominalgirth. A computed tomography scan of her abdomen and pelvisrevealed a 15 � 10 � 13-cm right pelvic mass and ascites. A par-acentesis was performed resulting in 4 L of bloody, cloudy perito-neal fluid with atypical cells and increased nuclear cytoplasmic ratio.Her cancer antigen 125 serum level was 519 U/mL. Abnormalphysical findings were confined to the abdomen, which was grosslydistended, with left lower quadrant tenderness, present bowelsound, and a positive fluid wave result with shifting dullness.Imaging studies did not reveal any overt distant metastases.

The patient underwent an optimal primary debulking proce-dure. She had an uneventful intraoperative course and received2 units of packed red blood cells. An intraoperative frozen-section

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Small Cell Carcinoma of the Ovary Within a Dermoid Cyst

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diagnosis revealed an undifferentiated carcinoma arising from amature cystic teratoma.

The final pathology report described a small-cell carcinomaarising in association with an 18-cm mature cystic teratoma of theright ovary. There was microscopic involvement of the diaphragm,omentum, and periaortic nodes, and the cancer was classified asInternational Federation of Gynecology and Obstetrics stage IIIC.Angiolymphatic invasion was present.

The patient had an uneventful postoperative course and receivedsix cycles of adjuvant chemotherapy with carboplatin and etoposide.She did not suffer any significant toxicity from the chemotherapy,with the exception of grade 1 myelosuppression and neuropathy.The patient never exhibited any laboratory or clinical sign ofhypercalcemia throughout her presentation. She currently exhibitsno evidence of recurrence at 33 months since her surgery.

Pathologic DescriptionGross Features

The right ovary and fallopian tube weighed 278 g and includedan intact right ovary measuring 18.0 � 13.5 � 11 cm with amottled pink-purple surface. Serial sections of the ovarian massrevealed a multiloculated and fleshy cut surface, with the cystscontaining thin, clear fluid, yellow gelatinous material, and gray-white grumous material with associated strands of hair. Areas ofsoftening consistent with necrosis were identified (Fig. 1).

Microscopic DescriptionThe malignant neuroendocrine population comprised approxi-

mately 90% of the ovarian tumor mass. The residual teratomatouscomponent consisted of ectodermally derived epithelium, skinadnexal structures, and intestinal epithelium. Definite bronchialepithelium was not identified. Immature teratomatous elementssuch as embryonic tissues or primitive neural tissue were not seen,nor were malignantly transformed mature elements other than thosedescribed in Figure 2.

Figure 1 Intraoperative Photograph of the Sectioned 18-cmRight Ovarian Mass. The Image Shows the Mass WithSolid Firm Fleshy tan Areas, Cystic Cavities FilledWith Clear Greenish-brown Fluid, and GrumousMaterial With Strands of Hair

Clinical Ovarian and Other Gynecologic Cancer December 2013

In sections from the ovarian mass, large areas of tumor necrosiswere identified, and sheets of undifferentiated malignant cells witha high nuclear-cytoplasmic ratio, nuclear molding, and some largercells with small nucleoli, in sheets, trabeculae, and islands, in abackground of teratomatous elements were observed. Mitotic fig-ures were abundant. Follicle-like structures were not seen. Withinthe fallopian tubal lumen, malignant neuroendocrine tissue frag-ments were identified. Small-cell carcinoma was also identified inthe alcohol-fixed Papanicolaou-stained cytologic preparation fromthe diaphragmatic smear, the omentum, para-aortic lymph nodes,and the nodule on the right infundibular pelvic ligament. Of 3 para-aortic lymph nodes, 2 had metastatic deposits, the largest measuring2.5 cm with extranodal tumor extension into soft tissue identified.

Immunohistochemical FeaturesThe malignant cell population was labeled with CD56 (neural

cell adhesion molecule [NCAM], the prototypic natural killer cellmarker; most neuroendocrine cells and tumors with neurosecretorygranules express NCAM protein) (Fig. 3), chromogranin, andsynaptophysin (the latter with weak granular cytoplasmic staining)(Fig. 4A and 4B). Chromogranin A remains the single most specificmarker of neuroendocrine differentiation, labeling the cytoplasmicchromogranin protein stored in secretory granules. Synaptophysin,a calcium-binding glycoprotein, is the most abundant membraneprotein in synaptic vesicles of neurons, and is present in neuroen-docrine neoplasms. The Ki-67 (mindbomb E3 ubiquitin proteinligase 1 [MIB-1]) index was high (> 90%), which is generallyassociated with aggressive clinical behavior (Fig. 5). Immunostainresults were negative for intermediate filaments of cytokeratins7 and 20 and thyroid transcription factor 1 (TTF-1).

DiscussionMCTs are a common neoplasm of the ovary accounting for 10%

to 20% of all ovarian tumors2,15 and occur most commonly inthe fifth to sixth decade of a patient’s life.4,13,14 However, only 1%to 2% of MCTs undergo malignant transformation,2,3,16 and the

Figure 2 Small-Cell Carcinoma With High Nuclear-CytoplasmicRatio, Nuclear Molding, Karyorrhexis, and Populationof Larger Cells With Nucleoli

Figure 3 CD56 Crisp Membranous Labeling With Neural CellAdhesions Molecules

Figure 5 Brisk Ki-67 (MIB0-1 Immunostain) ProliferationIndex

Karina E. Hew et al

majority of these are squamous cell carcinomas.4,5 However, therehave been only 3 case reports in the English literature of small-cellcarcinoma of the ovary arising from a MCT.6-8 In contrast, primarysmall-cell carcinomas of the ovaries are described more frequentlyin the literature and have been subclassified into pulmonary and hy-percalcemic subtypes.9 These 2 subtypes have characteristic pathologic,ultrastructural, flow cytometric, and immunohistochemical features.

Attempts at distinguishing between ovarian small-cell carcinomaof the hypercalcemic type and pulmonary type utilizes clinical in-formation including patient age, serum calcium levels, and whethertumor is unilateral or bilateral.9 Histologic features includingthe presence of follicular spaces; the presence of a large-cell com-ponent; and the presence of an associated endometrioid, mucinous,or Brenner tumor are utilized to help classify the 2 entities.9,10

Additionally, vimentin expression and DNA content are examinedby flow cytometry.9

This patient exhibited mixed features of both the pulmonaryand hypercalcemic subtype. Her age, the absence of postopera-tive elevated serum calcium levels, and the lack of follicle-likespaces favored a pulmonary subtype. However, the presence of apopulation of large cells with prominent nucleoli and no associated

Figure 4 Cytoplasmic Secretory Granules Show Positive Immunohisto

Brenner or endometrioid component were more indicative of thehypercalcemic type. Although no bronchial epithelium was identi-fied, it is postulated that small-cell carcinoma arose from a malig-nant transformation of a mature element within the teratoma. Thiswas similar to the findings noted by Chang et al, where bronchialepithelium was also not identified among the mature teratomatouselements.8 In the case report by Ikota et al, it was postulated thatthe adenocarcinoma arose from an intestinal epithelium in theteratoma, which then differentiated into pulmonary type small-cellcarcinoma among other types of carcinomas.6

Primary small-cell carcinomas of the ovary have been welldescribed in the literature and arise in the background of epi-thelialestromal tumors.9 These tumors exhibit aggressive biologicalbehavior with frequent relapses; they are usually treated with amultidisciplinary approach using combined surgery, chemotherapy,and occasionally radiation. There is no randomized study of thesetumors, and the majority of data originate from institutionalexperience and case series.11,17,18 The actual optimal sequence ofvarious treatment modalities such as adjuvant versus neoadjuvantsystemic chemotherapy has not been determined. In most cases,patients have received multiple cycles of platinum-based

chemistry Staining for (A) Synaptophysin and (B) Chromogranin A

Clinical Ovarian and Other Gynecologic Cancer December 2013 - 55

Table 1 Small-Cell Carcinomas Arising in Association With a Mature Cystic Teratoma

Authors Stage (FIGO) Ovary Site Size, cm Histologic Subtype Treatment Survival, months Prognosis

Hew et ala IIIC Right 18 Mixed Surgery þ etoposide/carboplatin � 6 cycles

33 NED

Ikota et al6 IA Left 12 Pulmonary Surgery 10 NED

Lim et al7 IV Left 28 Pulmonary Surgery þ etoposide/bleomycin/cisplatin � 6 cycles

34 NED

Chang e al8 IA Left 20 Pulmonary Surgery þ cisplatin/doxorubicin (Adriamycin)/cyclophosphamide � 8 cycles

84 NED

Abbreviations: FIGO ¼ International Federation of Gynecology and Obstetrics; NED ¼ no evidence of disease.aIndex case.

Small Cell Carcinoma of the Ovary Within a Dermoid Cyst

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chemotherapy in the adjuvant setting, with or without concomitantradiation therapy.11,14,17,18 One study looked at a fertility-sparingapproach to treating advanced-stage, primary, small-cell ovariancancer with a disease-free survival of � 60 months.19 Whereas mostpatients appear to have tolerated multiagent chemotherapy well,the risk of long-term toxicity, such as the incidence of myelodys-plastic syndromes and secondary bone marrow neoplasias, is recog-nized in small-cell lung cancer and has not been studied in womenwith primary small-cell ovarian cancer.20

Because of the rarity of this type of malignant transformation, thetreatment has been similar to that of primary small-cell carcinoma ofthe ovary. Clinicopathological characteristics, treatment regimens,and clinical outcomes of the 4 cases that have been reported aresummarized in Table 1. All 4 patients, including our case, had acomplete response to treatment and showed no evidence of diseasewith follow-up periods ranging from 10 to 84 months. Chen et alfound that survival was significantly affected by cancer stage andoptimal cytoreduction in patients with malignant transformationof MCT.13 However, there was no patient with small-cell carcinomain their study population. More recent data from Sakuma et al, whostudied 20 cases of transformed malignancies of the ovary retro-spectively, suggested that postoperative chemotherapy with plat-inum and taxane combination could improve clinical outcomes.14

However, the majority of their patients had undergone trans-formation to a squamous cell carcinoma.

To our knowledge, our case of an exceedingly rare small-cellcarcinoma transformed from MCT of the ovary demonstrates oneof the longest reported remissions after cytoreduction and systemicchemotherapy with a platinum-based regimen. The combination ofetoposide and carboplatin that was used, is the standard treatmentfor small-cell lung cancer. Though, in fact our patient did not haveall the features of the pulmonary subtype.

The prognostic significance of this uncommon subtype of ovariancancer is difficult to discern, as there are only 4 reported cases,including the case reported in this article. Therefore, large population-adjusted epidemiologic studies should be implemented to furtherevaluate the clinical impact of this rare entity.18,21

ConclusionSmall-cell carcinomas of ovary arising from a malignant trans-

formation of an MCT are very rare entities, with only a few casesreported. Whether there are any differences in clinical outcomes

Clinical Ovarian and Other Gynecologic Cancer December 2013

between primary and transformed small-cell carcinoma of the ovaryremains uncertain. The optimal management of these tumors isnot well defined, although in most centers they are treated with amultidisciplinary approach that includes multiagent platinum-based chemotherapy. Although optimal cytoreduction remainsthe main treatment modality, we report a long-term follow-up ofa patient remaining in prolonged remission after postoperativechemotherapy with a small-cell lung cancerelike regimen. In thefuture, molecular characterization of these tumors may aid inthe design and implementation of more effective therapies for thistype of cancer.

AcknowledgmentsRoy Hatch, Librarian, Mercy Medical Center.

DisclosureThe authors have stated that they have no conflicts of interest.

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Small-Cell Carcinoma in Association With a Mature Cystic Teratoma of the Ovary: A Case Report With Literature ReviewIntroductionCase DescriptionPathologic DescriptionGross FeaturesMicroscopic DescriptionImmunohistochemical Features

DiscussionConclusionAcknowledgmentsDisclosuresReferences