Combined large cell neuroendocrine carcinoma and papillary serous carcinoma of the endometrium with pagetoid spread.
Abstract: Neuroendocrine carcinomas of the endometrium are rare tumors that can be pure, combined with endometrioid adenocarcinoma, or a component of malignant mixed muilerian tumor. Recently, a case of combined small cell carcinoma and papillary serous carcinoma of the endometrium was described for the first time. We report the first case, to our knowledge, of combined large cell neuroendocrine carcinoma and papillary serous carcinoma of the endometrium, with an unusual pagetoid spread of the neuroendocrine component into normal endometrial and endocervical glands. The endometrial carcinoma had a small serous component, but most of the tumor was characterized by solid sheets of medium to large cells with abundant mitotic figures, numerous apoptotic bodies, and foci of necrosis. This component was diffusely positive for neuroendocrine markers. Following surgery, the patient was treated with radiation therapy and chemotherapy. She was without evidence of progression at 5 months of follow-up.
Article Type: Report
Subject: Carcinoma (Care and treatment)
Carcinoma (Case studies)
Cancer (Care and treatment)
Cancer (Case studies)
Radiotherapy (Methods)
Papillary muscles (Medical examination)
Endometrium (Medical examination)
Authors: Posligua, Lorena
Malpica, Anais
Liu, Jinsong
Brown, Jubilee
Deavers, Michael T.
Pub Date: 11/01/2008
Publication: Name: Archives of Pathology & Laboratory Medicine Publisher: College of American Pathologists Audience: Academic; Professional Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2008 College of American Pathologists ISSN: 1543-2165
Issue: Date: Nov, 2008 Source Volume: 132 Source Issue: 11
Topic: Canadian Subject Form: Neuroendocrine tumours; Neuroendocrine tumours
Geographic: Geographic Scope: United States Geographic Code: 1USA United States
Accession Number: 230246873
Full Text: Although mixed endometrial carcinomas with a neuroendocrine component are rare, (1,2) combined neuroendocrine carcinoma and papillary serous carcinoma of the endometrium is even more unusual. (3) We report the first case, to our knowledge, of a mixed large cell neuroendocrine carcinoma and papillary serous carcinoma of the endometrium, which had pagetoid spread of the neuroendocrine component into benign endometrial and endocervical glands. The morphologic pattern and immunohistochemical findings support a diagnosis of a primary endometrial tumor with divergent differentiation.


Clinical History

The patient was a 59-year-old woman (gravida 2, para 2), with a medical history significant for breast cancer diagnosed 8 years before presentation. She had been treated with a lumpectomy and axillary lymph node dissection, radiation, and chemotherapy. She had taken tamoxifen for 5 years, and her follow-up mammograms and breast ultrasound study results were normal. The breast specimen and pathology report were not available for our review.

The patient had a routine Papanicolaou test, which contained cells interpreted as atypical glandular cells of undetermined significance. This was followed by a loop electrocautery conization and dilation and curettage, which established a diagnosis of mixed serous and poorly differentiated carcinoma. A 1-cm nodule was found in the left vaginal wall on examination. A biopsy of this nodule was diagnosed as metastatic high-grade neuroendocrine carcinoma. A modified radical hysterectomy with bilateral salpingo-oophorectomy, omentectomy, and pelvic-aortic lymph node dissection was then performed. The vaginal lesion was incompletely excised because it extended into underlying soft tissue.

The uterus contained high-grade endometrial carcinoma, predominantly neuroendocrine carcinoma, with a serous component. The fallopian tubes, ovaries, omentum, and lymph nodes were negative for tumor. A pelvic washing performed during surgery was negative for malignant cells. The tumor stage was FIGO (International Federation of Gynecologists and Obstetricians) IIIB.

The residual vaginal lesion was treated with whole-pelvic radiation therapy and brachytherapy. The patient is currently receiving chemotherapy and was without evidence of progression at her 5-month follow-up visit.


Immunohistochemical studies were performed using the avidin-biotin-peroxidase method, with antisera to p53, p16, neuron-specific enolase, CD57, synaptophysin, chromogranin, and CD56. Antibody information and the immunohistochemical profiles of the neuroendocrine and papillary serous components are summarized in the Table.


The radical hysterectomy specimen consisted of a 2.02-kg uterus (12.5 X 7.2 X 5.0 cm) with attached unremarkable adnexae. The cervix was stenotic, with the ectocervix covered by tan, irregular mucosa. The endometrial lining was white-tan and diffusely friable; an area suggestive of myometrial invasion was seen. The fallopian tubes and ovaries were unremarkable.

On microscopic examination, most of the endometrial tumor was characterized by solid sheets of medium to large polygonal cells with scant to moderate amphophilic cytoplasm, foci with cords and trabeculae (Figure, A inset), and focal pseudorosette formation. There were abundant mitotic figures (up to 19 mitoses per 10 high-power fields), numerous apoptotic bodies (Figure, A), and foci of geographic necrosis. Nuclear molding and crush artifact were focally present, and some of the large cells were multinucleated. A small area of papillary serous carcinoma was present (Figure, A, B, and B inset). The serous carcinoma was surrounded by the poorly differentiated component, but a definitive transition between the elements was not seen (Figure, A and B). The poorly differentiated component also surrounded benign endometrial glands. Within some benign endometrial and endocervical glands, pagetoid spread of the poorly differentiated cells was identified (Figure, C, C inset, and D inset). This pagetoid involvement was characterized by tumor cells located between the normal endocervical or endometrial epithelium and the basement membrane. Involved endocervical glands were found up to 3 mm away from the main tumor. The poorly differentiated component invaded 0.9 cm into a 2.1-cm-thick myometrium; there was extensive lymph vascular-space invasion and focal involvement of the cervical stroma. No heterologous or sarcomatous components were identified.


The poorly differentiated carcinoma component was present in the vaginal specimens. The adnexae, omentum, and right and left pelvic and paraaortic lymph nodes were free of tumor.

The immunohistochemical results are summarized in the Table. The poorly differentiated component was diffusely positive for synaptophysin (Figure, D), with scattered staining for CD56, CD57, and neuron-specific enolase; chromogranin was negative. This immunohistochemical staining pattern, together with the histologic features, was diagnostic of large cell neuroendocrine carcinoma. The neuroendocrine carcinoma cells with pagetoid involvement of the endocervical glands were also positive for synaptophysin (Figure, D inset). The serous component was negative for the neuroendocrine markers, whereas p53 was overexpressed.


Neuroendocrine carcinomas of the endometrium are aggressive tumors, usually presenting in perimenopausal or postmenopausal women with a mean age of 60 years, 1 decade later than endometrioid carcinomas. (4) Abnormal uterine bleeding is the most frequent initial complaint. (1,2) Neuroendocrine carcinomas are often polypoid bulky tumors that are deeply invasive. Histologically, they can be pure small cell carcinoma or large cell carcinoma, admixed with endometrioid adenocarcinoma, or a component of a malignant mixed mullerian tumor. (1,2) The invasive component is generally the neuroendocrine carcinoma, but intermixed neuroendocrine and nonneuroendocrine components can also be present. (1) The presence of neuroendocrine features in an endometrial carcinoma appears to be associated with an increased frequency of deep myometrial invasion, metastasis to distant organs, and decreased survival. (5) Although both neuroendocrine and glandular components can be found in metastases, metastasis of the neuroendocrine component alone appears to be most common. (3)

Large cell neuroendocrine carcinomas have been previously described in the cervix and ovary and, morphologically, resemble large cell neuroendocrine carcinomas in other organs. They are characterized by large polygonal tumor cells, with organoid, trabecular, or cordlike growth patterns. Peripheral palisading, necrosis, vesicular nuclei, and frequent mitotic figures and apoptotic bodies are characteristic. (6) The diagnosis is confirmed by immunohistochemical staining for neuroendocrine markers.

There are only 2 previous reports, to our knowledge, of combined neuroendocrine carcinoma and papillary serous carcinoma: one (3) described a composite papillary serous carcinoma and small cell carcinoma of the endometrium, and the other (7) described a collision tumor with serous carcinoma and carcinoid tumor involving the mesentery. The endometrial tumor, in a 79-year-old woman with postmenopausal bleeding, was composed of several small polypoid lesions. Histologically, papillary serous carcinoma and small cell neuroendocrine carcinoma components were present. The serous component was present at the endometrial surface and deeply invaded the myometrium; the small cell component was only identified in the invasive tumor. (3)

The second tumor, in a 70-year-old woman with a history of colonic mucinous carcinoma, consisted of several nodules in the mesentery of the distal ileum. (7) On microscopic examination, the nodules were found to be composed of an admixture of carcinoid tumor and serous carcinoma. This was interpreted as a collision tumor after the serous carcinoma and the neuroendocrine carcinoma showed loss of heterozygosity on chromosomes 4q and 17 but involvement of different alleles at the same locus. (7)

Although controversial, it appears that there is an association between tamoxifen therapy and high-grade and advanced-stage endometrial tumors. Compared with sporadic tumors, there is an increased risk of poorly differentiated, nonendometrioid carcinomas and malignant mixed mullerian tumors. (8) This association appears to be time and dose dependent, and the risk of developing endometrial tumors remains even after discontinuation of tamoxifen. In patients who have had tamoxifen treatment, the median time to diagnosis of endometrial tumors is 40 months after the breast carcinoma diagnosis. (8)

In the only previously reported case of primary carcinoid tumor of the uterine corpus in a patient receiving tamoxifen therapy for breast cancer, the duration of treatment was not mentioned. Most likely, there is no causal relationship between tamoxifen therapy and uterine neuroendocrine carcinomas, but given the rarity of uterine neuroendocrine tumors and the reported concomitant exposure to tamoxifen in 2 cases, including our case, an association is difficult to rule out. (9)

To our knowledge, the current case is the first reported combined endometrial large cell neuroendocrine carcinoma and papillary serous carcinoma. Although the carcinoma in this case could be a collision tumor, it seems most likely to be a combined carcinoma with 2 distinct lines of differentiation because the 2 components were intimately admixed, both were positive for p53 and p16, and no other primary tumor was identified. The neuroendocrine and serous components may both have arisen from pluripotential cells that differentiated along 2 distinct paths, or the neuroendocrine carcinoma could have arisen secondarily from the serous cells. Given that combined serous and neuroendocrine carcinomas are rare and that mullerian tumors with divergent differentiation are comparatively common, the former seems more likely.

Epithelial pagetoid extension of neuroendocrine carcinoma has been recognized in tumors involving the anal canal and urethral mucosa and in Merkel cell carcinomas of the skin, (10-12) but, to our knowledge, epithelial pagetoid extension has not been reported previously in neuroendocrine tumors of the endometrium or cervix. In this case, pagetoid spread was identified in benign endometrial glands and in endocervical glands located at least 3 mm from the main tumor. This phenomenon is of interest because it could potentially lead to incomplete resection of a tumor. Neuroendocrine carcinoma did involve the vaginal apex in this case, although we did not identify pagetoid extension in the ectocervical sections examined. High-grade neuroendocrine carcinoma with pagetoid spread should also be included in the differential diagnosis of cervical melanomas because it could mimic melanoma with an in situ component.

In summary, we have reported a case of combined large cell neuroendocrine carcinoma and serous carcinoma of the endometrium, with pagetoid extension of the neuroendocrine component into benign endometrial and endocervical glands. This case further expands the known range of endometrial neuroendocrine carcinomas.

Accepted for publication April 2, 2008.


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Lorena Posligua, MD; Anais Malpica, MD; Jinsong Liu, MD, PhD; Jubilee Brown, MD; Michael T. Deavers, MD

From the Departments of Pathology (Drs Posligua, Malpica, Liu, and Deavers) and Gynecologic Oncology (Dr Brown), The University of Texas M. D. Anderson Cancer Center, Houston.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Michael T. Deavers, MD, Department of Pathology, Unit 85, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 (e-mail:
Summary of Immunohistochemical Staining *

Marker    Clone        Dilution    Source       Treatment   Component

p53       DO-7         1:100       Dako,        Citrate     D; D

p16       16P04        1:25        Lab          Citrate     D; D

NSE       Polyclonal   Predilute   Dako,        No          F; N
                                   Carpin-      pretreat-
                                   teria        ment

CD57      HNK-1        1:40        Becton       Tris        F; N
                                   San Jose,

Synapto   Sy 38        1:200       Dako,        Citrate     D; N

Chromo    LK2H10       1:4000      Chemicon,    Citrate     N; N

CD56      123C3        1:50        Zymed        Citrate     F; N
                                   Inc, South

* NSE indicates neuron-specific enolase; Tris, tris(hydroxymethyl)
aminomethane; synapto, synaptophysin; and chromo, chromogranin.

([dagger]) Distribution of staining: F indicates focal
(<50%); D, diffuse (>50%); and N, negative.
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