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Small Cell Neuroendocrine Tumor of the Cervix – additional opinion

Short summary

36-year-old otherwise healthy female presented with an atypical pap smear. Biopsy of cervix revealed poorly Differentiated Neuroendocrine Carcinoma. Immunohistochemical staining showed the cells positive for NSE, SYN, CHR, and 90% positive for Ki67 (proliferative index). The findings of the PET-FDG test showed pathological absorption of FDG as a primary tumor of the cervix, towards the left side of the body. Moreover, evidence is seen of nodal metastatic spread in the retroperitoneum and pelvis, mainly on the left.

Patient's questions

The patient asks about the type and classification of her neoplasm, the prognosis, the treatment options and known trials.


Medical Background

Age: 36
Gender Female

Current Complaint:
The patient is a 36 year old female. She is married with no children, and is generally healthy. She is not currently taking any medication, has no known sensitivities to any medication, and has never undergone surgery in the past.
Family history: Diabetic mother.
Normal menstrual cycle. Approximately 1 year ago, the patient underwent an abortion at week 16 of pregnancy, due to fetal abnormalities.
Routine tests found atypical cells in Pap smear.
Cervix was biopsied, and found CX POORLY DIFF NEUROENDOCRINE CA.
Tests found the patient to be in a good general state.
Belly was tender, groin was normal.
PS+PV – found on outer labia, diameter about 3cm, papillary.
Not spread to vagina: Parametrium normal.
Findings were explained, as were treatment options (surgery, chemotherapy, radiation), including options to preserve fertility.

Urgent PET CT is required, to evaluate these findings.

Report – Pathology test results
Clinical details and Diagnosis
36 year old with suspected cervical cancer
General Comments:
Copy of results sent to Israel National Cancer Registry, Jerusalem


Sample Type: Biopsy
Sample Location: Cervix Uteri
Material Sample: Tissue

Macroscopic Description
The material arrived in a container bearing the patient’s name, in formalin, matching the name on the order forms.
Three (3) samples, each approximately 0.6cm..

Microscopic Description:
Endocervical samples, coated with columnar epithelium. In stroma, diffuse area of small to medium sized cells with little cytoplasm, grainy, with a neuroendocrine appearance. Many mitoses seen. Lesion was accompanied by dense lymphocytic infiltration. Immunohistochemical staining showed the cells positive for NSE, SYN, CHR, and 90% positive for Ki67 (proliferative index).
Negative CK MNF116, CK5/6, CK18, EMA staining.

In Summary: The patient is suffering from a poorly differentiated neuroendocrine carcinoma. Size of the cells is small to medium.

Cervical Biopsy
Poorly Differentiated Neuroendocrine Carcinoma

Tests Undergone:
Date of Test  06.09             
Description of Service - PET-FDG mapping, glucose marked

Disease History
Tumor of the cervix with poor differentiation, with neuroendocrine characteristics.

List of Questions

Tests and Results - Description
Whole body PET FDG test was done, to mid-thigh level. The test was done with Discovery LS and combines a PET and CT, mapping simultaneously with FDG and CT sections.

Telebrix was given to demonstrate the intestinal loops while mapping with CT.

Pathological absorption of FDG is present, showing hypodense lesions of diameter 1.7cm on the left of the posterior aspect of the cervix. This lesion is very similar to the primary tumor. This lesion is not well differentiated from the rectum.
Increased, though not overly large absorption was seen in the uterine cavity, which appears hypodense. This finding is not necessarily a tumor, and may be a hydrometra.

Pathological absorption present in lymph nodes in the retroperitoneum and in the pelvis. The cranial node shows over-absorption is at L2 level, by the superior mesenteric, diameter 1mm on the short axis. The more caudal , the more absorption at the lymph nodes, with diameters up to 1.1cm at the short axis, joint internal iliac nodal chain on the right, and a greater number on the left, up to a diameter of 1.1cm, in the internal iliac chain up to diameter 1.1cm, at the bifurcation of the iliac blood vessels on the left, with dimensions of 1.4*1.5cm, and in the large nodes of the external iliac nodal chain on the left, the largest one has dimensions of 2.9*2.5cm.

No pathological absorption was demonstrated to prove metastatic spread with the PET scan to the lung area, liver, spleen, adrenals and skeleton.

In Summary:
The findings of the test showed pathological absorption of FDG as a primary tumor of the cervix, towards the left side of the body. Moreover, evidence is seen of nodal metastatic spread in the retroperitoneum and pelvis, mainly on the left.


Medical opinion

The patient is a 36 year old G1 P0 Tab 1 woman who presented with an atypical pap smear.

No information on size of the cervix or if visible lesion present
Vagina no lesion
Parametrium no involvement
Biopsy of cervix: Poorly Differentiated Neuroendocrine Carcinoma
Immunohistochemical staining showed the cells positive for NSE, SYN, CHR, and 90% positive for Ki67 (proliferative index).
Negative CK MNF116, CK5/6, CK18, EMA staining.
Size of the cells is small to medium.
PET CT scan up take in cervix left parametria , and bilateral pelvic and parametrial nodes.

COMMENT: (I have summarized abstracts from the world‘s literature below)

This cervical cancer has been designated a poorly differentiated Neuroendocrine Carcinoma with small to medium cells. Pathologic diagnosis of these cancers can be tricky. Immunohistochemistry markers are used in the diagnosis of cervical neuroendocrine neoplasms, including small cell and large cell neuroendocrine carcinoma. Small cell neuroendocrine carcinomas may be negative with most of the commonly used neuroendocrine markers and this does not preclude the diagnosis. p63, a useful marker of squamous neoplasms within the cervix, is of value in distinguishing small cell neuroendocrine carcinoma (p63 negative) from small cell squamous carcinoma (p63 positive) and in confirming that a poorly differentiated carcinoma is squamous in type. (1)

Neuroendocrine small and large cell tumors of the cervix have been described.

If this malignancy is a small cell neuroendocrine carcinoma, it could also be classified as an extrapulmonary small cell carcinoma. Extrapulmonary small cell carcinomas (EPSCCs) are uncommon malignant neoplasms with a reported incidence of 0.1% to 0.4% in the United States. Since their first description in 1930, they have been seen in nearly every organ system. Like their more common pulmonary counterparts, EPSCCs are thought to arise from a multipotential stem cell. However, there is recent molecular evidence that small cell elements may arise as a late-stage phenomenon in the genetic progression of more organ-typical carcinomas. The morphologic, immunohistochemical, and ultrastructural features are similar to those described in pulmonary small cell carcinomas (PSCCs). The differential diagnosis of EPSCC includes PSCC, other neuroendocrine tumors, small round blue cell tumors, metastatic melanoma, lymphoma, and poorly differentiated non-small cell carcinomas. (2)

There is scant literature on neuroendocrine tumors of the cervix. These tumors are aggressive and spread in unusual patterns. Leptomeningeal carcinomatosis has been reported in case series. Most cervix cases had squamous cell (8/14) or neuroendocrine histologic subtype (3/14), and when reported, differentiation was usually poor. (3). A large cell neuroendocrine tumor with HPV 16 has been reported. The patient presented with lymph node metastases. (4)

Another case series reported on 5 patients with large-cell neuroendocrine carcinoma (LCNEC) of the uterine cervix who were adult females, with an average age of 57.3 years. The majority were multiparous, with the most common presenting complaint being vaginal bleeding. Three of the 5 patients presented with advanced-stage cervical carcinoma, with evidence of metastases in 2 of them. Treatment responses and long-term survival was poor as 3 of the 5 patients died in less than 6 months. On histopathological examination, all 5 tumors showed features of a high-grade poorly differentiated malignant neoplasm with ulceration and extensive tumor necrosis including trabecular and organoid growth patterns. All 5 neoplasms also showed strong immunoreactivity for MNF116, while their endocrine nature was confirmed by staining for synaptophysin in all cases. None of the tumors showed positive straining for chromagranin A. (5)

The overall prognosis is poor. Neuroendocrine carcinomas of unknown primary site have been reported and given the rarity of these tumors in the cervix, information on treatment and prognosis may be useful. Most of these carcinomas probably arise from an occult/clinically undetectable primary site in one of several locations (bronchus, pancreas, stomach, colon, rectum and several other sites). The high-grade or poorly differentiated carcinomas, including small cell and large cell neuroendocrine tumors, are rapidly growing and aggressive but responsive to platinum-based combination chemotherapy. A review of cytotoxic chemotherapy for patients with high-grade neuroendocrine carcinomas, including a series of 99 patients, revealed an overall response rate of 70%, with a 20% complete response rate. The median survival was 15 months, and a minority of patients (13%) had long-term survival. Tumor grade/differentiation currently is an important determinant of the management of these patients. (6)

A phase II trial with seventy-eight patients using four courses of chemotherapy with paclitaxel, carboplatin, and etoposide, administered at 3-week intervals followed by three courses (24 weeks) of weekly paclitaxel in patients with objective response or stable disease. 53% had major responses (complete response rate, 15%), and five patients remain disease free from 18 to 66 months after therapy. Response rates were similar regardless of histology (small-cell v poorly differentiated carcinoma) or primary site. The median, 2-year, and 3-year survivals for the entire group were 14.5 months, 33%, and 24%, respectively. Myelosuppression was the major toxicity (7).

Another prospective trial reported on the efficacy of biotherapy or chemotherapy in metastatic neuroendocrine carcinomas (NECs). The choice of therapy was based on the revised histological classification criteria of the WHO in an effort to define a standardized protocol for therapy of these cancers. Patients with well-differentiated NECs (WD-NECs; n=11) received therapy with octreotide long-acting release and interferon-alpha-2b for a maximum of 1 year; cases with poorly-differentiated NECs (PD-NECs; n=8) were given combination cisplatin, L-leucovorin and 5-fluorouracil chemotherapy for a maximum of 9 cycles. Five patients (4 with WD-NECs) had carcinoid syndrome. Among the patients with WD-NECs (median follow-up 20 months, range 4-40), 4 had partial responses and 7 had stable disease. In patients with PD-NECs (median follow-up 10.5 months, range 3-30), 3 had partial response, 2 stable disease, and the disease progressed in 3 cases. The 2-year survival rate in WD-NECs and PD-NECs was 88% and 66%, respectively. Grade 3-4 side-effects were limited to 9% thrombocytopenia and 12.5% neutropenia. (8)

In a final study, Eighteen patients with metastatic neuroendocrine tumors (excluding small cell carcinoma) were treated with irinotecan, 65 mg/m2, and cisplatin, 30 mg/m2, administered weekly for 2 of every 3 weeks. Only one radiologic response was observed among four patients with poorly differentiated neuroendocrine tumors. No radiologic responses were observed in 14 patients with well-differentiated tumors. The median overall survival duration of patients treated with this regimen was 11.4 months (9).

Surgery seems to only be considered after good response to chemotherapy (10).

I would recommend the following radiologic workup:
- MRI of the uterus to fully evaluate extent of disease and parametrial extension
- MRI of brain to rule out metastatic disease
- LABS: calcium. Some of the neuro-endocrine tumors are associated with hypercalcemia.
- Pathologic review for second opinion on pathology.

While the work up is going on, I would immediately start chemotherapy with cisplatin and etoposide. I agree with Dr R. comments. I would suggest the following doses:

Cisplatinum at 75 mg/m2 /day 1 and etoposide 100 mg/m2 days 1-3 with growth factor support for three to four cycles. If her pelvic MRI suggests extension outside the cervix, after completing chemotherapy, I would recommend pelvic and para-aortic radiation. The role of surgery is questionable. It could be considered if the disease is confined to the cervix and follow up PET scan shows no FDG uptake.

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2. Frazier SR, Kaplan PA, Loy TS The pathology of extrapulmonary small cell carcinoma. Semin Oncol. 2007 Feb;34(1):30-8.
3. Asensio N, Luis A, Costa I, Oliveira J, Vaz F.Meningeal carcinomatosis and uterine carcinoma: three different clinical settings and review of the literature.Int J Gynecol Cancer. 2009 Jan;19(1):168-72.
4. Powell JL, McKinney CD.Large cell neuroendocrine tumor of the cervix and human papillomavirus 16: a case report. J Low Genit Tract Dis. 2008 Jul;12(3):242-4
5. Rhemtula H, Grayson W, van Iddekinge B, Tiltman A. Large-cell neuroendocrine carcinoma of the uterine cervix--a clinicopathological study of five cases.S Afr Med J. 2001 Jun;91(6):525-8.
6. Spigel DR, Hainsworth JD, Greco FA.Neuroendocrine carcinoma of unknown primary site. Semin Oncol. 2009 Feb;36(1):52-9.
7. Hainsworth JD, Spigel DR, Litchy S, Greco FA.Phase II trial of paclitaxel, carboplatin, and etoposide in advanced poorly differentiated neuroendocrine carcinoma: a Minnie Pearl Cancer Research Network Study. J Clin Oncol. 2006 Aug 1;24(22):3548-54
8. Artale S, Giannetta L, Cerea G, Maggioni D, Pedrazzoli P, Schiavetto I, Napolitano M, Veronese S, Bramerio E, Gambacorta M, Vanzulli A, Pisconti S, Pugliese R, Siena S. Treatment of metastatic neuroendocrine carcinomas based on WHO classification.Anticancer Res. 2005 Nov-Dec;25(6C):4463-9.
9. Kulke MH, Wu B, Ryan DP, Enzinger PC, Zhu AX, Clark JW, Earle CC, Michelini A, Fuchs CS.A phase II trial of irinotecan and cisplatin in patients with metastatic neuroendocrine tumors. Dig Dis Sci. 2006 Jun;51(6):1033-8.
10. Sørbye H, Westre B, Horn A.Curative surgery after neoadjuvant chemotherapy in metastatic poorly differentiated neuroendocrine carcinoma. Eur J Surg Oncol. 2007 Dec;33(10):1209-10. Epub 2007 Mar 12.