A 46 year old woman had an abnormal Pap smear. A cervical biopsy revealed adenocarcinoma in situ. A
cone biopsy, from which this slide was prepared, was performed.
Diagnosis: Large cell neuroendocrine carcinoma arising in association with well
differentiated adenocarcinoma of the cervix
Case 5 - Figure 1 - Irregular endocervical glands lined by cells with stratified, hyperchromatic nuclei.
Case 5 - Figure 2 - High magnification view of an endocervical gland showing the nuclear features.
The patient underwent a radical hysterectomy and lymph node dissection. There was residual
adenocarcinoma in situ in the transformation zone, but there was no residual invasive carcinoma or
neuroendocrine carcinoma. All of the lymph nodes were negative for tumor.
This case poses two interesting diagnostic problems. First, what is the nature of the atypical glandular
proliferation? Second, what is the nature of the small solid nodule that has arisen in association with
the atypical glandular proliferation?
The atypical glandular proliferation is clearly neoplastic. The cells lining the glands have
hyperchromatic atypical nuclei. There is nuclear stratification. Mitotic figures are frequent, and
apoptotic bodies are noted at the bases of many of the glands. In addition, the glandular cells show
loss of mucin secretion, and have dense eosinophilic cytoplasm. Thus, the glandular proliferation
represents at least adenocarcinoma in situ. The question here is: How does one decide whether an
atypical glandular proliferation is adenocarcinoma in-situ or a well-differentiated invasive
adenocarcinoma? In adenocarcinoma in situ there is replacement of normal glands by a population of
cytologically malignant cells. Thus, a glandular pattern that deviates from a normal glandular pattern (
i.e., crowded glands, abnormal configurations of glands, abnormal distributions of glands) is suspicious
for invasive adenocarcinoma. Second, if I identify a pattern of glands that corresponds to one that I
have seen with frequency in deeply invasive adenocarcinomas, I am highly suspicious that the abnormal
glands represent invasive adenocarcinoma. Finally if I identify a pattern, even a subtle one, which I
recognize as invasive, I make a diagnosis of invasive adenocarcinoma.
In this case, there is a subtle pattern of well-differentiated infiltrating adenocarcinoma. The glands
are elongated and branching, and have a haphazard distribution within the stroma. There are focal areas
in which small tubular glands are crowded together. Some glands are deep in the stroma adjacent to
vessels and nerves. Deep glands themselves are not necessarily indicative of malignancy, but the
presence of malignant glands deeper than 5 mm in the stroma supports the diagnosis of adenocarcinoma.
There is a subtle pattern of desmoplasia around some of the malignant glands, consisting of laminated
fibrosis as well as mononuclear inflammatory cells. The histologic picture is more complex and irregular
than would be found in adenocarcinoma in situ, and it goes deeper into the stroma than is usual for
adenocarcinoma in-situ. We measured the depth of invasion as 5.8 mm and the length as at least 10 mm.
The atypical glands extended to the endocervical and deep margins of the cone. No lymphovascular space
invasion was identified.
A second pattern of invasive carcinoma is noted in one of the slides. It measures 2.7 mm in maximum
dimension, and consists of cells growing in solid nests and trabeculae, as well as singly and in small
groups. The tumor cells have moderate amounts of granular amphophilic cytoplasm, and their nuclei are
larger and more atypical than those in the adjacent adenocarcinoma. In addition, there is a high mitotic
rate, and atypical mitoses are present. The tumor has the appearance of a neuroendocrine neoplasm, and,
accordingly, a panel of immunohistochemical stains was performed with the following results:
- Neuron specific enolase: positive
- Synaptophysin: positive
- Chromogranin: positive
Given the size of the tumor cells, their rather abundant cytoplasm, the degree of nuclear atypia, and the
high mitotic rate, we made a diagnosis of large cell neuroendocrine carcinoma (LCNEC). The tumor was not
present near any of the excision margins, there was no lymphovascular space invasion, and no residual
LCNEC was found in the hysterectomy specimen or in any of the dissected lymph nodes.
Neuroendocrine tumors of the cervix are rare. Any type of neuroendocrine tumor can occur in the cervix
(Table 2), 1 but the most common is small cell carcinoma. 2-9
Table 2. Neuroendocrine Tumors of the Cervix |
Atypical carcinoid |
Small Cell carcinoma |
Large Cell neuroendocrine carcinoma |
Carcinoid tumors of the cervix are extremely rare; I have never seen one myself. 4 Like carcinoid tumors
at other sites, they are viewed as low grade malignant neoplasms. The next step up, and a consideration
in this case, is an atypical carcinoid (aka, intermediate grade neuroendocrine carcinoma). The
diagnostic criteria proposed for pulmonary neuroendocrine tumors have been translated to the cervix, so
an atypical carcinoid would be an appropriate diagnosis if the mitotic activity were in the range of 2-10
mf/10 hpf. The presence of necrosis would also place a tumor in this category, at least, and exclude a
typical carcinoid. In the only study that has reported any survival information on atypical carcinoids
of the cervix, 2 of 4 patients had recurrences and were alive with tumor at last followup. 4 In this
case, the tumor is so small that it is difficult to find 10 high power fields in which to count mitoses!
Nevertheless, since I found 10 in one high power field I concluded that the tumor is best classified as a
high grade neuroendocrine tumor (10 or more mf/10 hpf), and, of the two possibilities, large cell
neuroendocrine carcinoma is the most appropriate.
Large cell neuroendocrine carcinoma was first described in detail by Gilks et al in 1997. 10 Gilks
reported 12 cases and cited 24 other non-small cell neuroendocrine tumors reported in the literature,
some of which might, as well, be examples of LCNEC. Others have subsequently reported additional
cases 4,11-15 but there are still few well documented cases in the literature. Lee described the
cytologic features of one case and noted that it would be difficult to make the diagnosis by
cytology. 13 Grayson found HPV 16 or 18 DNA in 9/12 LCNEC, 16 Yun found HPV 16 in his case, 15 and
Wistuba et al found HPV 18 in one of their cases, 17 so this appears to be another form of HPV
associated cervical cancer.
The clinical presentation is nonspecific, and similar to that of other forms of cervical cancer:
patients have an abnormal Pap smear or vaginal bleeding. The age range is wide, from the 20's to the
60's. In the original series of 12 cases reported by Gilks, 2 patients were stage IA2, 9 were stage IB,
and 1 was stage IIA. Most patients have been treated by some combination of radical hysterectomy,
chemotherapy, and radiotherapy, depending on the stage of their tumor. LCNEC appears to be an aggressive
neoplasm, but, stage for stage, the prognosis seems similar to that for more common cervical cancers such
as squamous cell carcinoma. As in this case, early stage tumors are small and may not be grossly
visible. Larger tumors are polypoid or exophytic, tan or brown, and, usually, extensively necrotic. The
tumor cells are larger than those of small cell carcinoma, and grow in neuroendocrine patterns, such as
solid, insular, or trabecular ones. The nuclei tend to show significant atypia and mitotic figures are
frequent. Immunostains for chromogranin and/or synaptophysin are positive, and confirm the diagnosis.
This case is associated with an adenocarcinoma. An immunostain for chromogranin revealed strong positive
staining of scattered cells in the adenocarcinoma, providing a possible site of origin for the
neuroendocrine carcinoma. Cui et al described a LCNEC in which adjacent ACIS stained for chromogranin,
which to them suggested the possibility of a common origin of the two elements. 11 Gilks and colleagues
found an associated adenocarcinoma in 3 of their 12 cases, and 9 of 12 were associated with
adenocarcinoma in situ (ACIS). In their cases, the associated adenocarcinomas were negative for
neuroendocrine markers and they speculated that the tumors originated from the neuroendocrine cells that
are occasionally identified in benign endocervical glands, a possibility also raised by Yun et al.(15)
Additional histologic variants, including tumors with squamous differentiation, with areas resembling
adenoid cystic or adenoid basal carcinoma, and tumors that contain both small cell carcinoma and LCNEC
have all been described.
- Albores-Saavedra J, Gersell D, Gilks CB, Henson DE et al. Terminology of endocrine tumors of the
uterine cervix: results of a workshop sponsored by the College of American Pathologists and the National
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- Conner MG, Richter H, Moran CA, Hameed A et al. Small cell carcinoma of the cervix: A
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- Straughn JM, Jr., Richter HE, Conner MG, Meleth S et al. Predictors of outcome in small cell
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- Mannion C, Park WS, Man YG, Zhuang ZP et al. Endocrine tumors of the cervix - Morphologic
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