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340 Neuroendocrine Tumors, Pathology of the Fallopian Tube
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Neuroendocrine Tumors, Pathology of the Fallopian
Tube, Fig. 1 Neuroendocrine carcinoma: Large cell neu-
roendocrine carcinoma of the fallopian tube. Diffuse and
organoid growth
Molecular Features
Not clinically relevant.
Differential Diagnosis
The differential diagnosis of the welldifferentiated NETs is limited, given the characteristic morphology and positivity for neuroendocrine markers chromogranin and synaptophysin.
Microscopic sex cord-like proli ferations resembling adult granulosa cell tumor or sex cord
tumor with annular tubules have recently been
reported involving the fallopian tube and might
be considered in the differential diagnosis. However, these tumors are positive for inhibin and
calretinin (McCluggage et al. 2015).
Neuroendocrine Tumors, Pathology of the Fallopian
Tube, Fig. 2 Neuroendocrine carcinoma: Large cell neu-
roendocrine carcinoma of the fallopian tube. Immunoreactivity is present for synaptophysin
The differential diagnosis of high-grade neuroendocrine carcinomas depends on whether this is
predominantly of small cell or large cell type but in
the fallopian tube potentially includes other highgrade epithelial neoplasms, such as high-grade
serous or endometrioid carcinomas (Grondin et al.
2019). The morphologic features and a combina-
tion of immunohistochemical markers should
allow ready distinction. High-grade serous and
endometrioid carcinomas are usually Pax 8 and
estrogen receptor positive, while high-grade neuroendocrine carcinomas are generally negative.
References and Further Reading
Astall, E. C., Brewster, J. A., & Lonsdale, R. (2000). Malig-
nant carcinoidtumour arising in amature teratoma of the
fallopian tube. Histopathology, 36,282–283.
Crochet, P., Luneau, F., Rojat-Habib, M. C., et al. (2012).
Primaryneuroendocrinecarcinoma of the fallopiantube:
Acasereport.Gynecologic Oncology Case Reports, 4,
38–40. https://doi.org/10.1016/j.gynor.2012.12.004.
PMID: 24371668; PMCID: PMC3862233.
Neuroendocrine Tumors, Pathology of the Uterine Corpus 341
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Dursun, P., Salman, M. C., Taskiran, C., et al. (2004).
Primary neuroendocrine carcinoma of the fallopian
tube: A case report. American Journal of Obstetrics
and Gynecology, 190, 568–571.
Grondin, K., Lidang, M., Boenelycke, M., Alvarado-
Cabrero, I., Herrington, C. S., & McCluggage, W. G.
(2019). Neuroendocrine tumors of the fallopian tube:
Report of a case series and review of the literature.
International Journal of Gynecological Pathology, 38
(1), 78– 84. https://doi.org/10.1097/PGP.
0000000000000458. PMID: 29019870.
Hung, Y. P. (2019). Neuroendocrine tumors of the lung:
Updates and diagnostic pitfalls. Surgical Pathology
Clinics, 12, 1055–1071.
Javellana, M., Hoppenot, C., & Lengyel, E. (2019). The
road to long-term survival: Surgical approach and longitudinal treatments of long-term survivors of
advanced-stage serous ovarian cancer. Gynecologic
Oncology, 152, 228–234.
Kim, K. M., Cho, D. H., Chu, H. H., et al. (2015). Combined
serous carcinoma and neuroendocrine carcinoma of the
fallopian tube. Pathology, 47(7), 711–714. https://doi.org/
10.1097/P AT.0000000000000339. PMID: 26517633.
McCluggage, W . G., Stewart, C. J. R., Iacobelli, J., et al.
(2015). Micro scopic extraovarian sex cord p roliferations:
An undescribed phenomenon. Histopathology, 66,
555–564.
Neumann, F., Diedhiou, A., Sainte-Rose, D., et al. (2010).
Primary neuroendocrine tumor of the fallopian tube:
A case report. Annales de Pathologie, 30,33–35.
Oronsky, B., Ma, P. C., Morgensztern, D., & Carter, C. A.
(2017). Nothing but NET: A review of neuroendocrine
tumors and carcinomas. Neoplasia, 19, 991–1002.
Raghunath, A., Adamus, G., Bodurka, D. C., et al. (2010).
Cancer -associated retinopathy in neuroendocrine carcinoma of the fallopian tube. J Neuroophtalmology, 30,
252–254.
Satoh, T., Takei, Y., Treilleux, I., et al. (2014). Gynecologic
cancer Intergroup consensus review for small cell carcinoma of the cervix. International Journal of Gyneco-
logical Cancer, 24, S102–S108.
Neuroendocrine Tumors,
Pathology of the Uterine
Corpus
Clinical Features
Typically occurring in postmenopausal patients,
primary neuroendocrine tumors of the endometrium have been reported in younger patients in
their reproductive years. The most common presenting complaint is vaginal bleeding. Rarely
paraneoplastic syndr omes are s een at pre sentation with Cushing’s syn drome and visual disturbances They are classified as small cell
carcinoma, large cell neuroendocrine carcinoma, and carcinoid tumors similar to their pulmonary counterparts. Of the two, small cell
neuroendocrine carcinoma is the relatively
more common histologic pattern with approximately less than 100 cases reported in the
English literature. Large cell neuroendocrine
carcinoma is even more infrequent with neuroendocrine tumors (carcinoid) being ex ceedingly
rare (Pocrnich et al. 2016). Neuroendocrine differentiationisnotuncommoninpoorlydifferentiated endometrial carcinomas and must be
differentiated from pure neuroendocrine
tumors.
• Treatment and Outcome
Neuroendocrine small cell and large cell car-
cinomas are high-grade malignant neoplasms
that have a poor prognosis. The tumors fre-
quently present at a high stage in the majority,
(approximately two-thirds) of patients. As
with neuroendocrine carcinomas elsewhere
in the body, traditional platinum-based che-
motherapy with added etoposide can be ther-
apeutic, thus making the recognition of this
pattern critically important. Additionally,
tumor exhibiting microsatellite instability
maybe treated with immune checkpoint
inhibitors.
N
Sanam Husain
Henry Ford Health System, Detroit, MI, USA
Definition
Primary neuroendocrine tumors of the endometrium are infrequent tumors, less than 1% of all
endometrial carcinomas.
Macroscopy
In contrast to other endometrial primary malignancies that frequently cause diffuse thickening
of the endometrium, neuroendocrine carcinomas are usually polypoid to exop hytic bulky
lesions (Albores-Saavedra et al. 2008). Sectioning of the tumors often shows necrosis and
342 Neuroendocrine Tumors, Pathology of the Uterine Corpus
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hemorrhage accompanied by variable degree of
my invasion.
Microscopy
Among the various types of tumor configuration,
trabecular, nested patterns are commonly
observed with occasional foci and rosette formation. Squamous differentiation may also be
present.
Small cell carcinoma demonstrates sheets,
rosettes, nests of tumor cells with hyperchromatic nuclei, high nucleus to cytoplasmic
ratios, and nuclear molding (Fig. 1). The high
proliferation rate of tumor cells manifests histologically with abundant mitotic activity, apoptosis, and zonal necrosis (Fig. 2). The cytology of
the tumor cells may be difficult to appreciate due
to crush artifact (Huntsman et al. 1994; Mulvany
and Allen 2008).
Large cell neuroendocrine carcinoma is characterized by sheets and nests of tumor cells with
prominent peripheral palisading and geographic
necrosis. The neoplastic cells have hyperchromatic nuclei with prominent nucleoli.
A mixed pattern of small cell and large cell carcinoma can be present in the same tumor. In addition, neuroendocrine tumors can occur in
association with a conventional endometrioid
component.
Immunophenotype
Neuroendocrine Tumors, Pathology of the Uterine
Corpus, Fig. 1 Small cell neuroendocrine carcinoma.
The tumor extensively involves the endometrium with
rare benign endometrial glands present at the periphery
Neuroendocrine Tumors, Pathology of the Uterine
Corpus, Fig. 2 Small cell neuroendocrine carcinoma.
The tumor cells exhibit increased apoptotic activity, atypical mitoses, and necrosis
Like neuroendocrine tumors in other organ systems, primary neuroendocrine tumors are positive for at least one of the three routinely used
immunoperoxidase stains including synaptophysin, chromogranin, and CD56. Expression of these immunohistochemical stains is not
required if the tumor morphology is otherwise
characteristic of small cell neuroendocrine carcinoma. Conversely, for large cell neuroendocrine
carcinoma immunoreactivity with at least one
neuroendocrine marker in 10% of tumor cells is
required if the histomorphology is not
diagnostic. PAX8 is usually negative; however,
up to a third of reported cases have been positive.
Keratins (AE1/AE, CAM5.2) are positive in the
vast majority of the cases. TTF-1 staining has
been observed in a few cases as can be seen in
extrapulmonary neuroendocrine tumors. Interestingly, some tumors have shown absent mismatch repair protein expression in primary
endometrial neuroendocrine tumors (Ka tah ira
et al. 2004).
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Molecular Features
Recent literature has shown that up to half of primary neuroendocrine carcinomas may be hypermutated (43%) or ultramutated with the POLE
mutation (7%), and may show improved survival
at 5 years (Howitt et al. 2020). Immune check point
inhibitor therapy may be beneficial in cases that
exhibit mismatch repair deficiency.
Differential Diagnosis
Differential diagnosis of neuroendocrine tumors
of the endometrium includes FIGO 3 endometrioid carcinoma, undifferentiated carcinoma,
dedifferentiated carcinoma, carcinosarcoma, lymphoma, and PNET.
FIGO3 endometrioid carcinomas lack the trabecular and organoid morphology observed in
neuroendocrine carcinomas. They lack the neuroendocrine immunophenotype and are mostly positive for ER, PR, and PAX8.
Undifferentiated carcinomas of th e endometrium
can demonstrate neuroendocrine expression; however, it tends to be focal, usually only limited to less
than 10% of all tumor cells. Diffuse expression of
any neuroendocrine immunohistochemical stain
argues against an undifferentiated ca rcinoma. Additionally, the tumor cells in undifferentiated carcinoma are not loosely cohesive, can be
plasmacytoid and may have a myxoid background.
High grade neuroendocrine carcinomas present as
nests, trabeculae, as well as sheets of cohesive neoplastic cells. Undifferentiated carcinomas lack diffuse keratin staining in 70% of tumors and are
usually only focally positive for EMA and
CAM 5.2.
Due to the crush artifact, neuroendocrine carcinomas may mimic lymphoma. While lymphomas
do not ef facenormal endometria lglands and stroma,
neuroendocrine carcinomas generally obliterate the
normal endometrium. Immunophenotype of the
tumors is distinctive and is an extremely helpful
tool in this situation with lymphomas being negative
for epithelial markers and expressing B and T cell
markers according to the specific lineage of the
neoplastic cells.
Neuroendocrine carcinomas are distinguished
from malignant mixed Mullerian tumors
(MMMT) by the lack of biphasic morphology
characteristic in the former and diffuse positive
expression of the neuroendocrine markers. At low
magnification, the small blue cell appearance may
mimic the sarcomatous component of MMMT but
careful histologic evaluation at high magnification
will highlight the typical cytologic features of neuroendocrine carcinoma with the hyperchromatic
nuclei,the nuclear molding in small cell carcinoma,
and the nuclear palisading with the prominent
nucleoli of large cell neuroendocrine carcinoma.
Ewing’s sarcoma/PNET as a metastasis or a
primary tumor of the endometrium is vanishingly
rare, how rare cases have been reported and the
morphologic features of the tumor cells with small,
hyperchromatic nuclei and staining with synaptophysin raises this as a diagnostic consideration.
Pankeratin and chromogranin are largely negative
in Ewing’s sarcoma/PNET. If the accurate
histotyping remains challenging, cytogenetics testing with fluorescence in situ hybridization (FISH)
with the defining EWS gene rearrangement is diagnostic and definitive.
Importantly, the possibility that the neuroendocrine tumor is not a metastasis from a pulmonary
or extrapulmonary site has to be established by a
careful review of the patient’s history and communication with the surgeon. In some cases, the
possibility of a metastasis cannot be entirely ruled
out based on the clinical information available at
the time of pathologic staging.
References and Further Reading
Albores-Saavedra, J., Martinez-Benitez, B., & Luevano,
E. (2008). Small cell carcinomas and large cells neuro-
endocrine carcinoma of the endometrium and cervix:
Polypoid tumors and thosearising in polyps may have a
favorable prognosis. International Journal of Gyneco-
logical Pathology, 27, 333–339.
Gyan Hoeven, K. H., Hudock, J. A., Woodruff, J. M., &
Suhrland, M. J. (1995). Small cell neuroendocrine
N
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carcinoma of the endometrium. International Journal
of Gynecological Pathology, 14(1), 21–29.
Howitt, B. E., Dong, F., Vivero, M., Shah, V., Lindeman,
N., Schoolmeester, J. K., Baltay, M., MacConaill, L.,
Sholl, L. M., Nucci, M. R., & McCluggage, W. G.
(2020). Molecular characterization of neuroendocrine
carcinomas of the endometrium: Representation in all
4 TCGA groups. The American Journal of Surgical
Pathology, 44(11), 1541–1548.
Huntsman, D. G., Clement, P. B., Gilks, C.G., et al.(1994).
Small cell carcinoma of the endometrium.
A clinicopathologic analysis of sixteen cases. The
American Journal of Surgical Pathology, 18, 376–390.
Katahira, A., Akahira, J., Niikura, H., et al. (2004). Small
cell carcinoma of the endometrium: Report of three
cases and literature review. International Journal of
Gynecological Cancer, 14, 1018–1023.
Mulvany, N. J., & Allen, D. G. (2008). Combine large cell
neuroendocrine and endometrioid carcinoma of the
endometrium. International Journal of Gynecological
Pathology, 27,49–57.
Pocrnich, C. E., Ramalingam, P., Euscher, E. D., &
Malpica, A. (2016). Neuroendocrine carcoinoma of
the endometrium: A clinicopathologic study of
25 cases. The American Journal of Surgical Pathology,
40(5), 577–586.
Neuroendocrine Tumors,
Pathology of the Vagina
Definition
Small cell neuroendocrine carcinoma is a highgrade carcinoma composed of small to mediumsized cells with scant cytoplasm, showing
evidence of neuroendocrine differentiation.
Clinical Features
Two-thirds present with vaginal bleeding or
discharge.
• Incidence
Rare.
• Age
Usually occur in post-menopausal women
(range 32–78 years, Bing et al. 2004).
• Site
Vagina.
• Treatment
No consensus has been reached regarding opti-
mal therapy. Current therapies usually result in
poor outcomes.
• Outcome
Most patients die of disease within 2 years.
Jason Wong
Department of Cellular Pathology, East Suffolk
and North Essex NHS Foundation Trust, Ipswich,
UK
In the WHO Classification of Female Genital
Tumors ( fifth edition), neuroendocrine neoplasms
are divided into neuroendocrine tumors (which
are well-differentiated and low- or intermediategrade) and neuroendocrine carcinomas, which are
poorly differentiated and high grade.
Neuroendocrine neoplasms of the vagina are rare
and only the most common, the small cell neuroendocrine carcinoma, will be further considered.
Synonyms
Neuroendocrine carcinoma, small cell type; Small
cell carcinoma.
Macroscopy
Small cell neuroendocrine carcinoma presents as a
mass lesion.
Microscopy
The histological features are similar to those of
small cell neuroendocrine carcinomas occurring
at other sites such as the cervix. These include
atypical cells with round to ovoid nuclei, scant
cytoplasm, and dispersed chromatin with absent
or inconspicuous nucleoli. Nuclear moulding,
mitotic figures, and apoptotic bodies are
frequent.
Immunophenotype
Tumors are usually positive for broad-spectrum
cytokeratins, and should be positive for at least one
Neuroendocrine Tumors, Pathology of the Vulva 345
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neuroendocrine marker, although this is not essential
when the histological criteria are met. Synaptophysin is the most sensitive and chromogranin
is the most specific. CD56 is less specificandcanbe
expressed in non-neuroendocrine carcinomas
(McCluggage et al. 2010).
Differential Diagnosis
Small cell variant of squamous cell carcinoma:
lacks the characteristic nuclear features of small
cell neuroendocrine carcinoma shows focal squamous differentiation.
Direct extension from the cervix.
Metastasis from the lung or elsewhere: TTF-1
and CDX2 expression do not exclude a
gynaecological origin.
References and Further Reading
Bing, Z., Levine, L., Lucci, J. A., Hatch, S. S., & Eltorky,
M. A. (2004). Primary small cell neuroendocrine carci-
noma of the vagina: A clinicopathologic study. Archives
of Pathology & Laboratory Medicine, 128(8), 857–862.
McCluggage, W. G., Kennedy, K., & Busam, K. J. (2010).
An immunohistochemical study of cervical neuroendo-
crine carcinomas: Neoplasms that are commonly TTF1
positive and which may express CK20 and P63. Amer-
ican Journal of Surgical Pathology, 34(4), 525–532.
and comprise ~2% of all malignancies (Basu et al.
2010). They are divided into two groups on the
basis of clinical behavior, histology, and proliferation rate: well-differentiated (low grade to intermediate grade/carcinoid or atypical carcinoids)
neuroendocrine tumors and poorly differentiated
(high-grade/small cell or large cell) neuroendocrine carcinoma (Bosman et al. 2010). The occurrence of NENs in the female genital tract is rare.
This entry provides the current WHO classification and descriptions of NENs of the female genital tract.
Neuroendocrine Tumors [Carcinoid
Tumor, Typical Carcinoid Tumor, and
Atypical Carcinoid Tumor]
Clinical Features
Neuroendocrine tumors (NETs) of the female genital tract are exceedingly rare except in the ovary. In
the current (2020) WHO classification of tumors of
the female genital tract, NETs of the female genital
tract are described together, without separation by
individual organs. NET is a low-grade or
intermediate-grade epithelial neoplasm with morphological and immunohistochemical features of
neuroendocrine differentiation (Malpica 2020).
Due to its rarity especially in the vulvar, NET of
the female genital tract will be discussed generally.
N
Neuroendocrine Tumors,
Pathology of the Vulva
Evi Abada
Department of Pathology, Wayne State University
School of Medicine, Detroit, MI, USA
Synonyms
Neuroendocrine neoplasms (NENs).
Definition
Neuroendocrine neoplasms (NENs) are a heterogenous group of tumors which are relatively rare
• Incidence and Age
NETs can rarely arise anywhere in the female
genital tract including the cervix, uterine corpus, fallopian tube, vagina, and vulva (Malpica
2020). In the ovary, these neoplasms are
referred to as carcinoid tumors (Malpica
2020). Patients with NETs of the cervix are
usually in their fourth or fifth decades
(Papatsimpas et al. 2017; Koch et al. 1999;
Ishikawa et al. 2019). Patie nts with vulvar
tumors have ranged in age from 38 to
56 years (Srivastava et al. 2012), and the rare
uterine corpus tumors have been in elderly
women (Chetty et al. 1993; González-Bosquet
et al. 1998).
• Treatment and Outcome
Treatment information for NETs of the female
genital tract are limited and evolving, and the
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prognosis depends on the site of occurrence
and stage.
Macroscopy
Macroscopically, cervical tumors are usually
2 cm and polypoid or indurated (Papatsimpas
et al. 2017), endometrial tumors have been
as large as 5 cm (Chetty et al. 1993), and vulvar
tumors are typically well circumscribed and small
(0.8–1.1 cm) with no involvement of the overlying epithelium (Srivastava et al. 2012).
Microscopy
Microscopically, these tumors show a trabecular,
ribbon-like, glandular, or nested growth pattern
(Malpica 2020)(Fig.1). The neoplastic cells are
monotonous and cuboidal/columnar/polygonal,
with a variable amount of cytoplasm (Malpica
2020). The nuclei can be either regular with uni-
form chromatinand small nucleoli (grade 1 tumors)
or variable in size and shape with irregularly distributed chromatin (grade 2 tumors). Grade
1tumorsshowraremitoticfigures, whereas grade
2 tumors can show 5–10 mitotic figures/2 mm
(5–10 mitotic figures/10 HPF of 0.5 mm in diameter and 0.2 mm
2
in area), as well as fociof necrosis
(Albores-Saavedra et al. 1997). By immunohistochemistry, the tumors express at least one neuroendocrine marker including synaptophysin (Fig. 2),
chromogranin, or CD56 (Fig. 3).
Neuroendocrine Tumors, Pathology of the Vulva,
Fig. 2 Carcinoid tumor. Immunohistochemistry shows that
the tumor cells are positive for synaptophysin
2
Neuroendocrine Tumors, Pathology of the Vulva,
Fig. 3 Carcinoid tumor. Immunohistochemistry shows that
the tumor cells are positive for CD56
Molecular Features
There have been very limited molecular associations with NETs. HPV 16 has been reported in a
single case of carcinoid of the uterine cervix
(Alejo et al. 2018), and HPV16 and HPV18 have
also been identified in atypical carcinoids from the
same location (Alejo et al. 2018; Wistuba et al.
1999).
Neuroendocrine Tumors, Pathology of the Vulva,
Fig. 1 Carcinoid tumor. Hematoxylin and eosin section
showing a monomorphic population ofround to ovoidcells
arranged in nests with uniform chromatin patterns
Differetial Diagnosis
The differential diagnosis includes NETs originating from sites outside the female genital tract as
they are morphologically and immunohistochemically similar. Inthese cases, a critical review
of the patient’s clinical history is paramount.
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Neuroendocrine Carcinoma [Small Cell and
Large Cell Neuroendocrine Carcinoma]
Small Cell Neuroendocrine Carcinoma [Small
Cell Carcinoma, Neuroendocrine Carcinoma,
and Small Cell Type]
Small cell neuroendocrine carcinoma (SCNEC) is
a high-grade carcinoma composed of small to
medium-sized cellswith scant cytoplasm and neuroendocrine differentiation (Alvarado-Cabrero
et al. 2020).
Clinical Presentation
• Incidence
SCNEC is rare and accounts for <1% of all
malignancies of the female genital tract
(Rouzbahman and Clarke 2013).
• Age
Neuroendocrine Tumors, Pathology of the Vulva,
Fig. 4 Small cell neuroendocrine carcinoma. Hematoxy-
lin and eosin section showing a pleomorhic population of
round to ovoid cells with hyperchromatic nuclei, molding,
and scant cytoplasm. A mitotic figure is also evident
SCNEC of the cervix typically occurs at a
median age of 49 years (Zhou et al. 2017),
whereas SCNEC at other sites presents after
menopause (Alvarado-Cabrero et al. 2020). It
can occur anywhere in the female genital tract;
however, the cervix is the most common site of
occurrence (Howitt et al. 2017).
• Treatment and Outcome
Treatment information for SCNECs of the
female genital tract are evolving, and
published reports are currently suboptimal.
SCNECs of the female genital tract are
aggressive, with a high propensity for lymphatic and hematogenous spread. Distant
metastasis at presentation is common
(Alvarado-Cabrero et al. 2020)andmortality
is high, even in patients diagnosed at an early
stage (Satoh et al. 2014).
Neuroendocrine Tumors, Pathology of the Vulva,
Fig. 5 Small cell neuroendocrine carcinoma. Hematoxylin
and eosin section showing tumor cells with nuclear fragmentation and abundant apoptotic activity
N
Macroscopy
Macroscopically, SCNEC presents as a mass
lesion (Alvarado-Cabrero et al. 2020).
Microscopy
Histologically, SCNEC is characterized by the
presence of a monotonous population of cells
with ovoid or somewhat spindled hyperchromatic nuclei, often exhibiting molding,
and scanty cytoplas m (Howitt et al. 2017)
(Fig. 4). There is usually abundant mitotic and
apoptotic activity. There may be extensive crush
artifact, nuclear fragmentation, and necrosis
(Fig. 5). The growth pattern is usually predominantly diffuse, but nests, trabeculae, pse udoglandular, and rosette-like structures are
sometimes present (Howitt et al. 2017). Vascular invasion is also common (Alvarado-Cabrero
et al. 2020).
Immunophenotype
Synaptophysin (Fig. 6), chromogranin (Fig. 7),
andCD56(Fig.8) are the most frequently used
immunohistochemical markers of
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Neuroendocrine Tumors, Pathology of the Vulva,
Fig. 6 Small cell neuroendocrine carcinoma. Immunohisto-
chemistry shows that the tumor cells are positive for
synpatophysin
Neuroendocrine Tumors, Pathology of the Vulva,
Fig. 7 Small cell neuroendocrine carcinoma. Immunohisto-
chemistry shows that the tumor cells are positive for
chromogranin
neuroendocrine differentiation (AlvaradoCabrero et al. 2020). Of note, no marker is
100% expressed in SCNECS (AlvaradoCabrero et al. 2020). Synaptop hysin is most
consistently expressed, and chromogranin is
most specific (McCluggage et al. 2010). CD56
is less specific and should only be used as evidence of neuroendocrine differentiation in the
proper histolo gical context (Alvarado-Cabrero
et al. 2020). Broad spectrum cytokeratins are
usually positive, and TTF1 and CDX2 expression does not exclude a gynecologic origin
Neuroendocrine Tumors, Pathology of the Vulva,
Fig. 8 Small cell neuroendocrine carcinoma. Immunohisto-
chemistry shows that the tumor cells are positive for CD56
(Alvarado-Cabrero et al. 2020). Diffuse blocktype p16 immunoreactivity is common in cervical SCNECs because of the association with
high-risk HPV, but it may also occur in
SCNEC arising elsewhere. SMARCA4,
SMARCA2, and SMARCB1 expression are
retained by immunohistochemistry (AlvaradoCabrero et al. 2020).
Most SCNECs arising from the cervix are
associated with high-risk HPV infection, primarily HPV 16 and 18 (Castle et al. 2018). Some
studies have reported a higher frequency of
HPV18 than HPV16 with SCNECs of the cervi x
(Grayson et al. 2002; Stoler et al. 1991). Some
cervical SCNECs have recurrent genetic alterations involving the MAPK, PI3K/AKT/mTOR,
and p53/BRCA pathways, as well as loss of heterozygosity involving the short arm of chromosome 3 (3p) (Xing et al. 2018). Abnormal
mismatch repair protein expression has been
described in endometrial SCNECs (Pocrnich
et al. 2016). The molecular alterations of SCNECs
arising from other parts of the female genital tract
are currently unknown.
Differential Diagnosis
The differential diagnosis includes SCNECs arising from other organs including the lung and
gastrointestinal tract. A thorough review of the
patients’ clinical history is paramount as these
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tumors share similar morphologic and immunohistochemical characteristics.
Large Cell Neuroendocrine Carcinoma
[Neuroendocrine Carcinoma, Large Cell Type]
Clinical Features
Large cell neuroendocrine carcinoma (LCNEC) is
a high-grade carcinoma composed of large cells
with neuroendocrine differentiation (AlvaradoCabrero et al. 2020).
• Incidence
LCNECs of the female genital tract are
extremely rare, and it can occur at any site in
the female genital tract, but occurrence in the
cervix is most common.
• Age
LCNEC of the cervix typically affects premenopausal women (mean: 34 years), whereas
these tumors commonly affect postmenopausal
women at other gynecological sites (Pocrnich
et al. 2016; Taraif et al. 2009; Howitt et al.
2017; Grondin et al. 2019).
• Treatment and Outcome
LCNECs are aggressive neoplasms, with a high
degree of lymphatic and hematogenous spread
(Alvarado-Cabrero et al. 2020). Distant metastasis is common and mortality is high, even
among patients presenting at an early stage
(Embry et al. 2011).
Macroscopy
Macroscopically, LCNEC presents as a mass
(Alvarado-Cabrero et al. 2020).
Neuroendocrine Tumors, Pathology of the Vulva,
Fig. 9 Large cell neuroendocrine carcinoma. Hematoxy-
lin and eosin section showing large cells with irregular
nuclei membranes, high nuclear to cytoplasmic ratios,
coarse chromatin, and prominent nucleoli
N
Neuroendocrine Tumors, Pathology of the Vulva,
Fig. 10 Large cell neuroendocrine carcinoma. Hematox-
ylin and eosin sectionshowing pseudoglandular andnested
LCNECs with tumor cells showing nuclear fragmentation
and abundant apoptotic activity
Microscopy
It is characterized by large polygonal cells with a
high nuclear to cytoplasmic ratio, nuclei with
coarse chromatin and prominent nucleoli, and
high mitotic activity (Howitt et al. 2017)
(Fig. 9). Insular/nested, trabecular, pseudoglandular, and solid growth patterns are often
present (Fig. 10), either alone or in combination
(Howitt et al. 2017). There is often extensive
geographic necrosis. Nuclear palisading may be
present around the periphery of cell nests, and
eosinophilic cytoplasmic granules are present in
some cases (Howitt et al. 2017). Areas of small
cell neuroendocrine carcinoma, as well as other
histologic types, may be seen in combination with
LCNEC (Alvarado-Cabrero et al. 2020). Ovarian
LCNEC may be associated with teratoma
(Miyamoto et al. 2012).
Immunophenotype
Expression of at least one neuroendocrine
marker (Figs. 11 and 12)isrequiredtoestablish
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