Neuroendocrine Tumor of the Fallopian Tube and Serous Adenocarcinoma of the Ovary: Multicentric Primary Tumors
Nataliia HYRIAVENKO1, Mykola LУNDІN1, Vladyslav SIKORA1, Ruslana CHYZHMA1, Yulia LУNDІNA2, Kateryna SIKORA1, Wireko Andrew AWUAH3, Anatolii ROMANIUK1
1Department of Pathology, Sumy State University, SUMY, UKRAINE
2Department of Morphology, Sumy State University, SUMY, UKRAINE
3Department of Student, Sumy State University, SUMY, UKRAINE
Keywords: Neuroendocrine tumor, Fallopian tube, Serous adenocarcinoma, Ovary, Multicentric primary tumors
Neuroendocrine tumors (NETs) comprise a large group of tumors that are most often localized in the gastrointestinal tract and lungs. They are
rarely found in the organs of the female reproductive tract; such NETs are primarily localized in the ovaries. We present a case of multicentric
primary low-grade NET of the fallopian tube and high-grade ovarian serous adenocarcinoma. In both tumor regions, the histotypes of
neoplasms were determined by morphological and immunohistochemical investigations. The NET of the fallopian tube was diffusely positive
for chromogranin A and CD56, but wild type for p53 and negative for CK7, CK20, and ER; Ki-67 expression was observed in 3% of the neoplastic
cells. The ovarian serous adenocarcinoma was positive for CK7 and ER, mutant for p53, but negative for chromogranin A, CK20, and CD56;
Ki-67 expression was observed in 45% of the tumor cells. These results support the possibility that NET can occur in the female reproductive
tract and coexist with other malignant tumors.
Neuroendocrine tumors (NETs) comprise a large
group of tumors that are characterized by biodiversity
and heterogeneity. They are mostly localized in the
gastrointestinal tract and lungs; however, there are a few
reports of diffuse endocrine system tumors in the female
reproductive tract, which are primarily localized in the
. Primary NETs of the fallopian tube are very
rare. A few reported cases describe primary neuroendocrine
cancers (NECs) of the fallopian tube 4-8
. There are only
three reported cases of carcinoid, one of which arose from
a teratoma 9
. In one case, the fallopian tube was affected
by a heterogeneous tumor (NEC and serous carcinoma)
. Due to the low incidence of NETs in the female
reproductive organs, it may be difficult to make a diagnosis
without additional investigations of the tumor tissue. The
presence of multiple primary tumors significantly affects
the course of the disease, its treatment, and the survival
In this report, we present a case of multicentric primary
tumors of the female reproductive system consisting of a
low-grade primary NET of the fallopian tube and a highgrade
ovarian serous adenocarcinoma.
A 58-year-old postmenopausal (five years) woman
visited the gynecologist with complaints of right-sided
lower abdominal pain for the past one month. Physical
examination identified a mass in the right ovary. Ultrasound
examination revealed a 12.0×7.0×6.0 cm tumor in the right
ovary. Blood Ca125 level was elevated (64.82 U/ml). There
were no pathological changes on computed tomography of
the chest and abdominal cavities. Fibrogastroduodenoscopy
revealed antral gastritis. General clinical and biochemical
analysis of the blood was without abnormalities. Surgery—
panhysterectomy with omentectomy— was performed.
Macroscopic examination of the postoperative specimens
showed a normal-sized uterus, retention cysts in the
uterine cervix, thickening of the endometrium (1.1 cm),
an endometrial polyp (0.7×0.5×0.5 cm) in the left uterine
corner, and no abnormalities in the left adnexa (only agerelated
changes). There was a yellow-pink colored, nodeshaped
tumor measuring 3.0×2.0×1.6 cm in the ampulla
of the right fallopian tube. Rest segments of fallopian
tube were without visible chances. In the right ovary, a
multi-chambered cyst measuring 12.0×7.0×6.5 cm with
cloudy fluid and light gray papillae on the inner surface
was observed. There was no pathology in the pelvic lymph nodes or omentum. The abovementioned changes were
considered to be a malignant tumor of the right ovary with
metastases into the wall of the right fallopian tube.
Morphological analysis revealed retention cysts in the
uterine cervix and simple hyperplasia without atypia. An
endometrial polyp was diagnosed. The tumor in the right
fallopian tube spread into the mucous and submucous
membranes without epithelial involvement, as well as
metastases in the lymphatic and blood vessels. It had a wellorganized
histological structure characterized by nests,
anastomotic chains, and structures, such as peripheral
“palisades” and “rosettes”, of the same type of cells with finely
granular (salt and pepper) nuclear chromatin (Figure 1A).
Mitotic count was 1 mitosis/2 mm2. Histological features
of a germ cell tumor (teratoma) and a precancerous lesion
in the tubal epithelium in the affected fallopian tube were
not found. Concurrently, the right ovarian neoplasm had
short (with dense fibrous stroma) and long thin papillae,
as well as slit-like glandular structures. They were lined by
single- and multilayered columnar epithelium with signs
of atypia (large polymorphic and hyperchromic nuclei,
prominent large and eosinophilic nucleoli, numerous
mitoses, some of which are atypical). In some areas, the
tumor formed papillary structures and cell clusters without
stroma. Psammoma bodies were observed rarely in the
tumor (Figure 1B).
Click Here to Zoom
|Figure 1: Fallopian tube (А) and ovarian tumors (В). Hematoxylin and eosin staining (Magnification: ×200).
An immunohistochemical study (IHC) was carried out
to determine the histogenesis of the ovarian and fallopian
tube neoplasms. The following antibodies were used:
chromogranin A (clone DAK-A3), CD56 (clone 1B6),
СK7 (OV-TL12/30), СK20 (Ks20.8), ER (SP1), CDX2
(EPR2764Y), TTF1 (2F4D8), p53 (SP5), and Kі-67 (SP6).
The fallopian tube tumor cells were diffusely positive for chromogranin A and CD56, but wild type for p53 and
negative for CK7, CK20 and ER. Ki-67 expression was
observed in 3% of the neoplastic cells (Figure 2A-G).
The ovarian tumor cells were positive for CK7 and ER,
mutant for p53, but negative for chromogranin A, CK20,
and CD56. Ki-67 expression was observed in 45% of the
tumor cells (Figure 2H-N). Both tumors were negative
for CDX2 and TTF1 (not shown). The morphology and
immunophenotype of the neoplasms corresponded to
primary low-grade neuroendocrine tumor of the fallopian
tube (Т1а), ICD-O code-8240/3 and high-grade ovarian
serous adenocarcinoma (Т1а), ICD-O code-8461/3.
Informed consent for publication purposes was obtained
from the patient.
Click Here to Zoom
|Figure 2: Neuroendocrine tumor
of the fallopian tube and ovarian
papillary serous adenocarcinoma.
CK7, CK20, Chromogranin
A, Kі-67, ER, CD56, p53.
Chromogen – diaminobenzidine;
nuclei were counterstained
with Mayer’s hematoxylin
We have presented a clinical case of multicentric tumor lesions
in the ovary and fallopian tube. The ovarian tumor
had short (with dense fibrous stroma) and long thin papillae,
as well as slit-like glandular structures. They were
lined by single- and multilayered columnar epithelium
with cellular atypia and psammoma bodies. IHC revealed
positivity of the tumor cells for СK7, p53, and ER and
negativity for chromogranin A, СK20, CD56, CDX2, and
TTF1. Moreover, the presence of hormonal changes in the
endometrium (endometrial hyperplasia and endometrial
polyp) and ER expression in ovarian tumor cells can testify
to the estrogen effect in carcinogenesis of serous adenocarcinoma
. These morphological features are specific
for high-grade serous adenocarcinoma. Concurrently, the
fallopian tube tumor was characterized by the formation
of nests, anastomotic chains, and structures, such as peripheral
“palisades” and “rosettes”, of the same type of cells
with finely granular (salt and pepper) nuclear chromatin.
It expressed an immunophenotype typical for NETs (cells
were diffusely positive for chromogranin A and CD56).
Consequently, the final diagnosis was made as follows:
low-grade neuroendocrine tumor of the fallopian tube and
high-grade ovarian serous adenocarcinoma.
NETs comprise a heterogeneous group of neoplasms that
consist of neuroendocrine cells that can be localized in any
human organ. They can produce peptide hormones and
biologically active amines. The incidence of NETs has been
increasing in recent years, which may become the basis for
establishing clear criteria to determine tumor differentiation
following appropriate treatment and disease prognosis
13. NETs of the female reproductive system account for
2% of all female reproductive system tumors 14,15. Modern
morphological diagnostics continue to develop optimal
classification and grading systems of NETs in various localizations,
taking into account novel molecular, biological,
genetic, and IHC studies. There is an active search for diagnostic
parameters, markers for the evaluation of individual
prognostic factors, and targets for antitumor therapy.
Modern morphological diagnostics of NETs are based on
recommendations from the World Health Organization
(WHO) 16. In addition, proposals from the European
Neuroendocrine Tumor Society (ENETS), which
developed the other TNM system for the classification and
identification of NET malignancies of the gastrointestinal
tract and pancreas (ENETS; 2006, 2007), are being taken
into account. Both are focused on NET prognosis. They are
based on numerous morphological parameters, including
the level of cellular mitotic activity and presence of necrosis.
Studying the peculiarities of terminology, staging, and
grading of malignancies—as proposed by WHO, ENETS,
the American Joint Committee on Cancer it was determined
that none of the classification systems could be
considered universal 16-18. Female reproductive system
NETs are classified according to the tumor grading system
for gastrointestinal tract NETs (19,20).
Malignant tumors of the fallopian tubes are extremely rare
(0.14-1.8% of all female reproductive system tumors) and
often misdiagnosed as ovarian or uterine pathology 21-26. Despite their rarity, however, fallopian tube cancers
can be the primary source of ovarian and peritoneal tumors
23. Another rare pathology is multicentric primary
tumors, which can affect one or more topographic regions
without carcinogen clonal relationships 24. NETs rarely
occur in the female reproductive system. They can occur
in the cervix, ovaries, and endometrium, and particularly
rarely in the fallopian tubes 4,20,25-31. Fallopian tube
NETs were not included to WHO (4th edition) classification of tumors, however in 2020 neuroendocrine neoplasms are
discussed as a separate chapter in the current 5th edition
of WHO classification of the female genital tract tumors
31,32. The rarity of NETs in gynecological practice makes
it difficult to predict and evaluate their clinical behavior
and prognosis 2,14. In recent years, the leading experts
have developed a comprehensive dataset of universal
IHC markers, which makes it possible to carry out the
differential diagnosis between NETs and other tumors
and thereby determine the neuroendocrine nature of
the neoplasm 15. To grade tumor malignancy, which
depends on tumor cell proliferation, the Ki-67 proliferation
index should be determined 16,18. The main diagnostic
IHC markers for NETs that are recommended for practical
use are chromogranin A and synaptophysin 17,29,32,33.
Other markers, such as CD56, are sensitive but not very
The morphological peculiarities and immunophenotypes
of NETs are clearly defined and identifiable among other
tumors, including those in the fallopian tubes. However,
in some cases, the differential diagnosis of a high-grade
NET presents some difficulties and depends on the size
of the tumor cells (small or large). Since other high-grade
epithelial neoplasms may occur in the fallopian tubes (such
as serous or endometrioid carcinoma), it is essential to
determine the immunophenotype of poorly differentiated
tumors using IHC markers. The important task for the
morphologist is to determine whether the fallopian tube
NET is a primary lesion or a metastatic lesion from another
anatomical region. In this regard, IHC studies are limited
because NETs from different organs usually have similar
immunophenotypes. Two primary IHC markers that are
recommended for the diagnosis of metastasis from a welldifferentiated
NET when no primary lesion is identified
are CDX2 and TTF1. In this case, there was no clinical
or radiological evidence of any lesions in other locations.
Furthermore, the low-grade tumor in the fallopian tube was
negative for CDX2 and TTF1, which led us to believe that it
was a primary NET. It is plausible that the neoplasm arose
from diffusely scattered neuroendocrine cells, as they are
present in the normal epithelium of the female reproductive
tract 4. Thus, the final diagnosis and stage of the neoplasms
changed - the diagnosis “serous adenocarcinoma of the
ovary with metastasis to the fallopian tube (stage 2A)” was
replaced with “primary low-grade NET of the fallopian
tube with serous adenocarcinoma of the ovary (stage 1A)”.
In this case, surgery followed by dynamic observation was
chosen; no chemotherapy was required, although it had
previously been planned.
Accumulated data on the etiology, pathogenesis, biological
characteristics, and peculiarities of the clinical
course of NETs will lead to further improvements in
the diagnostic and treatment approaches to these rare
malignancies, which have been shown to occur in the
female reproductive system. Simultaneously, accurate
histopathological diagnosis and determination of the
tumor differentiation grade are essential in the selection of
appropriate conservative treatment. Although carcinoids
are considered benign tumors in many anatomical regions,
there is no experience with the clinical behavior of these
neoplasms in the fallopian tubes.
Our results prove that it is possible for a primary
neuroendocrine tumor to occur in the fallopian tubes
and coexist with an ovarian serous adenocarcinoma. The
neuroendocrine tumor of the fallopian tube was diffusely
positive for chromogranin A and CD56, but wild for p53
and negative for CK7, CK20 and ER; Ki-67 expression was
observed in 3% of the neoplastic cells. The ovarian serous
adenocarcinoma was positive for CK7 and ER, mutant
for p53, but negative for chromogranin A, CK20, and
CD56; Ki-67 expression was observed in 45% of the tumor
cells. Thus, this case confirms the value of morphologic
methods of study, which support the differential diagnosis
of fallopian tube and ovary tumors that were previously
considered poorly and undifferentiated malignancies.
This work was supported by the Ministry of Education and Science
of Ukraine under Grant № 0121U100472; research theme of the
Department of Pathology of Sumy State University under Grant №
Conflict of Interest
The authors report no conflict of interest. The authors declare that
the research was conducted in the absence of any commercial or financial
relationships that could be construed as a potential conflict
The study involving human participants was conducted according
to the guidelines of the Declaration of Helsinki, reviewed and approved
by the Bioethics Committee of Sumy State University (protocol
№19/06 from 28/06/2021). The patient provided written informed
consent to the publication of the case report results. There are no potentially
identifiable human images or data is presented.
Concept: NH, ML, VS, AR, Design: NH, ML, VS, AR, Data
collection or processing: NH, ML, VS, RC, YL, KS, WAA, Analysis
or Interpretation: NH, ML, VS, RC, YL, KS, WAA, Literature search:
RC, YL, KS, WAA, Writing: NH, ML, VS, AR, Approval: NH, ML,
VS, RC, YL, KS, WAA, AR.
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