FIGURE 2 phrosis , which was associated with local and distant metastasis . At 7 months following initial diagnosis , the patient died from complications related to the carcinoma .
DISCUSSION
Neuroendocrine tumors ( NETs ) represent rare and aggressive neoplasms with a predilection for the respiratory and gastrointestinal tracts ; however , variants can be found in other systems , including the female gynecological tract . 1 NETs of the female gynecologic tract are rare , comprising only 2 % of all gynecological cancers , and they are associated with poor prognosis . 2 Travis et al . described four NET types , including typical carcinoid tumors ( TC ), atypical carcinoid tumors ( AC ), small cell neuroendocrine carcinoma ( SCNC ), and large cell neuroendocrine carcinoma ( LCNC ). 3 In 2014 , the World Health Organization further classified NETs into low-grade neuroendocrine carcinoma , consisting of TC and AC , and highgrade neuroendocrine carcinoma , consisting of SCNC and LCNC . 4 NETs found in the ovaries are more commonly lowgrade tumors , whereas NETs found in the uterus and cervix are more commonly high-grade tumors . 4 , 5
High-grade NETs arise from cells in the lymph nodes , endocrine glands , endocrine system , and skin . 6 The cervix is the most common site of high-grade NET , but 0.8 % of endometrium carcinomas are classified as small-cell carcinoma of the endometrium . 7 NETs of the endometrium are commonly found in conjunction with non-NET endometrium carcinomas , such as endometrioid adenocarcinomas , carcinosarcomas , and adenosquamous carcinoma . 6 Few reports have indicated that small-cell carcinoma can also be found with large-cell and serous carcinomas . 7 It is imperative to differentiate between NETs and non-NETs due to the variability in location of metastasis . NETs have a high rate of lymphatic and hematogenous metastasis , often involving the peritoneum and lymphovascular space , as seen in our patient . 8 Non-NETs , such as endometrial carcinomas , typically metastasize to the lymphatic system . 6 Notably , our patient ’ s lymph nodes were clear of any metastasis .
Patients most commonly present with vaginal bleeding , vaginal discharge , abdominal pain , or weight loss . 4 Rare paraneoplastic signs include retinopathy , Cushing ’ s syndrome , and membranous glomerulonephritis . 6 Our patient presented with postmenopausal bleeding followed by an endometrial biopsy that showed highgrade , poorly differentiated carcinoma . Following surgical intervention , the tumor underwent immunohistological staining in order to diagnose and stage the carcinoma .
Van Hoven et al . described the threshold for small-cell NET diagnosis as morphological features of small-cell carcinoma , evidence of endometrial origin , and immunohistochemical staining with one endometrium NET marker , such as synaptophysin , CD56 , or chromogranin A . 9 CD56 is not a specific marker ; therefore , if a tumor test is positive for only CD56 , NET of the endometrium can be ruled out . 4 Our patient ’ s tumor tested positive for synaptophysin in samples of the endometrium and omentum indicating high-grade NET with metastasis to the omentum . Additionally , our patient ’ s tumor tested positive for p16 ; this marker is positive in the majority of NETs of the gynecological tract and cannot be used to distinguish between cervical and endometrium . However , NET of the cervix is commonly associated with human papillomavirus , whereas NET of the endometrium is less likely . 4 Lastly , MSI testing allows for the identification of a genetic component and lends to determining the aggressive nature of the tumor . 7 The majority of NET cases are not
Figure 2 : Immunohistochemical stains : 2A ) Pancytokeratin highlighting adeno- and neuroendocrine carcinoma components of mass , 2B ) CD56 highlighting only neuroendocrine carcinoma component , 2C ) ER highlighting adenocarcinoma and smooth muscle ( internal control ), 2D ) and 2E ) CD56 and synaptophysin highlighting diffuse proliferation of neuroendocrine component
associated with MSI ; however , of the 44 % that are , the most common instability is associated with loss of MLH / PMS2 . 4 , 7 Our patient displayed intact expression of all tested DNA mismatch repair proteins .
There is limited evidence that supports a standard management protocol of NETs in conjunction with endometroid carcinoma due to the rarity of the disease . 6 , 7 For those who are surgical candidates , like our patient , it is recommended to perform cytoreduction with total hysterectomy , bilateral salpingo-oophorectomy , omentectomy , and lymphadenectomy . 7 , 10 Adjuvant therapy for high-grade neuroendocrine carcinoma is determined based on the similarities with small-cell carcinoma of the lung . 10 Treatment regimens that improve survival rates include platinumbased chemotherapy with etoposide and concurrent radiation therapy . 10 Alternative second-line therapies include vincristine , doxorubicin , cyclophosphamide , and topotecan . 10
While the initial response rate to surgical intervention and adjuvant therapy is 50- 79 %, there is a high recurrence rate within two years . 10 Specifically , tumor relapse rates are 50 % in patients who were diagnosed in early stages and 88 % in patients who were diagnosed in advanced stages . 6 The prognosis associated with this disease is poor , such that the mean overall survival is 22 months in patients who were diagnosed in early stages and 12 months in patients who were diagnosed in advanced stages . 6
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