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  • This patient presented to our emergency

    2019-05-10

    This patient presented to our emergency department with a three-day history of worsening headache six years after she was diagnosed with mixed adenoneuroendocrine carcinoma of the uterine cervix. Upon presentation, she reported rapidly progressive dizziness, vomiting and rightward deviation when walking. Magnetic resonance imaging (MRI) of the stat 3 inhibitor revealed one left cerebellar mass with mixed components of fluid and loose substance measuring 39 mm in diameter (Fig. 2). A whole-body CT scan for assessment of the extent of metastases revealed multiple nodular lesions in the right lower lobe (RLL) of the lung with right pleural effusion, right hilar lymph node enlargement, another smaller tumor in the left lower lobe and bilateral adrenal gland metastases (Fig. 3). The patient underwent a craniotomy procedure to remove the tumor. The specimen of brain tumor stained by hematoxylin-eosin showed acinar and tubular patterns similar to previous cervical carcinoma (Fig. 4A). The immunohistochemical stains were diffusely positive for synaptophysin (Fig. 4B), CD56 (Fig. 4C) and focally for TTF-1 (Fig. 4D). Ten days later, she underwent percutaneous CT-guided biopsy of her RLL nodules. The resulting biopsy specimen revealed small cell lung cancer with focal adenocarcinoma (Fig. 5A). The noted patterns of immunohistologic staining were CD56 (+), synaptophysin (+) and TTF-1 (+) (Fig. 5B–D). The genetic components for activating mutation of epidermal growth factor receptor were not detected in either brain or lung specimen. HPV DNA in the cervical, brain and lung tumor cells was detected and typed by a genechip (Easychip HPV Blot, King Car, Taiwan). HPV type 18 was identically found in these three specimens. She underwent whole-brain radiation therapy with 30 gray in 12 fractions. Then the patient was treated with systemic chemotherapy (cisplatin 25 mg/m2 and etoposide 100 mg/m2 for three days) monthly for six courses. Subsequently, her chemotherapy was shifted to triweekly CEV regimen (cyclophosphamide 1000 mg/m2, epirubicin 50 mg/m2, and vincristine 1.4 mg on day 1) due to the progress of her disease. After 3 cycles of CEV regimen, the treatment plan was adjusted to provide best supportive care due to the patient\'s poor performance status. Thereafter, this patient died 17 months after she was first diagnosed with mixed adenoneuroendocrine carcinoma of lung.
    Discussion Neuroendocrine carcinoma of the cervix represents only about 1–2% of all cervical malignancies. Patients with early stage disease treated with multimodality therapy reported a 3-year survival rate of up to 80%.This patient had survived for 6 years while maintaining her usual health status after the surgical resection of cervical cancer. However, the patient\'s brain metastasis as the first manifestation along with disseminated disease upon diagnosis was a noteworthy dilemma in this case. Distinguishing late recurrence of the previous cervical cancer and the second primary lung cancer can present a substantial diagnostic challenge. Two large case series reported that late recurrence (more than 5 years) was only found in cervical squamous cell carcinoma and adenocarcinoma, and patients with stage IA disease had no events of late recurrence. Regarding clinical manifestations, the extent of tumor spread from the whole-body CT scan is consistent with typical presentation of small cell lung cancer. However, similar histology features and immunohistochemical staining among brain, lung and cervical specimens may suggest the same clonal origin. It is very likely the patient later developed another primary neuroendocrine carcinoma from the lung, but the possibility of late recurrence from prior cervical site cannot be completely excluded. The relationship between HPV and neuroendocrine carcinoma has been seldom reported, and the pathogenesis of HPV-associated neuroendocrine carcinoma remains inadequately understood. An association with high-risk HPV infection (HPV 18 more than HPV 16) has been described for both small and large cell neuroendocrine carcinoma of the uterine cervix. Two studies described the clinical and pathologic features of 17 cases of HPV-associated poorly differentiated or small cell neuroendocrine carcinoma in the oropharynx. HPV-related small cell neuroendocrine carcinoma has also been reported in the sino-nasal tract and the lower gastro-intestinal tract. In terms of the association between HPV and neuroendocrine carcinoma of the lung, Thomas et al first reported HPV in primary lung neuroendocrine carcinoma. Another study reported five of 18 patients with small cell lung cancer were associated with HPV. High-risk HPV was known to encode for the oncogenic E6 and E7 proteins inactivating p53 and pRB, respectively, resulting in an increased proliferation of tumor cells. Inactivation of pRB by HPV type 18 E7 protein may be involved in carcinogenesis of small cell carcinoma of the cervix. Further studies are needed to investigate the detection rate of HPV and the role of HPV in lung neuroendocrine carcinoma.