Journal of Cancer Research and Practice 3 (2016) 89e93

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Journal of Cancer Research and Practice

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research-and-practice

Case report

Human papillomavirus type 18-associated cervical and lung mixed

adenoneuroendocrine carcinoma
Chan-Keng Yang a, Wen-Kuan Huang a, Shih-Ming Jung b, *
a
Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of
Medicine, Taoyuan, Taiwan
b
Department of Pathology, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan

a r t i c l e i n f o a b s t r a c t

Article history: Human papillomavirus (HPV) is associated with neuroendocrine carcinoma of the cervix and lung.
Received 23 July 2015 However, these two uncommon cancers rarely occur in a single patient, especially with the same HPV
Accepted 2 October 2015 type. We herein present a 65-year-old non-smoker female who developed mixed adenoneuroendocrine
Available online 8 June 2016
carcinoma of the lung with lymph node, brain and adrenal gland metastases 6 years after the diagnosis of
stage IA1 cervical mixed adenoneuroendocrine carcinoma. The patient's brain, lung and previous cervix
Keywords:
specimens were identically HPV type 18 positive. To our knowledge, this is the first report of a patient
Mixed adenoneuroendocrine carcinoma
with the same HPV type associated mixed adenoneuroendocrine carcinoma in different sites.
Neuroendocrine carcinoma
Human papillomavirus
Copyright © 2016, The Chinese Oncology Society. Production and hosting by Elsevier B.V. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction
The most common type of human papillomavirus (HPV)
reportedly associated with large cell1,2 and small cell3,4 neuroen-
docrine carcinoma of the cervix are type 16 and 18. HPV has rarely
been found in small cell lung cancer or neuroendocrine carcinoma
of the lung.5,6 We present a case of a female patient with cervical
mixed adenoneuroendocrine carcinoma who underwent radical
resection, whereafter lung nodules and multiple metastases later
developed after 6 years. The pathologic features of lung and brain
lesions were similar to previous cervical carcinoma. Moreover, the
HPV type 18 was identified in these three specimens.
2. Case report
A 59-year-old woman was diagnosed with stage IA1 adenocar-
cinoma of the uterine cervix in 2007. Following initial conization,
she underwent radical hysterectomy after which there was no gross
residual cancer. The pathologic finding from her conization spec-
imen revealed adenocarcinoma with infiltrative acinar pattern
(Fig. 1A). Immunohistochemical study displayed focal cytoplasmic
* Corresponding author. Department of Pathology, Chang Gung Memorial
Hospital at Linkou, No.5, Fusing St., Gueishan, Taoyuan, 333, Taiwan.
E-mail address: ming22@cgmh.org.tw (S.-M. Jung).
Peer review under responsibility of The Chinese Oncology Society.
staining for synaptophysin (Fig. 1B), CD56 (Fig. 1C) and thyroid
transcription factor-1 (TTF-1) (Fig. 1D), which confirmed the
neuroendocrine differentiation. The patient did not receive any
adjuvant treatment following the surgery, and annual follow-up
examinations with Pap smear showed no evidence of recurrence.
Until our recent medical intervention, the patient had remained in
her customary health status, with medically-controlled
hypertension.
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. Mag-
netic resonance imaging (MRI) of the brain revealed one left cere-
bellar 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 tu-
mor 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 cer-
vical 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

http://dx.doi.org/10.1016/j.jcrpr.2016.05.008
2311-3006/Copyright © 2016, The Chinese Oncology Society. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
90 C.-K. Yang et al. / Journal of Cancer Research and Practice 3 (2016) 89e93
Fig. 1. Specimen removed from the uterine cervix shows mixed adenoneuroendocrine carcinoma. (A) Representative section of the tumor showed adenocarcinoma with infiltrative
acinar pattern (H&E, 200). Tumor cells showing focal cytoplasmic staining for (B) synaptophysin (200), (C) CD56 (200) and (D) TTF-1 (200).
Fig. 2. Brain magnetic resonance imaging showed a nodule with mixed components of
fluid and loose substance measuring 39 mm in diameter in the left cerebellum.
percutaneous CT-guided biopsy of her RLL nodules. The resulting
biopsy specimen revealed small cell lung cancer with focal adeno-
carcinoma (Fig. 5A). The noted patterns of immunohistologic
staining were CD56 (þ), synaptophysin (þ) and TTF-1 (þ)
(Fig. 5BeD). 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 chemo-
therapy (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 treat-
ment 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 adenoneur-
oendocrine carcinoma of lung.
3. Discussion
Neuroendocrine carcinoma of the cervix represents only about
1e2% of all cervical malignancies.7,8 Patients with early stage dis-
ease treated with multimodality therapy reported a 3-year survival
rate of up to 80%.9,10This 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.
 C.-K. Yang et al. / Journal of Cancer Research and Practice 3 (2016) 89e93 91

Fig. 3. Whole body CT scan showed tumor spread extensively throughout the body.(A) One irregular nodule in the right lower lobe of lung with pleural effusion. (B) Right hilar
lymph node enlargement. (C) One small nodule in the left lower lobe. (D) One adrenal nodule in the left adrenal gland.

Fig. 4. (A) Specimen removed from the cerebellar tumor shows mixed adenoneuroendocrine carcinoma (H&E, 100). Diffuse immunohistochemical staining for (B) synaptophysin
(200), (C) CD56 (200) and (D) TTF-1 (200).
92 C.-K. Yang et al. / Journal of Cancer Research and Practice 3 (2016) 89e93
Fig. 5. (A) Small cell lung carcinoma with focal adenocarcinoma in lung specimen from needle biopsy (H&E, 100). (B) CD56, (C) synaptophysin and (D) TTF-1 were positively
stained in the area of the small cell lung cancer.
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 squa-
mous cell carcinoma and adenocarcinoma, and patients with stage
IA disease had no events of late recurrence.11,12 Regarding clinical
manifestations, the extent of tumor spread from the whole-body CT
scan is consistent with typical presentation of small cell lung can-
cer.13 However, similar histology features and immunohistochem-
ical 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.1e4 Two studies described the
clinical and pathologic features of 17 cases of HPV-associated
poorly differentiated or small cell neuroendocrine carcinoma in
the oropharynx.14,15 HPV-related small cell neuroendocrine carci-
noma has also been reported in the sino-nasal tract16 and the lower
gastro-intestinal tract.17 In terms of the association between HPV
and neuroendocrine carcinoma of the lung, Thomas et al first re-
ported HPV in primary lung neuroendocrine carcinoma.5 Another
study reported five of 18 patients with small cell lung cancer were
associated with HPV.6 High-risk HPV was known to encode for the
oncogenic E6 and E7 proteins inactivating p53 and pRB, respec-
tively, resulting in an increased proliferation of tumor cells.18
Inactivation of pRB by HPV type 18 E7 protein may be involved in
carcinogenesis of small cell carcinoma of the cervix.19 Further
studies are needed to investigate the detection rate of HPV and the
role of HPV in lung neuroendocrine carcinoma.
We described the first case, to our knowledge, of a patient with
the same HPV type associated mixed adenoneuroendocrine carci-
noma in different sites to generate awareness that HPV might play a
role in the carcinogenesis of neuroendocrine carcinoma.
Conflict of interest
The authors have claimed that no potential conflicts of interest.
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