Postradiotherapy small cell neuroendocrine carcinoma of base of tongue: An unusual clinical and site presentation.

Small cell neuroendocrine carcinoma (NEC) of the tongue is an extremely rare entity with only seven cases reported in literature till date. These are high-grade tumors with a dismal prognosis. There is much ambiguity regarding the classification, treatment protocols and prognostic factors of these tumors due to the paucity of studies. We describe an exceptionally rare and unusual case of small cell NEC of the base of tongue arising in an elderly man 6 years after receiving radiotherapy for the treatment of squamous cell carcinoma at the same site. The diagnosis was confirmed on histopathological examination and supported by immunohistochemical positivity for neuron-specific enolase, synaptophysin, chromogranin, pan-cytokeratin, and cytokeratin 7. To the best of our knowledge, this is the first case of intraoral NEC arising many years later within the irradiated field of the initial tumor.

Introduction

Neuroendocrine carcinoma (NEC) is a separate class of neoplasms arising in lungs, with well-defined clinical, morphological, and immunohistochemical features. Rare cases of extrapulmonary NECs have been described in stomach, ovary, cervix, urinary bladder, and colorectum.[1] However, head and neck regions are an exceeding unusual site for these tumors with larynx being most commonly affected.[2] The tongue is an extremely rare site for NECs with only seven cases reported in literature till date.[3456789] However, due to the paucity of studies, no definite prognostic factors and treatment protocols are defined for these tumors in the oral cavity.

We report an exceptionally rare and unusual case of small cell NEC of the tongue arising in an elderly man 6 years after the primary diagnosis and complete treatment of squamous cell carcinoma at the same site. To the best of our knowledge, this is the first case being reported in the setting of radiotherapy at this site.

Case Report

A 60-year-old male patient was being regularly followed up in the Department of Radiotherapy since 6 years. In the year 2010, he presented with a growth on the base of the tongue that had gradually increased in size over the preceding 8 months. He was a chronic smoker (15 pack years) and chewed tobacco. An irregular, friable growth was seen on the right side of the base of tongue measuring 1.5 cm × 1.5 cm × 0.5 cm along with the level I right cervical lymphadenopathy. All the routine laboratory investigations along with X-ray and computed tomography (CT) of the patient's chest and abdomen were within normal limits. Fine needle aspiration cytology smears from the enlarged cervical lymph node showed metastatic deposits of squamous cell carcinoma. We received an incisional biopsy in the Department of Pathology and histological examination showed features of moderately differentiated squamous cell carcinoma of the base of tongue. Thus, a final diagnosis of carcinoma of the base of tongue, stage III (T1N1M0) was made, and the patient was planned for radical radiotherapy. The patient received radiotherapy (dose 66 Gy/33 fractions/6.5 weeks) in the same year and achieved complete response. He was regularly followed up at an interval of 4–5 months with no recurrence for 6 years. He had stopped smoking as well as chewing tobacco. His oral hygiene was good. However, in the last follow-up session in May 2016, he complained of mild pain while swallowing. On examination, an irregular firm growth was seen on the base of tongue. There was no palpable lymphadenopathy. CT scan showed a growth on the right side of the base of tongue measuring 3 cm × 2 cm × 1 cm [Figure 1]. Salivary glands and vocal cords showed hyperechoic echogenicity caused by the fatty tissue infiltration, suggestive of mild radiotherapy-induced changes. There was no evidence of any malignancy or significant lymphadenopathy elsewhere in the body. There was no history of any immunosuppressive condition or immunosuppressant drug intake. Incisional biopsy showed monomorphic tumor cells arranged in diffuse sheets and small clusters infiltrating into the surrounding fibroconnective tissue. The individual tumor cells were round with scant amount of eosinophilic cytoplasm and a round to oval hyperchromatic nucleus. Abnormal mitotic figures (7–8/10 high power fields), necrosis, and crush artifact were also seen [Figure 2a–d]. There was no evidence of keratinization. Based on the morphology, a differential diagnosis of poorly differentiated squamous cell carcinoma, small cell carcinoma, nonHodgkin's lymphoma, and Merkel cell carcinoma were considered and an immunohistochemical panel was applied for definite categorization. On immunohistochemistry, the tumor cells showed positivity for neuron-specific enolase, synaptophysin, chromogranin, pan-cytokeratin (CK), and CK7 [Figure 3a–d]. The tumor cells were negative for p63, leukocyte common antigen, and CK20 thereby excluding squamous cell carcinoma, lymphoma, and Merkel cell carcinoma, respectively. The tumor showed high Ki-67 proliferation index of 75%–85%. Thus, on the basis of distinct immunohistomorphological features, a final diagnosis of small cell NEC of the base of tongue was rendered. The patient was then planned for wide local excision.

Figure 1

Computed tomography showing a primary tumor at the right side of the base of tongue measuring 3 cm × 2 cm × 1 cm

Figure 2

(a) Photomicrograph showing monomorphic tumor cells arranged in small clusters, nests, and sheets suggestive of neuroendocrine differentiation (H and E, ×100), (b) tumor cells are seen invading the fibroconnective stroma (H and E, ×200), (c) individual tumors cells are round with scant eosinophilic cytoplasm and round to oval hyperchromatic nucleus (H and E, ×400), (d) photomicrograph showing tumor necrosis and crush artifact commonly seen in small cell neuroendocrine carcinoma (H and E, ×200)

Figure 3

Immunohistochemistry: Tumor cells demonstrating positivity for neuron-specific enolase (a), synaptophysin (b), chromogranin (c), and cytokeratin 7 (d) (immunostain × 200)

Discussion

Neuroendocrine cells of the oral mucosa constitute an under-recognized component of the neuroendocrine system. These give rise to a spectrum of lesions in the oral cavity.[2] However, due to the rarity of intraoral neuroendocrine tumors, a definite classification has not been established yet. Only seven cases of NECs of the tongue have been described in literature till date. The mean age of presentation was 50.7 years (range 40-79 years) with a male: female ratio of 2.5: 1. Majority of these patients had a history of tobacco smoking.[3456789]

Preoperative diagnosis of these tumors is challenging, owing to rather nonspecific clinical and radiological features indistinguishable from other carcinomas arising in the oral cavity. The diagnosis of NECs is solely based on morphology and supported by immunohistochemistry. However, morphology alone cannot differentiate primary from metastatic NECs. Thus, a complete clinical and radiological workup is needed to rule out any focus of primary tumor elsewhere. Our patient showed no evidence of malignancy on CT scans of chest and abdomen thereby excluding the possibility of metastasis.

Our patient presented with a second malignancy 6 years after receiving radiotherapy for squamous cell carcinoma of the tongue. Since the second tumor with a different histological diagnosis appeared within the irradiated field of the initial tumor treated 6 years previously, we suspected radiation-induced cancer. While similar cases have been reported previously in skin, cervix, and lung,[10] ours is the first case of NEC in the tongue which occurred after radiotherapy treatment. Further, the rarity of the NEC in the tongue added to the diagnostic challenge. Thus, not only is development of radiation-induced cancer a problem in patients treated with radiotherapy, it can have a long incubation period as seen in the present case. Hence, close observation is suggested in long-term survivors.

High-grade NECs of the head and neck are most commonly found in patients with advanced age and carry a dismal prognosis.[1] There are no well-defined treatment protocols for high-grade NECs in oral cavity. Different treatment strategies such as surgery followed by chemoradiotherapy, chemotherapy alone, or chemoradiotherapy can be used. Treatment modality in our case remains debatable as it occurred in the setting of radiotherapy. Probably surgery will be the best in this case, but it is too early for us to comment upon the survival.

To conclude, NEC of base of the tongue is an extremely rare tumor. Our case highlights that these tumors can occur as a late complication of radiotherapy to the head and neck. More data are needed to form a consensus regarding the prognostic factors and treatment protocols.

Financial support and sponsorship

Nil.

Conflict of interest

There are no conflicts of interest.