Primary malignant tumors of the hypopharynx are predominantly squamous cell carcinomas (SqCCs), as primary small-cell carcinoma (SmCC) of the hypopharynx is rare. Combined primary SmCC and SqCC of the hypopharynx, referred to as composite tumor of the hypopharynx, is even more rare, with only 3 cases previously reported (1–3). Therefore, there is little information available on the optimal management of these patients. We herein report a the case of a patient with primary combined SmCC with an SqCC element and investigate the expression of specific proteins for molecular-targeted therapy.

A 74-year-old man, with a ~50-year history of excessive alcohol consumption and smoking, presented with a 3-month history of throat pain and hoarseness. There was no history of weight loss, dysphagia, or dyspnea. On hypopharyngoscopy, a tumor was identified in the right anterior wall of the piriform sinus (Fig. 1A). A pathologist analyzed the biopsy sample and diagnosed the lesion as SqCC, as no SmCC component was identified in the biopsy specimen. The right vocal cord was not fixed. A contrast computed tomography (CT) scan of the neck revealed a heterogeneously enhanced tumor sized 25×17×38 mm extending through the right piriform sinus (Fig. 1B). Moreover, fluorodeoxyglucose positron emission tomography (FDG-PET) revealed high-level accumulation in the primary tumor, with a maximum standardized uptake value of 14.6. There was no evidence of cervical lymph node metastasis, primary lung tumor, or distant metastasis. The patient was diagnosed with hypopharyngeal cancer classified as T2N0M0, according to the 2009 Union for International Cancer Control staging system (4). We performed a tracheostomy, total laryngectomy, right hemithyroidectomy and bilateral lateral neck dissection (level II–IV). The macroscopic surgical specimen is presented in Fig. 1C. The specimen consisted of the resected larynx and right piriform sinus tumor. A 25×20-mm deeply ulcerated tumor was found in the right piriform sinus. Microscopically, two components were identified in the lesion, namely a poorly differentiated SqCC and an SmCC containing chromatin-rich nuclei with scanty cytoplasm (Fig. 2A). Pathologically, multiple metastatic cervical lymph nodes were identifed bilaterally (right side, levels II and III; and left side, level III). Although the surgical margin was narrow, it was negative for cancer cells.

Concomitant chemoradiotherapy (cisplatin + etoposide with 45 Gy) was administered postoperatively. However, after the first course, adjuvant chemotherapy was discontinued due to prolonged bone marrow suppression, although the therapy was effective. However, despite treatment, distant metastases in the thoracic vertebrae (T5, 9 and 10) were confirmed by CT 6 months later. The patient's condition started to deteriorate and he succumbed to the disease 7 months after the initial treatment.

In the head and neck, SmCC most commonly arises in the larynx, but has also been reported in the sinonasal tract and salivary glands (10,11). Combined SmCC of the larynx has only been reported in 17 cases in the literature to date. The majority of these patients were men and in the 6th-7th decade of life. Moreover, the majority of the patients succumbed to the disease within 2 years of diagnosis, even with adjuvant radiation and chemotherapy (12–14). Despite the rarity of these tumors, the clinical behavior of combined SmCC of the larynx appears to be similar to that of the hypopharynx. Metastasis from a primary lung SmCC must be carefully distinguished from a primary hypopharyngeal or laryngeal SmCC by imaging studies of the lung (15). In this case, FDG-PET revealed high-level accumulation in the hypopharynx, without evidence of a lung tumor or distant metastasis. A chest contrast CT scan confirmed the absence of a primary lung tumor.

According to the World Health Organization classification of head and neck tumors in 2005, neuroendocrine carcinomas may be classified as typical carcinoid, atypical carcinoid, and SmCC (16). Neuroendocrine types of SmCC associated with an SqCC component are referred to as combined carcinomas. They are unusual, representing <10% of all neuroendocrine types (17). Neuroendocrine neoplasms of the hypopharynx and larynx constitute a morphologicaly heterogeneous group of tumors, with considerable differences in clinical behavior and very different treatment strategies (12). Combined SmCC of the hypopharynx is extremely rare and is often difficult to pathologically diagnose prior to surgical treatment. Moreover, the prognosis is very poor due to early metastasis, without established treatment regimen (3). Of the 4 reported cases of combined SmCC of the hypopharynx, including our case, 3 succumbed to the disease within 1 year (Table I). Multi-modality therapy should be performed for combined SmCC of the head and neck region. Therefore, new therapeutic strategies are required to improve the survival rate. The present case reports new findings: Positive expression of KIT and PDGFRα in the SmCC element and positive expression of EGFR and PDGFRα in the SqCC element. Furthermore, to the best of our knowledge, the present study is the first to report a KIT and PDGFRα mutation analysis in combined hypopharyngeal SmCC. KIT and PDGFRα, both mapped to chromosome 4q12, have structural similarities with other PDGFR family members. A majority of gastrointestinal stromal tumors (GISTs) display a gain-of-function mutation in the KIT proto-oncogene that encodes the KIT protein. The majority of mutations occur in KIT exon 11, but mutations may also be found in exon 9 and rarely in exons 13 and 17. The PDGFRα gene is also very similar to the KIT gene, and PDGFRα mutations have been found in exons 12, 14 and 18. Terada et al (18) reported KIT protein expression in 100% and PDGFRα expression in 65% of small-cell lung carcinoma cases; however, there were no genetic mutations of KIT and PDGFRα in small-cell lung carcinoma (18). In a previously reported case of esophageal combined SmCC, KIT and PDGFRα were expressed in the SmCC component, but not in the SqCC component (5). It was found that SmCC of the lung and extrapulmonary organs expressed KIT and PDGFRα, but there were no mutations in these genes within the hot spots of GISTs. These findings are almost completely in accord with those of our case study.

No biomarker has been yet proven to predict response to targeted therapy in either SmCC or SqCC. Moreover, a predictive biomarker in one cancer type may not be helpful in another cancer type, suggesting that different mechanisms may be involved in combined SmCC. To the best of our knowledge, a molecular-targeted therapy for treating combined SmCC of the hypopharynx and larynx has not yet been reported. Our case is the first to report KIT and PDGFRα expression in combined SmCC in the hypopharynx and larynx; if similar results are obtained from larger series, these data may have management and prognostic implications through the possible use of targeted biological therapy in these tumors. At present, SmCC treatment remains a significant challenge for the oncologists, with several targeted agents under evaluation. However, there is no effective molecular-targeted therapy for SmCC. Evaluating the expression of the KIT and PDGFRα genes within hypopharyngeal SmCC may facilitate the development of novel agents for the molecular-targeted therapy of this tumor. However, further investigations are necessary regarding these proteins expression and clinical application of molecular targeted therapy for hypophageal combined SmCC.