A retrospective study was conducted in Kasturba Hospital, Manipal during an eight year study period between January 2006 and December 2014. The medical records of 11 patients with diagnosis of primary esophageal SCC were reviewed for their clinical presentation, history of smoking or any comorbid disease, gastrointestinal and respiratory endoscopic findings, radiological investigations, type of treatment and clinical outcome. The histopathology slides and their confirmatory immunohistochemistry were reviewed with special reference to presence of associated changes in adjacent mucosa. Primary nature of SCC was defined by the presence of definite esophageal growth by endoscopy, confirmed by histopathological examination of the same along with absence of pulmonary lesion on radiology or bronchoscopy. The data obtained was thus tabulated and studied.

Between January 2006 and December 2014, 11 cases of primary small cell carcinoma of the esophagus were diagnosed on endoscopic biopsy specimens out of 935 patients with esophageal malignancies with incidence of 1.17%. The patient characteristics have been summarized in [Table/Fig-1]. The age range was between 40 and 76 years and included nine males and two females (male:female ratio-4.5:1). The most common presenting complaint was dysphagia. History of smoking was present in only one patient. Eight patients had ulceroproliferative growth detected in the esophagus on upper gastrointestinal endoscopy, predominantly affecting the mid esophagus (7 of 11 cases), followed by upper (3 cases) and lower (1 case) esophagus. One case also had multiple satellite nodules in the esophagus. Histopathological examination of these cases revealed small cell carcinoma with predominant nested pattern and irregular sheets [Table/Fig-2]. The neuroendocrine nature of tumour was confirmed by IHC markers like synaptophysin and/or chromogranin in nine of the eleven cases [Table/Fig-3]. Mucosa adjoining the tumour revealed squamous cell carcinoma, squamous cell carcinoma in situ and squamous dysplasia in three, one and two cases respectively [Table/Fig-4,5]. No glandular differentiation was noted. Eight patients had distant metastasis at presentation, with liver (6/11) being the common site; 3 with associated abdominal lymphnode involvement of whom one patient each also had pulmonary and bone metastasis. Abdominal lymphnodes involved included perigastric, para aortic, peripancreatic and periportal nodes. Six patients received chemotherapy, of which three also received radiotherapy. Five patients deferred treatment. Follow up data was available in two (cases 5 and 8) patients who were asymptomatic after one year. The esophageal, bone and pulmonary lesions in one of these patients (case 8) regressed following chemotherapy. Further follow up was not available.

[Table/Fig-2]:

Small cell carcinoma composed of uniform small round cells in irregular sheets and nested pattern (H&E X50)

[Table/Fig-3]:

Esophageal SCC showing immunoreactivity for a) chromogranin and b) synaptophysin (X400)

[Table/Fig-4]:

Esophageal SCC, adjacent mucosal squamous dysplasia (H&E X50) Inset: a) small cell carcinoma (top left) b) squamous dysplasia (bottom right) (H&E X200)

[Table/Fig-5]:

Squamous cell carcinoma adjoining esophageal SCC (H&E X50) Inset (H&E X200)

Small cell carcinoma is primarily described as a pulmonary malignancy accounting for 16% of all lung cancers [5]. Extrapulmonary sites of occurrence include nasal cavity and paranasal sinuses, gastrointestinal tract, salivary glands, uterus, prostate and urinary bladder [5–7]. Esophagus is reported as the most frequent digestive tract site of extrapulmonary SCC with an incidence of less than 1.5% [6–8]. The incidence of esophageal SCC in our series was 1.17%.

Esophageal SCC usually affects individuals from sixth to eighth decade with male predominance [5–9] similar to the demographic profile in our study. Risk factors include smoking, alcohol consumption and Barrett esophagus [5,10]. In the present study, one patient was a chronic smoker. No other risk factors were observed.

Patients usually present with dysphagia, chest or abdominal pain, vomiting, weight loss and anorexia [5,6,10,11]. Associated paraneoplastic syndromes such as sensorimotor neuropathy and ectopic hormonal secretion have also been reported [10,12]. Eight of the 11 cases in the present study presented with dysphagia, two of them with associated abdominal pain. None had symptoms suggestive of paraneoplastic syndrome.

Endoscopically, esophageal SCC have been documented as ulcerated or ulceroproliferative lesions involving mainly middle and the lower third of the esophagus [5,6,10], with similar findings being noted in the present study. Histopathological examination of lesion biopsies revealed features similar to pulmonary SCC characterized by small round to spindle cells, scant cytoplasm, granular nuclear chromatin and inconspicuous nucleoli. The diagnosis is confirmed by demonstration of immunoreactivity to neuroendocrine markers (example: chromogranin, synaptophysin, CD56 and neuron specific enolase). TTF-1 has also been shown to have high positivity in esophageal SCC [3,5,11]; hence is not useful to distinguish lung from esophageal origin. Recently, leucine-rich repeat containing G-protein coupled receptor 5 (Lgr 5) over expression have been reported to have significant correlation with tumour stage, response to therapy and prognosis [1].

Combined esophageal SCC and squamous cell carcinoma/dysplasia or adenocarcinoma has been reported in literature [3–6,11]. In the study by Yun PJ et al., and Wu Z et al., 2/11 cases and 3/9 had associated squamous cell carcinoma [3,11]. A study at Tata Memorial hospital also reported three of 18 cases of combined small and squamous cell carcinoma [6]. Such co-existence of neoplasms with more than one cell type provides evidence to the common cell of origin. Amine precursor uptake and decarboxylation (APUD)/Kulchitsky cells present in the esophageal cardiac glands and pleuripotent esophageal basal reserve cells are proposed to be the cell of origin of esophageal SCC [3,4,6,11]. In our study, we had a relatively high occurrence of squamous neoplasm (6/11 cases) in the adjacent mucosa with three cases of squamous cell carcinoma, one case of carcinoma in situ and 2 cases of squamous dysplasia. Hence, our study supports the above hypothesis and also suggests that finding of such dual morphology could serve as a clue to the primary nature of the disease.

Patient characteristics such as clinical presentation and location of both esophageal small cell and squamous cell carcinoma are similar. Early dissemination, rapid growth, difference in treatment and poor prognosis emphasizes the importance of early and accurate diagnosis of SCC [3]. Majority of the patients of esophageal SCC have widespread metastasis at presentation, the most common site being liver. Other sites include lungs, peritoneum, thyroid, lymph nodes and bone [5,6,11]. Eight of the 11 patients in the present study had metastatic disease of which six involved the liver. Isolated liver involvement was seen in two patients while rest had associated lymph node, lung and bone involvement.

Treatment of esophageal SCC has been controversial, since most of these are detected at an advanced stage at presentation. Options include surgical resection, chemotherapy and radiotherapy. Like pulmonary SCC, esophageal SCC is also highly chemosensitive. Hence, systemic chemotherapy remains the mainstay of therapy. Chemotherapy with radiotherapy and surgical resection has shown to provide long term remission and increase survival rates among these patients [2,6,11,13,14]. Rare cases of complete response to chemo radiotherapy have also been reported [2]. Three of our patients received chemotherapy while three received additional radiotherapy. Inspite of aggressive treatment, the prognosis remains poor, the median overall survival ranging from 4.2 to 18.5 months [6].

Small cell carcinoma of the esophagus is a rare, aggressive and rapidly progressive disease with widespread metastasis at diagnosis. Possibility of metastasis from a lung primary needs to be ruled out. In such a scenario, the presence of squamous or glandular differentiation in the adjacent mucosa in addition to suggesting pleuripotent stem cell origin, also provides a histologic pointer to the tumor being a primary esophageal neoplasm.