Dig Dis Sci (2016) 61:384–388 DOI 10.1007/s10620-015-3962-8

UNM CLINICAL CASE CONFERENCES

Small Cells, Big Problems Thomas Queen1,3 • Barakat A. Altamimi1 • Christopher Chang1 • Joseph Glass2

Received: 2 November 2015 / Accepted: 5 November 2015 / Published online: 18 November 2015  Springer Science+Business Media New York 2015

Case Presentation A 74-year-old man was initially evaluated in the Emergency Department with complaints of difficulty swallowing solid food and pills over the past 9 years that had progressed over the previous 2 months, accompanied by a 20-pound weight loss over the last year. Past history included an esophageal B-ring diagnosed 9 years ago and extensive use of alcohol and tobacco. He noted occasional vomiting shortly after eating solid food, but denied any abdominal pain, nausea, hematemesis, melena, hematochezia, or family history of cancer. The patient was previously followed in the gastroenterology clinic for recurrent dysphagia. Over the previous 9 years, his evaluation had included five esophagogastroduodenoscopy (EGD) examinations, with biopsies of an inflammatory stricture (B-ring) and dilatation each time. His last EGD, performed 8 months prior to his current presentation, again showed the B-ring at 38 cm from the incisors. Biopsy of the stricture again showed typical squamous mucosa without other diagnostic features. An upper GI barium swallow performed at that time showed the presence of a 5-cm-long hiatus hernia, mild gastroesophageal reflux to the middle third of the esophagus, and a short-segment benign-appearing lower esophageal stricture.

& Thomas Queen [email protected] 1

Division of Gastroenterology and Hepatology, Department of Medicine, University of New Mexico School of Medicine, Albuquerque, NM, USA

2

Department of Surgical Pathology, University of New Mexico School of Medicine, Albuquerque, NM, USA

3

Division of Gastroenterology and Hepatology, MSC 10-5550, 1 University of New Mexico, Albuquerque, NM 87131, USA

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Eight days prior to his visit to the Emergency Department, an esophagram, ordered for complaints of worsening dysphagia, showed a new, probably extrinsic mass compressing the proximal esophagus posteriorly, with a soft tissue density overlying the defect. The compression was suspected to be due to dilated brachiocephalic blood vessels, although this had not been noted on previous imaging (Fig. 1a, b). A computed tomographic (CT) scan with oral and IV contrast and a repeat EGD were ordered. Before these tests could be completed, the patient again visited the Emergency Department for worsening dysphagia where his initial evaluation revealed a thin, cachectic man who was afebrile (36.8 C), with a normal heart rate (69 beats/min), blood pressure (117/ 70 mmHg), respiratory rate (18/min), and a blood oxygen saturation [95 % on room air. On physical examination, the patient was noted to have bitemporal wasting. The oropharynx was clear and moist, and he had dentures that were securely in place. The remainder of his physical examination was unremarkable. A CT scan of the thorax with oral contrast revealed a 4 9 7 cm focal dilation of the cervical and proximal thoracic esophagus with suggestion of a subtle stricture seen distal to the dilation (Fig. 2a, b). Laboratory tests revealed a normal complete blood count, basic metabolic panel, and prothrombin time/international normalized ratio (PT/INR). The patient was taken to the endoscopy suite, and an EGD was carefully performed. First an ‘‘ultraslim’’ endoscope scope was passed through the mouth under direct vision. A nearly circumferential esophageal mass, extending from 15 to 23 cm from the incisors (Fig. 3a, b), was biopsied. The scope was successfully passed through and beyond the mass, where the esophageal B-ring was seen separately in the distal esophagus. Additional biopsies were obtained using a standard endoscope that was advanced to

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Fig. 1 a Esophagram, oblique view, showing compression of the posterior proximal esophagus with a soft tissue density projecting over the defect. b Esophagram, AP view, showing compression of the posterior proximal esophagus with a soft tissue density projecting over the defect

Fig. 2 a CT scan of the thorax with contrast, sagital view, showing a 4 9 7 cm focal diation of the cervical and proximal thoracic esophagus with suggestion of a subtle stricture seen inferior to the dilation. b CT scan of the thorax with contrast, coronal view,

showing a 4 9 7 cm focal diation of the cervical and proximal thoracic esophagus with suggestion of a subtle stricture seen inferior to the dilation

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Fig. 3 Histological characterisation of tumor as squamous. a Section of tumor stained with hematoxylin and eosin. b Section of tumor stained with synaptophysin. c Section of tumor stained with CK AE 1/3. d Section of tumor stained with CK 5/6

and through the mass. The patient was then admitted to hospital for further evaluation and care. Histologic examination of the biopsies revealed necrotic debris and two small fragments of viable neoplasm, which consisted of loosely cohesive clusters of hyperchromatic small cells, with nuclear molding and very scanty or no cytoplasm (Fig. 3a). The neoplastic cells stained positively for synaptophysin (Fig. 3b) and cytokeratin (CK) AE1/3 (Fig. 3c), and negative for CK 5/6 (Fig. 3d). The cells were also positive for cluster of differentiation (CD) 56 and nuclear p63, and negative for nuclear thyroid transcription factor-1 (TTF-1), neuronspecific enolase (NSE), CD45, CK 7, and chromogranin (not shown). These morphologic and immunohistochemical findings of the biopsies altogether were most consistent with the diagnosis of a small cell carcinoma. Subsequently, the patient had positron emission tomography (PET)/CT single-photon emission computed tomography (SPECT) imaging, which showed markedly fluorodeoxyglucose 18(FDG)-avid thickening of the proximal esophageal wall, with an average SUV of 8.5 (maximum SUV of 11.7). The thickest portions of the esophageal wall measured up to 1.9 cm. There were areas of increased metabolic activity adjacent to the inferior right and superior right poles of the lesion that probably represented local invasion rather than adjacent lymphadenopathy. The findings were reported as compatible with esophageal

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carcinoma without identifiable distant disease. There were no lesions of any kind in either lung.

Treatment His tumor was staged via the American Joint Committee on Cancer (AJCC) tumor-node-metastases (TMN) system as T4 N1 M0 primary small cell carcinoma of the esophagus (SmCCE). On the basis of the staging, concurrent chemotherapy and radiation therapy were recommended, as he was deemed not to be a candidate for surgical excision at that time. Magnetic resonance imaging (MRI) of the brain showed no intracranial metastases. He subsequently received two cycles of chemotherapy with cisplatinum and etoposide and then began combined-modality treatment with radiation on cycle 3 of chemotherapy. Currently, he is on cycle 4 of his chemo-radiation therapy and continues to have dysphagia. Despite eating problems, he has refused placement of a feeding tube. The prognosis is uncertain.

Discussion First described by McKeown in 1952, primary SmCCE is a rare, aggressive tumor with a poor prognosis [1, 2], thought to represent 0.5 % of all esophageal tumors in the USA,

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with most of the cases occurring in males in their sixth decade [2–5]. As in squamous cell carcinoma of the esophagus (SqCCE), occurrence of SmCCE is strongly correlated with prolonged use of tobacco and alcohol (in 90 and 70 % of patients, respectively) [4]. Patients afflicted with SmCCE commonly initially seek medical attention due to symptoms of esophageal obstruction, including rapidly progressive dysphagia, epigastric, or retrosternal pain [4]. Subsequently, cachexia and weight loss often progress rapidly due to anorexia and a decline in caloric intake [4, 6]. In a study of 24 SmCCE patients by Vos et al. [4], SmCCE occurred predominantly in the middle or lower third of the esophagus (52 and 35 %, respectively). More than half of the patients had extensive disease by the time of diagnosis. Histologically, primary SmCCE can be indistinguishable from small cell carcinoma of the lung as its cell type of origin is comprised of neuroendocrine cells; furthermore, it may have elements of adenocarcinoma or squamous cell carcinoma [2]. Some investigators believe that this is due to pluripotent stem cells serving as common precursors for all types of esophageal cancers [2, 7]. Furthermore, small cells have the capacity to differentiate further into either keratin-forming cells or mucin-producing cells [2, 8]. Some investigators theorize that the origin of SmCCE may be from neuroendocrine cells of the submucosal glands or basal stratum of the lining epithelium, but neurosecretory granules are not essential to the diagnosis of SmCCE and are not always present histologically [2, 9, 10]. Biopsy appearances of this neoplasm consisted of sheets of crushed-appearing, hyperchromatic, small cells with nuclear molding and scant-to-no cytoplasm, in conformity with the criteria set by the 2000 World Health Organization (WHO) histologic classification [11]. The cells were positive for CD56, synaptophysin, nuclear p63, and CK AE1/3 and negative for nuclear TTF-1, NSE, CD45, CK7, chromogranin, and CK5/6. The positive stains for synaptophysin, CD 56, p63, and CK AE1/3 are consistent with SmCCE but are not specific, as small cells are also usually positive for NSE, TTF-1, and chromogranin. Nevertheless, the positive stains in combination with a negative CK5/6 made SmCCE the most likely diagnosis [12]. Since there is not a specific cancer staging system for SmCCE, the disease is usually staged according to the 2002 AJCC TMN system and the criteria of the Veterans’ Administration Lung Study Group (VALSG) for primary pulmonary small cell carcinoma [5]. The VALSG classification consists of two staging categories, namely ‘‘limited disease’’ (tumor confined within a localized anatomic region with or without regional lymph node involvement) and ‘‘extended disease’’ (tumor outside loco-regional boundaries) [5, 13]. This patient was staged as T4 N1 MO and thus considered ‘‘limited disease’’ by VALSG staging.

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SmCCE is commonly treated with multimodal therapy including chemotherapy and chemo-radiation, with or without surgery [5]. In the past, surgical resection has been considered to be the primary treatment of the disease [5]. In limited-stage SmCCE, however, there are now data supporting the use of induction chemotherapy, followed by chemo-radiation without surgery, to achieve long-term survival [5]. In a retrospective study of 127 patients by Meng et al. [14], the safety and efficacy of surgery plus chemotherapy versus radiotherapy plus chemotherapy were evaluated in cases with limited SmCCE. The median overall survival of all patients was 21.0 months. The overall survival was longer in those who received radiation plus chemotherapy than in those who received surgery plus chemotherapy (33.0 vs. 17.5 months, P = 0.02), especially in those patients with N1 disease. Using univariate and multivariate analyses, the study also reported that tumor location (upper third of esophagus), as well as type of treatment (chemotherapy plus surgery), predicted poor overall survival. The authors concluded that radiation plus chemotherapy should be the primary treatment in patients with ‘‘limited disease’’ primary SmCCE [14]. The most common chemotherapy regimen for patients with primary SmCCE is a platinum-based compound and etoposide, but the choice of the regimen is usually based upon prior local experience with small cell carcinoma of the lung [14].

Summary A patient with worsening dysphagia and weight loss was diagnosed with primary SmCCE, a rare esophageal tumor with a poor prognosis. The patient had a history of alcohol and tobacco use, commonly associated with primary SmCCE. His tumor was located in the upper third of his esophagus, which is not only uncommon for SmCCE but also heralds a poor prognosis. As he was deemed not to be a surgical candidate, he was treated with chemotherapy plus radiation, which although possibly superior to chemotherapy plus surgery, given the low incidence of SmCCE with limited information on long-term follow-up and outcomes, much remains uncertain.

Key Points • • •

Cancer of the esophagus includes rare tumors of a small cell phenotype. The tumors are, like squamous cancers, strongly associated with long use of tobacco and alcohol. Most commonly, they occur in males in their sixth decade and present with rapidly progressing dysphagia, chest pain, anorexia, weight loss, and cachexia.

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When the disease is locally confined, combination radiation plus chemotherapy offers a better outcome than radical surgery, with or without co-treatment with other modalities. While uncertain in the individual, prognosis is generally poor, rarely exceeding 3 years.

References 1. McKeown F. Oat-cell carcinoma of the oesophagus. J Pathol Bacteriol. 1952;64:889–891. 2. Al Mansoor S, Ziske C, Schmidt-Wolfe IG. Primary small cell carcinoma of the esophagus: patient data metaanalysis and review of the literature. Ger Med Sci. 2013. doi:10.3205/000180. 3. Briggs JC, Ibrahim NB. Oat cell carcinomas of the oesophagus: aclinico-pathological study of 23 cases. Histopathology. 1983;7: 261–277. 4. Vos B, Rozema T, Miller RC, Hendlisz A, et al. Small cell carcinoma of the esophagus: a multicenter Rare Cancer Network study. Dis Esophagus. 2011;24:258–264. 5. Ku GY, Minsky BD, Rusch VW, Bains M, et al. Small-cell carcinoma of the esophagus and gastroesophageal junction: review of the Memorial Sloan-Kettering experience. Ann Oncol. 2008;19:533–537.

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6. Reyes CV, Chejfec G, Jao W, Gould VE. Neuroendocrine carcinomas of the esophagus. Ultrastruct Pathol. 1980;1:367–376. 7. Ho KJ, Herrera GA, Jones JM, Alexander CB. Small cell carcinoma of the esophagus: evidence for a unified histogenesis. Hum Pathol. 1984;15:460–468. 8. Wu Z, Ma JY, Yang JJ, Zhao YF, Zhang SF. Primary small cell carcinoma of esophagus: report of 9 cases and review of literature. World J Gastroenterol. 2004;10:3680–3682. 9. Casas F, Ferrer F, Farru´s B, Casals J, Biete A. Primary small cell carcinoma of the esophagus: review of the literature with emphasis on therapy and prognosis. Cancer. 1997;80:1366–1372. 10. Sun KL, He J, Cheng GY, Chai LX. Management of primary small cell carcinoma of the esophagus. Chin Med J (Engl). 2007;120:355–358. 11. Aaltonen LA, Hamilton SR. Pathology and Genetics of Tumors of the Digestive System. Lyon: World Health Organization; International Agency for Research on Cancer; 2000. 12. Kargi A, Gurel D, Tuna B. The diagnostic value of TTF-1, CK 5/6, and p63 immunostaining in classification of lung carcinomas. App Immunohistochem Mol Morphol. 2007;15:415–420. 13. Van Der Gaast A, Verwey J, Prins E, Splinter TA. Chemotherapy as treatment of choice in extrapulmonary, undifferentiated small cell carcinomas. Cancer. 1990;65:422–424. 14. Meng MB, Zaorsky NG, Jiang C, Tian LJ, et al. Radiotherapy and chemotherapy are associated with improved outcomes over surgery and chemotherapy in the management of limited-stage small cell esophageal carcinoma. Radiother Oncol. 2013;106:317–322.

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