Primary esophageal small cell carcinoma with concomitant invasive squamous cell carcinoma or carcinoma in situ

Primary Esophageal Small Cell Carcinoma With Concomitant Invasive Squamous Cell Carcinoma or Carcinoma In Situ JUNYA YAMAMOTO, MD, KOICHI OHSHIMA, MD, SEIYOU IKEDA, MD, AKINORI IWASHITA, MD, AND MASAHIRO KIKUCHI, MD Esophageal small cell carcinoma (SmCC) is a rarer, more highly aggressive, and more rapidly growing neoplasm than esophageal squamous cell carcinoma (SqCC). SmCC and SqCC also differ in terms of chemotherapy of choice, response to therapy, and prognosis. Accordingly, it is important to differentiate the 2 carcinomas. We studied the histology and immunohistochemical profiles of 6 cases of esophageal SmCC to elucidate the correct diagnosis of this tumor. We performed immunohistochemical analysis antibodies against cytokeratins (CKAE1/AE3, CKCAM5.2, CK34␤E12, CK7, CK8, CK10/ 13, and CK19), epithelial membrane antigen (EMA), neural cell adhesion molecule (NCAM; CD56), neuron-specific enolase (NSE), chromogranin-A, S-100 protein, carcinoembryonic antigen (CEA), Ecadherin, thyroid transcription factor-1 (TTF-1), and p53. In 3 of the 6 SmCCs, heterogeneous components of in situ or invasive SqCC were observed. SqCC was found in the mucosa adjacent to the main SmCC, and the boundary between SmCC and SqCC was distinct, with no transitional features. Staining for NCAM, NSE, and chromogranin-A was positive in SmCCs, but negative in SqCCs. Both SmCCs and

SqCCs were positive for CKAE1/AE3, CKCAM5.2, CK8, and EMA, but only SqCCs were positive for CK34␤E12 and CK19. Moreover, SmCCs containing SqCC components were positive for CEA and E-cadherin, whereas SmCCs without SqCC were negative. Our study suggests that NCAM and NSE are useful markers in diagnosing esophageal SmCC, and CK34␤E12 and CK19 are useful for differentiating SqCC components from SmCC. HUM PATHOL 34:1108-1115. © 2003 Elsevier Inc. All rights reserved. Key words: esophageal small cell carcinoma, squamous cell carcinoma, immunohistochemistry, neural cell adhesion molecule, neuron-specific enolase. Abbreviations: 5-FU, 5-fluorouracil; CDDP, cisplatin; CEA, carcinoembryonic antigen; CK, cytokeratin; EMA, epithelial membrane antigen; NCAM, neural cell adhesion molecule; NSE, neuron-specific enolase; SmCC, small cell carcinoma; SqCC, squamous cell carcinoma; TBS, Tris-buffered saline; TTF-1, thyroid transcription factor; VP-16, etoposide.

Extrapulmonary small cell carcinoma (SmCC) has been described in the salivary glands, hypopharynx, esophagus, stomach, small and large intestine, pancreas, nasal cavity and paranasal sinuses, larynx, cervix and endometrium, thymus, prostate and bladder, breast, and skin.1-3 Extrapulmonary SmCC is most common in the gastrointestinal tract,2 especially the esophagus,3 as first reported in 1952 by McKeown.4 SmCC reportedly accounts for 0.05% to 2.4% of all primary esophageal carcinomas and is associated with a poor prognosis compared with esophageal squamous cell carcinoma (SqCC).5-14 Thus its correct diagnosis is very important with respect to guiding treatment decisions. Heterogeneous carcinoma components,12-18 including SqCC or mucoepidermoid carcinoma and SqCC in situ, have been reported in about 50% of esophageal SmCCs. One hypothesis to explain this finding is that esophageal SmCC arises from multipotent neoplastic stem cells of the esophageal epithelium,

which are the common precursors for SqCC, mucoepidermoid carcinoma, and SmCC.16 Diagnosing esophageal SmCC generally involves evaluating tumor histopathology, immunohistochemistry, ultrastructural features, and clinical behavior. To our knowledge, no detailed immunohistochemical analysis of esophageal SmCCs has been undertaken to date. In the present study, we examined immunohistochemical profiles to elucidate the correct diagnosis of esophageal SmCC and to discern the relationship between SmCC and heterogeneous tumor components, such as carcinoma in situ or invasive SqCC.

From the Department of Pathology and First Department of Surgery, Fukuoka University School of Medicine, Fukuoka, Japan and the Department of Pathology, Chikushi Hospital, Fukuoka, Japan. Accepted for publication July 17, 2003. Address correspondence and reprint requests to Junya Yamamoto, MD, First Department of Pathology, Fukuoka University School of Medicine, Nanakuma 7-45-1, Jonan-ku, Fukuoka 814-0180, Japan. © 2003 Elsevier Inc. All rights reserved. 0046-8177/03/3411-0006$30.00/0 doi:10.1053/S0046-8177(03)00480-5

MATERIALS AND METHODS Six cases of primary esophageal SmCC were selected from 404 cases of esophageal carcinoma diagnosed between June 1982 and December 2002 at the Pathology Departments of Fukuoka University Hospital and Chikushi Hospital. Esophageal SmCC was diagnosed based on the classification systems of the World Health Organization19 and Armed Forces Institute of Pathology.20 Clinical and pathological data for the 6 patients are given in Table 1. Three of the 6 patients had concomitant SqCC. The TNM classification and staging were determined based criteria outlined in the American Joint Committee on Cancer’s Staging Manual (5th edition, 1997).21 To exclude the possibility of secondary spread from other primary sites, especially the lung, all 6 patients underwent a detailed preoperative diagnostic workup, including barium swallow, esophagogastroduodenoscopy, computed tomography scanning of the chest and abdomen, abdominal ultrasonography, and cardiopulmonary assessment.

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TABLE 1. Summary of 6 Cases with Esophageal Small Cell Carcinoma

Age (years) Gender Type Location Size (cm) Small cell carcinoma T classification Lymphatic invasion Blood vessel invasion Squamous cell carcinoma T classification Lymphatic invasion Blood vessel invasion N (histology) M (site of metastasis) Stage Adjuvant treatment (chemotherapy) Survival (months), status

Case 1

Case 2

Case 3

Case 4

Case 5

Case 6

75 M 3 Middle 10.5⫻4.7

64 M 1 sep Lower 4.3⫻2.8

73 M 0–1 sep Middle 1.5⫻1.3

56 F 0–1 sep Lower 2.9⫻1.8

62 F 1 sep Lower 5.5⫻3.0

82 M 1c Lower 8.5⫻8.5

T3 ⫹ ⫹

T2 ⫹ ⫹

T1 ⫹ ⫹

T1 ⫹ ⫺

T2 ⫹ ⫹

T3 ⫹ ⫹

T2 ⫹ ⫺ N1 (SmCC) M0 III ⫺ 5, DOD

Tis ⫺ ⫺ Nx M0 IIA or IIB 5-FU 7, DOD

Tis ⫺ ⫺ N0 M0 I 5-FU 31, DOD

N0 M1b (liver) IVB 5-FU 9, DOD

N1 (SmCC) M0 IIB CDDP, VP-16 9, DOD

Nx M0 IIA or III ⫺ 5, DOD

Abbreviations: M, male; F, female; Type 0 –1 sep, superficial type, predominantly subepithelial type; Type 1 sep, advanced type, predominantly subepithelial type; Type 1c, advanced type, cauliflower type; Type 3, advanced type, ulcerative and infiltrative type; Middle, middle thoracic esophagus; Lower, lower thoracic esophagus; SmCC, small cell carcinoma; SqCC, squamous cell carcinoma; Tis, carcinoma in situ; T1, tumor invades lamina propria or submucosa; T2, tumor invades muscularis propria; T3, tumor invades adventitia; ⫹, positive; ⫺, negative; N, lymph node metastasis; Nx, not done; M, distant metastasis; Stage, American Joint Committee on Cancer staging; DOD, dead of disease.

The surgically resected esophagus was fixed overnight in 20% neutral buffered formalin. The entire surgical specimen was then cut into 5-mm-thick slices, embedded in paraffin, and sectioned for microscopic examination. The sections were stained with hematoxylin and eosin and periodic acidSchiff alcian blue. The Grimelius technique was used to detect cytoplasmic argyrophilic granules. Immunohistochemical analysis was performed using the streptavidin-biotin-peroxidase complex technique22 with the primary polyclonal and monoclonal antibodies listed in Table 2. Sections were deparaffinized, then rinsed in ethanol and distilled water. To unmask the relevant epitopes, epitoperetrieval procedures, including autoclave (10 minutes at 121°C) or microwave (10 minutes at 95°C) in 0.01 mol citrate buffer, pH 6.0, or microwave (20 minutes at 95°C) in 0.01 mol

EDTA, pH 8.0, were used. After rinsing in 0.05 mol Trisbuffered saline (TBS), pH 7.4, nonspecific sites were blocked with 3% bovine serum albumin and 1% nonfat dry milk in TBS for 30 minutes. Then the sections were incubated with the following primary antibodies: cytokeratin (CK) AE1/AE3, 34␤E12, 7, 8, 10/13, and 19 (Dako, Glostrup, Denmark); CKCAM5.2 (Becton-Dickinson, PharMingen, San Diego, CA); epithelial membrane antigen (EMA) (Dako); neural cell adhesion molecule (NCAM) (CD56; Novocastra, Newcastle Upon Tyne, U.K.); neuron-specific enolase (NSE) (Dako); chromogranin A (rabbit anti-human chromogranin A; Dako); S-100 (Nichirei, Tokyo, Japan); carcinoembryonic antigen (CEA) (Nichirei); E-cadherin (Takara Shozo, Kyoto, Japan); thyroid transcription factor (TTF)-1 (Dako); and p53 protein (DO7, Novocastra) (Table 2). Immunoreactions were per-

TABLE 2. Immunohistochemical Reagents Antibody

Molecular weight (kDa)

Source

Dilution

CK AE1/AE3 CK CAM5.2 CK 34␤E12 CK 7 CK 8 CK 10/13 CK 19 EMA CD56 NSE Chromogranin A S-100 CEA E-cadherin TTF-1 p53

56.5,54,50,48,40/65.5,68,63,59,58,56,54,52 150 68,58,56.5,50 54 52.5 56.5/54 40

Dako Becton-Dickinson Dako Dako Dako Dako Dako Dako Novocastra Dako Dako Nichirei Nichirei Takara Shuzo Dako Novocastra

1:50 Kit 1:100 1:50 1:50 1:100 1:100 1:100 1:50 1:50 1:200 Kit Kit 1:50 1:50 1:100

MW, microwave; AC, autoclave.

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Antigen-retrieval method MW (10 MW (10 MW (10 MW (10 MW (10 MW (10 MW (10

min, 95°C) min, 95°C) min, 95°C) min, 95°C) min, 95°C) min, 95°C) min, 95°C)

MW (20 min, 95°C) MW (10 min, 95°C) AC (10min, 121°C) AC (10min, 121°C) AC (10min, 121°C)

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FIGURE 1. (A) SmCC with a SqCC component. Invasive SqCC adjacent to invasive SmCC (case 1). (B) Pure-type SmCC of the esophagus. The small cell component was mainly covered by nonneoplastic epithelium. Small solid nests of proliferating anaplastic small cells (case 4). Bar scale ⫽ 1.0 cm. (Original magnification, ⫻ 10.)

formed using a labeled streptavidin-biotin system and an alkaline phosphatase technique, followed by counterstaining with hematoxylin.

RESULTS Based on the findings of preoperative examinations, which were performed to exclude possible secondary spread from lung cancer, 6 cases were diagnosed as primary esophageal SmCC. Table 1 summarizes the clinicopathologic findings for these 6 cases. No other tumor was found outside the esophagus except in case 4, which had 3 small nodular lesions in the liver, considered metastatic lesions based on their size and the more frequent route of metastasis from the esophagus to the liver rather than the opposite. In the present series, esophageal SmCC comprised 1.5% of all primary esophageal carcinomas (n ⫽ 404). The study group comprised 4 men and 2 women, ranging in age from 56 to 82 years (median age, 68.7 years). Tumors were located in the middle third of the esophagus in 2 cases and in the lower third in the other 4 cases. Tumor length ranged from 1.5 to 10.5 cm (mean length, 5.5 cm).

Histopathology Macroscopically, esophageal SmCCs were often protruding lesions appeared to proliferate beneath the mucosal epithelium (Fig 1). Microscopically, 3 of the 6 carcinomas contained heterogeneous components of in situ (cases 2 and 3) or invasive (case 1) SqCC, and the remaining 3 contained only SmCC (cases 4, 5, and 6). All cases of SmCC exhibited histopathologic features similar to its intermediate-cell pulmonary counterpart (Fig 1). The tumor cells had scanty cytoplasm and round-to-oval nuclei with fine granular chromatin and were arranged in irregular sheets, various sized nests, ribbons, rosettes, or streaming patterns (Fig 2). Pleomorphic cells were also observed. SmCCs were covered by nonneoplastic epithelium or overlaid by SqCC. All heterogeneous components of in situ or invasive SqCC were well differentiated and were found in mucosa adjacent to the SmCC. The 2 types of carcinoma were not mixed and showed no transitional features. Invasive SqCC had invaded into the deep portion of the proper muscle layer. Two cases (cases 1 and 5), both of which originated from SmCC, exhibited lymph node

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FIGURE 2. Histopathologic appearance of an SmCC stained with hematoxylin and eosin. (A) The tumor shows small round or oval cells with scanty cytoplasm, nuclear molding, and inconspicuous nucleoli, (B) arranged in solid sheets, ribbons, and often with a streaming pattern; (C) they sometimes formed rosettes (arrows) containing mucin within their lumens. (D) Pleomorphic-type tumor cells were also observed. (Original magnification, B, ⫻ 50; A, C, and D, ⫻ 100.)

metastases. One case (case 4), also derived from SmCC, had distant metastasis to the live. Immunohistochemistry Immunohistochemical findings in tissue specimens from 6 patients with esophageal SmCC and 6 patients with esophageal SqCC for comparison are summarized in Table 3. Staining for NCAM and NSE was positive in all SmCCs, but negative in all normal epithelia and SqCCs (Fig 3A and B). Staining for chromogranin A was positive in 3 of the 6 SmCCs (Fig 3C), but negative in all of the SqCCs. A small number of tumor cells in 3 SmCCs contained argyrophilic granules (Grimelius) (Fig 3D). The positive reactivity for these neurogenic markers in SmCCs was no different in tumors with and those without SqCC components. SqCC and the SqCC component within SmCC were both positive for all antikeratin antibodies except that against CK7 and CK10/13, whereas the SmCC component was negative for CK34␤E12, CK19, CK7, and CK10/13 (Fig 4; Table 3). Therefore, CK34␤E12 and CK19 preferentially stained the SqCC component;

all 6 SqCCs were positive, whereas only 2 of the 6 SmCCs were focally positive. As for immunostaining for TTF-1, 2 of the 6 SmCCs were positive, and all 6 SqCCs were negative. SmCCs with or without SqCC components showed differences in CEA and E-cadherin staining patterns. SmCCs containing SqCC, but not tumors of SmCC alone, stained positive for both CEA and E-cadherin. In summary, NCAM and NSE were found to be useful markers for diagnosing esophageal SmCC, and CK34␤E12 and CK19 were found to be useful markers for differentiating SqCC components from SmCC. Prognosis All 6 patients with SmCC underwent surgical resection without preoperative adjuvant therapy. After the operation, 4 patients received chemotherapy, but none received radiotherapy. Three of these 4 patients (cases 2, 3, and 4) received a course of intravenous 5-fluorouracil (5-FU), 250 mg/day for 2 weeks. The other patient (case 5) received 100 mg cisplatin (CDDP) intravenously on day 1, and 300 mg etoposide (VP-16)

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TABLE 3. Immunohistochemical Staining of Tissues From Esophageal SmCC and SqCC Case 1 Antibody CKAE1/AE3 CKCAM5.2 CK34␤E12 CK7 CK8 CK10/13 CK19 EMA CD56 NSE Chromogranin A Grimelius S-100 CEA E-cadherin TTF-1 p53

Case 2

Case 3

Case 4 Case 5 Case 6 Case 7 Case 8 Case 9 Case 10 Case 11 Case 12

SmCC (SqCC) SmCC (SqCC) SmCC (SqCC) SmCC SmCC SmCC SqCC ⫹⫹ ⫹⫹ ⫺ ⫹ ⫹⫹ ⫺ ⫺ ⫹⫹ ⫹⫹ ⫹ ⫹⫹ ⫾ ⫺ ⫹⫹ ⫹ ⫹ ⫺

(⫹⫹) (⫹⫹) (⫹⫹) (⫺) (⫹⫹) (⫺) (⫹⫹) (⫹⫹) (⫺) (⫺) (⫺) (⫺) (⫺) (⫹) (⫹) (⫺) (⫾)

⫹ ⫹⫹ ⫺ ⫺ ⫹⫹ ⫺ ⫺ ⫹⫹ ⫹⫹ ⫹⫹ ⫹ ⫹ ⫺ ⫹ ⫹⫹ ⫺ ⫾

(⫹⫹) (⫹⫹) (⫹) (⫹) (⫹) (⫺) (⫹) (⫹⫹) (⫺) (⫺) (⫺) (⫺) (⫾) (⫾) (⫹) (⫺) (⫹)

⫹ ⫹⫹ ⫾ ⫺ ⫹⫹ ⫺ ⫺ ⫹⫹ ⫹ ⫹⫹ ⫺ ⫺ ⫺ ⫹ ⫹⫹ ⫺ ⫹⫹

(⫹) (⫹⫹) (⫹⫹) (⫺) (⫹) (⫹) (⫹) (⫹⫹) (⫺) (⫺) (⫺) (⫺) (⫺) (⫺) (⫹) (⫺) (⫹⫹)

⫹⫹ ⫹⫹ ⫹ ⫹ ⫺ ⫺ ⫹ ⫹⫹ ⫹⫹ ⫹⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ ⫹

⫺ ⫹ ⫺ ⫾ ⫺ ⫺ ⫺ ⫺ ⫹⫹ ⫹⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹⫹

⫹⫹ ⫹⫹ ⫺ ⫹⫹ ⫹⫹ ⫺ ⫹ ⫹⫹ ⫹⫹ ⫹⫹ ⫹⫹ ⫾ ⫺ ⫺ ⫺ ⫺ ⫺

⫹⫹ ⫹⫹ ⫹⫹ ⫾ ⫹⫹ ⫹ ⫹⫹ ⫹⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫾ ⫹ ⫺ ⫺

SqCC

SqCC

SqCC

SqCC

SqCC

⫹⫹ ⫹⫹ ⫹⫹ ⫺ ⫹ ⫹⫹ ⫹⫹ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫾ ⫹ ⫺ ⫺

⫹⫹ ⫹⫹ ⫹⫹ ⫺ ⫹⫹ ⫾ ⫹⫹ ⫹⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫾ ⫹ ⫺ ⫺

⫹⫹ ⫹⫹ ⫹⫹ ⫺ ⫹⫹ ⫹ ⫹⫹ ⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ ⫹ ⫺ ⫹⫹

⫹⫹ ⫹⫹ ⫹⫹ ⫺ ⫹⫹ ⫹ ⫹ ⫹⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫺ ⫹ ⫺ ⫾

⫹⫹ ⫹⫹ ⫹⫹ ⫺ ⫹⫹ ⫹ ⫹⫹ ⫹⫹ ⫺ ⫺ ⫺ ⫺ ⫺ ⫾ ⫹ ⫺ ⫺

NOTE: For abbreviation, see Table 1. ⫹⫹, diffusely positive; ⫹, focally positive; ⫾, scattered positive; ⫺, negative. Cases 1 to 3, SmCCs with SqCC components; cases 4 to 6, SmCC-only tumors; cases 7 to 12, SqCC-only tumors.

FIGURE 3. Immunochemical staining of SmCC. (A) Positive immunostaining for NCAM (CD56) (case 1). (B) Positive immunostaining with NSE (case 1). (C) Focal areas of chromogranin A-positive cells. (D) Tumor cells containing argyrophilic granules. Grimelius stain (arrow). (Original magnification, A and B, ⫻ 50; C, ⫻100; D, ⫻ 200.)

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FIGURE 4. Immunochemical staining of an SmCC containing a SqCC component (case 1). (A) SmCC and SqCC components stained with hematoxylin and eosin. (B) CK AE1/AE3-, (C) EMA-, and (D) CK CAM5.2-stained perinuclear or paranuclear regions of both SmCC and SqCC. (E) CK 34␤E12- and (F) CK 19-stained perinuclear or paranuclear regions of the SqCC component. (Original magnification ⫻ 50.)

on days 2 to 4. No significant effect of chemotherapy was seen. The median patient survival time was 11 months. Five of the 6 patients died within 10 months of diagnosis. One patient with SmCC and in situ SqCC (case 3) survived for 31 months. Only this case had stage I disease, with T1-sized SmCC that had invaded only down into the submucosa.

DISCUSSION Esophageal SmCC is generally rarer, more highly aggressive, and more rapidly growing than esophageal SqCC. Moreover, the 2 tumor types differ in terms of chemotherapy of choice, response to therapy, and prognosis. Therefore, differentiating SmCC and SqCC is crucial. In the present study, we studied the histopa-

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thology and immunohistochemical profiles of 6 cases of esophageal SmCC and found that NCAM and NSE are useful markers for diagnosing esophageal SmCC, and that CK34␤E12 and CK19 are useful for differentiating SqCC components from SmCC. NCAM is an adhesion molecule expressed by neural and neuroendocrine tumors and a few biphasic tumors, including synovial sarcomas and breast phyllodes tumors.23,24 NCAM is evolutionally related to immunoglobulins and is a product of the immunoglobulin gene superfamily.25 In lung cancer, NCAM is considered a very sensitive and specific marker of neuroendocrine differentiation.26 In our study, all SmCCs were NCAM-positive, but none of the normal squamous epithelium specimens or heterogeneous components of SqCC was positive. NSE, a neuronal form of the glycolytic enzyme enolase, is another important marker for endocrine cells of the central and peripheral divisions of the diffuse neuroendocrine system.27 NSE is produced by various types of neuroendocrine neoplasms, but by no nonendocrine neoplasms.28 In our study, immunoreactivity of NSE, as well as that of NCAM, was specific for esophageal SmCC cells. Chromogranin A and Grimelius stains were not suitable for detecting esophageal SmCC. In the first report of SmCC of the esophagus,4 1 of the 2 cases had coexisting SqCC. A series of subsequent studies12-18 also found occasional invasive or in situ SqCC components in SmCC of the esophagus. Overall, heterogeneous carcinoma components have been reported in approximately 46% of esophageal SmCCs. Three of the 6 (50%) SmCCs in our study coexisted with heterogeneous components of SqCC. Therefore, multiple biopsies are needed for accurate diagnosis. Our results showed diffuse positive staining for CK34␤E12 and CK19 in the SqCC components, but only 2 of the 6 SmCCs stained focally positive in the SmCC components. Thus, we conclude that CK34␤E12 and CK19 are also useful markers to diagnose esophageal SmCC. SmCCs containing SqCC, but not SmCCalone tumors, stained positive for CEA and E-cadherin. This was very interesting finding, but the antibodies could not detect esophageal SmCC. TTF-1 is expressed in 80% to 100% of pulmonary SmCCs29-32 and is also positive in extrapulmonary SmCCs, including gastrointestinal tract, prostate, bladder, and cervical SmCCs.31,32 In the present study, 2 of the 6 esophageal SmCCs were positive for TTF-1, and all SqCCs were negative. We confirmed that TTF-1 was also positive in primary esophageal SmCCs; however, it is not a suitable marker for diagnosing esophageal SmCC. Esophageal SmCC reportedly has an extremely poor prognosis compared with esophageal non-SmCC, such as SqCC and adenocarcinoma,5-14 a finding confirmed in the present study. The mean survival time after diagnosis of SmCC is about 8 months, and only 6% of patients survive longer than 2 years.6-14 In our series, the median survival time was 11 months. With regard to the 5-year survival rate, the rate was relatively satisfactory for esophageal non-SmCC, approaching 20% for cases treated by

surgery and adjuvant therapy,5,6 but very poor for esophageal SmCC, only 1% to 2%.6-14 Treatments of choice for esophageal SmCC and esophageal non-SmCC are similar and include surgical resection, chemotherapy, radiotherapy, and combinations thereof; the exact approaches and responses differ for the 2 types, however. Non-SmCC of the esophagus responds well to chemotherapy, as does esophageal SmCC, although to a lesser degree. In the present study, we could derive no clear results as to the significance of adjuvant therapies. However, other groups7-11 have reported that surgical resection with systemic chemotherapy, radiotherapy, or combination therapy could produce long-term remission and possibly long-term survival in esophageal SmCC. Lieberman et al11 reported that surgical resection combined with chemotherapy has proven especially effective. In esophageal SmCC, recent reports described the effectiveness of chemotherapy using either a single agent (ie, 5-FU) or a combination (ie, CDDP/VP-16, cyclophosphamide/5-FU, cyclophosphamide/doxorubicin hydrochloride/vincristine, or cyclophosphamide/doxorubicin hydrochloride/vincristine/CDDP), with or without radiotherapy.8,9 On the other hand, esophageal nonSmCC has been reported to respond to chemotherapy of either a single agent (ie, 5-FU or docetaxel) or several agents (ie, 5-FU/CDDP or docetaxel/CDDP), with or without radiotherapy.5 Furthermore, some studies have also indicated that chemotherapeutic agents show synergistic effects with radiotherapy. In the World Health Organization classification system,19 SmCC of the esophagus resembles the similarly named but much more common tumor found in the lung in terms of histopathology, immunohistochemistry, ultrastructure, and clinical behavior. Possible cells of origin for SmCCs are currently generically termed “neuroendocrine” cells.33-36 On the other hand, Ho et al16 reported that multipotent neoplastic stem cells are the common precursors for SqCC, adenocarcinoma, and SmCC of the esophagus. In our study, 3 of the 6 (50%) esophageal SmCCs coexisted with heterogeneous components of SqCC. The 2 carcinoma types were not mixed, and transitional features were not detected. These findings did not contradict the possibility that multipotent neoplastic stem cells are the common precursors, although this hypothesis needs further study. Molecular analyses of SmCC, including polymorphic DNA markers, polymerase chain reaction–loss of heterozygosity analysis, and K-ras codon 12 analysis, have identified molecular changes in SmCC at various extrapulmonary sites, including the breast, uterine cervix, and gallbladder.37,38 More research is needed to further analyze the molecular pathology of esophageal SmCC.

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