Human Pathology (2015) 46, 813–819

www.elsevier.com/locate/humpath

Original contribution

Granular cell tumor of the gastrointestinal tract: histologic and immunohistochemical analysis of 98 cases Soyeon An MD a , Jaejung Jang MD b , Kwangseon Min MD b , Min-Sun Kim BS c , Hosub Park MD a , Young Soo Park MD, PhD a , Jihun Kim MD, PhD a , Jeong Hoon Lee MD, PhD b , Ho June Song MD, PhD d , Kyung-Jo Kim MD, PhD d , Eunsil Yu MD, PhD a , Seung-Mo Hong MD, PhD a,⁎ a

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Republic of Korea Department of Pathology, Anyang Sam Hospital, Anyang, 430-733, Republic of Korea c Asan Institute for Life Science, Asan Medical Center, Seoul, 138-736, Republic of Korea d Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 138-736, Republic of Korea b

Received 26 November 2014; revised 11 February 2015; accepted 13 February 2015

Keywords: Granular cell tumor; Gastrointestinal tract; Esophagus; Stomach; Colon; Immunohistochemistry

Summary Granular cell tumors (GCTs) are uncommon benign neoplasms in the gastrointestinal (GI) tract, and our current understanding of GCT in GI tract is limited. A total of 98 GCTs were retrieved from 95 patients, and the clinicopathological and immunohistochemical features were compared. The male-to-female ratio was 2.2:1 and with a mean age of 49 years. The mean tumor size was 0.37 cm. Seventy-three esophageal (75%), 21 colorectal (21%), and 4 gastric (4%) GCTs were included. Gastric (mean, 0.75 cm) and colorectal (0.6 cm) GCTs were significantly larger than esophageal tumors (0.27 cm; P b .001). Colonic and gastric GCTs showed a more infiltrative growth pattern (P b .001) and peritumoral lymphoid cuffs (P b .001) than esophageal tumors. Involvement of mucosa, submucosa, and both were noted in 58 cases (59%), 11 cases (11%), and 28 cases (29%), respectively. One GCT from the sigmoid colon (1%) had infiltration to pericolic soft tissue and with lymph node metastasis. High frequency of immunolabeling for S-100 protein (81/81, 100%), CD56 (55/58, 95%), CD68 (58/61, 95%), SOX-10 (54/58, 93%), and inhibin-α (30/58, 52%) were observed. In summary, GCTs in the GI tract were observed with the following frequency: esophagus, colorectum, and stomach. Colorectal and gastric GCTs were larger and had infiltrative growth and more lymphoid cuffs than esophageal GCTs. Although invasive GCT was rare, it could be observed in the GI tract. Inhibin-α expression were more common in colonic GCTs than esophageal tumors. High S-100 protein, CD56, CD68, and SOX-10 expression rates were observed in GCTs from GI tracts. © 2015 Elsevier Inc. All rights reserved.

⁎ Corresponding author at: Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Olympic-Ro 43Gil 88, Songpa-Gu, Seoul, 138-736, Korea. E-mail address: [email protected] (S. -M. Hong). http://dx.doi.org/10.1016/j.humpath.2015.02.005 0046-8177/© 2015 Elsevier Inc. All rights reserved.

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1. Introduction Granular cell tumor (GCT) is a benign, mesenchymal tumor of Schwann cell origin [1–3]. These tumors can arise in any part of the body, although their common locations are the tongue, skin, and subcutaneous tissue [4,5]. GCTs in the gastrointestinal (GI) tract are uncommon and comprise approximately 4% to 6% of all GCTs [5]. The esophagus is the most commonly reported location of GCTs in the GI tract, with the colon being the second most common location [6,7]. GCTs cell tumors commonly manifest as solitary, submucosal nodules according to endoscopic examination [8]. Multifocal lesions are reported in 4% to 30.4% of patients with GCT [8,9]. Most GCTs are benign, with 1% to 2% of all of these tumors considered to be malignant [10]. Most of the reported GCT cases of the GI tract were single cases or case series with a small number of patients, and only a few studies dealt with single organ, that is, either esophageal or colorectal GCTs [7,11] or viewed them from the clinician’s perspective [7,12]. To the best of our knowledge, there have only been a few previous studies dealing with histologic comparisons in a large case number series of GCTs in the GI tract [5-7,11]. However, the previous studies did not systematically compare the histologic characteristics of GCTs arising in the different organs in the GI tract. In our study, we demonstrate the clinicopathological characteristics of 98 patients with GCTs arising from the GI tract and treated at a single medical institution.

2. Materials and methods A total of 163 GCTs were searched from the pathology database of Asan Medical Center from 1997 to 2014, and 98 GCTs from GI tract were in 95 patients (60%). Those 98 GCT cases from GI tract were retrieved after receiving approvals from the institutional review boards. Representative sections were selected from 1 to 4 hematoxylin-eosin–stained slides (median, 1 slide). Histologic features of all of the GCT cases were reviewed by 2 pathologists (S.A. and S.-M.H.). Data obtained from the gross examination included the location, size, and date of the endoscopic removal. The microscopic features that were evaluated, including the depth of involvement, growth pattern of the tumor (marginated versus infiltrative), presence of a lymphoid cuff, overlying epithelial

Table 1

changes, calcification, and nuclear pleomorphism, which have been previously described elsewhere [7]. Overlying epithelial changes were characterized by crypt architectural distortion, acute and chronic inflammation, and thinning of overlying epithelium [7]. Tissue microarrays were constructed with a 2-mm diameter tumor core from 58 available cases using a manual tissue microarryer (Uni TMA Co, Ltd; Seoul, Korea). The other 40 cases were inadequate for producing TMAs because of tiny size of remaining tumors because of small biopsied samples. Immunohistochemical labeling was performed at the immunohistochemical laboratory of the Department of Pathology, Asan Medical Center. Briefly, 4-μm tissue sections from tissue microarrays were deparaffinized and hydrated in xylene and serially diluted alcohol solutions, respectively. Endogenous peroxidase was blocked by incubation in 3% H2O2 for 10 minutes, and then, heat-induced antigen retrieval was performed. Primary antibodies with BenchMark autostainers (Ventana Medical Systems; Tucson, AZ) were used following manufacturer's protocol. Primary antibodies for S-100 protein, CD68, CD56, SOX-10, and inhibin-α were used. Information of the primary antibodies is summarized in Table 1. Sections demonstrating more than 5% positivity of tumor cells were interpreted to be positive as previously described [13]. Statistical analyses were performed with SPSS 17.0 software (SPSS Inc; Chicago, IL). A comparison of means was performed using an unpaired Student t test and analysis of variance. To examine the associations between the categorical variables, the χ2 and Fisher exact tests were performed. A P b .05 was considered statistically significant.

3. Results The clinicopathological features of the patients are shown in Table 2. The male-to-female ratio was 2.2:1 (57 males and 26 females). The mean patient age at the time of their diagnosis was 49 ± 11 years (range, 21-75 years). The specimens included 58 biopsy samples and 40 excisions. GCTs of GI tract were mainly observed in the esophagus (73 specimens from 72 patients, 75%), colorectum (21 specimens from 20 patients, 21%), and stomach (4 specimens from 3 patients, 4%) in that order. No GCT case was observed in the small intestine.

Antibodies for immunohistochemical staining for study

Antibody

Clone

Dilution

Source

S-100 protein CD68 CD56 SOX-10 Inhibin-α

Rabbit polyclonal (18-0046) Mouse monoclonal (NCL-CD56-1B6-L) Mouse monoclonal (M0814) Rabbit polyclonal (383A-76) Mouse monoclonal (MCA951S)

1:200 1:2000 1:100 1:25 1:100

Zymed; South San Francisco, CA Dako; Glostrup, Denmark Novocastra; Newcastle, UK Cell marque; Rocklin, CA AbD Serotec; Kidlington, UK

Granular cell tumor of the gastrointestinal tract Table 2 patients

Clinicopathological features of 98 GCTs from 95

Characteristics

Case no. (%)

Age (mean ± SD) Size (mean ± SD) Sex Male Female Specimen type Biopsy Excision Location Esophagus Stomach Colon Depth of involvement Mucosa Submucosa Mucosa and submucosa Mucosa to pericolic soft tissue

49 ± 11 y 0.37 ± 0.37 cm 66 (69%) 29 (31%) 58 (59%) 40 (41%) 73 (75%) 4 (4%) 21 (21%) 58 11 28 1

(59%) (11%) (29%) (1%)

Among 73 esophageal GCTs, 69 cases had information regarding the specific location of the tumor in the esophagus, with the most common location of the GCTs in the esophagus being the distal (52/69 cases, 75%), followed by the middle (10/69, 15%) and the proximal (7/69, 10%) esophagus. Most of the 21 colorectal GCTs (72%) were located in the right side of the colon. Ten colorectal GCT cases were located in the cecum (48%), 5 in the ascending colon (24%), 2 in the sigmoid colon (10%), and 4 in the rectum (19%). The tumor size ranged from 0.1 cm to 3.0 cm (mean ± SD, 0.37 ± 0.37 cm). Gastric (mean, 0.75 cm) and colorectal (0.6 cm) GCTs were significantly larger in size than esophageal tumors (0.27 cm; P = .001). Representative endoscopic images are depicted in Fig. 1. The tumors showed yellowish nodules with intact overlying mucosa. Comparison of the pathologic features including the growth pattern (marginated and infiltrative), the presence of calcification, lymphoid cuff, overlying epithelial changes, and nuclear pleomorphism are summarized in Table 3. Most

815 tumors had a well-marginated growth pattern (n = 78, 80%; Fig. 2A and E), whereas an infiltrative growth pattern was observed in 20 cases (20%; Fig. 2F). Colonic (11/21 cases, 52%) and gastric (2/4 cases, 50%) GCTs had a more infiltrative growth pattern than esophageal GCTs (7/73 cases, 10%; P b .001). Lymphoid cuffs were observed at the periphery of the tumors, including predominantly mucosa and occasionally deep portions of the tumors. The lymphoid cuffs at mucosa manifested as “mucosa-associated lymphoid tissue” (Fig. 2B). Colonic (11/21 cases, 52%) and gastric (2/4, 50%) GCTs were more commonly surrounded by a lymphoid cuff than esophageal tumors (6/73 cases, 8%; P b .001). Overlying mucosal changes including acute and chronic inflammation and atrophy (Fig. 2C) were noted in 61 cases (62%), although these mucosal changes did not differ significantly based on the location of the tumors. Nuclear pleomorphism (Fig. 2D) was frequently observed (n = 67, 68%), although no significant difference was observed according to the location of the GCTs. Calcification was observed only in 2 cases in the esophagus. The larger tumors (16/38, 42%) showed a more infiltrative growth pattern (Fig. 2F) than smaller tumors (4/60, 7%; P b .001), and The larger tumors (13/38; 34%) were more commonly surrounded by a lymphoid cuff (Fig. 2B) than were the smaller tumors (6/ 60, 10%; P =.004). Involvement of mucosa, submucosa, and both mucosa and submucosa (Fig. 2A) were noted in 58 cases (59%), 11 cases (11%), and 28 cases (29%), respectively. One infiltrative GCT (Fig. 2G) from the sigmoid colon (1%) involved mucosa to pericolic soft tissue with lymph node metastasis. This case could be classified as a malignant GCT based on the clinical behavior. However, except for focal nuclear pleomorphism, no accompanying malignant pathologic features such as tumor necrosis, spindling of tumor cells, vesicular nuclei, large nucleoli, and increased mitotic activity (2/10 high-power fields) were observed. Ninety-two patients (97%) had a single lesion, whereas only 3 patients (3%) had 2 GCTs (multiple tumors). The locations of the multiple tumors were close to each single lesion and were observed in the esophagus, stomach, and colon, respectively. No tumor recurrence was observed

Fig. 1 Representative endoscopic images of (A) esophageal and (B) colonic GCTs. A yellow submucosal tumor is noted with normal overlying mucosa.

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Table 3

Comparisons of pathologic features based on location of GCTs

Features

Growth pattern Well marginated Infiltrative Calcification Absent Present Lymphoid cuffing Absent Present Mucosal changes Absent Present Nuclear pleomorphism Absent Present

Location, n (%)

P

Esophagus

Stomach

Colon

66 (90%) 7 (10%)

2 (50%) 2 (50%)

10 (48%) 11 (52%)

71 (97%) 2 (3%)

4 (100%) 0 (0%)

21 (100%) 0 (0%)

67 (92%) 6 (8%)

2 (50%) 2 (50%)

10 (48%) 11 (52%)

22 (30%) 51 (70%)

3 (75%) 1 (25%)

12 (57%) 9 (43%)

23 (32%) 50 (68%)

2 (50%) 2 (50%)

6 (29%) 15 (71%)

b.001 ⁎

1 b.001 ⁎

.17

.71

⁎ Significant at the level of P b .05.

during the 36.8 months of the median follow-up period (range, 1-136 months). Most of GCTs were immunolabeled to S-100 protein, CD56, CD68, and SOX10. Immunohistochemical staining for S-100 protein was performed in 81 cases with available paraffin blocks, and all cases had diffuse cytoplasmic and nuclear S-100 protein immunolabeling in tumor cells (81/81 cases, Fig. 2H). Diffuse cytoplasmic CD56 (Fig. 2I) and CD68 (Fig. 2J) labeling was noted in 95% (55/58) and 95% (58/61) of GCT cases, respectively. Similarly, nuclear SOX-10 labeling (Fig. 2K) was observed in 93% (54/58) of GCT cases. The relationships between protein expressions and location of GCTs are summarized in Table 4. There was no statistically significant correlation between location and expression of S-100 protein, CD68, CD56, and SOX-10. However, diffuse cytoplasmic inhibin-α labeling (Fig. 2L) was observed in 52% (30/58) of GCTs. Inhibin-α immunolabeling was more commonly noted in colorectal (14/18, 78%) tumors than those in esophageal (15/37, 41%) or gastric (1/3, 33%) GCTs.

4. Discussion Granular cell tumor was firstly described by Weber in 1854 [7]. In 1926, Abrikossoff [14] reported a tongue neoplastic lesion as granular cell myoblastoma because of its morphological similarity to skeletal muscle, and he described the tumor as having striated muscle origin. As Feyrter [15] subsequently noted that these tumors were frequently observed adjacent to peripheral nerves, the name was changed to granular cell neuroma in 1935. Several literatures have demonstrated that the tumor originated from Schwann cells by immunohistochemical labeling of S-100 protein [2,3]. Although GCTs can arise in any part of the body,

common locations of these tumors included the tongue, skin, and subcutaneous tissue [4,5]. Granular cell tumors from the GI tract are relatively uncommon and comprise approximately 4% to 6% of all GCTs [5]. In the present study, we observed that 60% of the entire GCTs were from GI tracts in our cohort. Although this proportion is much higher than that of the previous report [5], this significant discrepancy could be explained by referral bias because our institution is a referral hospital in our nation. The age (mean, 49 ± 11 years) and sex (male-to-female ratio, 2.2:1) of the patients with GCT in our study was similar to that of the previous ones [5-7]. In our study, 75% (73/98 cases) of GCTs from GI tract were in the esophagus and 21% (21 cases) from the colorectum. Esophageal GCTs were most commonly observed in the distal portion (75%), and colorectal GCTs were predominantly noted in the right side of the colon (71%). In the literatures, one third of GCTs in the GI tract developed in the esophagus. Our result is concordant with those of previous studies [6,11]. One previous Dutch pathology registry study with 44 esophageal GCT cases reported that the most frequent location of esophageal GCTs were the distal esophagus (75%, 33/44 cases) [11]. Another study of 75 GCT cases from the GI tract of an AFIP series also reported the predominance of a distal location of esophageal GCTs (58%, 14/24 cases) [6]. The colorectum is the second most common location of GCTs of the GI tract [6], and the cecum and ascending colon are most commonly reported locations in the colorectum [7]. Our results are in agreement with those of previous studies [12]. Recently, Singhi and Montgomery [7] presented a large, colorectal GCTs series and described infiltrative or marginated growth patterns, nuclear pleomorphism, a lymphoid cuff, focal calcification, and reactive mucosal surface changes as histologic features of colorectal GCTs. We attempted to compare the histologic features of esophageal

Granular cell tumor of the gastrointestinal tract

817

Fig. 2 Representative images of GCTs (A-G, hematoxylin-eosin staining; H-L, immunohistochemical staining). A, Scanning images demonstrate a well-circumscribed, solid mass. B, Peritumoral lymphoid cuffs are noted in colonic GCTs (original magnification ×40). C, Mucosal involvement of tumor causes mucosal puckering (×100). D, Nuclear pleomorphism (×400). E, Granular cell tumor with a marginated growth pattern (×200). F, Granular cell tumor with an infiltrative growth pattern (×400). G, Malignant GCT. Infiltrating tumor cells in the proper muscle layer (×400). Tumor cells show diffuse nuclear and cytoplasmic S-100 protein (H, ×200), diffuse cytoplasmic CD56 (I, ×200), cytoplasmic CD68 (J, ×200), nuclear SOX-10 (K, ×200), and cytoplasmic inhibin-α (L, ×200) labeling.

and colorectal GCTs using their histologic criteria. Lymphoid cuffing was observed at the periphery of GCTs. In agreement with the study by Singhi and Montgomery, the infiltrative growth pattern and lymphoid cuffing were more frequent histologic features observed in colonic tumors than

in esophageal GCTs in our study. In addition, we observed that gastric GCTs showed more infiltrative growth pattern and lymphoid cuffing than esophageal tumors. We also observed that both colorectal and gastric GCTs had a larger tumor size than esophageal tumors. The larger tumor size

818 Table 4

S. An et al. Immunohistochemical staining results of GCTs according to the locations

IHC markers

Location Esophagus

Stomach

Colorectum

Total

S-100 protein CD68 CD56 SOX-10 Inhibin-α

57/57 (100%) 38/40 (95%) 34/37 (92%) 33/37 (89%) 15/37 (41%)

4/4 (100%) 2/3 (67%) 3/3 (100%) 3/3 (100%) 1/3 (33%)

20/20 18/18 18/18 18/18 14/18

81/81 58/61 55/58 54/58 30/58

(100%) (100%) (100%) (100%) (78%)

P (100%) (95%) (95%) (93%) (52%)

1 .165 .611 .430 .018 ⁎

Abbreviation: IHC, immunohistochemical. ⁎ Significant at the level of P b .05.

was associated with a more infiltrative growth pattern and lymphoid cuffing, both of which are frequently observed histologic features of colonic and gastric GCTs rather than of esophageal tumors. The endoscopic findings of these tumors are variable. The most common appearance was a submucosal nodule with overlying normal mucosa with occasional yellow discoloration. A polypoid or sessile mass was also described as endoscopic features [8]. They also appeared white or with reddish mucosa [8]. Most of the GCTs occurred as solitary lesions, although multiple tumors were occasionally reported in 4% to 30.4% of patients [8,9]. In our study, 3 of 95 patients (3%) had multiple GCTs, which was similar to that seen in previous reports. In patients with multiple GCTs, the tumor locations were confined within the same organs. In 1 patient with double colonic GCT, the first GCT was observed in the cecum and the second tumor in the ascending colon. Similarly, in the 1 double esophageal GCT case, the first was in the distal, and the second GCT was in the same area. In the other patient with multiple gastric GCTs, the first tumor was in the antrum, whereas the second GCT was in the same area. Malignant GCTs are extremely rare and are categorized into 2 types, one of which is both histologically and clinically malignant tumor and the other is clinically malignant despite a histologically benign appearance [16]. Several previous case reports described the histopathologic features of malignant GCT as local recurrence, including rapid tumor growth, a large tumor size (N4 cm), increased cellularity, and cytologic atypia [17,18]. Fanburg-Smith et al [19] proposed the diagnostic criteria for malignant soft tissue GCTs as necrosis, spindling, vesicular nuclei with large nucleoli, increased mitotic activity (N2 mitoses/10 high-power fields at ×200 magnification), a high nuclear-to-cytoplasmic ratio, and nuclear pleomorphism. Malignant GCTs could be considered if more than 3 of these criteria were met [19]. In addition to these histologic criteria, malignant GCTs could also suggest GCTs showing high Ki-67 values (N10%) and p53 immunolabeling [19]. On the other hand, David and Jakate [20] reported 1 case of multifocal GCT with an infiltrative pattern, which had marked infiltration into the proper muscle layer despite a cytologically benign

appearance. They proposed an extensive infiltrating pattern as a predictor of malignant behavior regardless of a benign histologic appearance [20]. One case included in our study had an extensive, infiltrating growth pattern with lymph node metastasis without accompanying malignant histologic features, except for focal nuclear pleomorphism and increased mitotic activity. This case did not meet the diagnostic criteria of malignant GCT proposed by FanburgSmith; however, the extensive infiltrating pattern and lymph node metastasis could be classified as malignant GCT, as proposed by David and Jakate. This case underwent surgical resection of the tumor in another hospital and was transferred to our hospital for follow-up. A brief history of this patient was presented in part of 1 case report [21]. After surgical excision, no recurrence or metastasis to other organs was observed for 24 months after the tumor resection. In this study, we performed several immunohistochemical stainings, including S-100 protein, CD56, CD68, SOX-10, and inhibin-α, which are used as ancillary tests for diagnosis of GCTs. We demonstrated that almost all GCTs from GI tracts were labeled to S-100 protein (100%), CD68 (95%), CD56 (95%), and SOX-10 (93%). High frequency of S-100 protein and SOX-10 expression in the present study were concordant with the results of the previous studies [22,23]. Several previous studies have reported CD68 expression in GCTs, with 65% to 100% of GCTs expressing CD68 [1,17,22,24-27]. CD68 expression was observed in 95% (58/61) of GCT cases in the present study, which was concordant with results of the previous studies [1,17,22,24-27]. However, our results were discordant with the study by Gurzu et al [28], which reported CD68 negativity in all 15 GCTs. Only 2 previous studies reported 93% to 100% CD56 expression rate in GCTs [22,28]. Gurzu et al [28] previously described that only benign GCTs demonstrated diffuse CD56 labeling, but all atypical GCTs showed CD56 negativity. However, all 3 CD56-negative GCT cases in the present study were histologically benign and are discordant with report of Gurzu et al. We observed inhibin-α labeling in 52% (30/58) of GCT cases in the present study. This is a significantly higher percentage than the results of the previous studies [22,29], and this discordance might be related to different ethnicity or use of different condition of inhibin-α immunohistochemical studies.

Granular cell tumor of the gastrointestinal tract In summary, (1) GCTs in the GI tact are observed with the following frequency: esophagus, colorectum, and stomach; (2) colorectal and gastric GCTs are larger than esophageal GCTs; (3) an infiltrative growth pattern and lymphoid cuffing are more commonly observed histologic features in colorectal and gastric GCTs than esophageal tumors; (4) malignant GCT is rare (1%) but can be observed in GI tract; (5) inhibin-α expression is more common in colorectal GCTs than esophageal tumors; and (6) high S-100 protein, CD56, CD68, and SOX-10 expression rates are observed in GCTs from GI tracts.

Acknowledgment This study was supported by a grant (2013-554) from the Asan Institute for Life Sciences, Seoul, Korea.

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Granular cell tumor of the gastrointestinal tract: histologic and immunohistochemical analysis of 98 cases.

Granular cell tumors (GCTs) are uncommon benign neoplasms in the gastrointestinal (GI) tract, and our current understanding of GCT in GI tract is limi...
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