Stromal Tumors of the Esophagus

Background

Stromal tumors of the esophagus are most commonly leiomyomas, tumors derived from smooth muscle. Rarely sarcomas, usually leiomyosarcomas may occur. These tumors are variable in size but larger tumors may present with clinical symptoms of obstruction and dysphagia. Symptom duration may last 2 years or more, mimicking chronic gastroesophageal reflux. A large number of tumors, however, may be found as incidental findings during chest radiographs or endoscopic evaluation for other medical conditions. About 90 percent are in the lower and middle thirds.

OUTLINE

Epidemiology

Disease Associations

Pathogenesis

Laboratory/Radiologic/
Other Diagnostic Testing

Gross Appearance and Clinical Variants

Histopathological Features and Variants

Special Stains/
Immunohistochemistry/
Electron Microscopy

Differential Diagnosis

Prognosis

Treatment

Commonly Used Terms

Internet Links

EPIDEMIOLOGY CHARACTERIZATION

AGE RANGE-MEDIAN Mean is mid to late 5th decade

SEX (M:F)
2:1

DISEASE ASSOCIATIONS CHARACTERIZATION

AIDS

Primary gastrointestinal stromal tumor of the esophagus in an HIV-positive patient.

Padula A, Chin NW, Azeez S, Resetkova E, Andriko JA, Miettinen M.

Department of Hematophatology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

Ann Diagn Pathol. 2005 Feb;9(1):49-53. Abstract quote

We describe a rare case of malignant gastrointestinal stromal tumor (GIST) of the esophagus presenting in an HIV-positive man. Not only did the tumor arise from an unusual anatomic site for GIST, namely, the esophagus, but it also had a predominant epithelioid cell morphology that is uncommon and preferentially associated with aggressive behavior.

Exhaustive immunohistochemical studies showed strong reactivities to the classic GIST marker, CD34, and to the current more sensitive and more specific GIST marker, CD117/ c-kit protein. This immunophenotype corresponded to that of stromal tumors arising in the more common sites like stomach and small intestine as well as to that of a reported series of esophageal GISTs in the general population. Mutations of the c-kit protein was detected in the tumor, confirming previous observations.

This further documents that esophageal GIST and the more common benign esophageal spindle cell lesions are pathologically distinct entities and despite its rarity, esophageal GIST should be recognized by pathologists and clinicians. The occurrence of this tumor in an HIV-positive patient is coincidental, and it resulted in an extremely unusual metastatic site that has not been reported for GISTs.

GROSS APPEARANCE/
CLINICAL VARIANTS CHARACTERIZATION

General

VARIANTS

Leiomyomatosis
Uncommon condition
Occurs in the distal esophagus

Muscularis propria becomes diffusely nodular, hypertrophied, and disorganized and resembles a continuous cluster of leiomyomas

Sarcomas
Extremely rare

Most are intramural

Leiomyosarcomas account for 90 percent of esophageal sarcomas

Rare case reports of rhabdomyosarcomas, synovial sarcomas, malignant nerve sheath tumors, osteosarcoma, chondrosarcoma, fibrosarcoma, malignant fibrous histiocytoma, and liposarcoma

Granular cell tumors
Second most common stromal tumor after leiomyomas

Usually small and asymptomatic

Most of the patients are in their 40s with men and blacks seem at risk

Endoscopic features include:
Sessile, yellow or yellow-white tumors, firm to palpation

HISTOLOGICAL TYPES CHARACTERIZATION

General

"Seedling" Mesenchymal Tumors (Gastrointestinal Stromal Tumors and Leiomyomas) are Common Incidental Tumors of the Esophagogastric Junction.

Abraham, Susan C. MD *; Krasinskas, Alyssa M. MD +; Hofstetter, Wayne L. MD ++; Swisher, Stephen G. MD ++; Wu, Tsung-Teh MD, PhD [S]

American Journal of Surgical Pathology. 31(11):1629-1635, November 2007.

Abstract:
Gastrointestinal stromal tumors (GISTs) are the most common nonepithelial neoplasm of the gastrointestinal tract and show a predilection for the stomach. Most are detected because of symptoms, but some are incidental findings at autopsy or surgery for other reasons. Incidental GISTs tend to be smaller at diagnosis, but even small (<1 cm) GISTs have been shown to harbor activating KIT mutations at rates similar to advanced GISTs. However, the prevalence and characteristics of small GISTs in surgical resections of the esophagogastric junction (EGJ) remains unclear.

We studied 150 esophagogastric resections for esophageal or EGJ carcinomas (100 with preoperative chemoradiation and 50 untreated cases) that had been extensively embedded for histologic examination (mean 30 sections/case). Number, size, morphology, and location of all GISTs and leiomyomas were recorded. All potential GISTs were evaluated with CD117 and CD34 immunohistochemistry, and a subset (35) leiomyomas with smooth muscle actin, desmin, and CD117.

We found 18 incidental GISTs in 15 of 150 (10%) patients; 3 patients harbored 2 separate lesions. Prevalence of GIST was identical in treated (10 of 100) and untreated (5 of 50) cases. All (100%) showed positivity for both CD117 and CD34 and all were of spindle cell morphology. Lesions ranged from 0.2 to 3.0 mm in size (mean 1.3 mm). Eight (44%) were based in the outer muscularis propria, 7 (39%) in inner muscularis, and 3 (17%) between the muscle layers. The lesions tended to cluster near the EGJ, with 8 (44%) on the gastric side, 9 (50%) on the esophageal side, and 1 (6%) undetermined owing to overlying ulceration. Leiomyomas were even more common than GIST, occurring in 47% of patients (44% of treated and 52% of untreated, P=0.39), with a mean of 3 leiomyomas per patient (range 1 to 13) and mean size of 1.7 mm (range 0.2 to 12 mm). Unlike colorectal leiomyomas, most (91%) EGJ leiomyomas were located in the inner muscularis propria and only rarely (1%) in muscularis mucosa. These results suggest that GIST and leiomyoma are common incidental "seedling" lesions of the EGJ, found in 10% and 47% of patients undergoing surgery for esophageal carcinoma.

The common occurrence of microscopic GISTs compared with the rarity of clinically manifest and malignant esophagogastric GISTs suggests that additional genetic or epigenetic alterations must happen for neoplastic progression.

Esophageal stromal tumors: a clinicopathologic, immunohistochemical, and molecular genetic study of 17 cases and comparison with esophageal leiomyomas and leiomyosarcomas.

Miettinen M, Sarlomo-Rikala M, Sobin LH, Lasota J.

Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.

Am J Surg Pathol 2000 Feb;24(2):211-22 Abstract quote

Although rare elsewhere in the gastrointestinal tract, leiomyomas (LMs) are the most common esophageal mesenchymal neoplasms. In contrast, gastrointestinal stromal tumors (GISTs) predominate in the stomach and intestines but have not been documented in the esophagus.

This study was undertaken to determine the clinicopathologic features and frequency of esophageal GISTs compared with LMs and leiomyosarcomas (LMSs) of the esophagus. A total of 68 stromal/smooth muscle tumors from the Armed Forces Institute of Pathology and the Haartman Institute of University of Helsinki were reclassified by current histologic and immunohistochemical criteria. There were 17 GISTs, 48 LMs, and three LMSs. The esophageal GISTs occurred in 12 men and five women with a median age of 63 years (range, 49-75 years). All tumors were from the lowest third of the esophagus, and the most common complaint was dysphagia, whereas two tumors were detected incidentally.

Histologically the tumors had an overall basophilic appearance and showed combinations of solid, myxoid, and perivascular collarlike patterns with a spindle cell histology in 13 patients and epithelioid histology in four patients. All tumors were positive for CD117 and for CD34, whereas two patients were also positive for alpha-smooth muscle actin (SMA) and three patients were positive for desmin. One patient showed a unique immunophenotype with coexpression of CD117, CD34, SMA, and desmin.

Nine patients died of disease, including all who had a tumor larger than 10 cm, and also one patient whose tumor showed five mitoses per 50 high-power fields. In comparison, esophageal LMs (n = 48) occurred in a younger population (median age, 35 years) but, similar to the GIST group, men predominated (67%). All LMs were clinically indolent tumors with no tumor-related mortality. The LMs showed eosinophilic cytoplasm, and were positive for desmin and SMA, and negative for CD117 and CD34. All three LMSs were large high-grade tumors that showed muscle cell markers but no CD117. All patients died of disease. Esophageal GISTs showed mutations in exon 11 of c-kit as described previously in gastric and intestinal GISTs.

The separation of GISTs from esophageal LMs is important diagnostically because the former group has a high risk of malignant behavior.

VARIANTS

Leiomyoma
Mature-appearing smooth muscle cells arranged in fascicles and whorls

Mitotic figures are rare

Hyalinization with deposition of dense collagen is common in the center and a few cases havecollagenized foci which become calcified

Sarcomas
Spindle cells with varying degrees of pleomorphism, mitoses, necrosis, calcification, and differentiation along specialized cell lines including smooth muscle, rhabdomyoblastic, synovial, chondroid, and osteoid

Granular cell tumors
Plump spindled or epithelioid cells with small nuclei and abundant cytoplasm is filled with coarse red granules

Squamous epithelium may show pseudoepitheliomatous hyperplasia that may be confused with well-differentiated squamous carcinoma

Macpherson and Pincus. Clinical Diagnosis and Management by Laboratory Methods. Twentyfirst Edition. WB Saunders. 2006.
Rosai J. Ackerman's Surgical Pathology. Ninth Edition. Mosby 2004.
Sternberg S. Diagnostic Surgical Pathology. Fourth Edition. Lipincott Williams and Wilkins 2004.
Robbins Pathologic Basis of Disease. Seventh Edition. WB Saunders 2005.
DeMay RM. The Art and Science of Cytopathology. Volume 1 and 2. ASCP Press. 1996.
Weedon D. Weedon's Skin Pathology Second Edition. Churchill Livingstone. 2002
Fitzpatrick's Dermatology in General Medicine. 6th Edition. McGraw-Hill. 2003.
Weiss SW and Goldblum JR. Enzinger and Weiss's Soft Tissue Tumors. Fourth Edition. Mosby 2001.

Commonly Used Terms

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Special Stains
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Last Updated November 8, 2007

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Epidemiology
Disease Associations
Pathogenesis
Laboratory/Radiologic/ Other Diagnostic Testing
Gross Appearance and Clinical Variants
Histopathological Features and Variants
Special Stains/ Immunohistochemistry/ Electron Microscopy
Differential Diagnosis
Prognosis
Treatment
Commonly Used Terms
Internet Links

EPIDEMIOLOGY	CHARACTERIZATION
AGE RANGE-MEDIAN	Mean is mid to late 5th decade
SEX (M:F)	2:1

GROSS APPEARANCE/ CLINICAL VARIANTS	CHARACTERIZATION
General
VARIANTS
Leiomyomatosis	Uncommon condition Occurs in the distal esophagus Muscularis propria becomes diffusely nodular, hypertrophied, and disorganized and resembles a continuous cluster of leiomyomas
Sarcomas	Extremely rare Most are intramural Leiomyosarcomas account for 90 percent of esophageal sarcomas Rare case reports of rhabdomyosarcomas, synovial sarcomas, malignant nerve sheath tumors, osteosarcoma, chondrosarcoma, fibrosarcoma, malignant fibrous histiocytoma, and liposarcoma
Granular cell tumors	Second most common stromal tumor after leiomyomas Usually small and asymptomatic Most of the patients are in their 40s with men and blacks seem at risk Endoscopic features include: Sessile, yellow or yellow-white tumors, firm to palpation

HISTOLOGICAL TYPES	CHARACTERIZATION
General
"Seedling" Mesenchymal Tumors (Gastrointestinal Stromal Tumors and Leiomyomas) are Common Incidental Tumors of the Esophagogastric Junction. **Abraham, Susan C. MD ; Krasinskas, Alyssa M. MD +; Hofstetter, Wayne L. MD ++; Swisher, Stephen G. MD ++; Wu, Tsung-Teh MD, PhD [S]***	American Journal of Surgical Pathology. 31(11):1629-1635, November 2007. Abstract: Gastrointestinal stromal tumors (GISTs) are the most common nonepithelial neoplasm of the gastrointestinal tract and show a predilection for the stomach. Most are detected because of symptoms, but some are incidental findings at autopsy or surgery for other reasons. Incidental GISTs tend to be smaller at diagnosis, but even small (<1 cm) GISTs have been shown to harbor activating KIT mutations at rates similar to advanced GISTs. However, the prevalence and characteristics of small GISTs in surgical resections of the esophagogastric junction (EGJ) remains unclear. We studied 150 esophagogastric resections for esophageal or EGJ carcinomas (100 with preoperative chemoradiation and 50 untreated cases) that had been extensively embedded for histologic examination (mean 30 sections/case). Number, size, morphology, and location of all GISTs and leiomyomas were recorded. All potential GISTs were evaluated with CD117 and CD34 immunohistochemistry, and a subset (35) leiomyomas with smooth muscle actin, desmin, and CD117. We found 18 incidental GISTs in 15 of 150 (10%) patients; 3 patients harbored 2 separate lesions. Prevalence of GIST was identical in treated (10 of 100) and untreated (5 of 50) cases. All (100%) showed positivity for both CD117 and CD34 and all were of spindle cell morphology. Lesions ranged from 0.2 to 3.0 mm in size (mean 1.3 mm). Eight (44%) were based in the outer muscularis propria, 7 (39%) in inner muscularis, and 3 (17%) between the muscle layers. The lesions tended to cluster near the EGJ, with 8 (44%) on the gastric side, 9 (50%) on the esophageal side, and 1 (6%) undetermined owing to overlying ulceration. Leiomyomas were even more common than GIST, occurring in 47% of patients (44% of treated and 52% of untreated, P=0.39), with a mean of 3 leiomyomas per patient (range 1 to 13) and mean size of 1.7 mm (range 0.2 to 12 mm). Unlike colorectal leiomyomas, most (91%) EGJ leiomyomas were located in the inner muscularis propria and only rarely (1%) in muscularis mucosa. These results suggest that GIST and leiomyoma are common incidental "seedling" lesions of the EGJ, found in 10% and 47% of patients undergoing surgery for esophageal carcinoma. The common occurrence of microscopic GISTs compared with the rarity of clinically manifest and malignant esophagogastric GISTs suggests that additional genetic or epigenetic alterations must happen for neoplastic progression.
Esophageal stromal tumors: a clinicopathologic, immunohistochemical, and molecular genetic study of 17 cases and comparison with esophageal leiomyomas and leiomyosarcomas. Miettinen M, Sarlomo-Rikala M, Sobin LH, Lasota J. Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.	Am J Surg Pathol 2000 Feb;24(2):211-22 Abstract quote Although rare elsewhere in the gastrointestinal tract, leiomyomas (LMs) are the most common esophageal mesenchymal neoplasms. In contrast, gastrointestinal stromal tumors (GISTs) predominate in the stomach and intestines but have not been documented in the esophagus. This study was undertaken to determine the clinicopathologic features and frequency of esophageal GISTs compared with LMs and leiomyosarcomas (LMSs) of the esophagus. A total of 68 stromal/smooth muscle tumors from the Armed Forces Institute of Pathology and the Haartman Institute of University of Helsinki were reclassified by current histologic and immunohistochemical criteria. There were 17 GISTs, 48 LMs, and three LMSs. The esophageal GISTs occurred in 12 men and five women with a median age of 63 years (range, 49-75 years). All tumors were from the lowest third of the esophagus, and the most common complaint was dysphagia, whereas two tumors were detected incidentally. Histologically the tumors had an overall basophilic appearance and showed combinations of solid, myxoid, and perivascular collarlike patterns with a spindle cell histology in 13 patients and epithelioid histology in four patients. All tumors were positive for CD117 and for CD34, whereas two patients were also positive for alpha-smooth muscle actin (SMA) and three patients were positive for desmin. One patient showed a unique immunophenotype with coexpression of CD117, CD34, SMA, and desmin. Nine patients died of disease, including all who had a tumor larger than 10 cm, and also one patient whose tumor showed five mitoses per 50 high-power fields. In comparison, esophageal LMs (n = 48) occurred in a younger population (median age, 35 years) but, similar to the GIST group, men predominated (67%). All LMs were clinically indolent tumors with no tumor-related mortality. The LMs showed eosinophilic cytoplasm, and were positive for desmin and SMA, and negative for CD117 and CD34. All three LMSs were large high-grade tumors that showed muscle cell markers but no CD117. All patients died of disease. Esophageal GISTs showed mutations in exon 11 of c-kit as described previously in gastric and intestinal GISTs. The separation of GISTs from esophageal LMs is important diagnostically because the former group has a high risk of malignant behavior.
VARIANTS
Leiomyoma	Mature-appearing smooth muscle cells arranged in fascicles and whorls Mitotic figures are rare Hyalinization with deposition of dense collagen is common in the center and a few cases havecollagenized foci which become calcified
Sarcomas	Spindle cells with varying degrees of pleomorphism, mitoses, necrosis, calcification, and differentiation along specialized cell lines including smooth muscle, rhabdomyoblastic, synovial, chondroid, and osteoid
Granular cell tumors	Plump spindled or epithelioid cells with small nuclei and abundant cytoplasm is filled with coarse red granules Squamous epithelium may show pseudoepitheliomatous hyperplasia that may be confused with well-differentiated squamous carcinoma