Clinical History
The patient is a 38-year-old female who underwent a partial
mastectomy for invasive ductal carcinoma with 1 of 4 lymph nodes positive for metastatic disease. A CT
scan of the chest showed esophageal thickening suggestive of a mass. Upper endoscopy revealed a
submucosal mass in the lower esophagus from 33 to 37 cm. There was a central ulcer with umbilication.
Multiple biopsies were obtained and the patient ultimately underwent a transhiatal esophagectomy. The
slides and photomicrographs are from the resection specimen.
Case 2 - Figure 1 - Low-power scan of the lesion showing a well-circumscribed nodule in the submucosa.
|
Case 2 - Figure 2 - Medium-power view showing nests of eosinophilic spindle cells with an organoid pattern.
|
Case 2 - Figure 3 - High-power view showing relationship of the tumor to the overlying squamous mucosa with pseudoepitheliomatous hyperplasia.
|
Case 2 - Figure 4 - High-power view of tumor cells showing granular cytoplasm and single atypical nucleus.
|
Pathologic Findings
The resection specimen consisted of a 7 cm length of
esophagus with an additional 4 cm length of proximal stomach. Just above the gastroesophageal junction
was a well-circumscribed 3.0 x 2.6 x 1.0 cm nodular mass. The cut surface revealed a yellow mass that
appeared to be between the mucosa and the muscularis propria.
Microscopic examination revealed a fairly well-circumscribed hypocellular spindle cell tumor that was
largely confined to the submucosa. The tumor cells did invade through the muscularis mucosae to involve
the surface epithelium. The overlying squamous mucosa was hyperplastic. The individual tumor cells were
quite bland and were without mitotic activity. The cytoplasm of many of the tumor cells had a granular
appearance.
Special stains revealed the tumor cells were strongly S100 positive and were weakly positive for CD117
(c-kit). A PAS digest stain showed patchy granular cytoplasmic staining within many tumor cells.
Clinical Follow-up
The patient had an uneventful recovery from her
surgery and is undergoing chemotherapy for her breast cancer.
Diagnosis
Granular Cell Tumor of the Esophagus
Discussion
Granular cell tumors were first described by Abrikossoff in
1926 when he reported 5 such tumors in the tongue. In 1931 Abrikossoff reported the first granular cell
tumor of the esophagus. These tumors are now known to occur in many areas of the body (skin, breast,
respiratory tract) including the GI tract. While the gut is home to a relatively small percentage of
granular cell tumors (5-8%) nearly a third arise in the esophagus. Once considered to be a rare tumor,
the reported incidence of esophageal granular cell tumors has increased dramatically. In 1981 only 29
cases of granular cell tumors of the esophagus had been reported in the literature. By 1985, 86 cases
had been reported and by 1996 the number was approximately 200. The advent and popularity of fiber optic
endoscopy as well as improved radiologic detection of small lesions has probably played a role in this
"epidemic" (as has the ambition of residents, fellows and untenured academicians everywhere).
Esophageal granular cell tumors are reported to be more common in women and blacks. The age range is
from 20 to 70. Most lesions occur in the distal esophagus and multifocal lesions within the esophagus as
well as the entire GI tract have been reported. The vast majority of granular cell tumors of the
esophagus are smaller than 1 cm. Nearly all of these lesions are discovered incidentally, while patients
with tumors larger than 1 cm can present with dysphagia.
Given the small size of most of these lesions, it is not surprising that nearly all granular cell
tumors of the esophagus behave in a benign fashion. However, there are a handful of reports of malignant
granular cell tumors of the esophagus (as in other body sites). One such report found lymph node
metastases while several others reported larger tumors with transmural invasion of the esophageal wall.
An abstract by Fanburg and colleagues proposed that the presence of at least three of the following
criteria were needed for the diagnosis of malignancy; tumor cell necrosis, tumor cell spindling,
increased nuclear size, large nucleoli, mitotic activity, and nuclear pleomorphism. Other retrospective
studies of granular cell tumors that have metastasized have found no reliable pathologic variables that
allow one to distinguish benign from malignant tumors. Despite this, most esophageal granular cell
tumors are small benign "incidentalomas" that can safely be left alone. A recent study by Voskuil et al
found that of 44 esophageal tumors treated in the Netherlands between 1988 and 1994, only one was
resected and 4 were removed via polypectomy or incisional biopsy. The remaining cases were not treated.
Follow-up found that only one tumor grew while the remaining lesions either remained stable or regressed.
Current management recommendations suggest that only large and/or symptomatic tumors be excised.
Granular cell tumors were originally thought to be myogenic in origin and were called granular cell
myoblastomas. More recent immunohistochemical and electron microscopic evidence is supportive of a
peripheral nerve or Schwann cell origin. These tumors stain diffusely with antibodies to S100 protein
and NSE. In addition PAS digest stains typically show granular positivity secondary to lysosomes within
the tumor cells.
The differential diagnosis in endoscopic biopsy specimens can be challenging as these tumors typically
evoke psuedoepitheliomatous hyperplasia in the overlying squamous mucosa, which can mimic squamous cell
carcinoma. Often times only a few small clusters of pink granular cells may cling to this squamous
hyperplasia. An S100 stain can save the day, as these few cells will usually light right up.
Interestingly, there a few case reports of invasive squamous cell carcinomas occurring in esophagi with
granular cell tumors. Granular cell tumors may be also be confused with metastatic carcinomas and
melanomas. This can be particularly problematic during frozen sections. Generally speaking, the bland
cytology should cause one to question a malignant diagnosis in such cases.
In this particular case, the diagnosis of a granular cell tumor was made on endoscopic biopsy
material. Once the H&E slides from the resection specimen were reviewed, however, it caused some
confusion, as many pathologists in our department thought it might be a small GIST. The strong diffuse
staining with S100 and the very faint staining with CD117 confirmed the diagnosis of a granular cell
tumor. The faint CD117 staining was something I had not seen before. Just for fun I pulled out 3 other
granular cell tumors and found that they had an identical staining pattern with CD117. What this means
is anybody's guess!
References
- Goldblum JR. Rice TW. Zuccaro G. Richter JE. Granular cell tumors of the esophagus: a clinical and pathologic study of 13 cases. Annals of Thoracic Surgery. 62(3):860-5, 1996
- Joshi A. Chandrasoma P. Kiyabu M. Multiple granular cell tumors of the gastrointestinal tract with subsequent development of esophageal squamous carcinoma. Digestive Diseases & Sciences. 37(10):1612-8, 1992
- Vuyk HD. Snow GB. Tiwari RM. van Velzen D. Veldhuizen RW. Granular cell tumor of the proximal esophagus. A rare disease. Cancer. 55(2):445-9, 1985
- Lack EE. Worsham GF. Callihan MD. Crawford BE. Klappenbach S. Rowden G. Chun B. Granular cell tumor: a clinicopathologic study of 110 patients. Journal of Surgical Oncology. 13(4):301-16, 1980
- Ohmori T. Arita N. Uraga N. Tabei R. Tani M. Okamura H. Malignant granular cell tumor of the esophagus. A case report with light and electron microscopic, histochemical, and immunohistochemical study. Acta Pathologica Japonica. 37(5):775-83, 1987
- David O. Jakate S. Multifocal granular cell tumor of the esophagus and proximal stomach with infiltrative pattern: a case report and review of the literature. Archives of Pathology & Laboratory Medicine. 123(10):967-73, 1999
- Voskuil JH. van Dijk MM. Wagenaar SS. van Vliet AC. Timmer R. van Hees PA. Occurrence of esophageal granular cell tumors in The Netherlands between 1988 and 1994. Digestive Diseases & Sciences. 46(8):1610-4, 2001
- Brady PG. Nord HJ. Connar RG. Granular cell tumor of the esophagus: natural history, diagnosis, and therapy. Digestive Diseases & Sciences. 33(10):1329-33, 1988
- Marinho A. Moura A. Baptista M. Macedo G. Pimenta A. David L. Granular cell tumour and leiomyomatosis of the esophagus--a non-coincidental association? Pathology, Research & Practice. 192(5):492-5, 1996
- Fotiadis C. Manolis EN. Troupis TG. Gorgoulis VG. Sechas MN. Endoscopic resection of a large granular cell tumor of the esophagus. Journal of Surgical Oncology. 75(4):277-9, 2000
- van der Peet DL. Berends FJ. Klinkenberg-Knol EC. Cuesta MA. Endoscopic treatment of benign esophageal tumors: case report of three patients. Surgical Endoscopy. 15(12):1489, 2001
- Szumilo J. Dabrowski A. Skomra D. Chibowski D. Coexistence of esophageal granular cell tumor and squamous cell carcinoma: a case report. Diseases of the Esophagus. 15(1):88-92, 2002
- Fanburg JC, Meis-Kindbloom JM, Kindbloom LG. Malignant, atypical and multicentric granular cell tumors: Diagnostic criteria and clinicopathologic correlation (abstract) Mod Pathol 9:6A, 1996
