Rodger C. Haggitt Slide Seminar: Lesions of Esophagus, Stomach, and Duodenum
Moderators: Dr. Cecilia Fenoglio-Preiser and Dr. Wendy Frankel
Case 8 -
Gastric Stromal Tumors
Elizabeth Montgomery, MD
Johns Hopkins Medical Institute
Female, 61-year-old, This slide was prepares from a 7 cm mass excised from the stomach.
Case 8 - Slide 1
Gastric Stromal Tumors
The stomach is the most common site for gastrointestinal stromal tumors (GIST, efig 325) and they are
occasionally diagnosed on mucosal biopsies. Typically those diagnosed on biopsies are aggressive lesions
that have invaded the mucosa. GISTs are mesenchymal tumors arising in the GI tract and occasionally
within the abdomen with no GI connection. The earlier literature attempted to classify them as smooth
muscle or nerve sheath tumors, but even in the benign tumors evidence for such differentiation was
difficult to find. Mazur and Clark coined the term stromal tumor in 1983  . GISTs show
differentiation towards (and supposedly arise from a precursor of) interstitial cells of Cajal which are
normally concerned with motility of the gut
. This category is considered to subsume the
ultrastructurally defined rare lesions previously known as gastrointestinal autonomic nerve tumors
(GANT). The availability of specific antibodies and clarification of their immunohistochemical profile
has facilitated diagnosis. However, careful morphologic examination and clinicopathological correlation
remain essential for excluding mimics and for assessment of likely behavior in this heterogeneous group
GISTs comprise 5-10% of all sarcomas (for comparison, retroperitoneal = 15% and extremity 42%), and
around 25% of GISTs are malignant, representing about 1% of all GI malignancies. They are most common in
adults aged 50-60. These tumors vary in differentiation and prognosis according to their location within
the GI tract. Esophageal GISTs are rare, but 50-70% involve the stomach, 25-40% the small intestine (of
which 10-20% arise in duodenum, 27-37% in jejunum, 27-53% in ileum) and < 10% are colorectal (50%
colonic, 50% rectal). They are least frequent in the esophagus (where smooth muscle tumors are more
usually found), colon and rectum. GIST-type tumors arising in omentum, peritoneum and retroperitoneum
have been identified, comprising 6.7% of the large AFIP series of 1008 GISTs  .
Tumors present with primary mass, pain or bleeding (46%) or metastasis (47%) and two
thirds exceed 5cm at presentation. Malignant GIST are rare with about 5 per million of population
(compared with 25 per million for soft tissue sarcomas). There is an increased incidence of GIST
including multiple tumors in small intestine in patients with NF-1, possibly associated with interaction
between the NF-1 gene product and c-kit) and GIST is occasionally familial (associated with a germline
c-kit mutation, see below). Some patients have second cancers, and some epithelioid gastric stromal
tumors are associated with paraganglioma and pulmonary chondroma in Carney's triad.
About 20% are malignant. The consensus is that 5 mitoses per 50 hpf and >5cm are adverse
prognostic factors  . The five-year survival of gastric GISTs is about 40%, with improvement in
completely resected cases. There is no evidence that radical surgery improves survival, so that the
least extensive surgical procedure compatible with complete excision is advisable. Gastric GISTs are
more frequent in males, but young patients, especially female, have an improved outcome; Persson et al
(1992) reported 4 patients less than 26 years old who had metastasizing gastric epithelioid
leiomyosarcomas, involving liver, nodes, peritoneum, and who all survived for 17-48 years.
Epithelioid GISTs are the old leiomyoblastomas of Stout (the term epithelioid leiomyoma
was introduced in the 1969 WHO). They comprise about 11% of gastric GISTs, of which 73-81% are benign.
Large tumors in the fundus or cardiac area and posterior wall are more likely to be malignant. 47-60% of
tumors metastasize, usually within 2 years and survival after metastasis is about 8 months. Lee et al
found tumors larger than 6 cm had a worse outcome, and in the series of Appelman et al, no tumor <5.5
cm metastasized, and only one < 6cm. In the latter series, 1 case with no mitoses metastasized, 12%
with 1-5 mitoses per 50 hpf metastasized and all cases with >10 mitoses per 50 hpf. (None had 6-10).
Benign tumors had 0-5 mitoses per 50 hpf. Metastasis occurred from 55% of well differentiated and 75% of
poorly differentiated epithelioid leiomyosarcomas. Ma et al also found that tumors with >5 mitoses
per 50 hpf had malignant potential. In our series, necrosis had significant negative impact  .
Most GISTs are spindle cell tumors with variable palisading, peculiar paranuclear
vacuoles, and collagen fibrils. On a practical note, it is epithelioid GISTs that are most likely to
cause diagnostic problems on mucosal biopsies as they are readily mistaken for a host of epithelioid and
epithelial neoplasms. It is advisable to perform an immunohistochemical panel in assessing them to
include CD117/c-kit, S100 protein (to address melanoma) and a cytokeratin stain to address signet cell
carcinoma. The majority of GIST have kit mutations and are CD117/c-kit stain positive, but 5-10% lack
kit mutations and some in the c-kit negative subset have alternate mutations of platelet derived growth
factor alpha instead
. Since about 70% of GISTs express CD34, this can also be included in a
diagnostic panel. On mucosal biopsies, it is difficult to assess tumor size and mitotic counts to
prognosticate but it is possible to make a diagnosis in many cases and allow the patient to be scheduled
for an operation to remove the tumor. On resection specimens a "recipe" for this has been published 
, Table 1. Some observers took issue with this as it assumes that all GISTs are potentially malignant
and does not take site into account but is still a useful construct for attempting a prognostic
"forecast". Trupiano et al have published criteria that they believe allow separation of benign gastric
stromal tumors from those they regard as not benign 
(efig 333). We have attempted to apply these to
a series of gastric GISTs and had one "outlier" case  so we continue to add a note of caution to
reports on large gastric stromal tumors that appear otherwise benign.
The AFIP group has the largest accumulated series of gastric stromal tumors, and has
reported a large series of 1,765 GISTs confined to the stomach with good follow-up information  .
There was a slight male predominance (55%) and a median age of 63 years. Only 2.7% of tumors occurred
before the age of 21 years and 9.1% before the age of 40 years. The tumors varied from 0.5 to 44 cm
(median, 6.0 cm) and most commonly presented with GI bleeding; 12% were incidentally detected.
Histologic variants recognized among the spindle cell tumors included sclerosing, palisaded-vacuolated,
hypercellular, and sarcomatous and among the epithelioid tumors, sclerosing, dyscohesive, hypercellular,
and sarcomatous. Outcome was strongly dependent on tumor size and mitotic activity. Only 2% to 3% of
tumors <10 cm and <5 mitoses/50 HPFs metastasized, whereas 86% of tumors >10 cm and >5
mitoses/50 HPFs metastasized. However, tumors >10 cm with mitotic activity <5/50 HPFs and those
<5 cm with mitoses >5/50 HPFs had a relatively low metastatic rate (11% and 15%). A small number
of patients survived intra-abdominal metastasis up to over 20 years. Tumor location in fundus or
gastroesophageal junction, coagulative necrosis, ulceration, and mucosal invasion were all unfavorable
factors (P < 0.001), whereas tumor location in antrum was favorable (P < 0.001). Probably the key
feature of this very large series is that it allowed separating out a "benign" category of gastric GISTs
based on large numbers of cases  . This group has proposed malignancy criteria specific to the
stomach which are shown in Table 2. Another important feature of the AFIP study is that mucosal
extension by gastric GISTs was evidence that the tumor would behave badly. This feature remained
equivocal based on several earlier smaller studies (including our own!
). However, based on these
data from Miettinen et al  , if we encounter a gastric GIST on a mucosal biopsy, it is likely
malignant and we should suggest this in our reports. Based on the large AFIP series of gastric GISTs,
KIT/CD117 is found in 91% of gastric GISTs, CD34 in 82%, SMA in 18%, and desmin in 5%; the latter 2 tend
to be focal.
As a last diagnostic "tip", pathologists should be aware that a number of lesions other
than GIST display CD117. Perhaps fibromatoses are most likely to result in diagnostic errors
We have had some success with using beta catenin for this separation [only fibromatoses show nuclear
Table 1. Suggested Prognostic Criteria for Resected GISTs FROM ALL ANATOMIC SITES 
|Risk Category ||Size (cm) ||Mitotic counts/50 high power fields|
|Very low risk ||<2 ||<5|
|Low risk ||2-5 ||<5|
|Intermediate risk ||<5 |
|High risk ||>5|
Table 2. Suggested Prognostic Criteria for Resected GISTs SPECIFIC TO STOMACH 
|Risk Category ||Size ||Mitotic Counts (per 50 high power fields)|
|Benign ||No larger than 2 cm ||No more than 5/50|
|Probably Benign ||>2, < 5 cm|
>5, < 10 cm
|No more than 5/50|
No more than 5/50
|Uncertain ||No larger than 2 cm ||>5/ 50|
|Low to Moderate Malignant Potential ||>10 cm|
>2, < 5 cm
|Not more than 5/ 50|
|High Malignant potential ||>5, < 10 cm|
> 10 cm
|> 5/ 50|
> 5/ 50
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