Case 4 -
Metastatic Gastrointestinal Stromal Tumor
Chris S. Jensen
Department of Pathology
University of Iowa
Click on each slide thumbnail image for an enlarged view
The patient is a 24-year-old female with no significant
past medical history. She presented with sudden onset of upper abdominal pain, which was constant and
severe but not associated with nausea or vomiting. A CT scan of her abdomen showed multiple large
low-density lesions scattered throughout the liver. The patient had no history of prior liver disease
and was not jaundiced. An initial fine needle aspiration under ultrasound guidance was inconclusive due
to low cellularity. A subsequent MRI exam again revealed multiple liver lesions as well as a large mass
between the liver and the anterior wall of the stomach impinging upon the gastric orifice. A fine needle
aspiration was performed of an enlarged celiac lymph node under endoscopic ultrasound (EUS) guidance.
Case 4 - Figure 1 - Papanicolaou stain, low power (100X) - View shows larger tissue fragments which are composed of the mixture of fibrillar stroma and tumor cells. Tumor cells are present as epithelioid clusters as well as dispersed single cells. There is some tendency of small clusters of cells to group together in small gland-like structures.
Case 4 - Figure 2 - Diff-Quik stain, high power (400X) - This high power view shows small cohesive groups of epithelioid cells. The cells have fairly abundant, slightly granular cytoplasm. Nuclei are round to slightly oval. Individual cell borders are not distinct. There are several stripped nuclei noted in the background. A rare intranuclear cytoplasmic inclusion is noted.
Case 4 - Figure 3 - Papanicolaou stain, high power (600X) - This high power field shows a group of loosely cohesive cells. Several cells show prominent intranuclear cytoplasmic inclusion. The nuclei are somewhat ovoid with slight nuclear irregularities, chromatin is granular to slightly clumped. Cytoplasm is granular, with a suggestion of fibrillar cytoplasmic processes.
Smears are quite cellular and composed of
predominantly epithelioid cells in loosely cohesive aggregates. There is, however, significant
discohesion and numerous stripped nuclei as well. Larger fragments show fibrillar stroma between nests
of cells which stains intensely metachromatic on Diff-Quik stained smears. The cells have variable
amounts of cytoplasm with the suggestion of fine granularity in some areas. Cytoplasmic borders are
predominantly not distinct. In areas fibrillar cytoplasmic processes are noted extending from many of
the cells as are a few spindled cells. Nuclei are round to oval with slightly irregular contours. The
chromatin is finely granular to slightly clumped. Small nucleoli are present in many cells and numerous
intranuclear cytoplasmic inclusions are noted.
Additional cytologic material was collected at the time of the procedure for a cell block
preparation. H&E stained sections have clusters of epithelioid cells with similar nuclear features.
These cells are arranged in solid sheets or clusters. There was no additional identifiable architectural
arrangement including no trabecular architecture, gland formation or rosettes. A spindled morphology is
again not prominent. Additional sections of the cell block for immunohistochemical analysis demonstrate
expression of CD117, vimentin and CD34. There was no expression of keratins, smooth muscle actin,
neuroendocrine markers (synaptophysin, chromogranin) or melanoma associated antigens (S100, HMB45, MART
1). Given the characteristic immunohistochemical the cytologic final diagnosis was as follows.
Cytologic Diagnosis: Metastatic gastrointestinal stromal tumor
On EUS examination, extrinsic compression of the
lesser curvature of the stomach was appreciated. Endosonographic examination showed this compression to
be due to a large (10 x 7 cm) mass likely originating in the muscularis propria of the stomach and
growing in an extra-gastric fashion. The mass was solid, heterogenous and well defined. It contained
areas with an echogencity consistent with necrosis. This mass was noted to abut the liver. In addition,
many enlarged lymph nodes were visualized in the celiac region and perigastric region. The diagnostic
fine needle aspiration was taken from one of these nodes.
Given the size and extent of the tumor along with hepatic and nodal metastasis, the patient was not a
candidate for surgical therapy. She was started on Gleevec (imatinib) for treatment of metastatic
gastrointestinal stromal tumor. Follow-up radiologic examination revealed some reduction in size of the
gastric and liver lesions without complete resolution.
Gastrointestinal stromal tumors
(GIST's) are mesenchymal tumors arising
within the gastrointestinal tract (or attached structures) which are immunohistochemically c-KIT (CD117)
positive and characteristically signal driven by the presence of KIT activating mutations. These lesions
represent the majority of mesenchymal lesions arising within the gut. Immunohistochemical and
ultrastructural features suggest an origin from interstitial cells of Cajal (ICC's) or a related
undifferentiated mesenchymal precursor cell with potential to differentiate toward ICC's or smooth
The classification of stromal neoplasms occurring with the gastrointestinal tract has historically
been an area of controversy in pathology resulting in confusing, ambiguous and overlapping terminology.
The recent recognition of c-KIT (CD117) expression in most of these tumors by immunohistochemistry along
with the identification of associated oncogenic mutations resulting in activation of the KIT receptor
tyrosine kinase has clarified the diagnosis of GIST's and as noted above CD 117 positivity now
essentially defines these tumors from a diagnostic standpoint. The recent development of a successful
therapy (Gleevec, imatinib, STI-571) based on the underlying molecular pathology in these tumors has
fueled further interest in these tumors. Prediction of individual tumor behavior remains a challenge.
GIST's are relatively uncommon neoplasms but according to SEER data represent approximately 2.2% of
gastric malignancies and 13.9% of small bowel cancers. The tumors can occur throughout the tubular
intestine, as well as in the adjacent omentum, mesentery and retroperitoneum. The proportion of tumors
at different sites is shown below.
Stomach (50-60%) > Small intestine (20-30%) > Large intestine (10%) > Esophagus (5%) >
Extraintestinal- omentum, mesentery, etc. (5%)
A significant proportion, if not the majority, of GIST's are relatively small incidentally noted
lesions which are identified at the time of endoscopy, abdominal surgery for other reasons or abdominal
imaging studies. The tumors occur in middle aged or older individuals with a median age in the late 50's
in most studies. Symptoms are dependent on the location of the tumor. Symptoms most commonly associated
with gastric GIST's include vague abdominal pain (50-70%) and gastrointestinal bleeding (20-50%). Small
intestinal tumors may result in pain, gastrointestinal bleeding or symptoms of intestinal obstruction.
Large (usually malignant) tumors may present with a palpable abdominal mass.
Endoscopic features are variable, but typically demonstrate an intramural tumor which may have
ulceration of the overlying mucosa. Polypoid projection of the tumor into the intestinal lumen can
occur, but outward extension with associated extrinsic compression or distortion is more common. The
most common pattern of dissemination of malignant tumors at presentation is diffuse intraabdominal
spread. Liver followed by lung are the next most common metastatic sites following the hematogenous
route usually associated with sarcomas. Lymph node metastases as seen in this case are uncommon.
The most common histomorphology associated with GIST's is that of a spindle cell proliferation
resembling smooth muscle tumors, although typically fairly cellular, the cellularity can vary
significantly within the tumor. A fascicular arrangement may be seen as well as whorls. Nuclei tend to
be ovoid with fairly bland vesicular chromatin. Prominent vacuoles adjacent to the nuclei are a feature
noted in some cases. The second most common histologic pattern (20-30%) is that of an epithelioid tumor
as was prominent in this case. These tumors are composed of rounded cells with variable amounts of
eosinophilic or occasionally clear cytoplasm. The nuclei again tend to be round to oval with vesicular
chromatin. Epithelioid tumors are most commonly seen in the stomach. Occasional tumor showing a mixture
of epithelioid and spindle cell areas are seen. Tumors arising within the small bowel have been
associated with a pattern of prominent fibrillar hylan fibers known as skeinoid fibers.
Cytologic features of GIST
The cytologic features of stromal tumors by fine needle aspiration have been well-described. This is
especially true with the advent of evaluation and aspiration by endoscopic ultrasound (EUS) as in the
current case. In addition, to allowing cytologic sampling of tumors, EUS can accurately gauge tumor size
which may be an important predictor of prognosis.
There are two distinct, predominant cytologic patterns which may occasionally occur together. The
most common pattern is that of a spindle cell neoplasm. The smears are typically quite cellular and may
have large three dimensional tissue fragments with prominent vascularity and varying amounts of
fibrillar, collagenous stroma between cells. Individual cells are discohesive or loosely cohesive with
indistinct cell borders and fibrillar cytoplasmic processes. Individual stripped nuclei may occasionally
be quite numerous. Nuclei are typically ovoid to spindled and often wavy with bland granular chromatin.
Nucleoli may be prominent and there may be nuclear grooves or inclusions. Nuclear pleomorphism is
generally uncommon in spindled GIST's.
The second cytologic pattern is that of an epithelioid neoplasm, typically with prominent
discohesion. The epithelioid cells may be admixed with spindle cells as described above. The smears
are again typically quite cellular with loosely cohesive sheets and clusters as well as numerous
discohesive single epithelioid cells. Individual cells have round to slightly ovoid nuclei. Cytoplasm
is typically granular but may be clear or slightly vacuolated. Wispy or fibrillar cytoplasmic processes
may be noted extending from individual cells. Dong etal.  evaluated the cytologic features of nine
cases of epithelioid GIST. Nucleoli and intranuclear cytoplasmic inclusion were the two features
evaluated which were present in all cases. Other cytoplasmic features present in a majority these cases
included irregular nuclear contours, binucleation and collagenous stroma. Although nuclear pleomorphism
is typically not a prominent cytologic feature of GIST's, nuclear atypia may be more common in
The cytologic differential diagnosis of spindled GIST's includes other
stromal neoplasms of the gastrointestinal tract. Although true smooth muscle and peripheral nerve sheath
tumors do occur in the gastrointestinal tract, the tumors are much less common than GIST's in all sites
except the esophagus where leiomyomas are more common. In addition, at sites such as the liver, lymph
nodes or mesentery other mesenchymal tumors (primary or metastatic), malignant melanoma (spindled) and
spindled carcinomas must also be considered.
As noted earlier, CD117 expression by immunohistochemistry essentially defines GIST. As such, the
cytologic diagnosis of GIST (as with surgical pathology) rests on obtaining cytologic material for
immunostaining and demonstration of CD117 expression. The appropriate material for this testing is a
matter of preference based on personal experience, laboratory capabilities, and limitations related to
the aspirator or patient. In our laboratory cell blocks have been most reliable as demonstrated in this
case. Destained papanicolaou smears and cytospin preparations are also acceptable. In tumors which
produce particularly hypocellular aspirations, needle core biopsies may be preferable or necessary if
possible. The immunohistochemical profile and differential diagnosis is summarized in the table below.
| ||KIT (CD117) ||CD34 ||SMA ||Desmin ||S-100|
|GIST ||pos ||pos (60-70%) ||Pos(30-40%) ||neg(rare +) ||neg(5% pos)|
|Smooth muscle tumor ||neg ||pos(10-15%) ||Pos ||pos ||neg|
|Schwannoma ||neg ||pos ||Neg ||neg ||pos|
Adapted from Fletcher et al. Human Path 33:459 (2002)
The cytologic differential diagnosis of epithelioid GIST as in this case is
much more diverse and includes hepatocellular carcinoma, metastatic carcinoma from a variety of primary
sites, malignant melanoma, neuroendocrine carcinoma (carcinoid) and epithelioid sarcomas (especially
leiomyosarcoma). Since, again, the diagnosis rests at least partially on immunostaining for CD117, the
first key in cases such as this is including GIST in the differential diagnosis and insuring that
material for immunostaining is obtained. Obviously this should not be a problem for tumors of the bowel
wall. The larger problem is in cases without an obvious intestinal mass or with disseminated
intraabdominal or metastatic disease which obscures the site of the primary tumor.
Hepatocellular carcinoma is prominent in the differential diagnosis on
patients with single or multiple liver lesions. HCC may have tissue fragments or cluster and typically
has a distinct vascular pattern with transgressing endothelium or trabeculae with peripheral endothelium
(the trabecular pattern when present essentially excludes GIST). However, vessels in tissue fragments
may appear similar to the transgressing endothelium of HCC. Other features shared with GIST include
stripped atypical nuclei, prominent nucleoli and intranuclear cytoplasmic inclusions. HCC typically has
more distinct cytoplasmic borders and bile if present, is diagnostic. Immunohistochemical analysis
should clearly distinguish HCC from GIST. Similarly other carcinomas will also be distinguished by
epithelial markers and CD117.
Metastatic malignant melanoma can share the pattern of discohesive
epithelioid cells with prominent nucleoli and intranuclear cytoplasmic inclusions. Melanoma may also
show a mixture of epithelioid and spindled cells as well. Cytoplasmic melanin is not a feature of GIST,
but is only identifiable in a minority of cases of metastatic melanoma. CD117 positvity has been
described in melanoma, although it is quite uncommon and a small percentage of GIST's mark with S100.
Other melanoma markers,HMB-45 and Mart-1 are usually negative in GIST.
Neuroendocrine tumors, especially low to intermediate grade neuroendocrine
carcinoma, (carcinoid, atypical carcinoid) also share the cytologic pattern of dishesive epithelioid
cells with round nuclei and moderate amounts of granular cytoplasm. The cytoplasmic granularity of
neuroendocrine tumors may be somewhat coarser, especially on Diff Quik stained smears. An organoid
arrangement may be seen in both GIST and neuroendocrine carcinoma, however rosettes are not typically
seen in GIST. The typical bland granular chromatin of GIST may appear similar to bland "salt and pepper"
chromatin of a neuroendocrine tumor. Both tumors may have some spindled to oval nuclei and cytoplasmic
processes. Adding to the similarity is the fact that both tumors may occur in the small bowel or stomach
and have diffuse intraabdominal spread or liver metastases. Immunostaining with chromogranin and
synaptophysin as well as epithelial antigens and absence of CD117 all distinguish neuroendocrine tumors
Prognostic factors / Prediction of behavior:
The identification of
individual prognostic factors has long been recognized as a challenge in stromal tumors. No individual
cytologic feature is predictive of behavior. In general, GIST's show a spectrum of clinical behavior
ranging from apparently benign tumors to aggressive malignant neoplasms. Size and proliferative activity
(mitotic rate) have been the most reliable predictors of outcome. However, although the majority of
tumors may behave in a benign fashion, occasional small bland tumors, with a low proliferative activity
may recur or metastasize. As such, it is probably best to consider that all GIST's have at least some
malignant potential. Diagnoses can then be qualified with an assessment of risk based on the factors
present in the individual case. As with other tumor types, tumors arising in different portions of the
intestine may have differing behaviors. In general, intestinal (small or large) GIST's may have greater
malignant potential than comparable gastric tumors. The uncommon esophageal GIST is usually malignant.
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