Mesenchymal Tumors of the Gastrointestinal Tract

Clinical Features

GIST can develop at any age but is most common in middle-aged to elderly adults; the median age is 58 years. It occurs approximately equally in males and females. GIST can be seen at any site along the GI tract, including unusual sites such as the gallbladder, pancreas, and appendix, but is most common in the stomach (60%) and small intestine (30%). Rarely, GISTs appear to arise from extragastrointestinal soft tissues within the abdomen (mesentery or omentum), pelvis, or retroperitoneum; collectively, such tumors are known as extragastrointestinal GISTs. However, careful analysis of such lesions indicates that a major subset originates from the GI musculature, grow in an exophytic manner, and subsequently lose their attachment to the GI tract. True extragastrointestinal GISTs are exceedingly rare.

GIST has a tendency to ulcerate the mucosa; it typically presents with GI bleeding, anemia, or intestinal obstruction. Affected patients may present with a palpable mass. Massive intraabdominal hemorrhage is uncommon. Some tumors are identified incidentally by radiography, whereas other cases are found incidentally during endoscopy or surgery for unrelated reasons. Small, clinically insignificant tumors known as microGISTs are very common in the stomach, and are present in up to 35% of middle-aged to elderly adults.

Aggressive GISTs have a propensity for dissemination throughout the surfaces of the abdominal cavity and metastasis to the liver. Although GISTs are capable of metastasizing outside of the abdomen, primarily to lung and bone, this is a rare occurrence. Importantly, in contrast to carcinomas, GISTs rarely metastasize to lymph nodes (with notable exceptions; see subsequent discussion), making compulsory lymph node dissection unnecessary.

Rarely, GISTs occur in children (1%–2%), mainly in girls. Such tumors arise in the stomach, often as multifocal lesions, and commonly metastasize to lymph nodes. Gastric GISTs are also a major feature of two tumor syndromes: Carney triad (along with pulmonary chondroma and paraganglioma) and Carney-Stratakis syndrome (along with paraganglioma). Pediatric GISTs, the GISTs in patients with Carney triad and Carney-Stratakis syndrome, and up to 10% of gastric GISTs in adults outside of these syndromes have distinctive histologic features, clinical behavior, and molecular pathogenesis, and are now referred to collectively as succinate dehydrogenase (SDH)-deficient GISTs. GISTs are also a less common tumor type of type 1 neurofibromatosis (NF1); when present, such tumors typically arise as multiple lesions in the small intestine.

Pathologic Features

GISTs range from incidental minute lesions no more than 1 mm in size to large masses more than 40 cm in greatest dimension. The median size for clinically significant GISTs is 6 cm in the stomach, 4.5 cm in the duodenum, and 7 cm in the jejunum/ileum. Lesions are usually centered in the bowel wall with frequent mucosal ulceration ( Fig. 16.1 ). On cut section, they may be either fibrous or fleshy with central degeneration (see Fig. 16.1 ). Some GISTs are almost entirely cystic, whereas others are gelatinous or extensively necrotic.

GISTs range from pure spindle cell neoplasms ( Fig. 16.2 ) to pure epithelioid neoplasms ( Fig. 16.3 ). A subset of tumors contains both spindle cells and epithelioid cells. Lesions vary considerably in terms of cellularity. Less-cellular neoplasms are generally smaller, tend to have hyalinized stroma, and may exhibit dystrophic calcifications ( Fig. 16.4 ). Spindle cell GISTs contain elongated nuclei with vesicular chromatin, inconspicuous nucleoli, and moderate amounts of fibrillary palely eosinophilic cytoplasm ( Fig. 16.5 ). The spindle cells are usually arranged in short fascicles. Nuclear palisading and paranuclear vacuolization are not unusual ( Fig. 16.6 ); the latter is a feature of gastric tumors. The vasculature may be minimal or prominent, hyalinized, or hemangiopericytoma-like, but there are no characteristic vascular features. A sparse chronic inflammatory component may be observed, most often scattered lymphocytes. So-called skeinoid fibers, variably sized collections of collagen fibrils, can also be found in the stroma of GISTs; this is seen almost exclusively in the small bowel ( Fig. 16.7 ). Epithelioid GISTs contain round nuclei, vesicular chromatin, variably prominent nucleoli, and abundant eosinophilic cytoplasm with ill-defined cell borders or clear cytoplasm with distinct cell borders ( Fig. 16.8 ). Binucleation is not unusual. The epithelioid cells are arranged in sheets or nests. When tumor cells are arranged in nests, this may impart a paraganglioma-like appearance. Myxoid stroma is more common in epithelioid GISTs ( Fig. 16.9 ).

A distinctive multinodular or plexiform architecture is observed in SDH-deficient GISTs ( Fig. 16.10 ). This histologic pattern is characterized by coarse lobules of tumor separated by bands of normal smooth muscle or small nodules with irregular margins extending from the main tumor ( Fig. 16.11A ). Such a growth pattern should raise the possibility of this unusual subset of GISTs, because they show distinct clinical behavior. These tumors nearly always have epithelioid or mixed epithelioid and spindle cell morphology (see Fig. 16.11B ).

Mitotic activity is usually low in both epithelioid and spindle cell GISTs; the mitotic rate must be determined in 5 mm ² to perform risk stratification (see the section “ Prognosis and Treatment ”). Furthermore, atypical mitotic figures are very rare. Nuclear pleomorphism is also highly unusual in GIST, observed in no more than 2% of tumors. More often than not, cytologic pleomorphism suggests the diagnosis of other sarcomas such as leiomyosarcoma. One notable exception is the very rare dedifferentiated GIST. Analogous to dedifferentiated liposarcoma, dedifferentiated GIST is defined by a transition from morphologically and immunohistochemically typical GIST to an anaplastic sarcomatous appearance that lacks the histologic features of GIST, as well as KIT and DOG1 expression ( Fig. 16.12 ). The dedifferentiated component may show a wide range of histologic appearances, ranging from a fascicular spindle cell appearance to wildly pleomorphic or resembling “inflammatory malignant fibrous histiocytoma.”

Immunohistochemistry

Approximately 95% of GISTs are strongly positive for KIT (CD117). KIT immunoreactivity is usually diffuse and cytoplasmic but may occasionally show a membranous or a dot-like (Golgi) pattern ( Fig. 16.13 ). The membranous pattern is the least common. Interestingly, KIT-negative GISTs tend to have epithelioid morphology, arise in the stomach, and harbor PDGFRA mutations. All other GIST genotypes usually express KIT diffusely and strongly. Approximately 70% of GISTs are positive for CD34, 30% for smooth muscle actin (SMA), and 5% for S-100. Desmin or keratin expression is observed in 2% and less than 1% of tumors, respectively. However, up to 20% of duodenal GISTs can be immunoreactive for S-100, usually focally, and 10%–15% of gastric epithelioid GISTs are focally positive for desmin. The smooth muscle marker h-caldesmon is positive in about 80% of GISTs; this marker therefore cannot be used to distinguish between GISTs and smooth muscle tumors. DOG1 (also known as ANO1, anoctamin 1) has been developed as an additional immunohistochemical marker. DOG1 is sensitive and relatively specific for GIST, and is diffusely and strongly positive in 98% of GISTs (see Fig. 16.13D ). It is especially useful in the diagnosis of KIT-negative GISTs and GISTs with only limited KIT expression ( Fig. 16.14 ).

One warning regarding KIT staining: it is important to maintain good controls. Overzealous antigen retrieval or inadequate dilution may occasionally result in false positive staining. Mast cells, which are nearly always present in sections of bowel wall, show strong membranous staining for KIT and thus serve as an excellent internal control ( Fig. 16.15 ). The muscle wall should be entirely negative. When antigen retrieval is used, gastric glands may show weak nonspecific cytoplasmic staining for KIT. No such staining is seen without antigen retrieval.

Immunohistochemistry for the mitochondrial protein succinate dehydrogenase subunit B (SDHB) can be used to identify SDH-deficient GISTs. These distinctive gastric GISTs show loss of SDHB expression (irrespective of the underlying mutation), whereas conventional adult GISTs show normal granular cytoplasmic (mitochondrial) staining ( Fig. 16.16 ). SDH-deficient GISTs with SDHA mutations (see below) show loss of SDHA expression as well as SDHB; SDHA can therefore be used to identify SDHA -mutant tumors.

Molecular Genetics

About 80% of advanced GISTs contain activating KIT mutations. There are four mutation “hotspots,” which makes identification of mutations relatively straightforward ( Fig. 16.17 ). In about 65% of GISTs, KIT mutations are identified in exon 11, 10% in exon 9, and approximately 1% each in exons 13 and 17. Activating mutations in PDGFRA are identified in 5%–10% of advanced GISTs (see Fig. 16.17 ). The most common “hotspot” in PDGFRA is exon 18 (nearly always the D842V substitution), followed by exons 12 and 14. PDGFRA mutations are found predominantly in gastric and omental GISTs with epithelioid cytomorphology. KIT or PDGFRA mutations are found in the smallest, subcentimeter microGISTs and thus are thought to constitute the earliest molecular events in most GISTs. KIT and PDGFRA mutations are mutually exclusive. All of the mutant forms of KIT and PDGFRA encode virtually full-length, constitutively activated KIT and PDGFRA, which drive cellular proliferation. Inhibition of KIT or PDGFRA has a dramatic therapeutic effect in GIST. Those GISTs without identifiable KIT or PDGFRA mutations are known as wild-type GISTs. This group is comprised predominantly of SDH-deficient GISTs (5% of all GISTs), BRAF V600E-mutant GISTs (1% of all GISTs; Fig. 16.18 ), and NF1 -mutant GISTs (1% of all GISTs). Very recently, extremely rare gene fusions involving FGFR1 and NTRK3 have been identified in GISTs. Finally, there is still a group of exceedingly rare, truly wild-type GISTs known as quadruple-wild-type GISTs that do not have any apparent oncogenic driver mutations. The genetics of GISTs is also discussed in Chapter 18 .

Multiple families have been identified with familial GIST. Affected patients harbor germline mutations in KIT or PDGFRA of exactly the same types that are found in sporadic GISTs. Patients who harbor germline KIT or PDGFRA mutations develop GIST with nearly 100% penetrance. As mentioned earlier, GIST is also associated with several tumor syndromes. Approximately 7% of patients with NF1 develop GISTs. NF1-associated GISTs typically arise in the small intestine as multiple small tumors. GIST is also associated with Carney-Stratakis syndrome, which is characterized by paraganglioma and gastric GIST. Similar to familial paraganglioma, patients with Carney-Stratakis harbor germline mutations in the SDH subunit genes SDHB, SDHC, or SDHD. Sporadic (non-syndromic) SDH-deficient GISTs also harbor germline or less commonly somatic mutations in SDHA, SDHB, SDHC, or SDHD . Overall, SDHA mutations are the most common alterations in this group of tumors, found in 35%–40% of SDH-deficient GISTs. As mentioned previously, pediatric GISTs, similar gastric GISTs in adults, and GISTs in patients with Carney triad and Carney-Stratakis syndrome show loss of SDHB protein expression by immunohistochemistry and SDH function, irrespective of whether they have germline mutations in SDH subunit genes (or which particular gene is mutated). Patients with Carney triad develop epithelioid gastric GIST, pulmonary chondroma, and extraadrenal paraganglioma. The genetic basis of Carney triad has recently been elucidated; in most cases, this syndrome is due to hypermethylation of the SDHC promoter, which also leads to loss of SDHB expression. Mutational analysis for KIT and PDGFRA is recommended if imatinib therapy is initiated for unresectable or metastatic disease (see later discussion). Mutational analysis should also be performed for patients with primary localized disease, when tumors are intermediate or high risk; adjuvant imatinib therapy prevents recurrence in such patients. This analysis is straightforward and does not require frozen tissue; the genomic “hotspots” can be amplified from DNA derived from paraffin-embedded tissue.

It is taken for granted that KIT or PDGFRA mutation is the initiating event in the pathogenesis of most GISTs. However, not as much is known about the secondary events involved in malignant progression. The accumulated data from cytogenetic and comparative genomic hybridization analysis indicate that losses at chromosomes 14q and 22q are very frequent and are not believed to contribute to malignant behavior. However, losses at 1p, 9p/9q, 11p, and 15q, as well as gains at 5p, 8q, 17q, and 20q, are reported more often in clinically aggressive GISTs. In general, greater numbers of genetic changes correlate with more aggressive behavior.

Loss of 9p is associated with an aggressive clinical course and appears to represent loss of the CDKN2A locus. The CDKN2A locus encodes two distinct tumor suppressor genes, p16 ( INK4A ) and p14 ( ARF ). Loss of both transcripts contributes to the aggressive phenotype.

Differential Diagnosis

The differential diagnosis for GIST is broad, but it is important to remember that GISTs are the most common mesenchymal neoplasms of the GI tract. Therefore when confronted with a mesenchymal neoplasm that involves the tubal gut, especially the stomach and small intestine, the diagnosis is very likely to be GIST. However, other tumor types can mimic GIST: leiomyoma, leiomyosarcoma, schwannoma, and desmoid fibromatosis, among others. Fortunately, immunohistochemistry is very helpful in resolving this differential diagnosis ( Table 16.1 ). Mural leiomyomas are most common in the esophagus, whereas polypoid leiomyomas of the muscularis mucosae arise in the colorectum; at both of these sites, leiomyoma is more common than GIST. In contrast to GIST, leiomyoma is composed of fascicles of spindle cells with blunt-ended (cigar-shaped) nuclei, brightly eosinophilic cytoplasm, and well-defined cell borders. Leiomyoma is invariably diffusely and strongly positive for SMA and desmin, and negative for KIT and DOG1. Of note, esophageal leiomyomas often contain numerous KIT-positive mast cells and interstitial cells of Cajal, which can be a diagnostic pitfall if mistakenly interpreted as positive staining in tumor cells. Primary leiomyosarcomas of the GI tract are very rare, vastly outnumbered by GISTs. In contrast to GIST, leiomyosarcomas usually have prominent cytologic pleomorphism and a high mitotic rate, including atypical mitotic figures. Leiomyosarcoma is usually positive for SMA, very often positive for desmin, and negative for KIT. In the GI tract, schwannomas are most common in the stomach, and in this location, they tend to have prominent peripheral lymphoid aggregates. Gastric schwannomas generally lack the varying cellularity (Antoni A and B zonation), Verocay bodies, and hyalinized vessels typical of schwannomas of peripheral nerves. GI schwannomas have a greater degree of cytologic variability than GIST and often contain prominent stromal collagen. Schwannomas are invariably positive for S-100 and negative for KIT. Desmoid fibromatosis usually involves the mesentery with secondary invasion into the bowel wall. Desmoid tumors are composed of long fascicles of spindle cells often with prominent stromal collagen. These tumors are focally positive for SMA but are negative for KIT and DOG1. About 80% of desmoid tumors show aberrant nuclear staining for β-catenin, which can be used to confirm the diagnosis.

Epithelioid GIST should be distinguished from well-differentiated neuroendocrine (carcinoid) tumor, poorly differentiated adenocarcinoma, and glomus tumor. Carcinoid tumors often have a predominantly trabecular or nested architecture, and the uniform tumor cells contain scant cytoplasm and finely granular (“salt and pepper”) chromatin. Keratin and chromogranin are strongly positive, whereas KIT and DOG1 are negative. Poorly differentiated adenocarcinomas of the stomach frequently have signet-ring–cell morphology with eccentric nuclei and a single mucin-containing cytoplasmic vacuole, and they are positive for broad-spectrum keratins, often for CK20 and CDX-2, and usually negative for KIT and DOG1 of note, a subset of gastric adenocarcinomas is positive for DOG1, which is a potential diagnostic pitfall. Glomus tumors rarely develop in the GI tract, most often in the wall of the stomach. Like a subset of epithelioid gastric GISTs, glomus tumors are composed of sheets of uniform rounded to epithelioid cells with sharply demarcated cytoplasmic borders. A helpful diagnostic clue is subendothelial growth within blood vessel walls, often most easily appreciated at the periphery of the tumor. Glomus tumors are strongly positive for SMA and caldesmon but negative for KIT and DOG1.

Prognosis and Treatment

GISTs range from those with essentially no risk of metastasis to those with a high risk of aggressive behavior. The system of risk stratification most commonly used is based on anatomic site, tumor size, and mitotic activity ( Table 16.2 ). Importantly, this risk stratification system does not apply to SDH-deficient GISTs; tumor size and mitotic rate do not predict progression in these tumors. There are three Food and Drug Administration–approved targeted therapies for GIST. Imatinib mesylate, sunitinib malate, and regorafenib are small molecule inhibitors that directly target KIT and PDGFRA. Imatinib is used as first-line therapy primarily in the setting of metastatic or unresectable GIST, and sunitinib is used in patients who do not tolerate imatinib or have progressed on imatinib therapy. Regorafenib is used primarily in patients who fail both imatinib and sunitinib. Interestingly, although patients with most tumors respond well to imatinib, some genetic subsets do not respond as well or at all. As is expected, GISTs associated with NF1, SDH-deficient GISTs, and BRAF -mutant GISTs do not respond to KIT/PDGFRA inhibitors. KIT exon 9 mutant tumors tend to respond less well; increasing the daily dose of imatinib from 400 to 800 mg can overcome the lack of response in KIT exon 9 mutant tumors. GIST patients with the most common PDGFRA mutation, D842V, do not respond to any of the FDA-approved GIST therapies and should be enrolled in clinical trials with experimental agents. Secondary resistance to imatinib, defined as those GISTs that initially respond to imatinib but after a period of 6 months or more show tumor progression on therapy, is seen within 2 years in about 50% of patients with GIST. Secondary resistance is usually due to second-site intraallelic mutations in KIT , which abrogate binding to imatinib. Patients who develop secondary resistance to imatinib can benefit from treatment with sunitinib and regorafenib. Interestingly, although only few cases have been reported, GISTs with BRAF V600E mutations appear to respond to BRAF inhibitors.

Occasionally, GISTs are resected after treatment with targeted therapies. Although changes such as hypocellularity, hyalinosis, myxoid stroma, and necrosis have been described, these changes do not appear to correlate reliably with clinical response. It is reasonable to note the histologic appearance of treated GISTs in pathology reports; however, evaluating treatment response histologically does not play a role in the current management of patients with GIST. Occasionally, treated GISTs may show morphologic changes, such as a shift from spindle cell to epithelioid morphology or the development of pleomorphism, and rare GISTs lose KIT expression or otherwise change their immunophenotype, such as acquiring expression of smooth muscle markers. A very rare form of tumor progression in GISTs following tyrosine kinase inhibitor therapy is the development of heterologous rhabdomyosarcomatous differentiation, indistinguishable from embryonal or pleomorphic rhabdomyosarcoma. This unusual form of clonal evolution is associated with extremely aggressive clinical behavior.

GISTs rarely recur at anastomotic sites, and relatively narrow surgical margins are therefore adequate to achieve local control (e.g., wedge resection or partial gastrectomy for gastric tumors). The one notable exception is SDH-deficient GISTs, which often recur locally in the stomach, sometimes years or even decades following primary excision.

Clinical Features

Leiomyomas are most common in the colorectal region. Approximately 80% of leiomyomas occur in this area, where they almost always present as small submucosal polyps that arise from the muscularis mucosae ( Fig. 16.19 ). The second most common site for leiomyoma is the esophagus. Approximately 10% of leiomyomas are found in this location. Esophageal leiomyomas usually arise from the muscularis propria, where they form intramural masses, but may rarely occur as polyps. Intramural leiomyomas tend to form much larger masses than polypoid leiomyomas. Leiomyomas of the stomach and small intestine are rare and predominantly intramural.

Leiomyomas are more common in men, with a 2.4 : 1 male-to-female ratio in the colorectal region and a 2 : 1 ratio in the esophagus. Leiomyomas can occur over a wide age range. In the colon, they are more common in middle-aged to elderly adults with a median age of 62 years, whereas in the esophagus they occur in a younger population with a median age of 35 years.

Presenting symptoms depend on location. In the esophagus, patients present with dysphagia, cough, or GI bleeding, or tumors can present as incidental masses. On occasion, they can mimic mediastinal masses. In the colorectal region, leiomyomas are most often identified incidentally during screening colonoscopy.

Pathologic Features

Leiomyomas present in the colorectal region as small polyps, ranging in size from 1 to 22 mm (median, 4 mm; see Fig. 16.19 ). Mural leiomyomas of the esophagus are larger, ranging in size from 1 to 18 cm (median, 5 cm; Fig. 16.20 ). Leiomyomas are well circumscribed but unencapsulated and are often lobulated, with a firm consistency. On cut section, the tumors are white to tan with a whorled, fibrous appearance.

Histologically, leiomyomas are composed of fascicles of spindle cells with brightly eosinophilic cytoplasm and elongated, broad (cigar-shaped) nuclei with tapering or blunt ends ( Fig. 16.21 ). Cytologic atypia is rare, but degenerative nuclear atypia has been described in several cases that contained bizarre cells similar to symplastic leiomyoma of the uterus. Mitotic activity is very low or absent, usually less than 1 per 50 high-power fields. Necrosis is not seen. Epithelioid leiomyomas of the GI tract have not been described.

As is seen in GIST, if a concerted effort is made to detect clinically inapparent leiomyomas, they are actually quite common. In one study, 150 esophagogastric resection specimens that were removed for carcinomas were examined in detail with an average of 30 sections per case. Small (mean, 1.7 mm) esophageal leiomyomas were identified in 47% of patients. Interestingly, many patients had multiple lesions with a mean of three leiomyomas (one patient had 13 individual lesions).

Immunohistochemistry

All leiomyomas are uniformly positive for SMA, desmin, and caldesmon (see Fig. 16.21D and E ). They are negative for CD34, KIT, DOG1, and S-100. Esophageal mural leiomyomas often contain numerous KIT-positive mast cells (see Fig. 16.21F ), as well as KIT- and DOG1-positive interstitial cells of Cajal.

Molecular Genetics

Very limited data are available regarding the molecular features of GI leiomyomas. Deletion of COL4A5 and COL4A6 at Xq22, encoding collagen type IV alpha 5 and alpha 6, has been reported in a single case of esophageal leiomyoma. This gene region is also lost in diffuse esophageal leiomyomatosis, which is characterized by replacement of the esophageal muscularis propria by an abnormal nodular smooth muscle proliferation. Diffuse leiomyomatosis predominantly affects children and adolescents but can occur at any age. Leiomyomatosis can occur sporadically or as a familial syndrome, usually associated with Alport syndrome, which is characterized by an inherited nephropathy. One case of a large discrete leiomyoma has been described in the setting of familial diffuse leiomyomatosis.

Differential Diagnosis

The differential diagnosis of leiomyoma primarily includes GIST and to some extent schwannoma. It is important to remember that clinically apparent leiomyomas occur in an inverse anatomic distribution compared with GIST. Leiomyomas are more common than GIST in the esophagus and colorectal region, whereas GISTs are vastly more common in the stomach and small intestine. Schwannomas are rare in the GI tract and occur most often in the stomach. Leiomyomas are generally less cellular and more brightly eosinophilic than GIST, lack mitotic activity, and in contrast to GIST, are diffusely and strongly positive for desmin and negative for KIT and DOG1. In contrast to leiomyomas, schwannomas are negative for desmin and diffusely and strongly positive for S-100. As previously mentioned, numerous KIT-positive mast cells can be seen in leiomyomas (as well as schwannomas), which is a potential diagnostic pitfall.

Prognosis and Treatment

Leiomyomas are universally benign. Colorectal polypoid leiomyomas are treated by polypectomy alone, whereas intramural leiomyomas can be excised by myomectomy or segmental resection.

Clinical Features

Leiomyosarcomas can occur at any site within the GI tract but are most common in the small intestine and colon. Patients may present with anemia, GI bleeding, dysphagia, or bowel obstruction, depending on the anatomic location. For instance, individuals with esophageal leiomyosarcomas are more likely to present with dysphagia, whereas those with leiomyosarcomas of the small intestine are more likely to present with obstruction. Leiomyosarcomas can develop over a broad age range but tend to predominate in middle-aged to elderly adults, and the tumors are slightly more common in men.

Pathologic Features

Grossly, GI leiomyosarcomas are usually large ( Fig. 16.22 ). In one report of leiomyosarcomas of the duodenum, the five lesions ranged from 10 to 19 cm (median, 13 cm). The tumors generally involve the full-thickness of the bowel wall, including the mucosa, which is often ulcerated, as well as the serosal surface. Leiomyosarcomas can also occur as ulcerated intraluminal polypoid masses. These tumors may be lobulated, and on cut section they are gray, pink, or tan fleshy masses, often with areas of necrosis.

Histologically, GI leiomyosarcomas are similar to leiomyosarcomas elsewhere. They are composed of fascicles of spindle cells with elongated nuclei with blunt or tapering ends and brightly eosinophilic cytoplasm ( Fig. 16.23 ). Nuclear pleomorphism is often prominent and can be extensive. Mitotic activity is usually very high, often more than 10 per 10 high-power fields. Nuclear palisading, paranuclear vacuoles, and skeinoid fibers (features of GIST) are not present. Coagulative necrosis is common. Epithelioid cytomorphology is exceedingly rare. Due to the rarity of primary GI leiomyosarcomas and the relatively recent separation of true smooth muscle tumors from GIST, the minimal criteria for malignancy have not been established. However, any mitotically active smooth muscle neoplasm of the bowel wall with nuclear atypia should be regarded as at least low-grade malignant. If in doubt about whether a given lesion is malignant, the designation “smooth muscle tumor of uncertain malignant potential” (STUMP) may be used.

Immunohistochemistry

Leiomyosarcomas are usually diffusely and strongly positive for SMA. Expression of desmin and caldesmon is more variable and can be focal or diffuse. CD34 can be positive in smooth muscle tumors, including leiomyosarcomas. Broad-spectrum keratins are often at least focally positive. GI leiomyosarcomas are negative for S-100, KIT, and DOG1.

Molecular Genetics

Leiomyosarcomas are characterized by complex genetic changes and do not possess KIT or PDGFRA mutations.

Differential Diagnosis

The differential diagnosis primarily includes GIST, leiomyoma, and schwannoma. Bright cytoplasmic eosinophilia and prominent nuclear pleomorphism distinguish leiomyosarcomas from GISTs. Furthermore, in contrast to leiomyosarcomas, GISTs are rarely positive for desmin and almost always positive for KIT and DOG1. GI leiomyomas lack cytologic pleomorphism and mitotic activity. Generally, distinguishing between GI leiomyomas and leiomyosarcomas is straightforward, because leiomyosarcomas usually show striking mitotic activity and marked nuclear atypia. However, occasionally, GI leiomyosarcomas are well differentiated with only focal cytologic atypia and a low mitotic rate. GI schwannomas usually arise in the stomach, an especially rare primary site for leiomyosarcomas. Unlike leiomyosarcomas, schwannomas have a peripheral lymphoid cuff and lack significant pleomorphism. Schwannomas are negative for desmin, and they are diffusely and strongly positive for S-100.

Prognosis and Treatment

Leiomyosarcomas exhibit locally aggressive behavior and a high rate of distant metastasis. Leiomyosarcomas have a tendency to metastasize to intraabdominal surfaces and the liver, and they less often spread to the lungs and bone. GI leiomyosarcomas can also spread to regional lymph nodes, but this is rare. Many GI leiomyosarcomas ultimately lead to patient death. Aggressive multimodal therapy is required.

Clinical Features

Schwannoma can occur anywhere in the GI tract but is most common in the stomach, followed by the colon and rectum. The esophagus and small intestine are rarely affected. There is an equal sex predilection. Schwannomas develop in patients over a wide age range (18–87 years), with a median between 53 and 68 years.

Presenting symptoms depend on location. Patients with gastric schwannomas present with dyspepsia, indigestion, abdominal pain, a mass, or GI bleeding; those with colorectal schwannomas present with rectal bleeding, obstruction, constipation, or abdominal pain; and those with esophageal schwannomas present with chest pain or dysphagia. Schwannomas are generally located within the muscularis propria or submucosa with bulging into the lumen. The overlying mucosa is prone to ulceration. Interestingly, colorectal schwannomas have a tendency to appear as ulcerated polypoid lesions.

Pathologic Features

Grossly, most GI schwannomas are circumscribed, mural tumors ( Fig. 16.24A ). They range in size from 0.5 to 12 cm, with a median of 3–5 cm. On cut section, they are homogenous, firm or rubbery, and usually yellow. Hemorrhage, cystic change, or necrosis is not typically seen.

GI schwannomas differ histologically from conventional schwannomas of peripheral nerves. They are circumscribed but unencapsulated and usually surrounded by a dense lymphoplasmacytic cuff, often with germinal centers (see Fig. 16.24B ). They have overall pushing borders, but it is not unusual to see tumor cells infiltrate among the muscle bundles at the periphery. The vast majority of GI schwannomas are moderately cellular lesions composed of spindle cells with a variably prominent collagenous stroma (see Fig. 16.24C ). The lesional cells are admixed with lymphocytes and arranged in short bundles. In contrast to conventional schwannomas, Verocay bodies, nuclear palisading, perivascular hyalinization, or foamy histiocytes are not typically evident. The spindle cells contain elongated nuclei with tapering ends and a single inconspicuous nucleolus (see Fig. 16.24D ). There is often scattered mild nuclear atypia with hyperchromasia. Mitotic figures are usually absent or rare. Atypical mitotic figures are not identified.

Rarely, GI schwannoma can have epithelioid cytomorphology, similar to epithelioid schwannoma of the superficial soft tissues (see Chapter 15 ). The epithelioid cells are usually arranged in sheets or cords and sometimes in a pseudoglandular pattern. In a series of colorectal schwannomas, all four epithelioid examples were located in the descending or sigmoid colon, three of which were submucosal.

A rare variant of schwannoma referred to as microcystic/reticular schwannoma appears to have a predilection for the GI tract. In the largest reported series, 5 of the 10 tumors arose in the GI tract, 4 in the submucosa. These lesions had the typical clinical features of GI schwannoma but distinctive histologic features. All were circumscribed and unencapsulated, but none were surrounded by a lymphoid cuff. As their name implies, the lesional cells are arranged in a striking microcystic and reticular growth pattern composed of anastomosing spindle cells set in a myxoid, fibrillary, or collagenous stroma ( Fig. 16.25 ). Of note, the microcystic pattern may display a pseudoglandular appearance suggestive of mucinous adenocarcinoma. A case of signet-ring–cell schwannoma of the stomach has also been described; the appearance is similar to those tumors described as microcystic/reticular schwannoma.

Immunohistochemistry

GI schwannomas are diffusely and strongly positive for S-100 ( Fig. 16.26 ) and glial fibrillary acidic protein (GFAP), but they are negative for KIT, desmin, and SMA. CD34 may be focally positive. Unlike conventional schwannomas, an epithelial membrane antigen (EMA)–positive perineurial capsule is absent.

Molecular Genetics

GI schwannomas are sporadic tumors that are not associated with either NF1 or NF2. In contrast to conventional schwannoma, loss of heterozygosity at 22q12, the region of NF2 , is unusual. Loss of heterozygosity at 17q11.2, the region of the NF1 gene that encodes neurofibromin, is more common, being present in 50% of cases, which is similar to neurofibromas.

Differential Diagnosis

The main differential diagnosis of the most common spindle cell variant of schwannoma includes GIST, leiomyoma, inflammatory myofibroblastic tumor (IMT), and metastatic melanoma. Immunohistochemistry is helpful in distinguishing among different lesions in the differential diagnosis (see Table 16.1 ). GIST usually has a more hypercellular, syncytial appearance with minimal stroma and remarkably uniform cytology, and it lacks the distinctive peripheral lymphoid cuff of GI schwannoma. In contrast to schwannoma, GIST is positive for KIT and DOG1, and it is negative for S-100 in most cases. Leiomyoma has a uniformly fascicular architecture and bright cytoplasmic eosinophilia, and is negative for S-100 and diffusely and strongly positive for SMA, desmin, and caldesmon. IMT is composed of loose fascicles of plump spindle cells admixed with predominantly chronic inflammatory cells. IMT shows variable expression of SMA and desmin, and 50% for anaplastic lymphoma kinase (ALK), but it is consistently negative for S-100. Finally, metastatic melanoma also typically has extensive S-100 immunoreactivity. However, in contrast to schwannoma, these lesions may be positive for other melanocytic markers, including HMB-45 and melan A, and they usually have marked mitotic activity and striking nuclear atypia with prominent nucleoli.

Prognosis and Treatment

GI schwannomas are invariably benign. Conservative excision is adequate therapy.