Gastrointestinal Mesenchymal Tumors

Clinical Features

In the United States, GIST has an estimated annual incidence of 3300 to 6000 cases per year and most commonly occurs in middle-aged to older adults (median age, 60 years). Clinically detected tumors in the GI tract most commonly occur in the stomach (60%) and small intestine (35%), with most remaining cases accounted for by colorectal tumors; GISTs of the esophagus and appendix are rare. GIST can also present as omental, peritoneal, and retroperitoneal tumors, although these are typically large tumors that very likely originally originated in the GI tract but may have detached from their point of origin. GIST exhibits a wide range of behavior, from benign “micro-GISTs,” present in approximately 30% of the population based on autopsy series, to aggressive sarcomas. Prognosis depends in part on tumor location; for example, small intestinal GISTs are about twice as likely as gastric GISTs to behave in a clinically aggressive fashion.

Clinical presentation depends on tumor size and location. Large masses can cause abdominal pain, anemia, or GI bleeding. Micro-GISTs are found incidentally during surgery and may often be sent for frozen section analysis. GIST can also present as a component of multiple hereditary syndromes, including Carney-Stratakis syndrome, Carney triad, and neurofibromatosis. Carney-Stratakis syndrome (the dyad of gastric GIST and paraganglioma) is a familial syndrome caused by mutations in SDHx genes; these mutations account for about 65% of SDH-deficient GISTs. Patients with SDHA germline mutations mostly present with GISTs as young to middle-aged adults, whereas patients with other SDH germline mutations present in childhood and adolescence. Carney triad (gastric GIST, paraganglioma, and pulmonary chondroma) is a nonfamilial syndrome associated with SDHC promoter hypermethylation and not germline mutations. Neurofibromatosis type 1 (NF1) is the most common autosomal dominant genetic disorder and is associated with development of neurofibromas, ganglioneuromas, and malignant peripheral nerve sheath tumors (MPNSTs), among other tumor types. NF1 also predisposes patients to GISTs that are predominantly found in the small intestine and can be multiple in the same patient. These tumors are mostly low risk and are associated with interstitial cell hyperplasia. Last, there are rare instances of familial germline mutations in KIT and PDGFRA ; patients with these mutations develop GISTs with nearly 100% penetrance, in a background of interstitial cell hyperplasia. Patients with KIT germline mutations also develop urticaria pigmentosa and cutaneous hyperpigmentation.

Radiologic Features

Radiologic features are not specific, but most large mural gastric masses are GISTs. An example of a gastric GIST is shown in Fig. 7.1 .

Pathologic Features

Gross Findings

Gastrointestinal stromal tumors vary in greatest dimension from smaller than 1 cm (micro-GISTs) to larger than 20 cm, and they can be submucosal, intramuscular, or subserosal, although most are centered in the muscularis propria. They can be solid or cystic with variable hemorrhage and necrosis, and there may be overlying mucosal ulceration. Generally, GISTs are well circumscribed. SDH-deficient GISTs have a characteristic multinodular or plexiform growth pattern. Fig. 7.2 shows a cross-section of a small intestinal GIST.

Microscopic Findings

About 70% of gastric GISTs and nearly all of those in the small and large intestine exhibit spindle cell morphology, with short fascicles of bland cells with indistinct cell borders, palely eosinophilic cytoplasm, and uniform, tapered nuclei with evenly dispersed chromatin ( Figs. 7.3 and 7.4 ). Nuclear palisading is at least focally present in more than half of tumors. About 20% of GISTs have purely epithelioid morphology; these tumors nearly all occur in the stomach and are associated with PDGFRA mutations ( Fig. 7.5 ) or SDH deficiency ( Fig. 7.6 ). Epithelioid GISTs are composed of sheets and nests of cells with palely eosinophilic cytoplasm and uniform nuclei, often in a myxohyaline stroma ( Fig. 7.7 ; see also Figs. 7.5 and 7.6 ). The cell membranes are often better defined than spindle cell variants. SDH-deficient GIST has a characteristic multinodular or plexiform growth pattern and the cytomorphology is usually epithelioid (see Fig. 7.6 ). Gastric GISTs commonly have paranuclear vacuoles (see Figs. 7.3 and 7.7 ), and nearly half of small intestinal GISTs contain skeinoid fibers. Mitotic activity varies widely and is an important prognostic factor. Treatment effect can manifest as stromal hyalinization, decreased cellularity, or reduced mitotic activity. Rarely, tumors can develop heterologous rhabdomyosarcomatous differentiation after treatment, and both treated and treatment-naïve tumors can undergo dedifferentiation, in which there is a sharp transition from conventional morphology to high-grade pleomorphic regions that do not resemble GIST ( Fig. 7.8 ). Both rhabdomyosarcomatous differentiation and dedifferentiation are associated with imatinib resistance and a poor prognosis.

Ancillary Studies

Immunohistochemistry

KIT (also known as CD117) is a receptor tyrosine kinase expressed in interstitial cells of Cajal, mast cells, melanocytes, a variety of epithelia, fetal endothelial cells, and a subset of CD34-positive hematopoietic stem cells. Oncogenic KIT mutations were discovered in the late 1990s to be present in the majority of GISTs, along with KIT overexpression. DOG1 (discovered on GIST1), a chloride channel normally expressed in the interstitial cells of Cajal, was also found to be expressed in GIST (hence the name “discovered on GIST 1”). Overall, KIT is positive in 95% of GISTs ( Fig. 7.9 ), and DOG1 is also positive in 95% ( Fig. 7.10 ). Fewer than 3% of tumors are negative for both markers; these tend to be epithelioid PDGFRA -mutant GISTs, and PDGFRA immunohistochemistry (IHC) is strongly and diffusely positive in essentially 100% of these tumors (see Fig. 7.5 ). PDGFRA is also weakly expressed in stromal cells, presenting a potential pitfall; only strong and diffuse staining should be used to support the diagnosis of GIST. CD34 is positive in about 70% of GISTs, although its diagnostic utility is now limited, given the superior sensitivity and specificity of KIT, DOG1, and PDGFRA IHC. Caldesmon is positive in 70% of GISTs, S-100 in 1% to 2% (especially duodenal GISTs), and desmin in 1% to 2% (but up to 10% in epithelioid PDGFRA -mutant GISTs; see Fig. 7.5D ). Keratin positivity is rare.

Immunohistochemistry is also useful for diagnosing SDH-deficient GIST, which are generally positive for KIT and DOG1. The four SDH subunits (A–D) form a protein complex that is necessary to stabilize the SDHB protein. Therefore, loss of expression of any one of the subunits leads to loss of expression of SDHB. Thus, SDHB IHC can be used to screen for loss of expression of any subunit. SDHA expression is lost in about 35% of tumors, an event that is reliably detectable using SDHA IHC and that generally indicates underlying SDHA mutations. Of the 65% of SDH-deficient GISTs that express SDHA, about 30% have mutations in SDHB , SDHC , or SDHD , and the remaining 35% have SDHC promoter hypermethylation.

Molecular Genetics, Pathologic Phenotypes, and Prognosis

Gastrointestinal stromal tumors are not classified as benign or malignant tumors; instead, a risk stratification scheme is used, with prognosis determined by using site, size, and mitotic index ( Table 7.2 ). Mitoses should be counted in a 5-mm ² area; on most modern microscopes, 5 mm ² is close to 20 hpf. When GISTs behave in a clinically aggressive fashion, they most commonly metastasize to the abdominal cavity and liver. Metastasis can occur more than 10 years after surgical resection, underscoring the need for long-term follow-up.

Several studies have established relationships between specific GIST genotypes and their corresponding clinicopathologic phenotypes. The protein structures of KIT and PDGFRA receptors are similar, and activating a mutation in either one of these two genes leads to activation of similar signal transduction pathways and these mutations are thought to be initiating events in GIST tumorigenesis.

Eighty percent of GISTs have KIT mutations, and 7% have PDGFRA mutations. KIT mutations occur in exon 11 (overall accounting for 70% of GISTs), exon 9 (8%), exon 13 (1%), and exon 17 (1%) (see Table 7.1 ). Exon 11 (juxtamembrane domain) mutant GISTs occur in the stomach and small intestine, and they have spindle cell or mixed morphology. Exon 11 mutations include in-frame deletions (60%–70%), missense point mutations (20%–30%), and internal tandem duplications; whereas exon 11 point-mutant GISTs have a better prognosis than other GISTs, tumors with exon 11 deletions behave more aggressively. Recent clinical trials demonstrated that patients with exon 11 deletions benefit from an extended course of adjuvant imatinib therapy.

Exon 9 (dimerization motif domain) mutations occur in tumors typically located in the small and large intestines; these tumors have spindle cell or mixed morphology, and they require higher doses of imatinib to achieve treatment response. Exon 13 and exon 17 mutations together account for 2% of GISTs; these tumors mostly occur in the small intestine, have spindle cell morphology, and have inconsistent responses to imatinib.

About 8% of GISTs harbor mutations to PDGFRA ; as in KIT -mutant GISTs, these occur in different exons corresponding to different protein domains. PDGFRA mutations occur in exon 18 (accounting for 7% of GISTs overall), exon 12 (1.5%), and exon 14 (0.5%). PDGFRA -mutant GISTs predominantly occur in the stomach, and essentially all have purely epithelioid morphology. A particular missense mutation (D842V) accounts for the majority of exon 18 mutations and confers imatinib resistance; recently, the Food and Drug Administration (FDA)-approved avapritinib to treat patients with these GISTs. Exon 12– and exon 14–mutant GISTs have variable responses to imatinib.

PDGFRA mutations, KIT mutations, and biallelic NF1 inactivation are thought to be initiating events in GIST tumorigenesis; all three subtypes undergo the same additional chromosomal deletions as part of an apparent stepwise progression toward higher- risk tumor biology. Given that they share the same progression, it is perhaps not surprising that the prognosis of these three GIST subtypes can be determined using the same risk stratification system (see Table 7.2 ).

SDH deficiency is seen in about 8% of GISTs and is mutually exclusive with PDGFRA and KIT mutations and NF1 inactivation. SDH-deficient GIST represents the majority of pediatric GIST but also occurs in a significant subset of adults. SDH-deficient GISTs are almost always gastric and show an epithelioid morphology with a unique plexiform architectural growth pattern (see Fig. 7.6 ). SDHA, SDHB, SDHC, and SDHD proteins form a multimeric complex in the inner mitochondrial membrane that is critical for cellular metabolism. Whereas SDHA mutations are present in about 35% of SDH-deficient GISTs, about 30% have mutations in SDHB , SDHC , or SDHD . The remaining 35% of SDH-deficient GISTs have SDHC promoter hypermethylation, which silences expression of SDHC, leading to SDH deficiency. SDHB, SDHC , or SDHD mutations are usually present in the germline, and these patients also develop paragangliomas in the familial Carney-Stratakis syndrome, as discussed earlier.

The prognosis of SDH-deficient GIST is different from the other described genetic subtypes, so the risk stratification system developed for KIT - and PDGFRA -mutant tumors does not apply. Instead, SDH-deficient GISTs frequently give rise to slowly growing lymph node metastases that progress over the course of several years to decades. SDH-deficient GISTs do not respond to imatinib therapy, and as of now, there is no targeted therapy to treat patients with these tumors.

BRAF -mutant GISTs are rare. Tumors harboring BRAF V600E occur in the small intestine and have spindle cell morphology. Although they do not respond to imatinib, they have been shown to respond to dabrafenib, a BRAF inhibitor.

Differential Diagnosis

The differential diagnosis for spindle cell GIST includes leiomyoma, leiomyosarcoma, schwannoma, and desmoid fibromatosis. Leiomyoma and leiomyosarcoma have more brightly eosinophilic cytoplasm, and they exhibit distinct cell borders in contrast to the indistinct cell borders of GIST. Leiomyoma and leiomyosarcoma also have blunt-ended nuclei, unlike the tapered nuclei of GIST. IHC is useful to resolve the differential diagnosis: leiomyoma and leiomyosarcoma commonly have diffuse desmin expression, which would be unusual in GIST, and they are negative for KIT and DOG1.

Gastric schwannoma typically has a peripheral cuff of lymphocytes and neural cytomorphology with buckled nuclei and mild atypia. The cells of schwannoma show diffuse S-100 expression and are negative for DOG1 and KIT.

Desmoid fibromatosis is more infiltrative than GIST and has longer fascicles. IHC demonstrates nuclear β-catenin positivity in 70% to 80% of desmoid fibromatoses, which is negative in GIST. Desmoid fibromatosis does not express KIT or DOG1.

The differential diagnosis for epithelioid GIST includes neuroendocrine tumors and gastric adenocarcinoma. Neuroendocrine tumors usually have smaller cells and darker nuclei with speckled chromatin. IHC for synaptophysin, chromogranin, KIT, and DOG1 readily distinguishes the two. Gastric adenocarcinoma exhibits significant nuclear pleomorphism and hyperchromasia, in contrast to the uniform nuclei and evenly dispersed chromatin of epithelioid GIST.

Treatment

Surgical excision is the treatment for patients with resectable GIST. Narrow margins suffice because tumors tend not to recur at the surgical site; the exception is SDH-deficient GISTs, likely because of their multinodular, infiltrative growth pattern. For most KIT -mutant GISTs and some PDGFRA -mutant GISTs, imatinib is the first-line therapy in the setting of metastases or locally advanced disease and as adjuvant therapy in GISTs that stratify into intermediate- or high-risk groups (see Table 7.2 ). Neoadjuvant imatinib is also used in some cases to reduce the size of locally advanced tumors prior to surgery. Imatinib resistance eventually develops in all treated GISTs, usually by means of secondary KIT mutations. Sunitinib and regorafenib are FDA-approved second- and third-line therapies, respectively, that are used in the setting of imatinib resistance. As mentioned earlier, avapritinib was recently FDA approved for first-line treatment of patients with PDGFRA exon 18–mutant GIST, which is resistant to imatinib, sunitinib, and regorafenib.

Clinical Features

Smooth muscle tumors of the GI tract consist of leiomyoma and the much rarer leiomyosarcoma. Colonic leiomyomas classically arise in association with the muscularis mucosae and present as distal polyps on screening colonoscopy, usually in men in their seventh decade. Esophageal leiomyomas often present as intramural masses; patients have a median age of 35 years, there is a male predominance (∼70%), and the clinical course is indolent. In the esophagus, the vast majority of spindle cell tumors are leiomyomas. Smooth muscle tumors of the stomach and small intestine are rare; GIST is much more common at these locations. Leiomyosarcoma of the GI tract is very rare and generally follows an aggressive course. Leiomyosarcoma of the colon shows a slight male predominance and presents in adults. Leiomyosarcoma is exceptional in the stomach. Leiomyomatosis has been described in the small intestine and colon.

Pathologic Features

Gross Findings

Esophageal leiomyomas form whorled white to pale yellow masses similar to uterine leiomyomas. Leiomyomas arising in the muscularis mucosae of the colorectum present as mucosal polyps, usually smaller than 1 cm. Leiomyosarcomas of the colorectum tend to be intraluminal bulging exophytic and polypoid masses, which may show necrosis and hemorrhage.

Microscopic Findings

Smooth muscle tumors of the GI tract have the same features of smooth muscle differentiation seen at other anatomic sites, namely perpendicularly oriented fascicles of spindle cells with distinct cell borders, brightly eosinophilic cytoplasm, longitudinal striations, and blunt-ended or cigar-shaped nuclei ( Figs. 7.11 to 7.15 ). Leiomyomas are bland and resemble normal smooth muscle. They lack atypia and pleomorphism and generally show no or minimal mitotic activity. Leiomyosarcoma is characterized by conspicuous mitotic activity, cytologic atypia, and necrosis.

Clinical Features

Granular cell tumors are benign tumors that exhibit Schwannian differentiation. Although they can occur anywhere along the luminal GI tract, they have a striking predilection for the esophagus. Granular cell tumors usually occur in middle-aged adults and are more common in women and African Americans. Although they usually occur as unifocal tumors in the distal esophagus, they can also present as multiple sporadic esophageal tumors.

Pathologic Features

Gross Findings

Most granular cell tumors are small (<1 cm) with a yellow-white cut surface and infiltrative peripheral growth.

Microscopic Findings

Granular cell tumors are composed of sheets and nests of large polygonal cells with brightly eosinophilic, granular cytoplasm, and centrally located, small, hyperchromatic nuclei ( Figs. 7.16 and 7.17 ). There is frequently overlying squamous cell hyperplasia, a useful diagnostic clue. Occasionally, tumors can have spindle cell morphology, although the spindle cells still contain abundant granular cytoplasm. In conventional granular cell tumor, mitotic activity is low, and there is no necrosis.

Ancillary Studies

Immunohistochemistry

Diffuse strong expression of S-100 protein and SOX10 is present in esophageal granular cell tumors ( Fig. 7.18 ). Granular cell tumors also overexpress transcription factor enhancer 3 (TFE3), but they do not harbor underlying TFE3 rearrangements.

Molecular Studies

Granular cell tumors were recently found to have recurrent loss of function mutations in ATP6AP1 and ATP6AP2 , which are endosomal pH regulatory proteins; loss of expression of these proteins was shown to be oncogenic and to lead to accumulation of intracytoplasmic granules.

Clinical Features

Clear cell sarcoma-like tumor of the GI tract, also known as malignant GI neuroectodermal tumor (malignant GNET), is a rare tumor with distinctive pathologic and genetic features, different from conventional clear cell sarcoma of tendons and aponeuroses. These tumors have also been called “osteoclast-rich tumors of the GI tract with features resembling clear cell sarcoma of soft parts.” In contrast to conventional clear cell sarcoma of tendons and aponeuroses, these tumors usually show less nested growth pattern, contain osteoclast-like giant cells, and lack evidence of melanocytic differentiation ultrastructurally and immunohistochemically. They both, however, express S-100 and harbor the EWSR1-ATF1 or EWSR1-CREB1 fusion genes.

The most common site of involvement is the small intestine followed by the stomach and colon. Patients are usually young to middle-aged adults (mean age, 42 years; range, 17–77 years), and there is no apparent gender predilection. Presenting symptoms and signs include abdominal pain, intestinal obstruction, weight loss, anemia, and fever. Metastasis at the time of presentation is common.

Microscopic Findings

Malignant GNET is composed of sheets of round to epithelioid cells and in some cases ovoid to spindled cells ( Fig. 7.19 ). Tumor cells have small amounts of pale eosinophilic cytoplasm and round to oval nuclei with vesicular chromatin and small nucleoli ( Fig. 7.20 ). Mitotic activity is variable. The growth pattern is usually mixed, with focal areas of nested, pseudoglandular, pseudopapillary, microcystic, and fascicular architecture. Osteoclast-like giant cells are present in 50% of cases.

Ancillary Studies

Immunohistochemistry

Strong diffuse expression of S-100 is present in all cases ( Fig. 7.21 ). SOX10 expression is also seen, reflecting the neuroectodermal differentiation of this tumor. In contrast, melanocytic markers HMB45 (human melanoma black), Melan-A, microphthalmia transcription factor (MiTF), and tyrosinase are negative. Tumor cells are also negative for KIT, DOG1, CD34, glial fibrillary acidic protein (GFAP), keratins, desmin, and SMA. Expression of synaptophysin and neuron-specific enolase (NSE) is seen in up to 50% of cases. Ultrastructural features of neural differentiation are seen by electron microscopy.

Molecular Genetics

Malignant GNET is a translocation-associated tumor, with EWSR1-ATF1 and EWSR1-CREB1 fusion genes in approximately 90% of cases caused by t(12;22)(q13;q12) or t(2;22)(q34;q12), respectively. FISH for EWSR1 rearrangement is useful to exclude a diagnosis of malignant melanoma.

Clinical Features

Plexiform fibromyxoma is a benign tumor that virtually always arises in stomach, most often at the gastric antrum. Very rare cases arise in the small intestine. Patients are usually in their fifth decade, and there is no gender predilection. Presenting symptoms include abdominal pain, gastric outlet obstruction, and GI bleeding.

Pathologic Features

Gross Findings

Tumors usually measure between 2 and 15 cm. They are typically intramural but may extend into mucosa or serosa. Tumors are lobulated and the cut surface variably red, tan, or white, with a gelatinous and glistening appearance because of the myxoid stroma.

Microscopic Findings

Tumors arise within the muscularis propria and show a multinodular or plexiform growth pattern on low power examination, resulting in separation of smooth muscle bundles ( Fig. 7.24 ). The nodules are relatively hypocellular and contain bland oval-spindled tumor cells with at most minimal atypia, within a variably myxoid and collagenous stroma ( Fig. 7.25 ). There is typically a prominent capillary proliferation. The tumor cells have indistinct cytoplasm and small nuclei. Mitotic activity is low or absent. Extension into mucosa may result in mucosal ulceration. Subserosal or serosal tumor nodules may be present.