Gross findings

Tumors vary in diameter from less than 1 cm to greater than 20 cm, and can be submucosal, intramuscular, or subserosal, although most are centered in the muscularis propria. Generally GISTs are relatively well marginated. They can be solid or cystic with variable hemorrhage and necrosis, including mucosal ulceration and tumor cavitation. Figure 7-2 shows a small intestinal GIST.

Small intestinal stromal tumor. This lesion is malignant with metastases to the liver.

Microscopic findings

There are spindle, epithelioid, and (rare) pleomorphic forms in a variety of patterns and with modifications resulting from stromal features. The two principal cell types are spindle and epithelioid ( Figs. 7-3 through 7-7 ), which can coexist in varying proportions. About 70% of gastric GISTs and most of those in the small and large intestine are spindled. Most esophageal and rectal GISTs are malignant spindle cell tumors. The spindle cells are relatively short, are often uniform, and have tapered nuclei with amphophilic or eosinophilic slightly fibrillary cytoplasm. They form cellular sheets and fascicles with whorled, storiform, or palisaded patterns. The epithelioid cells have more abundant cytoplasm, with perinuclear halos and well-defined cell borders. Epithelioid GISTs have also been termed leiomyoblastomas or epithelioid smooth muscle tumors . Clear cell, signet ring, oncocytic, and plasmacytoid variants occur, but multinucleated cells are uncommon. Mitoses vary from none to many. Truly pleomorphic tumors are rare, although both pleomorphism and even unusual differentiation (e.g., skeletal muscle) can be seen in lesions that have been treated with imatinib or related tyrosine kinase inhibitors. The stroma is scanty, but fibrous septa sometimes delineate tumor nests in an organoid pattern. Myxoid or cystic change or hyalinization is sometimes seen, and there can be a variable lymphoplasmacytic inflammatory infiltrate.

Gastric stromal tumors exhibiting paranuclear vacuoles. A, Such vacuoles are also a feature of smooth muscle tumors, but they are seldom so numerous in true smooth muscle tumors. B, Myxoid stroma is seen, a feature that would not be present in a smooth muscle tumor, and the nuclei have more tapered ends than smooth muscle tumor nuclei.

Small intestinal GIST. Corresponds to the gross lesion depicted in Figure 7-1 and is highly cellular and mitotically active.

Epithelioid gastric GIST. Such tumors have been termed “leiomyoblastomas” in the past.

Epithelioid gastric GIST. On the left portion of the field, this lesion has invaded the mucosa, a feature associated with a poor prognosis. Note that the tumor is centered in the muscularis propria.

Epithelioid gastric GIST. Note the prominent cytoplasmic vacuoles and uniform nuclei; nuclear pleomorphism is unusual in GISTs and its presence should prompt the pathologist to consider other diagnoses.

Ultrastructural findings

Early studies failed to reveal well-developed smooth muscle differentiation. A minority (about 20%) of GISTs show focally incomplete features of smooth muscle differentiation, with arrays of cytoplasmic intermediate filaments and dense bodies. Many GISTs show neuronal-like differentiation with interdigitating neurite-like cytoplasmic processes that contain microtubules, smooth endoplasmic reticulum, and intermediate filaments. Dense core neuroendocrine granules, some of which are also associated with the prominent Golgi apparatus, and synapse-like structures have been described, but these are not usual features of ICC and might represent entrapped autonomic nerve. There are numerous mitochondria and occasional cell-to-cell junctions (including with smooth muscle cells and neurons).

Skeinoid fibers, which are amorphous periodic acid-Schiff–positive foci of haphazardly arranged modified collagen fibers with a periodicity of 45 nm, are seen rarely, usually in (small) intestinal tumors, benign and malignant, including those in the duodenum. Some GISTs, including CD117/CD34-positive cases, show no ultrastructural differentiation.

Immunohistochemistry

In the 1980s and early 1990s, immunohistochemical studies attempted to confirm supposed smooth muscle, neural, or dual differentiation in GISTs and to relate immunophenotype to behavior. Varying proportions were shown to have smooth muscle actin (SMA), muscle-specific actin (MSA), and desmin, with smaller numbers of cases displaying S-100 protein positivity. Significant numbers remained, however, with no specific markers or only vimentin. Gastrointestinal autonomic neural tumors (GANTs) were variably immunoreactive for neuron-specific enolase (NSE), neurofilaments, synaptophysin, and S-100 protein. In 1994, CD34 was shown to be a reliable marker for the majority of GISTs, and from 1998, CD117 positivity became definitional ( Fig. 7-8 ).

CD117/C-kit expression in GIST, with cytoplasmic and membranous labeling. CD117 staining is seen regardless of malignant potential in the vast majority of stromal tumors.

CD117 (KIT), the product of the C-KIT gene, is expressed among normal ICCs, mast cells, melanocytes, a variety of epithelia, fetal endothelial cells, and a subset of CD34-positive hematopoietic stem cells. Staining is usually cytoplasmic, but can be membranous in mast cells, melanocytes, and germ cells.

With immunohistochemistry, CD117 is positive (diffuse cytoplasmic staining with membranous accentuation) in the vast majority of benign and malignant GISTs. GISTs with spindle cell and epithelioid morphology are both positive, although less intensely in the latter. Smooth muscle tumors (SMA and desmin positive) and schwannomas (S-100 protein positive) are negative for CD117.

A variety of commercial antibodies to CD117 are available, with varying specificity and sensitivity. For example, using the rabbit polyclonal CD117 antibody marketed by Santa Cruz Biotechnology (C-19, sc-168) positivity is essentially confined to GISTs, among the similar tumors in the differential diagnosis. The rabbit polyclonal antibody A4502, manufactured by Dako (Carpinteria, CA), however, has been reported to stain (the cytoplasm of) lesional fibroblasts and myofibroblasts, including some examples of fibromatosis, and solitary fibrous tumor; awareness of this may prevent misdiagnosis of such tumors as GISTs. These “falsely positive” tumors lack kit mutations and respond only minimally to imatinib treatment.

A small number (2% to 10%) of otherwise typical GISTs are CD117 negative. These are predominantly epithelioid in cell morphology. It has been shown that protein kinase C theta (PKCT) is constitutively activated in all GISTs, including those that are C-kit negative, although by immunoblotting, PKCT expression in these is 50% lower than in C-kit-positive GISTs. Virtually all GISTs were positive with an antibody to PKCT phospho Thr ⁵³⁸ . DOG1 (discovered on GIST-1) antibodies also label most GISTs and may be helpful in that they tend to label GISTS that lack CD117 expression.

CD34 is positive in 47% to 100% of GISTs, and its expression varies with location within the GI tract. Miettinen and associates found, among CD117-positive tumors, 100%, 90%, 47%, 65%, 96%, and 64% of cases to be CD34-positive in esophagus, stomach, small intestine, colon, rectum, and extraintestinal locations, respectively. Among malignant gastric and small intestinal GISTs, 88% and 55% were CD34-positive. Tumors that are CD34-positive are almost always CD117-positive, and most CD34-negative tumors are CD117 positive. CD117 is sometimes lost in metastases. It should be noted that CD34 is also positive in occasional smooth muscle tumors, including epithelioid variants.

Antibodies against platelet-derived growth factor receptors α and β (PDGFRA and PDGFRB), which are produced by Santa Cruz Biotechnology (pAb, no.sc-338 for PDGFRA and pAb, no. sc-339 for PDGFRB), are also available and label a subset of CD117-negative GISTs. However, some fibromatoses cases also show labeling with PDGFRA and PDGFRB antibodies.

SMA is found only focally in up to half of GISTs in an inverse frequency of expression to that of CD34 (the two sometimes showing a mosaic distribution); benign GISTs of the small intestine have the highest proportion of SMA positivity. h-Caldesmon (an actin-binding cytoskeleton-associated protein) is positive in about 80% of GISTs, supporting myoid differentiation, and calponin in about 25%. Desmin is focally positive in up to 20% of tumors of the esophagus and omentum/peritoneum and in a small proportion of benign (but not in malignant) GISTs in the stomach and small intestine. Cytokeratins are rarely positive but are occasionally seen in malignant epithelioid GISTs.

A few have neurogenic differentiation, with positivity for S-100 protein (especially in small bowel tumors), PGP9.5, and NSE, and a few of these additionally express SMA, implying both neurogenic and myoid differentiation. Both GISTs and ICCs express embryonic smooth muscle myosin heavy chain messenger RNA.

Fine-needle aspiration biopsy

Fine-needle aspiration can be used to diagnose GISTs with appropriate immunohistochemistry but cannot be used to assess malignant potential.

Molecular studies

Two receptors in the type III receptor tyrosine kinase subfamily have been shown to play an important role in the pathogenesis of GIST: (1) C-kit receptor and (2) platelet-derived growth factor receptor-α ( PDGFRA ). The genes encoding for these two receptors are both located in chromosome 4. The protein structure of these receptors are also similar, including an extracellular (EC) domain, transmembrane (TM) domain, juxtamembrane (JM) domain, and tyrosine kinase (TK) domains. As a result of their similarities, activating mutation in either one of these two genes will lead to activation of similar signal transduction pathways leading to GIST formation.

In sporadic GISTs, 85% to 90% of the cases have mutations in the C-KIT gene while 10% to 15% of the remaining cases do not. The mutations of C-KIT gene occur in order of decreasing frequency: exon 11, exon 9, exon 13, and exon 17. The types of mutations in exon 11 include: in-frame deletions (60% to 70%) of one to several codons at 5′ end of codon 11 and region between codons Gln ⁵⁵⁰ to Glu ⁵⁶¹ ; missense point mutations (20% to 30%) at Trp ⁵⁵⁷ , Val ⁵⁵⁹ , Val ⁵⁶⁰ , and Leu ⁵⁷⁶ ; and internal tandem duplications of 1 to more than 20 codons at 3′ end of codon 11. The clinical significance associated with mutations in exon 11 is that they may play a role in predicting response to treatment. Most mutations of the C-KIT gene occur at this exon (juxtamembrane domain). The juxtamembrane domain is an intracytoplasmic domain located between the transmembrane and tyrosine kinase domains and its function, after activation, is to induce dimerization of two C-kit receptors, which leads activation of the downstream signal transduction pathways.

At exon 9, encoding the extracellular domain, most of the cases show 6-nucleotide duplications encoding Ala ⁵⁰² -Tyr ⁵⁰³ and this mutation is usually encountered in intestinal GISTs. At exon 13, the most common mutation is the 1945A>G substitution leading to Lys ⁶⁴² Glu. At exon 17 encoding the tyrosine kinase II domain, the most common mutation is the 2487T>A substitution leading to Asn ⁸²² Lys. Interestingly, seminoma and mastocytoma are two neoplasms that also express CD117; these both commonly have mutations in exon 17. In contrast, CD117-positive GIST rarely shows mutations at codon 17 and more commonly has exon 11 mutations.

As noted, 10% to 15% of sporadic GIST lack C-KIT gene mutations. About 35% to 63% of these cases have mutations in the PDGFRA gene. Mutations of PDGFRA gene occur, in order of decreasing frequency, in exon 18 (>80%), exon 12, and exon 14. In exon 18, a missense mutation leading to Asp ⁸⁴² Val is commonly seen. In exon 12, a missense mutation is reported, Val ⁵⁶¹ Asp. In exon 14, a missense mutation is seen, Asn ⁶⁵⁹ Lys/Tyr.

Understanding the specific mutations in C-KIT and PDGFRA genes is important because of the following five clinical implications. First, in terms of prognosis, GISTs with exon 11 mutations are associated with longer event-free and overall survival than GISTs with exon 9 mutations and GISTs with no detectable kinase mutation. Second, GISTs with exon 11 mutations have a better response to imatinib than GISTs with exon 9 mutation in C- KIT gene, GISTs with PDGFRA mutation, and wild-type GISTs. Third, in terms of dosing of imatinib, cases of metastatic/advanced GISTs with exon 9 mutation require higher doses of imatinib to achieve a response. Fourth, knowing the mutation status in the C-KIT and PDGFRA genes occasionally identifies patients who have unidentified genetic diseases. Specifically, in patients with wild-type GISTs, there is enrichment for NF-1 and Carney triad. Finally, when GISTs show resistance to first-line tyrosine kinase inhibitor such as imitanib, identification of secondary mutations can help in choosing a second-line tyrosine kinase inhibitor (e.g., sunitinib) for treatment. An excellent resource for arranging for molecular testing of GISTs, as well as other molecular tests, is found through the Association for Molecular Pathology at http://www.amptestdirectory.org/ .

Behavior

Regional

Esophagus . GISTs account for a minority of esophageal stromal tumors (and leiomyomas for the majority), and involve the lower third or gastroesophageal junction, predominantly in males. They can be spindled or epithelioid and display the usual variety of patterns. All are CD117 and CD34 positive, and about 15% have SMA or desmin. The majority are malignant. In the series of Miettinen and coworkers, 9 of 16 patients died of disease, including all with tumors larger than 10 cm, and none with tumors smaller than 5 cm. Median survival was 29 months. However, a subset of GISTs of the gastroesophageal junction is minute, multiple, and presumably does not progress, because these “seedling” GISTS are encountered commonly (approximately 10%) in autopsies and resections when the entire gastroesophageal junction is embedded ( Fig. 7-9 )

“ Seedling” GISTs of the gastroesophageal junction are common and apparently do not progress to clinically evident lesions. Several small nodules are seen on H&E (A), and highlighted by CD117 (B) and CD34 (C) staining.

Stomach . About 20% are result in patient deaths. The consensus is that 5 mitoses per 50 high-power fields (hpf) and size greater than 5 cm are adverse prognostic factors. The 5-year survival rate of gastric GISTs is about 80%, with improvement in completely resected cases. There is no evidence that radical surgery improves survival, so the least extensive surgical procedure compatible with complete excision is advisable. Gastric GISTs are more frequent in males.

Epithelioid GISTs (formerly called leiomyoblastomas ) comprise about 10% of gastric GISTs, of which about 80% are benign. Large tumors in the fundus or cardiac area and posterior wall are more likely to be malignant.

Duodenum. Duodenal GISTs are most common in the second part, and 35% to 50% are malignant. Miettinen and associates studied 156 duodenal GISTs, with the following results: 12 patients whose tumors were less than 2 cm with mitoses less than or equal to 5/50hpf had no recurrence, metastases, or tumor-related death during follow-up of 6 years. However, 18 of 21 patients (86%) with tumors greater than 5 cm with greater than 5 mitoses/50 hpf had metastases and disease-related death with a median survival time of 21 months.

Jejunum and Ileum. About 40% result in patient deaths. These GISTs can be spindled, epithelioid, or mixed; mixed and epithelioid tumors are associated with worse behavior than spindled tumors. The presence of skeinoid fibers, PAS-reactive thick collagen fibers, present in about 45% of the cases, is a favorable prognostic factor. As in other sites, the most important factors determining the prognosis are tumor size and mitotic index. Small (<5 cm) with few mitoses (≤5 mitoses/50 hpf), convey an excellent prognosis. In contrast, large (>10 cm) mitotically active (>10 mitoses/50 hpf) GISTs are highly aggressive. Most small intestinal GISTs have mutation in exon 11 of C-KIT with few cases showing mutations in exons 9 and 17 of C-KIT . These mutations lack prognostic significance. PDGFRA mutations are rare in small bowel GISTs.

Colon . Tumors are most common in adults in the sixth decade of life in the ascending and descending portions of the colon and usually present with pain or a mass. Except for small subserosal lesions, they are typically transmural tumors with intraluminal and outward-bulging components. Morphologically they are heterogeneous, with spindle cells in fascicles, palisades or storiform arrangement, and sometimes an organoid pattern; a minority have epithelioid cells in varying proportions.

Moyana and colleagues and Tworek and associates have taken a size of 5 cm and 5 mitoses per 10 hpf as thresholds for malignancy, but Miettinen and coworkers found lower levels. In their series, tumors smaller than 1 cm did not recur, whereas in larger tumors 20% with minimal mitoses and all with more than 5 mitoses per 50 hpf metastasized or caused patient deaths. Interestingly, the few cases with skeinoid fibers had a better prognosis.

Appendix. GISTs of the appendix are rare. Miettinen and Sobin described four cases in men 56 to 72 years of age (mean 63 years). Two tumors occurred in patients who had undergone surgery for appendicitis-like symptoms: one was an incidental finding during surgery for a malignant gastric epithelioid GIST and one was an incidental autopsy finding. One was a polypoid GIST projected outward from the proximal part of the appendix. Three tumors were partially obliterating nodules, eccentrically expanding the appendiceal wall. All four were spindle cell tumors, and three of them contained extracellular collagen globules (skeinoid fibers); none had atypia or mitotic activity (< 1 mitosis per 50 hpf). Follow-up revealed death resulting from cardiovascular disease in one case (4 years after appendectomy) and liver failure because of malignant gastric epithelioid GIST metastatic to the liver in another case 15 years after the appendectomy.

Anorectum . These are rare tumors. St. Mark’s Hospital in London (a specialist lower GI institution) had only 25 “leiomyosarcomas” of the rectum in a 25-year period. Thirty-two percent to 54% of rectal GISTs are malignant, the smallest being 1.6 cm, but most exceed 5 cm and have greater than 5 mitoses per 50 hpf. In the series of Miettinen and colleagues of 133 anorectal GISTs, 54% recurred or metastasized (to liver, lung, or bone), sometimes after a long interval. Seventy percent of patients whose tumors were larger than 5 cm and with greater than 5 mitoses per 50 hpf died. One tumor smaller than 2 cm and with fewer than 5 mitoses per 50 hpf recurred, but no patients died. Eighteen of 29 cases (62%) had GIST-specific C-KIT mutations, mainly in exon 11. Survival rates are around 60% at 5 years and 20% to 50% at 10 years (for patients with curative rather than palliative resections).

Extragastrointestinal GISTs. These GISTs have been described by a number of observers. Some data suggest that single omental GISTs unattached to the GI tract resemble gastric lesions, raising the possibility that they are gastric GISTs that have extended into the omentum. In contrast, multiple omental GISTs are more reminiscent of small bowel GISTs and thus may arise in the small bowel and metastases/extensions. Solitary examples are associated with a better prognosis than multiple ones. Kit reactive Cajal cells are absent in the omentum.

Gross findings

The gross appearance of these tumors is nonspecific. Esophageal leiomyomas form whorled masses similar to uterine leiomyomas. The occasional leiomyomas arising in the muscularis mucosae of the colorectum present as polyps. Leiomyosarcomas of the colorectum have been described as intraluminal bulging polypoid masses.

Microscopic findings

True smooth muscle tumors have the same features of smooth muscle differentiation seen elsewhere in the body, namely perpendicularly oriented fascicles of spindle cells with brightly eosinophilic cytoplasm with longitudinal striations and blunt-ended nuclei with paranuclear vacuoles ( Figs. 7-10 through 7-14 ). Leiomyosarcoma is characterized by mitoses, cytologic atypia, and necrosis.

This gastric leiomyoma has arisen in association with the muscularis mucosae. It is brightly eosinophilic at low magnification.

This distal colonic leiomyoma is hypocellular and merges with the residual muscularis mucosae. The nuclei are blunt ended.

Leiomyosarcoma showing perpendicularly oriented fascicles of spindle cells with striking cytoplasmic eosinophilia (A). Compare the cellularity of this lesion (B) to that seen in Figure 7-11 .

This leiomyosarcoma is similar to the one depicted in Figure 7-12 A, but has more striking nuclear alterations.

Leiomyosarcoma. The nuclei have blunt ends and there are scattered paranuclear vacuoles. The cytoplasm has delicate longitudinal striations.

Ultrastructural findings

The ultrastructural features are those of smooth muscle differentiation elsewhere (thin filaments, pinocytotic vesicles, attachment plaques, and interrupted external lamina).

Immunohistochemistry

True smooth muscle tumors are actin and desmin reactive and lack CD117/C-kit. Calponin and h-caldesmon are expressed and CD34 is typically absent. S-100 protein is absent. Some lesions display keratin expression, a feature of leiomyosarcomas in general.

Gross findings

Schwannomas are grossly similar to GISTs, having a whitish cut surface and well-circumscribed outline without a capsule.

Microscopic findings

GI tract schwannomas are not encapsulated, a feature that distinguishes them from schwannomas in the peripheral nervous system. They have a lymphoid cuff with germinal centers, and intralesional lymphocytes can be seen. They are composed of interlacing bundles of spindle cells that are only loosely palisaded (in contrast to GISTs, which, ironically, often display striking palisading). They appear similar to GISTs, but the lymphoid cuff is a tip-off that these are schwannian ( Figs. 7-15 through 7-18 ). In the colon, schwannomas can be classified into two types: spindle cells and plexiform. Schwannoma with spindle cell features are composed of spindle cells with wavy elongated nuclei with tapering ends, scanty eosinophilic cytoplasm, and indistinct cell borders. Schwannomas with plexiform features form nodules of spindle cells.

Gastric schwannoma. Note the striking lymphoid cuff at low magnification. This is a helpful diagnostic feature in separating these tumors (always benign) from GISTs (which may behave in a malignant fashion).

If this gastric schwannoma were mistaken for a GIST, the nuclear variability would result in an interpretation of a GIST of uncertain potential. The lymphoid cuff, as well as scattered intratumoral lymphocytes, are tip-offs that this is instead a benign schwannoma.

Gastric schwannoma. At intermediate magnification there is a mild inflammatory backdrop within the lesion.

Gastric schwannoma. At high magnification the tapered ends of the nuclei are apparent.

Immunohistochemistry

These benign tumors are strongly labeled with S-100 protein ( Fig. 7-19 ) and low-affinity nerve growth factor receptor (p75). Schwannomas can show labeling with C34, glial fibrillary acidic protein (GFAP), and collagen type IV with a pericellular pattern. Calretinin is unusually negative in GI tract “schwannomas” (in contrast, schwannomas of the somatic soft tissues typically express calretinin). The tumors lack muscle markers and CD117.

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