Clinical Features

Approximately 4500 to 6000 GISTs are diagnosed annually in the United States.^18,19 GISTs can arise at almost any age, including childhood, but are most common in middle-aged and elderly patients, with approximately 75% diagnosed in patients older than 50 years.^20–22 They may arise anywhere in the GI tract but are most common in the stomach (60%), followed by the jejunum and ileum (30%), the duodenum (5%), and the colorectum (<5%).^23,24 Very few cases have been described in the esophagus²⁵ or appendix.^26,27 GISTs may also occur as primary tumors outside the GI tract, in the retroperitoneum or abdomen (e.g., omentum or mesentery); such tumors are referred to as extraintestinal GISTs.^28,29

The presenting manifestations of GIST depend on the site of involvement in the GI tract, the size of the tumor, and the portion of the gut wall in which the tumor is located. A significant number of tumors are asymptomatic and are found incidentally at surgery performed for other reasons.^30,31 The most common symptoms are GI bleeding with subsequent anemia, abdominal pain, nausea, vomiting, and weight loss.³² Signs and symptoms may lead to endoscopy and biopsy. In some cases, a histologic diagnosis of GIST can be made if a deep endocscopic biopsy is obtained or if the neoplasm infiltrates the overlying mucosa. Radiographic imaging studies, including use of barium contrast, computed tomography, and endoscopic ultrasound, are commonly used for evaluation and diagnosis of these neoplasms.^33,34 In addition, GISTs can be diagnosed by fine-needle aspiration cytology.³⁵

The behavior of GISTs ranges from benign to malignant. In adults, GIST behavior can be predicted by anatomic site, tumor size, and mitotic activity.^{18,20,23,36,37} Metastases usually develop within 2 years of diagnosis, and the expected pattern of metastatic spread is to the liver and serosa within the abdominal cavity.²⁰ Rare cases of metastatic disease outside the abdominal cavity have been seen, most commonly in the lungs, bone, soft tissue, and, very rarely in advanced cases, intracranial sites.^20,38,39 Historically, nodal metastases in GISTs have been extremely uncommon (<1% of cases). However, more recent studies show that succinate dehydrogenase (SDH)-deficient GISTs (described later) have a propensity for nodal metastases.^40–42

Most GISTs are uninodular and centered on the bowel wall; however, multifocal nodules have been described, especially in the pediatric population and in GIST syndromes. The tumor may ulcerate the overlying mucosa or grow exophytically and protrude toward the serosal aspect. Some GISTs are predominantly extramural and may be attached to the serosa of the tubal gut by only a thin stalk of tissue. On cut section, lesions may show areas of hemorrhage, necrosis, or cystic change—features that are not indicative of malignancy in GISTs (Fig. 30.2). The histomorphology varies greatly and includes pure spindle cell, pure epithelioid cell, and mixed spindle and epithelioid cell types.¹⁸ Epithelioid and mixed cell type GISTs are most commonly encountered in the stomach.^43,44

Spindle cell GISTs are composed of uniform, elongated cells that are consistent in size and shape. The cells have nuclei with evenly dispersed chromatin, inconspicuous nucleoli, and moderate amounts of pale to eosinophilic fibrillary cytoplasm (Fig. 30.3). Particular to gastric GISTs is the frequent presence of perinuclear vacuoles (due to fixation artifact) that indent the nucleus at one pole (Fig. 30.4). The architecture is that of intersecting short fascicles (Fig. 30.5). The vasculature can range from inconspicuous to hemangiopericytoma-like, whereas the stromal component may be inconspicuous or may exhibit prominent myxoid change, hyalinization, or dystrophic calcifi­cation (Fig. 30.6). Prominent collagen fibrils, so-called “skeinoid” fibers, have been described in small bowel GISTs (Fig. 30.7).^45,46

Epithelioid GISTs are composed predominantly of cells with either abundant eosinophilic or clear cytoplasm, typically arranged in nests and sheets. The nuclei are round with vesicular chromatin and variable nucleoli (Fig. 30.8). Scattered multinucleated giant cells, binucleated cells, or cells with bizarre nuclei may be present (Fig. 30.9).⁴⁷ The stromal alterations may include hyalinization or myxoid change (Fig. 30.10). Confusion with other epithelioid malignancies can be problematic on endoscopic biopsies, especially when an epithelioid GIST involves the mucosa (Fig. 30.11).

Immunohistochemical Features

CD117 (KIT), the product of the KIT gene, is a sensitive marker of GISTs, irrespective of site; it is expressed in as many as 95% of GISTs.⁴⁸ The pattern of immunoreactivity is typically diffuse and pancytoplasmic (Fig. 30.12), although membranous staining and a perinuclear dotlike immunoreactivity have been described (Fig. 30.13). Approximately 5% of GISTs do not react with antibodies to KIT^49,50; often, these tumors belong to the subset of GISTs that contain a PDGFRA mutation.⁵¹ The KIT-negative tumors are often located within the stomach and have epithelioid morphology. CD34, a hematopoietic stem cell marker, is expressed in roughly 70% of GISTs.^52,53 Approximately 20% to 30% of GISTs are positive for smooth muscle actin, 5% express some positivity for S100 protein, and 1% to 2% are positive for desmin or keratin.^5,18,48

Gene expression profiling studies of GISTs have identified two additional immunostains that appear diagnostically useful. Discovered on GIST 1 (DOG1),⁵⁴ also known as anoctamin 1 (ANO1), encodes a calcium-regulated chloride channel protein.^55,56 The corresponding ANO1/DOG1 antibody appears to be immunoreactive with GISTs regardless of their KIT/PDGFRA mutational status^57,58 and has a sensitivity similar to that of KIT (approximately 95%). However, DOG1 positivity has also been identified in a small subset of mesenchymal tumors, including leiomyomas and synovial sarcomas.⁵⁹ Gene expression studies have shown protein kinase C-theta to be consistently overexpressed in GISTs,^60,61 and the initial immunohistochemical studies have shown this protein to be sensitive and specific for the diagnosis of GIST.⁶²

Differential Diagnosis

GISTs with a spindle cell morphology must be distinguished from other spindle cell proliferations of the GI tract, including smooth muscle neoplasms, nerve sheath tumors, inflammatory fibroid polyps, inflammatory myofibroblastic tumors (IMTs), and intraabdominal fibromatoses (desmoid tumors) (Table 30.2).

Although smooth muscle tumors of the GI tract are much less common than GISTs, location is important because leiomyomas are more common than GISTs in the colon, rectum, and esophagus. GI leiomyomas are composed of spindle cells with cigar-shaped nuclei and eosinophilic fibrillar cytoplasm arranged in fascicles. Leiomyosarcomas of the GI tract are exceptionally rare and have cytologic pleomorphism and atypical mitotic figures, both of which are uncommonly seen in GISTs. The cells are strongly and diffusely immunoreactive for actin (smooth muscle actin and muscle-specific actin) and are often immunoreactive for desmin, but there is no expression of KIT.^38,45

Nerve sheath tumors are also a consideration, including neurofibromas, schwannomas, and malignant peripheral nerve sheath tumors. GI schwannomas, the most common of these nerve sheath tumors, usually occur in the stomach. They are composed of bundles of spindle cells with focal atypia, often arranged in a microtrabecular growth pattern, and they are associated with a dense peripheral lymphoid infiltrate. They stain strongly for S100 protein and for glial fibrillary acidic protein (GFAP) and are negative for KIT. Malignant peripheral nerve sheath tumors have rarely been described as arising within the GI tract; they resemble their counterparts in the peripheral soft tissues. In contrast to GISTs, these lesions do not express KIT and are variably immunoreactive for S100 protein.

Less commonly, inflammatory fibroid polyps (see Chapter 20) enter the differential diagnosis. They have been described throughout the GI tract,⁹¹ but they have a propensity for the stomach and ileum, where they a form an intramural mass. These lesions are composed of randomly distributed, spindle- and stellate-shaped cells associated with numerous blood vessels and inflammatory cells, especially eosinophils, plasma cells, lymphocytes, and mast cells. Frequently, there is a concentric whorling of the spindle cells in an onion-skin pattern around blood vessels. KIT highlights the scattered mast cells, whereas the spindle cells are negative for KIT. The spindle cells and vessels are immunoreactive for CD34, posing potential confusion with GISTs.⁹² Additionally, inflammatory fibroid polyps have been found to harbor gain-of-function mutations in PDGFRA within the same genomic hot spots as those identified within GISTs that lack an activating KIT mutation.⁹³ Despite having similar activating mutations, inflammatory fibroid polyps behave in a benign fashion and are not thought to be related to GIST.

IMTs are most common in children and young adults and can arise as an intraabdominal mass involving the GI tract. The constituent cells have the light microscopic and immunohistochemical features of myofibroblasts, intermingled with inflammatory cells and collagen. The cells are KIT negative and frequently express anaplastic lymphoma kinase (ALK) caused by rearrangements of the ALK gene on 2p23.⁹⁴

Intraabdominal fibromatosis (desmoid tumor) is the most common primary tumor of the mesentery; it often originates from the gastrocolic ligament and omentum. Mesenteric fibromatosis is arranged in long, sweeping fascicles that have finger-like projections extending into the surrounding soft tissue. Scattered keloid-type collagen fibers may be present, as are dilated thin-walled vessels. The lesional spindled or stellate-shaped cells are cytologically bland and monotonous and are distributed evenly within a collagenous or myxoid stroma. By immunohistochemistry, the lesional cells are immunoreactive for vimentin, smooth muscle actin, and muscle-specific actin, and they frequently have β-catenin nuclear immunoreactivity.⁹⁵ These lesions are typically KIT negative, although one group has reported KIT immunoreactivity in these tumors.⁹⁶

GISTs with epithelioid features raise a broad differential diagnosis that includes melanoma, neuroendocrine tumors, and carcinoma; judicious use of immunohistochemical stains is warranted in this setting given the histologic overlap (Table 30.3). Because expression of KIT has been identified within a subset of melanomas,^97–99 excluding the possibility of melanoma by performing a panel of melanocytic markers including S100 protein, human melanoma black (HMB)-45, or melan-A is warranted. Rare examples of epithelioid GISTs show focal cytokeratin immunoreactivity, so the coexpression of CD34 and DOG1 with KIT (or without KIT in epithelioid GISTs containing PDGFRA mutations) is essential to avoid misdiagnosis of such cases as carcinoma.

Overall, nuclear pleomorphism is unusual in GISTs, and the finding of marked cytologic pleomorphism could suggest sarcoma, sarcomatoid carcinoma, or the very rare dedifferentiated GIST. This dedifferentiation is akin to dedifferentiation in other sarcomas, wherein a transition from a morphologically recognizable low-grade tumor to an anaplastic or pleomorphic morphology is appreciated (Fig. 30.14). In the setting of GIST with dedifferentiation, the morphology changes, and the immunophenotype undergoes a transition as well, with loss of KIT immunoreactivity within the anaplastic cells.¹⁰⁰ Dedifferentation has been described both as a de novo event and as occurring after treatment with the selective tryosine kinase inhibitor imatinib mesylate (ST1571 or Gleevec; Novartis Pharmaceuticals, East Hanover, N.J.).¹⁰⁰

Prognosis and Treatment

Tyrosine kinase inhibitors have played a pivotal role in the management of GISTs, and the U.S. Food and Drug Administration (FDA) has approved two targeted therapies. Imatinib mesylate is a selective tryosine kinase inhibitor that targets KIT and PDGFRA. Sunitinib malate (SU11248 or Sutent; Pfizer, New York, N.Y.) targets several receptors including those for KIT, PDGFRA, and vascular endothelial growth factor.^101–103 The original indication for imatinib was for the treatment of metastatic or unresectable GISTs, with patients showing clinical responses in as many as 80% of cases¹⁰⁴; current FDA-approved labeling includes use in the adjuvant setting after complete gross resection of GISTs.¹⁰⁵ Sunitinib is approved for patients who do not tolerate imatinib or who have tumor progression on imatinib therapy. Tumor genotype has been shown to correlate with response to these drugs. For example, tumors with an exon 11 KIT mutation have shown the best imatinib response rates, whereas tumors without a KIT mutation and those with a PDGFRA D842V mutation are less likely to have a favorable or a sustained response to imatinib.^51,106 Other studies suggest that patients with an exon 9 KIT mutation benefit from a higher dose of this drug.^107,108 Approximately 50% of GIST patients being treated with imatinib will acquire a secondary mutation that confers tumor resistance to imatinib,^109–112 and in such cases, sunitinib is approved as a second-line therapy. The most common secondary KIT mutations that escape imatinib are KIT V654A and KIT T670I, both of which are sensitive to sunitinib. Regorafenib (Stivarga; Bayer HealthCare, Whippany, N.J.) has been approved by the FDA as third-line therapy for patients whose disease progresses on sunitinib.

GISTs are risk stratified based on mitotic rate, size, and anatomic location; these features define the Miettinen criteria for risk stratification (Table 30.4),²³ which establish a risk of progressive disease, defined as either metastatic disease or tumor-related death. The criteria are based on large studies by the Armed Forces Institute of Pathology (AFIP) that evaluated how the clinicopathologic features of GISTs within different sites (gastric, small intestinal, duodenal, and rectal locations) affected prognosis in the pre-imatinib era.^38,43,45,46 To assign an accurate risk of progressive disease, a precise gross tumor measurement with a thorough mitotic count should be performed, evaluating a total area of 5 mm². For modern wide-field microscopes with wide-field eyepieces, the mitotic count correlating with the total area of 5 mm² is obtained from 20 high-power fields (HPFs).⁵

Other factors that have been reported to be associated with poor outcome include tumor necrosis, mucosal invasion, and ulceration.^43,113,114 Tumor rupture, either spontaneous or at the time of surgery, increases the risk of recurrence with intraabdominal seeding.^115,116 Patients whose complete resection is complicated by tumor rupture have a significantly shortened survival time, compared with patients with complete resection without tumor rupture.^116–118

Immunohistochemistry and Molecular Findings

Similar to their soft tissue counterparts, GI schwannomas are strongly and diffusely immunoreactive for S100 protein and GFAP, and they can show focal CD34 staining. These lesions are consistently negative for KIT, cytokeratins, and muscle markers.

Not only are GI schwannomas histologically different from their conventional soft tissue counterparts, but they are also different molecularly. The somatic NF2 gene mutations that are common in sporadic soft tissue schwannomas are unusual events in GI schwannomas.¹⁵³ GI schwannomas lack an association with neurofibromatosis, with only one reported instance of identification of a gastric schwannoma in a patient with NF1.^129,147,154 In contrast to GIST, which falls in the differential diagnosis, GI schwannomas lack KIT and PDGFRA mutations.

Gangliocytic paraganglioma is typically a circumscribed lesion centered on the submucosa and may extend into the muscularis propria. The lesion is a triphasic tumor composed of nests of epithelioid neuroendocrine cells resembling a paraganglioma, ganglion cells or ganglion-like cells, and spindle-shaped Schwann cells with neuromatous stroma. The components are haphazardly arranged, and one component may predominate. The neuroendocrine component have a ribbon-like or trabecular growth pattern (Figs. 30.18 and 30.19), whereas the ganglion cells have variable degrees of differentiation (Fig. 30.20). The neuromatous stroma may have a fascicular architecture.

Immunohistochemistry and Molecular Findings

Immunohistochemically, a variety of antigens, including CAM 5.2, neuron-specific enolase (NSE), insulin, glucagon, somatostatin, serotonin, synaptophysin, and sometimes chromogranin, may be expressed in the neuroendocrine component. The ganglion cells express NSE, synaptophysin, neurofilament protein, and variable chromogranin. The Schwann cells and neuromatous stroma are positive for expression of neurofilament, S100 protein, and NSE. S100 protein highlights a sustentacular network surrounding the neuroendocrine cell nests (Fig. 30.21). To date, no recurrent molecular alterations have been described in gangliocytic paraganglioma.

Treatment and Prognosis

Most gangliocytic paragangliomas behave in a benign fashion, and local resection typically provides adequate treatment. However, rare cases with regional nodal metastases^165–168 or distant metastases have been reported.^161,169 It has been suggested that prominent nuclear pleomorphism, mitotic activity, and an infiltrative margin raise concern for aggressive behavior,¹⁷⁰ although many of the cases described in the literature with nodal involvement or more distant disease lacked these features. More importantly, the involvement of lymph nodes is not necessarily predictive of an adverse outcome, because patients with nodal disease were alive and well as long as 91 months after surgical resection.¹⁵⁸

Solitary polypoid ganglioneuromas are usually sessile polyps measuring less than 2 cm.¹⁸⁰ Ganglioneuromatous polyposis has a varied extent of involvement; in some cases polyps are few and small, whereas other examples have shown extensive mucosal involvement. The sporadic and syndromic polypoid ganglioneuromas are histologically similar and contain a hypercellular lamina propria composed of cytologically bland, spindle-shaped cells with schwannian features (Fig. 30.22). Ganglion cells may be arranged in clusters but are often isolated and can be difficult to identify (Fig. 30.23). The glandular epithelium is often splayed apart by the expanded lamina propria, resulting in a distorted appearance at low magnification.

Diffuse ganglioneuromatosis may manifest as a bowel wall thickening or a more discrete mass.^177,178,180 Histologically, the submucosal or myenteric plexi may be involved and may show a nodular expansion by Schwann cells and ganglion cells that typically extend insidiously into the adjacent submucosa or muscularis propria. Involvement of the mucosa is seen more commonly in NF1.¹⁸¹

Treatment and Prognosis

These lesions are benign, and management is ultimately determined based on whether a germline mutation is identified. Given the involvement of the bowel wall by a diffuse ganglioneuromatosis, resection of the affected segment of bowel may be required for symptom management.

Mucosal perineuriomas average 4 mm in diameter and are predominately solitary lesions composed of bland spindle cells that expand the lamina propria and splay the crypts, often with a whorled growth pattern around crypts. The proliferation is centered in the mucosa but may extend into the superficial submucosa. The spindle cell nuclei have fine chromatin, lack nucleoli, and have eosinophilic cytoplasm. In most cases, the associated colonic epithelium has a serrated architecture akin to a hyperplastic polyp or a sessile serrated polyp (Figs. 30.24 and 30.25).^183,185,186

Treatment and Prognosis

Mucosal perineuriomas are benign, and recurrences have not been documented.

Mucosal Schwann cell hamartomas have a mean size of 2.5 mm and typically are described as small sessile polyps.¹⁸⁹ Histologically, the polyps are composed of an ill-defined proliferation of spindle cells within the lamina propria that entrap colonic crypts and have an irregular border with the adjacent uninvolved lamina propria (Fig. 30.26). The lesion is composed of uniform, bland spindle cells with elongated or wavy nuclei with fine chromatin, inconspicuous nucleoli, eosinophilic cytoplasm, and indistinct cell borders (Fig. 30.27). Cytologic atypia and mitotic activity have not been described.

Immunohistochemistry

By immunohistochemistry, the lesional cells show strong and diffuse reactivity for S100 protein (Fig. 30.28). Other markers that are typically negative include GFAP, EMA, CD34, smooth muscle actin, and KIT.¹⁸⁹

Treatment and Prognosis

Mucosal Schwann cell hamartoma was first fully described in 2009 by Gibson and Hornick¹⁸⁹; limited studies with clinical outcome are available in the literature. However, the lesion appears to be benign, and recurrences have not been documented. To date, these lesions have not been associated with specific inherited syndromes (NF1, MEN IIb, or PTEN hamartoma tumor syndrome).

Granular cell tumors are predominantly located in the submucosa but may involve the muscularis propria, the muscularis mucosae, and the mucosa. The lesional cells are either plump and epithelioid or spindled with abundant eosinophilic granular cytoplasm (Fig. 30.29) containing numerous periodic acid–Schiff (PAS)-positive, diastase-resistant phagolysosomes. The nuclei may be small and hyperchromatic or large with open chromatin. The cells are typically arranged in nests with intervening fibrous tissue or broad sheets (Fig. 30.30).

Immunohistochemistry and Molecular Findings

Granular cell tumors are uniformly immunoreactive for S100 protein (Fig. 30.31) and NSE. Because of the presence of numerous lysosomes, the panmacrophage marker CD68 is typically immunoreactive.^193,194

Treatment and Prognosis

Essentially, granular cell tumors behave in a clinically benign fashion, and local excision is considered adequate therapy. However, rare examples of malignant granular cell tumor have been described in the soft tissues, and it may be fair to extrapolate these findings to granular cell tumors within other sites (Fig. 30.32). The largest series of malignant granular cell tumors was reported by Fanburg-Smith and colleagues, who evaluated six histologic variables that they considered potentially indicative of malignancy: necrosis, vesicular nuclei with large nucleoli, increased mitotic rate (>2 mitoses per 10 HPFs at 200× magnification), spindling of tumor cells, a high nucleus-to-cytoplasm (N : C) ratio, and pleomorphism. Multivariate analysis showed that spindling, increased N : C ratio, and vesicular nuclei with large nucleoli were the features most closely related to the classification as malignant.¹⁹⁵

Colorectal leiomyomas are described as small polyps, typically with a gross or endoscopically described pedunculated appearance.¹⁹⁷ Esophageal leiomyomas are larger lesions given their mural location, with a median size of 5 cm.²⁵ Histologically, GI leiomyomas, regardless of their site of origin, are characterized by a proliferation of bland, spindle-shaped cells with elongate, cigar-shaped nuclei and brightly eosinophilic cytoplasm. The lesions are of low or moderate cellularity and have a fascicular architecture (Figs. 30.33 and 30.34). Mitotic activity is minimal (0 to 1 per 50 HPFs).

Treatment and Prognosis

Leiomyomas have a benign behavior, and those in the colon and rectum are usually excised easily by endoscopic polypectomy.¹⁹⁷ Rarely, they develop as intramural masses in the rectum and require more invasive treatment. For esophageal leiomyomas, resection via enucleation has been recommended for symptomatic patients, and asymptomatic patients may be observed.

GI leiomyosarcomas have a variable gross presentation as either large lesions that involve the full thickness of the bowel wall or ulcerated polypoid masses that project into the luminal aspect of the GI tract.^38,45 Leiomyosarcomas of the GI tract are indistinguishable histologically from leiomyosarcomas of other sites. They are composed of spindle cells with elongated nuclei and eosinophilic fibrillary cytoplasm arranged in fascicles (Fig. 30.35). Rather prominent atypia with enlarged, hyperchromatic and pleomorphic nuclei is seen, with brisk mitotic activity (Fig. 30.36). Areas of necrosis are common.

Treatment and Prognosis

Based on the limited data that exist, GI leiomyosarcomas are locally aggressive; they metastasize frequently to intraabdominal surfaces and the liver, and rarely to lymph nodes.²⁰¹ Given the rarity of these lesions, minimal criteria for malignancy have not been established. However, malignant features extrapolated from retroperitoneal and abdominal lesions considered to be leiomyosarcomas include a minimum mitotic rate of 1 to 4 per 10 HPFs, some degree of nuclear atypia, and coagulative necrosis.^202,203

Immunohistochemistry and Molecular Findings

Immunohistochemically, fibromatoses frequently express nuclear β-catenin and smooth muscle actin but overall are negative for KIT, DOG1, and desmin.^57,59 The lesions that arise in the setting of FAP are caused by germline mutations in APC, whereas 52% to 89% of sporadic cases have been shown to contain somatic mutations in CTNNB1 (which encodes β-catenin)^206–209 or, rarely, somatic mutations in APC.²¹⁰ Either mutation can lead to the abnormal intranuclear accumulation of β-catenin and is thought to activate the downstream genes that result in tumor formation.

Grossly, most IMTs are lobular or multinodular with a rubbery cut surface; sometimes the presence of calcifications provides a gritty sensation when the lesion is cut. Although most are solitary lesions, multiple nodules restricted to the same anatomic location are found in as many as one third of cases.²¹¹ Histologically, a variety of patterns may be seen, either in the same tumor or in different tumors. Some are composed of cytologically bland, spindle- or stellate-shaped cells arranged in a variably collagenous or myxoid stroma with scattered inflammatory cells, closely resembling nodular fasciitis. Others are composed of a compact proliferation of spindle cells arranged in a fascicular growth pattern (Figs. 30.39 and 30.40). Other foci may be sparsely cellular, with cytologically bland cells deposited in a sclerotic stroma. A lymphoplasmacytic infiltrate is often conspicuous, and small areas of calcification or metaplastic bone may also be observed.

Treatment and Prognosis

Although most of these tumors act in a clinically benign fashion, it is clear that some tumors in this location have a propensity for more aggressive behavior than their extraabdominal counterparts, with recurrence rates of 23% to 37%.^211,213 A small minority of patients develop metastatic disease, usually to the lung and brain.²¹³

GI glomus tumors typically involve the muscularis propria (Fig. 30.41) and are histologically similar to their peripheral soft-tissue counterparts. The distinctive glomus cell has a round uniform shape and a discrete round nucleus surrounded by pale to eosinophilic cytoplasm. The cells are arranged in sheets and nests surrounding hemangiopericytoma-like vascular spaces in a myxoid or hyalinized stroma (Figs. 30.42 and 30.43). Mitotic activity is typically low (<5 per 50 HPFs). Focal atypia and vascular invasion have been observed in rare cases.

Treatment and Prognosis

Most glomus tumors in the GI tract behave in a clinically benign fashion. In the study by Miettinen and associates, follow-up of 32 GI glomus tumors revealed development of metastatic disease in only one patient.²¹⁶ In this case, the primary tumor had cytologic atypia with focal areas of spindle cell morphology, a low mitotic count, and vascular invasion. In long-term follow-up (median 219 months), the remaining patients all have remained disease free.²¹⁶

Grossly, both lesions can have a varied appearance as polypoid mucosal nodules, mucosal ulcerations, or mural and serosal masses with prominent hemorrhage. Angiosarcoma is typified by the presence of spindled or epithelioid cells that form primitive vascular channels that dissect through the tissue. In the GI tract, epithelioid morphology is common and may mimic a poorly differentiated carcinoma (Figs. 30.44 and 30.45).²¹⁷ The presence of only rudimentary lumen formation or rare intracytoplasmic lumina can also confound the diagnosis. Histologically, KS is composed of monomorphic spindle cells that are separated by slitlike vessels and are arranged in vague fascicles. Frequently, PAS-positive, diastase-resistant hyaline globules are present, both intracellularly and extracellularly.

Immunohistochemistry and Molecular Findings

In both angiosarcoma and KS, the vascular endothelial markers CD31, CD34, ERG, and von Willebrand factor are typically expressed (Fig. 30.46). The more poorly differentiated the histology, the greater the likelihood that expression of CD34 will be diminished. It is important to bear in mind that the epithelioid variant of angiosarcoma may show cytokeratin immunoreactivity that may be diffuse, mimicking carcinoma.²¹⁷

Human herpesvirus 8 (HHV-8) has been identified as the causative agent of KS.²²³ Antibodies to latent nuclear antigen (LAN-1), a protein encoded by HHV8, have shown excellent sensitivity and specificity in identifying KS.^224,225

Treatment and Prognosis

Given the rarity of angiosarcoma involving the GI tract, treatment experience is limited. However, localized disease is typically treated with surgical resection, chemotherapy, and radiation therapy. As with angiosarcoma in other sites, the course of disease is rapidly progressive despite aggressive therapy.

The behavior of KS depends on several factors including the immune status of the host, the presence of opportunistic infections, and the stage of the disease. Surgery, other than for tissue diagnosis, is not a mainstay of treatment; rather, chemotherapy and/or radiation therapy are the preferred treatment modalities.

Immunohistochemistry and Molecular Findings

Lipoma is a histologic diagnosis rendered on hematoxylin and eosin–stained slides. Difficulty in establishing a diagnosis of WDLS/ALT can be challenging, especially with small biopsy specimens. That said, the usual clinical scenario is that of a retroperitoneal mass, which can help guide appropriate ancillary testing when one is faced with a lipomatous lesion. WDLS/ALT are typified by giant marker and ring chromosomes^230,231 that contain amplified sequences of 12q13-15, resulting in amplification of the MDM2 gene (12q14) as well as other nearby genes. In cases of potential WDLS/ALT that lack diagnostic cytologic atypia, fluorescence in situ hybridization (FISH) to identify the presence of MDM2 gene amplification can be useful.²³²

Grossly, the lesions may be either small and centered in the mucosa and submucosa or larger (>5 cm) and involve the full thickness of the bowel wall.^238,239 Histologically, most PEComas have a nested architecture and are composed of epithelioid cells with round to oval nuclei, variable nucleoli, and clear or granular eosinophilic cytoplasm (Figs. 30.48 and 30.49). Often, the lesional cells condense around blood vessels. Rarely, a spindle cell component is identifiable.

Treatment and Prognosis

Some PEComas behave in a benign fashion, whereas others follow an aggressive clinical course; currently, there is uncertainty as to which pathologic features may be predictive of a poor outcome. It is believed that non-GI PEComas with malignant behavior commonly contain areas of coagulative necrosis, a high mitotic index, and marked cytologic atypia.^236,239,241 Doyle et al have published a series of 35 GI tract PEComas with outcome; the histologic features in this series that were significantly associated with metastatic disease included marked nuclear atypia, diffuse pleomorphism, and ≥2 mitoses per 10 high power field.²³⁹ Resection is the mainstay of treatment while in patients with metastatic disease, mTOR inhibitors have demonstrated some treatment benefit.²⁴²

The lesions have a mean size of 6.3 cm (range, 1.9 cm to 15 cm), and they arise in the antrum, with one third of cases extending into the duodenum.^243–248 Grossly, the lesions have been described as unencapsulated and lobulated masses that may be submucosal or transmural with serosal extragastric components that may form submesothelial nodules; on cut section, a typical gelatinous or mucoid appearance is appreciated.^243–248 Histologically, these lesions have a multinodular appearance at low power, with discontinuous myxoid nodules typically interspersed within the muscularis propria (Fig. 30.50). The myxoid nodules are relatively hypocellular; intercellular or fibromyxoid matrix separate the component spindle cells, which are bland with eosinophilic cytoplasm and inconspicuous nucleoli (Fig. 30.51). Frequently, a rich arborizing capillary network is appreciated within the stroma (Fig. 30.52). Mitotic figures are scarce; the maximum number reported has been 4 per 50 HPFs.

Treatment and Prognosis

Plexiform fibromyxoma appears to be a benign tumor: Neither recurrences nor metastatic disease have been reported after surgical resection. Miettinen and associates reviewed the largest series with long-term follow-up after excision and found that histologic features typically worrisome for aggressive behavior (e.g., ulceration, mucosal invasion, vascular invasion) were not indicative of an adverse outcome.²⁴⁷

These lesions typically involve the full thickness of the bowel wall, with ulceration of the overlying mucosa (Fig. 30.53). Similar to soft tissue CCS, GI CCS-like tumors may have areas of a nested architecture caused by prominent fibrous tissue septa that divide the tumor. However, other architectural patterns are common, including sheetlike or alveolar growth. The neoplastic cells have eosinophilic to clear cytoplasm and may be round, oval, or spindled. The nuclei have an overall uniform appearance, with vesicular chromatin and prominent nucleoli; mitotic activity is frequent (Fig. 30.54). GI CCS-like tumors often have prominent osteoclast-like giant cells (Fig. 30.55), in contrast to soft tissue CCS, which may have rare multinucleated giant cells with peripherally placed nuclei.²⁵²

Treatment and Prognosis

Although the number of cases with follow-up is limited, GI CCS appears to have an aggressive behavior, with frequent regional lymph node and liver metastases.²⁵²

The most common description is that of a submucosal polypoid mass that has a luminal component. Although monophasic, biphasic, and poorly differentiated morphologies have been described within these lesions involving the GI tract, the monophasic pattern has predominated (Fig. 30.56). This pattern is composed of elongated, uniform spindle cells with tapered nuclei growing in a haphazard arrangement, with alternating relatively hypocellular areas adjacent to hypercellular areas. A variably collagenous background may be present.

Treatment and Prognosis

The prognosis of these lesions is variable and appears to be dependent on tumor size and differentiation, with larger tumors and those containing a poorly differentiated component exhibiting aggressive behaviour.²⁷⁰

The tumors have ranged in size from 3.8 to 15 cm and were described as multinodular with cystic areas. They have shown variable involvement of the gastric wall and may be transmural or limited to the muscularis propria or serosa. Microscopically, they contain varying proportions of epithelial and mesenchymal elements with an overall infiltrative growth pattern. The mesenchymal component consists of a uniform population of mildly atypical, spindled to ovoid cells with blunt-ended nuclei. The epithelial component is variable, with primitive epithelioid clusters merging with the spindled component; more well-developed tubules with open lumina containing eosinophilic inspissated secretions have also been described. Mitotic figures are also variable, with some cases essentially devoid, whereas one case had up to 30 mitotic figures per 50 HPFs. Importantly, neither the epithelial nor the mesenchymal components have shown the requisite atypia to be diagnostic of carcinoma or sarcoma.

Treatment and Prognosis

Given the varied morphology, accurate diagnosis of this lesion on endoscopic biopsy is unlikely, and thorough evaluation of the resection specimen would be required. In the series by Miettinen and colleagues, no recurrent or metastatic disease was observed in their three patients with follow-up at 3.5 years, 5 years, and 14 years. Because of the limited number of cases, the authors suggested that the prognosis of gastroblastoma is uncertain, and this lesion is best considered a low-grade malignancy.²⁷⁹ Wey and coworkers²⁸¹ described a gastroblastoma with evidence of histologically confirmed regional lymph node metastasis as well as clinically evident metastatic disease to the liver and pelvis with peritoneal studding, confirming that some gastroblastomas have malignant potential. After surgical resection of the duodenoblastoma, there was no evidence of recurrence or disease progression at 16 months of follow-up.