Chapter Outline
Gastrointestinal Stromal Tumors (GISTs)
Tumors of Smooth Muscle Origin
Perivascular Epithelioid Cell Tumor
Plexiform Fibromyxoma (Plexiform Angiomyxoid Myofibroblastic Tumor)
Gastrointestinal Clear Cell Sarcoma–Like Tumors
Introduction
Although epithelial neoplasms predominate in the tubal gut, a variety of mesenchymal neoplasms may originate from or secondarily involve the gastrointestinal (GI) tract. Given the rarity of these lesions and the fact that many have overlapping histologic features, their accurate classification can be challenging, especially in the setting of limited endoscopic biopsy material. That said, knowledge of a few key details can help narrow an often wide differential diagnosis. For example, mesenchymal neoplasms have favored anatomic locations within the tubal gut as well as characteristic sites of involvement or origin from the various components of the gastrointestinal tract (mucosa, submucosa, muscularis, or serosa), as described in Table 30.1 . An important consideration when faced with an apparent spindle cell lesion involving the tubal gut is to exclude the possibility of a sarcomatoid or spindle cell carcinoma. In this instance, a panel of cytokeratin stains can usually correctly identify the lesion as a carcinoma. It is also important to remember that gastrointestinal stromal tumors (GISTs) account for as many as 90% of clinically significant mesenchymal neoplasms within the GI tract; for that reason, GISTs will receive major emphasis within this chapter.
| Neoplasm | Most Common Anatomic Location | Most Common Layer Involved within the Gastrointestinal Tract |
|---|---|---|
| Gastrointestinal stromal tumor (GIST) | Stomach (60%), jejunum and ileum (30%) | Muscularis propria and submucosa |
| Schwannoma | Stomach | Muscularis propria and submucosa |
| Gangliocytic paraganglioma | Duodenum | Submucosa |
| Polypoid ganglioneuroma | Colon | Mucosa |
| Mucosal perineurioma | Colon | Mucosa |
| Mucosal Schwann cell hamartoma | Colon | Mucosa |
| Granular cell tumor | Esophagus | Submucosa |
| Leiomyoma | Colon and rectum Esophagus | Muscularis mucosae Muscularis propria |
| Lipoma | Colon | Submucosa |
| Glomus tumor | Stomach | Muscularis propria |
| Inflammatory myofibroblastic tumor | Intraabdominal | Mesentery and omentum |
| Plexiform fibromyxoma | Stomach | Muscularis propria |
| Perivascular epithelioid cell tumor (PEComa) | Colon and rectum | Variable; mucosa and submucosa or entire thickness of bowel wall |
| Clear cell sarcoma–like tumor | Small bowel | Entire thickness of the bowel wall |
Gastrointestinal Stromal Tumors (GISTs)
Although GISTs were once believed to represent smooth muscle neoplasms, it has now been established through ultrastructural and immunophenotypic studies that they arise from either the interstitial cells of Cajal (ICC) or the precursors of those cells. ICCs are present throughout the wall of the GI tract. They function to coordinate peristalsis by generating and propagating electrical slow waves of depolarization. Although the location and density of ICC vary, in most portions of the GI tract, the largest density occurs around the circumference of the myenteric plexus with extension between the inner and outer layers of the muscularis propria ( Fig. 30.1 ).
KIT (CD117) has been identified as a receptor tyrosine kinase that plays a role in the development and maintenance of ICCs : the binding of KIT ligand leads to phosphorylation of signal transduction proteins that modulate cell proliferation and inhibit apoptosis. Mice that are deficient in Kit or in stem cell factor (the normal ligand for Kit ) do not have ICCs and show evidence of intestinal dysmotility. Activating mutations in KIT or in platelet-derived growth factor receptor-α (PDGFRA) have been identified in as many as 80% and 10% of GISTs, respectively, and these mutually exclusive gain-of-function mutations play a fundamental role in GIST development by leading to constitutive activation.
Clinical Features
Approximately 4500 to 6000 GISTs are diagnosed annually in the United States. 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. 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%). Very few cases have been described in the esophagus or appendix. 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.
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. The most common symptoms are GI bleeding with subsequent anemia, abdominal pain, nausea, vomiting, and weight loss. 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. In addition, GISTs can be diagnosed by fine-needle aspiration cytology.
The behavior of GISTs ranges from benign to malignant. In adults, GIST behavior can be predicted by anatomic site, tumor size, and mitotic activity. 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. 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. 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.
Pathologic Features
Gross and Microscopic Features
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. Epithelioid and mixed cell type GISTs are most commonly encountered in the stomach.
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 ).
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 ). 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. 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 ; often, these tumors belong to the subset of GISTs that contain a PDGFRA mutation. 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. 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.
Gene expression profiling studies of GISTs have identified two additional immunostains that appear diagnostically useful. Discovered on GIST 1 ( DOG1 ), also known as anoctamin 1 ( ANO1 ), encodes a calcium-regulated chloride channel protein. The corresponding ANO1/DOG1 antibody appears to be immunoreactive with GISTs regardless of their KIT / PDGFRA mutational status 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. Gene expression studies have shown protein kinase C-theta to be consistently overexpressed in GISTs, and the initial immunohistochemical studies have shown this protein to be sensitive and specific for the diagnosis of GIST.
Molecular Findings
KIT and PDGFRA encode homologous transmembrane glycoproteins that contain an extracellular ligand-binding domain with five immunoglobulin-like loops that function in ligand binding and dimerization. The corresponding cytoplasmic domain is composed of a juxtamembrane domain and a tyrosine kinase domain; the juxtamembrane domain regulates KIT tyrosine kinase activity by inhibiting activity in the absence of KIT ligand. As mentioned previously, mutually exclusive mutations in KIT or PDGFRA have been identified in GISTs (as many as 80% and 10%, respectively). The identification of these mutations in small, incidentally identified GISTs confirms their role as drivers of early tumorigenesis. Although most of these mutations are somatic, germline mutations have been identified in rare families (see GIST Syndromes and Succinate Dehydrogenase–Deficient GISTs ).
Approximately 70% of the mutations involving KIT are identified at the juxtamembrane domain in exon 11, resulting in ligand-independent activation of tyrosine kinase activity and ultimately promoting proliferation and cell survival. The mutations cluster at either the 3′ or the 5′ end of the exon, with the mutation type frequently determining the clinical course. For example, internal tandem duplication mutations have been identified at the 3′ end of exon 11, and these patients typically have gastric GISTs that follow an indolent course. In comparison, an aggressive clinical course with a higher risk of recurrence and shorter survival time has been observed in GISTs harboring deletions involving exon 11. The second most common KIT mutation site, seen in approximately 10% of GISTs, has been identified within exon 9 (distal extracellular domain). Patients whose GISTs harbor this mutation commonly have small bowel involvement and a more clinically aggressive neoplasm. Mutations in exons 13 and 17 affect the tyrosine kinase domain of KIT and are seen in fewer than 5% of sporadic GISTS. The corresponding morphology is typically spindle cell with frequent involvement of the small bowel.
The subset of GISTs that harbor a mutation in PDGFRA most commonly have a missense mutation in exon 18. GISTs containing this mutation almost always involve the stomach and have an epithelioid morphology. Less commonly, PDGFRA exon 14 and exon 12 mutations are seen; exon 14 mutations are also associated with epithelioid morphology, location within the stomach, and a favorable clinical course. In general, PDGFRA mutations are found within GISTs of the stomach and omentum, and these lesions typically have epithelioid morphology. A primary BRAF V600E mutation has been identified in a small subset of GISTs that lack either KIT or PDGFRA mutations.
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 ).
| Tumor | KIT | CD34 | SMA | Desmin | S100 |
|---|---|---|---|---|---|
| GIST | + (95%) | + (70%) | + (30-40%) | Very rare | Very rare |
| Schwannoma | − | − | − | − | + |
| Fibromatosis | − | Very rare | + | Very rare | − |
| Smooth muscle neoplasms | − | + (10-15%) | + | + | Very rare |
| Inflammatory myofibroblastic tumor | − | − | + | + | − |
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.
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, 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. 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. 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.
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. These lesions are typically KIT negative, although one group has reported KIT immunoreactivity in these tumors.
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, 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.
| Tumor | KIT | CD34 | Cytokeratin | S100 | Neuroendocrine Markers |
|---|---|---|---|---|---|
| GIST | + (95%) | + (70%) | Very rare | Very rare | − |
| Melanoma | + (up to 50%) | − | Very rare | + | − |
| Neuroendocrine tumor | − | − | + | Very rare | + |
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. 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.).
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. 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 cases ; current FDA-approved labeling includes use in the adjuvant setting after complete gross resection of GISTs. 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. Other studies suggest that patients with an exon 9 KIT mutation benefit from a higher dose of this drug. Approximately 50% of GIST patients being treated with imatinib will acquire a secondary mutation that confers tumor resistance to imatinib, 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 ), 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. 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 mm 2 . For modern wide-field microscopes with wide-field eyepieces, the mitotic count correlating with the total area of 5 mm 2 is obtained from 20 high-power fields (HPFs).
| Tumor Parameters | Risk of Progressive Disease * (%) | ||||
|---|---|---|---|---|---|
| Mitotic Index | Size | Gastric | Duodenum | Jejunum/Ileum | Rectum |
| ≤5 per 5 mm 2 | ≤2 cm | None (0%) | None (0%) | None (0%) | None (0%) |
| >2 to ≤5 cm | Very low (1.9%) | Low (8.3%) | Low (4.3%) | Low (8.5%) | |
| >5 to ≤10 cm | Low (3.6%) | Insufficient data | Moderate (24%) | Insufficient data | |
| >10 cm | Moderate (10%) | High (34%) | High (52%) | High (57%) | |
| >5 per 5 mm 2 | ≤2 cm | None † | Insufficient data | High † | High (54%) |
| >2 to ≤5 cm | Moderate (16%) | High (50%) | High (73%) | High (52%) | |
| >5 to ≤10 cm | High (55%) | Insufficient data | High (85%) | Insufficient data | |
| >10 cm | High (86%) | High (86%) | High (90%) | High (71%) | |
* Based on long-term follow-up of 1055 gastric, 629 small intestinal, 144 duodenal, and 111 rectal GISTs. Progression is defined as metastasis or tumor-related death.
Other factors that have been reported to be associated with poor outcome include tumor necrosis, mucosal invasion, and ulceration. Tumor rupture, either spontaneous or at the time of surgery, increases the risk of recurrence with intraabdominal seeding. Patients whose complete resection is complicated by tumor rupture have a significantly shortened survival time, compared with patients with complete resection without tumor rupture.
GIST Syndromes and Succinate Dehydrogenase–Deficient GISTs
Although most GISTs are sporadic, almost 5% are associated with a tumor syndrome, including familial GIST syndrome, neurofibromatosis type 1 (NF1), the Carney triad, and Carney-Stratakis syndrome.
Familial GISTs arise from germline mutations in exons 8, 11, and 13 of KIT and in exon 12 of PDGFRA , identical to the mutations identified in sporadic GISTs. GISTs will develop in almost all patients who harbor these germline mutations, typically within the stomach and small bowel. These lesions most commonly develop in middle-aged patients, but they have been documented in patients as young as 18 years. Other clinical manifestations of KIT activation, such as mastocytosis (urticaria pigmentosa) and hyperpigmented macules on the skin of the perineum, axilla, hands, and face, may also be found in these patients, as well as a background of diffuse ICC hyperplasia in the bowel wall. This latter finding raises the possibility of a hyperplasia to neoplasia sequence, with additional clonal genetic alterations needed to progress from ICC hyperplasia to GIST.
GISTs arising in patients with NF1 have been recognized for some time and may even be the most common GI tract tumor associated with NF1. As estimated from a series of duodenal GISTs reported by the AFIP, patients with NF1 have an increased risk for GIST of as high as 180-fold compared with the general population. Most NF1-associated tumors arise in the small bowel, often in a multifocal fashion. Distinguishing patients with NF1 and multiple GISTs from patients with sporadic GIST and multiple metastatic nodules is of major clinical significance. Most NF1-associated GISTs are relatively small, are mitotically inactive, and follow an indolent course. Therefore, the index of suspicion for NF1 should be high when one encounters multiple small GISTs, particularly in the small bowel. Diffuse ICC hyperplasia is often seen in the myenteric plexus adjacent to these tumors. The pathogenesis of NF1-associated GISTs appears to be different from that of sporadic GISTs because several studies have shown a very low frequency of associated KIT or PDGFRA mutations in these tumors.
The identification of GIST arising in the setting of a germline mutation in the SDH complex family has led to the recognition of a distinctive group of SDH-deficient GISTs that are found in the stomach and share histologic, immunohistochemical, and clinical similarities. These GISTs arise in the setting of Carney-Stratakis syndrome, Carney triad, pediatric GIST, or “pediatric-type” GISTs in adults. They have a multinodular or plexiform growth with lobules of tumor separated by bands of smooth muscle, are hypercellular, and have epithelioid cytomorphology. In contrast to conventional GISTs, which show granular cytoplasmic staining for succinate dehydrogenase subunit B (SDHB), GISTs arising in these settings show a loss of immunohistochemical staining for SDHB. Clinically, these tumors metastasize to lymph nodes and are insensitive to imatinib mesylate; however, despite recurrences and distant metastases, they typically follow a more indolent clinical course.
Carney-Stratakis syndrome is characterized by paraganglioma and gastric GISTs. It has been shown to result from a germline mutation in one of the SDH complex subunit genes and is inherited in an autosomal dominant manner. GISTs arising in this setting lack KIT and PDGFRA mutations.
Carney triad, which includes epithelioid gastric GISTs, paraganglioma, and pulmonary chondroma, occurs exclusively in the stomach and usually arises in much younger patients with a striking female predilection (approximately 85%). Although mutations in KIT and PDGFRA have not been identified so far in this subset of GISTs, they typically stain with KIT. Recent literature suggests that GISTs in the setting of Carney triad are quite different from sporadic GISTs.
GISTs may arise in children, albeit rarely, accounting for fewer than 1% of all GISTs. In the pediatric population, GISTs predominate in girls, are usually located in the stomach, and are frequently multifocal with epithelioid or mixed morphology. These lesions often metastasize to lymph nodes, and although they stain with KIT, they often lack mutations in KIT and PDGFRA ; approximately 50% harbor mutations in SDH complex subunit genes. Approximately 3% of adults with GISTs have so-called “pediatric-type” GISTs, which are SDH-deficient; this subtype accounts for roughly 7% of gastric GISTs in adults. These tumors have histomorphology identical to that seen in pediatric patients and a similar clinical course, with nodal metastases, imatinib resistance, and an overall indolent course.
Tumors of Neural Origin
Schwannoma
Clinical Features
Schwannomas are thought to arise from the myenteric plexi and are most commonly encountered in the stomach, followed by the colon and rectum. These lesions have been rarely described in the esophagus or small intestine. Schwannomas have been documented in patients as young as 18 years, but they arise most commonly during middle to late adulthood, with a peak in the sixth decade. The largest series evaluating gastric schwannomas documented a female predominance, with a 1 : 4 male-to-female ratio. Schwannomas typically involve the muscularis propria and submucosa, with frequent ulceration of the overlying mucosa. Those arising in the stomach are usually a mural mass, whereas schwannomas in the colon and rectum often manifest as ulcerated polypoid lesions. The presenting clinical symptoms are typically specific to site. Schwannomas arising in the colon and rectum frequently manifest with rectal bleeding, abdominal pain, and colonic obstruction, whereas those arising in the stomach manifest with gastric discomfort and bleeding. That said, it is not unusual for gastric schwannomas to be identified incidentally during other procedures.
Pathologic Features
Gross and Microscopic Findings
Schwannomas are grossly well circumscribed, round or ovoid mural lesions that are devoid of a true capsule. Grossly, the lesions are homogenous and firm with a tan to yellow cut surface without areas of cystic change or necrosis. Histologically, GI schwannomas are quite different from schwannomas of the central nervous system and peripheral soft tissue. The nuclear palisading, Verocay bodies, and hyalinized vessels typically seen in peripheral schwannomas are essentially absent in GI schwannomas. Also, unlike their soft tissue counterparts, GI schwannomas have a discontinuous cuff of lymphoid cells, often with germinal center formation at the periphery of the lesion ( Fig. 30.15 ). The cellularity of these lesions varies in different portions of the tumor because of the amount of collagenous or myxoid stroma present. Some areas may be highly cellular and contain abortive fascicles or whorls ( Fig. 30.16 ); other, less cellular areas may have a prominent hyalinized or myxoid stroma imparting a microtrabecular pattern. Scattered lymphocytes and plasma cells are often found within the tumor. The spindle cells composing the lesions have elongated, hyperchromatic nuclei with tapered ends, occasional intranuclear inclusions, and an inconspicuous nucleolus ( Fig. 30.17 ). Scattered cells with nuclear atypia may be present, but mitotic activity is usually low (<5 mitoses per 50 HPFs); rarely, mitotic activity can be greater than 10 per 50 HPFs. Atypical mitotic figures should not be identified. Although the lesion is circumscribed, it can infiltrate the muscularis mucosae and entrap epithelium.
Although GI schwannomas are predominantly spindled, rare cases of epithelioid schwannoma have been described with the cells arranged in cords, sheets, and even a pseudoglandular pattern. Another rare histologic variant of schwannoma described within the GI tract is the microcystic/reticular schwannoma. This variant is different from the conventional GI schwannoma in that the usual peripheral lymphoid cuff is lacking and the lesions are composed of anastomosing strands of tumor cells with either round, oval, or tapered nuclei and eosinophilic cytoplasm set within a myxoid, fibrillary, or collagenous stroma.
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. GI schwannomas lack an association with neurofibromatosis, with only one reported instance of identification of a gastric schwannoma in a patient with NF1. In contrast to GIST, which falls in the differential diagnosis, GI schwannomas lack KIT and PDGFRA mutations.
Treatment and Prognosis
Studies of GI schwannoma with follow-up have shown a benign behavior with no malignant variants or evidence of metastasis identified. Complete excision and follow-up is the preferred management of this lesion.
Gangliocytic Paraganglioma
Clinical Features
The term gangliocytic paraganglioma ” was coined by Kepes and Zacharias in 1971 when they recognized features of both paraganglioma and ganglioneuroma within the same lesion. Gangliocytic paraganglioma is a rare tumor that most commonly arises in the second portion of the duodenum. However, examples have been described in the esophagus, stomach, appendix, pancreas, nasopharynx, bronchus, and lung. Common presenting symptoms include GI bleeding, abdominal pain, and obstruction. Rarely, cases have been identified incidentally at endoscopy or even at autopsy.
Pathologic Features
Gross and Microscopic Findings
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 or distant metastases have been reported. It has been suggested that prominent nuclear pleomorphism, mitotic activity, and an infiltrative margin raise concern for aggressive behavior, 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.
Ganglioneuroma and Ganglioneuromatosis
Clinical Features
Ganglioneuromas are benign Schwann cell and ganglion cell proliferative lesions that may occur within the GI tract. These lesions may manifest as mucosa-based polyps that arise as sporadic solitary polypoid ganglioneuromas, as a ganglioneuromatous polyposis with multiple polyps involving the lower and upper GI tract (e.g., in the setting of Cowden syndrome), or as diffuse ganglioneuromatosis that may involve the deeper aspects of the bowel wall (e.g., in multiple endocrine neoplasia type IIb [MEN IIb]) and NF1). Solitary polypoid ganglioneuroma is usually identified incidentally at the time of colonoscopy; accordingly, it is seen most often in the middle-aged to older adult population who are undergoing screening colonoscopy. In the setting of Cowden syndrome, multiple polypoid ganglioneuromas are seen in addition to several other polyp types, including hyperplastic polyps, adenomas, inflammatory polyps, and hamartomatous polyps. Diffuse ganglioneuromatosis may occur across a wide age range, typically with vague symptoms including abdominal pain, constipation, or diarrhea. Given the multiple cancer risks associated with Cowden syndrome, MEN IIb and NF1, it is prudent to mention the association of these syndromes when diagnosing a ganglioneuroma or ganglioneuromatosis, so that appropriate genetic testing may be initiated if clinically warranted.
Pathologic Features
Gross and Microscopic Findings
Solitary polypoid ganglioneuromas are usually sessile polyps measuring less than 2 cm. 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. 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.
Immunohistochemistry and Molecular Findings
The ganglion cells are immunoreactive for NSE, and neurofilament protein highlights their processes; the Schwann cells are immunoreactive for S100 protein.
As mentioned earlier, these lesions raise the possibility of MEN IIb, NF1, or Cowden syndrome with germline mutations identified in RET , NF1, and PTEN, respectively. To date, no recurrent molecular alteration has been identified in sporadic polypoid ganglioneuromas.
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 Perineurioma
Clinical Features and Background
The mucosal polypoid lesion that is now referred to as a mucosal perineurioma represents what was described in the earlier literature as a “benign fibroblastic polyp.” Mucosal perineuriomas are benign nerve sheath tumors composed of perineurial cells and are commonly identified incidentally at colonoscopy. These small, sessile lesions appear to be female predominant and have a predilection for the rectosigmoid.
Pathologic Features
Gross and Microscopic Findings
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 ).
Immunohistochemistry and Molecular Findings
Mucosal perineuriomas express perineurial markers, including epithelial membrane antigen (EMA), GLUT1, claudin-1, and vimentin, although EMA staining may be very weak. Mucosal perineuriomas are negative for KIT, S100 protein, smooth muscle actin, and desmin.
The serrated epithelium in these lesions has been shown to harbor the V600E BRAF mutation typical of sessile serrated polyps and hyperplastic polyps. Based on this molecular finding and the frequent association of perineuriomatous stroma within serrated polyps, some authors have suggested that the stroma represents a reactive phenomenon driven by the serrated epithelium.
Treatment and Prognosis
Mucosal perineuriomas are benign, and recurrences have not been documented.
Mucosal Schwann Cell Hamartoma
Clinical Features
Mucosal Schwann cell hamartomas are sporadic polypoid lesions that have been recognized in the colon. They are asymptomatic and are usually identified on screening colonoscopy, predominantly within the sigmoid and rectum. They are most commonly detected in middle-aged to elderly patients, the same group that tend to undergo colonoscopy. There is a female predominance.
Pathologic Features
Gross and Microscopic Findings
Mucosal Schwann cell hamartomas have a mean size of 2.5 mm and typically are described as small sessile polyps. 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.
Treatment and Prognosis
Mucosal Schwann cell hamartoma was first fully described in 2009 by Gibson and Hornick ; 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 Tumor
Clinical Features
Most granular cell tumors of the gut arise within the esophagus, but they may arise anywhere throughout the GI tract. Occasionally, one encounters multiple lesions arising in different portions of the GI tract, either metachronously or synchronously.
Pathologic Features
Gross and Microscopic Findings
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 ).
