Fig. 5.1.
Histologic and ultrasound correlation of the GI wall concentric layers. 1. Mucosa/interface (clear line); 2. Deep mucosa (lamina propria, muscularis mucosa) (dark line); 3. Submucosa (clear line); 4.Muscularis propria (dark line); 5. Serosa/adventitia (clear line).
The cytopathologist must be familiar with the EUS anatomy of the GI wall, because some intramural masses may be related to certain layers, favoring one diagnosis over the other, i.e., a gastrointestinal stromal tumor (GIST ) generally originates in layer 4 (muscularis propria) (Fig. 5.2). Also important is the echogenicity of the lesion, i.e., hypoechoic (the most common pattern), anechoic, or hyperechoic, which conveys a distinct differential diagnosis (Fig. 5.3). Not less important is the topographic location of the lesion in the GI tract, as seen in Table 5.1.
Fig. 5.2.
GIST arising from layer 4 (muscularis propria) of the stomach.
Fig. 5.3.
Echogenicity by EUS: hyperechoic (a), hypoechoic (b), and anechoic (c).
Table 5.1.
Where in the gut is the lesion?
Lesion | Most common location(s) |
|---|---|
GIST | Stomach, small bowel |
Smooth muscle neoplasms | Esophagus, stomach |
Signet ring cell carcinoma (diffuse) | Stomach, esophagus |
Eosinophilic gastroenteritis | Small bowel, stomach |
Congenital cysts | Esophagus, stomach |
Heterotopic pancreas | Duodenum, stomach |
Granular cell tumor and schwannoma | Esophagus, stomach |
Endocrine cell tumor | Rectum, stomach, small bowel |
Glomus tumor | Stomach |
Brunner’s gland heterotopias | Stomach |
Brunner’s gland hamartoma | Duodenum |
Lymphoma | Stomach, small bowel |
Combining these characteristics (layer of origin/wall location, GI tract location, and ultrasound pattern) narrows the differential diagnosis of intramural lesions of the GI tract, as seen in Table 5.2. On note, EUS alone is 30 and 67 % accurate to predict neoplastic and nonneoplastic small (< 2 cm) intramural (layers 2 and 3) lesions, respectively, and due to this poor accuracy , these lesions are treated by endomucosal resection with subsequent histopathologic diagnosis. However, depending on the location and size of lesions and operator skill, these lesions may be evaluated by EUS-FNA , avoiding unnecessary resection for a benign lesion such as pancreas rest. Larger intramural lesions (> 2 cm) should be sampled by EUS-FNA and the rate of nondiagnostic samples is inverse to mass size (68 % in < 2 cm, 13 % in 2–5 cm, and 6 % in > 5 cm).
Table 5.2.
Where in the GI wall is the lesion?
EUS Layer | Lesions and differential diagnosis |
|---|---|
Layer 2 (lamina propria, muscularis mucosa) | Leiomyoma from the muscularis mucosa, neuroendocrine tumor , possibly GIST |
These lesions are rare and almost always hypoechoic | |
Due to the superficial nature, these lesions may be accessible to endoscopic mucosal resection or repeated “tunnel” forceps biopsy | |
Layer 3 (submucosa) | If lesion is hypoechoic: neuroendocrine tumor , pancreas rest, granular cell tumor, schwannoma. Cysts are anechoic; may be hypoechoic |
If lesion is hyperechoic: lipoma, lymphoma, Brunner’s gland adenoma, fibroma, and some metastasis | |
Layer 4 (muscularis propria) | If lesion is hypoechoic: GIST , schwannoma , smooth muscle tumor, metastasis ; others are rare |
Hyperechoic lesions such as lipoma are rare in Layer 4 |
We encourage the pathologist to be aware of the EUS characteristics, relationship to the wall layer, and location of the lesion at time of evaluation to narrow the differential diagnosis.
Intramural Lesions of the Esophagus and Upper GI Tract: A Pattern-Based Diagnosis
EUS is used for diagnosing a variety of GI lesions that cannot be reliably visualized by CT or MRI. The cost-effectiveness of EUS is maximized when EUS-FNA is used to characterize GI intramural lesions and guide the most appropriate therapy. EUS-FNA is the preferred modality for evaluating and providing an accurate diagnosis, particularly in patients for whom a previous endoscopic forceps biopsy was unsuccessful in establishing a diagnosis. The sensitivity , specificity , and diagnostic accuracy of EUS-FNA in diagnosing such lesions are 89, 88, and 89 %, respectively. In contrast, endoscopic forceps biopsy gives a definitive tissue diagnosis in 60 % of such cases. Sampling or interpretative errors can result in both false-negative (i.e., gastric lymphoma and GIST ) and false-positive (i.e., endometriosis, duodenal diverticulum with muscle hyperplasia, and ectopic pancreas) diagnoses.
In our practice, the initial approach to intramural lesions is with a 25-gauge needle. When EUS is consistent with a mesenchymal neoplasm and rapid interpretation supports such an impression, it is our practice to have the lesion sampled with a 19-gauge needle to obtain material for cell block or to attempt core biopsy (Fig 5.4).
Fig. 5.4.
The initial approach of a mural lesion of the GI tract is with a 25-gauge needle. If material is limited or no material is obtained, then proceed with a 19-gauge needle to obtain not only small tissue fragments for immediate interpretation but also material for a cell block and perform special studies including immunohistochemistry or even molecular tests.
Cytomorphologically, the intramural masses of the esophageal and GI tract can be classified into spindle- and epithelioid-cell patterns. The latter pattern can be subdivided into large- and small-cell patterns. We will describe the main entities to be considered in the differential diagnosis of these cytologic patterns.
The Spindle-Cell Pattern
GIST, the most common intramural tumor is the prototype of this pattern. The final diagnosis and differentiation from other spindle-cell tumors are essentially based on immunohistochemical analysis applied to cell blocks, as listed in Table 5.3.
Table 5.3.
GIST : differential diagnosis by immunohistochemistry
GIST | SMT | Schwannoma | SFT | IPT | Fibromatosis | Neuroendocrine tumors | |
|---|---|---|---|---|---|---|---|
CD117 | + memb (95 %) | − | − | − | − | − or variable cytoplasmic + (Ab-dependent) | − in low-grade + focal in high-grade |
DOG-1b | +a | − | − | − | − | − | − |
CD34 | + diffuse (70 %) | + (10 %) | Rarely focal | + | − | − | − |
Desmin | + focal (20 %) | + strong | − | − | − | Variable focal | − |
SMA | + focal variable | + strong | − | − | Variable | Variable focal | − |
S-100 protein | + (5 %) | − | + | − | |||
β-catenina | − | − | + nuclear | ||||
ALKa | + (60 %) | ||||||
Synaptophysin & chromogranina | +a |
Gastrointestinal Stromal Tumor (GIST )
GIST is the most common primary nonepithelial neoplasm of the gut. It has a phenotype similar to that of the interstitial cells of Cajal (ICCs), and occurs predominantly in males with a median age of 60 years. However, it can occur in children, with a predilection for girls. The stomach is the most common organ of origin (60–70 %) (Fig. 5.5a) followed by the small bowel (20–30 %), esophagus , colon, rectum , mesentery, and omentum (all < 10 %). In general, GISTs have an unpredictable behavior; however, GISTs arising in the stomach are less likely to be malignant than those arising in the small bowel, peritoneum, or omentum. Prognosis is based on three parameters: size, tumor location, and proliferation (mitotic) index. GIST can occur in patients with type I neurofibromatosis, pulmonary chordomas, and/or extraadrenal paragangliomas. When possible, complete surgical resection of the tumor is the treatment of choice for localized GIST; however, for inoperable or metastatic tumors, imatinib mesylate (Gleevec®), a c-kit tyrosine kinase receptor inhibitor approved by the FDA in February 2002, is the drug of choice. Sunitinib malate was approved by the FDA in February 2006 for the treatment of patients with recurrent GIST that developed secondary resistance to, or cannot tolerate Gleevec®. The recently FDA-approved (February 2013) regorafenib (Stivarga®), an oral multikinase inhibitor that targets angiogenic, stromal, and oncogenic tyrosine kinase receptors may be used in patients with advanced GIST that cannot be removed and do not respond to imatinib and sunitinib.
Fig. 5.5.
Gastrointestinal stromal tumor, spindle-cell pattern. Endoscopic view of a submucosal mass in the gastric body (a). Tissue section shows fascicles of bland-appearing spindle cells with blunt ends arranged in a palisade fashion mimicking a neurogenic origin (b). Immunostains are positive for CD117 (c), CD34 (d), and DOG1 (e). Smears show interlacing fascicles of uniform spindle cells with slight cell dissociation in the periphery of the cell aggregates (f); nuclear palisading is evident (g). Fragments of normal submucosa (h) and smooth muscle (i) are less cellular and exhibit less cell dissociation. EUS shows a hypoechoic and heterogeneous intramural mass with smooth and well-defined margins (j). Ultrasound features suggestive for an aggressive behavior include hyperchoic foci (k), irregular tumor margins (l), and cystic degeneration (m). (b, H&E stain intermediate magnification; c–e Immunoperoxidase stain intermediate magnification; f Papanicolaou stain intermediate magnification; g–i DiffQuik stain intermediate magnification).
Histopathology
Most GISTs (approximately 70 %) have a spindle-cell pattern (Fig. 5.5b). Tumors are composed of interlacing fascicles or whorls of bland-appearing spindle cells with elongated nuclei showing blunt tips, and slightly eosinophilic cytoplasm. The stroma may be sclerosed, hyalinized, or calcified. Tumor cellularity is variable and pleomorphism is uncommon, but is associated with malignant potential. Prognostic factors for aggressive behavior include size, mitotic index (number of mitoses per 50 high-powered fields (HPF)), mucosal invasion and/or ulceration, and cystic or necrotic areas within the tumor, all best assessed in resected specimens. Based on tumor size and mitotic count per 50 HPF, the National Institute of Health proposed a consensus to classify GISTs into very low, low, intermediate, and high risk categories. GISTs of < 2 cm and < 2 mitotic index have a very low risk of aggressive behavior; GISTs of > 5 cm and > 5 mitotic index as well as > 10 cm or > 10 mitotic index regardless of mitotic index or size respectively have a high risk. Proliferation markers such as Ki67 > 10 % can be more objective than the mitotic index. Ezrin, p16, low apoptosis, high telomerase, and vascular endothelial cell markers have been described as predictors of aggressive behavior. Although most patients with intermediate or lower risk behave in a benign manner, less than 10 % of GISTs in such patients will have an unpredicted behavior. Therefore, no lesion can be definitely labeled as benign. For the same reason, all GISTs should be excised, and patients are carefully and regularly followed indefinitely. Special mention goes to colonic GIST which is more common and more aggressive than leiomyosarcoma , and is usually identified late in the course of the disease, underscoring the usefulness of immunohistochemistry in the diagnosis.
Gastrointestinal autonomic nerve tumor (GANT), originally described as plexosarcoma (based on the ultrastructural resemblance to cells of the autonomic nervous system), is a phenotypic variant of GIST . It has the same immunohistologic phenotype (CD117 +) and genotype (c-kit gene mutation) as does GIST.
Normally, there are CD117 + cells in the omentum, just underneath the mesothelial lining, that may be the origin for extragastrointestinal (E) GISTs. EGISTs are more likely to have epithelioid cell morphology, arise in the omentum and mesentery, behave like small-bowel tumors, and have CD117 expression similar to GISTs. The pattern of c-kit and platelet-derived growth factor receptor-α (PDGFRA) gene mutations is similar to GIST and plays an important role in tumorigenesis of EGIST. Thus, Gleevec® seems to provide a therapeutic strategy for advanced EGIST. It should be stressed that GISTs should be defined by virtue of any degree of association with the muscularis propria of the gut (no matter how minimal), and not by localization of the bulk of the tumor; keeping this in mind, Agaimy et al. identified that only 1.5 % of 200 tumors initially considered to be EGISTs after extensive pathologic exam were found to be truly EGISTs.
Immunoprofile
CD117 cytoplasmic and/or membranous positivity is detected in 95 % of GISTs (the pattern is usually cytoplasmic with membranous accentuation). CD34 (a hematopoietic stem-cell marker) shows diffuse strong cytoplasmic staining in 70 % of cases, with the least positivity in small-bowel tumors; colonic GISTs rarely stain with CD34 (Table 5.3). Staining with other markers is more variable: BCL-2 (80 %), smooth-muscle actin (SMA, 40 %), S-100 protein (5 %). Positive CD117 and CD34 staining in the appropriate clinical context with compatible microscopic features confirms the diagnosis of these tumors (Fig. 5.5c, d). Appropriate positive and negative controls must be run simultaneously. h-caldesmon (an actin-binding cytoskeleton-associated protein) and calponin are positive in 80 and 25 % of GISTs, respectively.
Approximately 5 % of GISTs have a negative CD117 phenotype. These are histologically and clinically similar to CD117( + ) GISTs; however, they are more likely to have epithelioid cell morphology, contain PDGFRA oncogenic mutations, and arise in the omentum/peritoneal surface as EGISTs. It has been shown that some CD117(−) GISTs contain Gleevec-sensitive PDGFRA or c-kit gene mutations and may still benefit from Gleevec® therapy.
New immunomarkers such as CD171 (L1), a cell adhesion molecule, and DOG1 (Fig. 5.5e), a protein of unknown function, are positive in GIST and are expressed independently of c-kit or PDGFRA gene mutations; they are useful for the diagnosis of CD117(−) GIST. CD117 and DOG1 each stain > 95 % of GISTs, and stain all GISTs when both are used together.
Not every CD117( + ) tumor is a GIST ; i.e., synovial sarcoma, malignant fibrous histiocytoma, dermatofibrosarcoma protuberans, and vascular tumors, among others, may react at least focally with antibodies directed against CD117. Fortunately, most do not occur in the gut. Metastatic spindle-cell melanoma can be distinguished based on clinical and imaging findings as well as on S100 protein positivity. DOG1 is rarely expressed in other mesenchymal tumors.
Molecular Profile
Genes encoding for the c-kit receptor and PDGFRA of the tyrosine kinase subfamily are located in chromosome 4 and are important in the pathogenesis of GIST . KIT (a transmembrane glycoprotein) has a receptor for stem cell factor (SCF), and it has been shown that mice deficient in KIT or SCF fail to develop ICCs, indicating that this axis is critical for the development of these pacemaker cells. Binding of SCF ligand to KIT produces dimerization of KIT, which activates tyrosine kinase, resulting in phosphorylation of substrates and activation of signal transduction cascades. This leads to well-controlled cell functions (proliferation, adhesion, apoptosis, and differentiation) of hematopoietic progenitor cells, melanocytic cells, mast cells, germ cells, and ICCs. KIT glycoprotein is recognized by the CD117 antibody. CD117 is expressed in ICCs and in GISTs, substantiating the hypothesis that GISTs arise from or share a common stem cell with the ICCs and providing a new specific and sensitive marker for the diagnosis of GIST.
Most GISTs express activated KIT oncoproteins, and thus the activation does not depend on binding SCF ligand (in contrast to KIT glycoprotein). KIT oncoproteins in GISTs commonly have oncogenic mutations of the c-kit juxtamembrane domain, exon 11, and less commonly exons 9, 13, and 17, which results in a ligand-independent KIT dimerization and activation of the tyrosine kinase, followed by receptor autophosphorylation, activation of intracellular signaling cascades, and ultimately aberrant cell proliferation, apoptosis, chemotaxis, and adhesion. It is interesting to note that various mutations have different responses to Gleevec®, i.e., c-kit mutations (exon 11, excellent response; exon 9, intermediate response; exon 17, resistant) and PDGFRA mutations (exon 12, sensitive; exon 18, poor response). GISTs exhibit typical activating mutations of c-kit and less commonly in the PDGFRA protooncogenes; however, 15 % are negative for these two mutations. Pediatric GISTs often have no c-kit (exons 9, 11, 13, and 17) or PDGFRA (exons 12, 14, and 18) mutations (wild type). Some wild-type GISTs may show c-kit exon 8 mutations and be imatinib-sensitive. Wild-type GISTs may have various oncogenic mutations such as neufibromatosis (NF) type I, RAS, and BRAF V600E (13 % of wild-type cases) genes. Of note, 7 % of patients with NF1 develop GISTs, mainly in the small bowel. The recently described succinate dehydrogenase- (SDH) deficient GISTs are always wild-type, show an epithelioid morphology, and often occur in association with the Carney triad.
Lastly, molecular analysis of GISTs, looking for the various mutations, can be done in paraffin-embedded cell-block samples obtained by EUS -FNA . This molecular analysis is a step forward in the diagnosis from a small sample. We should emphasize that since type and dose of tyrosine kinase inhibitors depends on the mutation identified, routine genotyping is strongly recommended for appropriate GIST management.
FNA Findings
EUS -FNA cytology smears show variable numbers of spindle cells arranged in fairly cellular and cohesive short fascicles or whorls. The spindle cells are uniform and show indistinct cytoplasmic borders, giving a syncytial aspect to the fragment. Nuclei are elongated, with blunt ends and small inconspicuous nucleoli in a fibrillary background stroma. Variable numbers of single stripped nuclei are usually scattered mostly at the periphery of the cell fragments. The spindle cells are aligned in a Schwannian pattern, with prominent nuclear palisading mimicking schwannoma (Fig. 5.5 f, g). The stromal collagen is minimal. Mitosis, necrosis, and cell pleomorphism may be indicators of aggressive behavior. The cell block usually shows a densely cellular spindle-cell pattern and may show juxtanuclear vacuoles and palisading. Juxtanuclear vacuoles are seen in ~ 5 % of all GISTs, and particularly in gastric tumors. It has been observed that malignant gastric GISTs tend to lose these vacuoles.
GISTs can be misinterpreted as benign fibrous tissue or fragments of smooth muscle of the GI wall that one might encounter in a routine transmural EUS -FNA (Fig. 5.5h, i). Larger cell size and haphazardly arranged cell fascicles are clues in favor of GIST over normal gut wall fragments. When smears and cell blocks are combined, EUS-FNA is accurate in the diagnosis of GIST. The accuracy of EUS and EUS-FNA for the diagnosis of probably malignant GIST is 78 and 91 %, respectively. EUS-FNA with Ki-67 immunoshistochemical stain is an accurate, sensitive, and specific method for differentiating potentially aggressive from less aggressive GISTs. In our experience, GISTs, schwannomas, and leiomyomata share a similar cytomorphology, and only cell-block immunostain results help to differentiate one from the other. The differential diagnosis also includes fibromatosis (nuclear catenin + ), sclerosing mesenteritis (nuclear catenin −), inflammatory myofibroblastic tumor, and spindle cell-neuroendocrine tumor s (synaptophysin + and chromogranin + ); the distinction is based mainly on immunohistochemistry (Fig. 5.6a–e, Table 5.3).
Fig. 5.6.
Spindle-cell neuroendocrine tumor. A trabecular and nested pattern composed of bland-appearing spindle cells embedded in a dense and fibrillary stroma (a, b). Histopathology (c) recapitulates the EUS-FNA pattern, which stains positive for synaptophysin (d). Ultrasound features a hypoechoic heterogeneous solid mass involving the submucosa with no involvement of the muscularis propria (e). (a, b DiffQuik stain, low- and high-magnification; c, H&E stain, low magnification; d Immunoperoxidase stain, high magnification).
EUS Features
Lesions are hypoechoic and covered by sonographically and endoscopically normal mucosa (occasionally with small areas of ulceration) (Fig. 5.5j). Generally, a point of attachment is identified between the mass and the muscularis propria (Fig. 5.2); however, this may at times be unapparent. The EUS features that predict an adverse behavior include hyperechoic foci, irregular margins, cystic spaces, and size > 5 cm (Fig. 5.5k–m).
Leiomyoma and Leiomyosarcoma
Although rare elsewhere in the GI tract, leiomyomas are the most common esophageal mesenchymal neoplasms. Leiomyomas are 5 times more common than GISTs in the esophagus and 50 times less common than GISTs in the stomach and small bowel. Gastric and small-bowel smooth-muscle tumors are exceedingly rare (Fig. 5.7a). Most leiomyomas of the GI tract are sporadic but they may occur in association with Alport syndrome (hearing loss and renal disease) and multiple endocrine neoplasia (MEN) type 1 syndrome (pituitary and parathyroid adenomas, and pancreas neuroendocrine tumor ). Most, if not all esophageal leiomyomas involve the entire esophageal wall and are clinically indolent intramural tumor masses with no tumor-related mortality. Patients usually seek help for dysphagia. However, leiomyomas are also found incidentally during endoscopic work-up for other causes. Colorectal leiomyomas are occasionally found incidentally as polyps on screening colonoscopy and are more common than colorectal GISTs.
Fig. 5.7.
Leiomyoma and leiomyosarcoma. Endoscopic view of a gastric fundus submucosal mass (a). Note the eosinophilic glassy stroma surrounding spindle cells (b). Smooth-muscle actin stain is positive in leiomyoma (c) and leiomyosarcoma (d). The eosinophilic stroma is best seen in the Papanicolaou stain (e) and the glassy features in the DiffQuik stain (f). Fragments of muscularis propria (g) are impossible to distinguish from those of leiomyoma (h). Cellular pleomorphism is present in leiomyosarcoma (i). EUS of leiomyoma showing a hypoechoic gastric fundus submucosal mass (31.2 × 29.5 mm) with central anechoic cystic space (MP muscularis propria) (j). (b, H&E stain intermediate magnification; c, d Immunoperoxidase stain for actin intermediate magnification; e, g & i Papanicolaou stain low and high magnification; f, h DiffQuik stain intermediate magnification).
Fig. 5.7.
(continued)
Leiomyosarcomas of the GI tract are much less common than GISTs and can occur anywhere in the tract; however, esophageal and gastric leiomyosarcomas are exceedingly rare. The incidence increases in the small bowel and colorectum. Of note, colorectal leiomyosarcomas are ten times less common than colorectal GISTs. Most GI tract leiomyosarcomas follow an aggressive course. Small tumors may have a good prognosis, better than GISTs of the same size and proliferation rate.
Histopathology
Leiomyomas show fascicles of spindle cells with eosinophilic cytoplasm and cigar-shaped nuclei that have blunt ends (Fig. 5.7b). Atypia, mitoses, and necrosis are seen in leiomyosarcoma ; however, they may have features overlapping with those of leiomyoma . Large size ( > 5 cm), intratumoral necrosis or hemorrhage, and a mitotic count > 5 per HPF are features suggestive of leiomyosarcoma. Colorectal leiomyosarcomas are typically transmural, with both intraluminal and outward-bulging components, and they are more often spindle shaped than epithelioid (rate 9:1). The differential diagnosis includes GIST , spindle-cell carcinoma, and amelanotic melanoma.
Immunoprofile
Immunohistochemistry for smooth-muscle markers conclusively defines these lesions and can be performed readily in the cell block. Leiomyomas are positive for desmin and SMA (Fig. 5.7c), and negative for CD117, CD34, and S-100 protein. Leiomyosarcoma shows positive smooth-muscle markers (Fig. 5.7d), but no CD117 (Table 5.3). They are also positive for calponin and h-caldesmon.
FNA Findings
Smears show clusters of elongated cells with bland nuclei and rare, if any, mitoses. Cell nuclei are placed in an abundant stroma. DiffQuik stain may show a dense glassy stroma. Papanicolaou stain shows the characteristic eosinophilia in the cytoplasm (Fig. 5.7e, f).
In our experience, except for the low-group cellularity and lack of background stripped nuclei observed in leiomyomata, the cytomorphologic features of leiomyomata observed in DiffQuik-stained smears are similar to those of GISTs. Scattered stripped nuclei with scant fibrillary cytoplasm present in a more cellular, haphazardly arranged fragment are commonly seen in GIST , in contrast to leiomyoma . The characteristic eosinophilic cytoplasm of leiomyoma is best seen in cell-block slides. Cells may be more ovoid, less crowded, lack schwannoid features, and have greater cell cohesion in leiomyoma. The distinction of leiomyoma from normal smooth muscle from the GI wall is more problematic. They may have similar cytologic features, particularly in marginally sampled leiomyomas; ultrasound correlation assuring that the mass was sampled is necessary for a correct interpretation (Fig. 5.7g, h). Leiomyosarcoma often shows marked cellular pleomorphism (Fig. 5.7i).
EUS Features
Tumors may arise from either layer 2 or layer 4. The sonographic features by themselves are indistinguishable from those of GIST . Leiomyomas are hypoechoic, with homogeneous echotexture, oval or round, and have well-defined margins (Fig. 5.7j). Malignant tumors are hypoechoic, have irregular infiltrating margins, fuzzy borders, and may show heterogeneous echotexture that indicates necrosis.
Schwannoma
Although most mesenchymal tumors of the gut are GISTs, other mesenchymal tumors, including nerve sheath tumors, do occur. Like GISTs, schwannomas are more frequent in the stomach than in other GI locations. Colonic schwannomas are sometimes found incidentally on screening colonoscopy. These tumors are not associated with neurofibromatosis. Ultrastructural findings are those of peripheral schwannomas and show rudimentary cell junctions, basal lamina, and intracytoplasmic electron-dense crystalloids.
Histopathology
Schwannomas are not encapsulated, show interlacing cell fascicles, are surrounded by a lymphoid cuff with germinal centers, and have intratumoral lymphoid cells. In contrast to GISTs, GI schwannomas do not have a schwannoid pattern and may be mitotically active and be benign. Thus, proper diagnosis and differentiation from GIST is important because of the difference in prognosis and therapy (Fig. 5.8a).
Fig. 5.8.
Schwannoma. Histologic (a) and EUS-FNA (b, c) findings are indistinguishable from those of spindle-cell GIST. Stain for S-100 protein is required for final characterization (d). (a, H&E stain intermediate magnification; b DiffQuik stain high magnification; c Papanicolaou stain high magnification; d nuclear stain for S-100 protein, intermediate magnification).
Immunoprofile
In our laboratory: a panel of CD117, CD34, S-100 protein, desmin, and SMA is routinely applied to spindle-cell tumors of the GI tract. S-100 protein ( + ) and CD117(−) applied to cell blocks are confirmatory of schwannoma (Fig. 5.8d). CD34 may be focally positive. In contrast with peripheral schwannomas, calretinin is negative.
Molecular Profile
GI schwannomas usually lack NF2 gene alterations, in contrast to peripheral schwannomas.
FNA Findings
Schwannomas show moderately cellular groups that may have haphazardly arranged bland cells within a dense stroma when stained with DiffQuik. Nuclei may be oval, elongated, or round and only occasionally wavy. The stroma is fibrillary when stained with Papanicolaou stain. In contrast to GIST and similar to leiomyoma , stripped nuclei are only occasionally present in the smear background. Rarely, these tumors may be epithelioid. Nuclear palisading and Verrocay bodies, so characteristic of peripheral schwannomas, are virtually absent in GI schwannomas (Figs. 5.8b, c). Furthermore, schwannoid features are not uncommonly seen in GISTs (Figs. 5.5g).
EUS Features
Similar to GIST , schwannoma arises in the fourth layer (muscularis propria) of the GI wall and is hypoechoic, round to oval, and has well-defined margins and homogeneous echotexture.
Sclerosing Mesenteritis
This entity is an IgG4-related disease, recognized as a systemic syndrome characterized by mass-forming lesions in the pancreas, retroperitoneum, mesentery, lung , head, and neck, with lymphoplasmacytic infiltration and sclerosis. Patients with sclerosing mesenteritis are usually adults who have a solitary abdominal mass involving the mesentery of the small bowel without involvement of the bowel wall. This mass shows varying degrees of inflammation, necrosis, and fibrosis. IgG4 serum levels are high and are helpful in the diagnosis.
Immunoprofile
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