Gastrointestinal System, Pancreatobiliary Tract and Liver

Abstract

Esophageal adenocarcinomas are believed to follow the intestinal metaplasia–dysplasia–carcinoma pathway. The metaplastic glandular epithelium is lined by a layer of periglandular myofibroblastic cells which regulate many aspects of the epithelial cells like in the intestine (refer to the intestine section for more detailed discussion) [4]. Due to the presence of the periglandular myofibroblastic sheath, benign intestinal epithelial proliferations have a characteristic serrated appearance. Except for the rare serrated adenocarcinomas in the colon which possess other easily discernible characteristic features, genuine serration is rarely seen in gastrointestinal epithelial malignancies. This important feature can be very useful in the diagnosis of well-differentiated carcinomas where invasion is insidious and desmoplasia is not evident.

Appendices

Appendix

Key Morphological Features of Low-Grade Appendiceal Mucinous Neoplasm (Well-Differentiated Appendiceal Mucinous Adenocarcinoma)

• Circumferential mucosal replacement by mucin-containing cells

• Undulating or flat growth with a broad pushing border (Fig. 7.24)

  Fig. 7.24

  

  Low-grade appendiceal mucinous neoplasm. Circumferential mucosal replacement by mucin-containing cells. Note undulating (a) and flat growth pattern (Surgical Pathology of the GI tract, Liver, Biliary Tract and Pancreas, Elsevier/Saunders, 2009 with permission)

Discussion

Appendiceal adenocarcinomas are uncommon, and in most cases, they resemble their colonic counterparts in histopathological presentation. Here we discuss a unique entity: low-grade appendiceal mucinous neoplasm (well-differentiated mucinous adenocarcinoma).

Low-grade appendiceal mucinous neoplasms are characterized as a circumferential growth with an undulating or flat surface. The growth enlarges, deforms, or even destroys the appendix [103, 104]. The tumor cells are usually tall, thin with basal nuclei and thin mucin vacuoles. In general, they show a broad pushing border with no overt invasion of the mucosa. However, occasional diverticulum-like protrusions into the deep tissue are present. Denudation of the epithelium is also common. The appendiceal wall is usually fibrotic and lacks lymphoid tissue.

Differential Diagnosis

Simple Mucocele

Simple mucoceles are small cystic spaces lined by atrophic epithelium with associated inflammation. They lack the circumferential involvement pattern.

Adenoma with Mucocele

Adenomas with mucocele formation lack circumferential undulating or flattening of the luminal epithelium characteristic of low-grade appendiceal neoplasms. The cells have typical adenomatous features.

Anus

Key Morphological Features of Well-Differentiated Anal Gland Adenocarcinoma

• Small glands infiltrating the wall

• Lack of a myoepithelial cell layer (Fig. 7.25)

  Fig. 7.25

  

  Anal gland carcinoma. There is haphazard infiltration of the wall of the anorectal wall (a). Malignant glands lack a layer of myoepithelial cells (b) and are reactive with CK7 (c) (Archives of Pathology and Laboratory Medicine, American Society of Clinical Pathology, 2007 with permission)

Discussion

Most adenocarcinomas of the anal canal are secondary involvement by a primary rectal adenocarcinoma. Primary anal gland adenocarcinomas are characterized by small infiltrative glands without an intraluminal component and surface mucosal dysplasia [105–107]. Instead, the tumors are centered within the anorectal wall. The infiltrative pattern is not to be confused with normal distribution of anal glands in the internal and even external sphincter muscles [108]. In this aspect, immunostaining for p63 might be very useful in making the distinction since malignant glands lack a myoepithelial layer which is present around benign anal glands. Immunostainings for CK7 and CK20 are useful in differentiating them from rectal adenocarcinomas. Primary anal canal adenocarcinomas are positive for CK7 and negative for CK20 [105] (1).

Differential Diagnosis

Tailgut Cyst

Tailgut cysts are well circumscribed, multicystic with the cyst lining cells being mainly stratified squamous epithelium and occasional cuboidal or columnar cells. Disorganized smooth muscle fibers in the cyst wall can be seen.

Anal Duct or Gland Cyst

Anal duct or gland cysts can present in all three anatomical zones of the anus. Characteristically, they form intraepithelial microcysts and contain goblet cell metaplasia. The benign gland might penetrate the internal sphincter muscle or even the external sphincter muscle fibers. Presence of myoepithelial cells distinguishes them from anal gland adenocarcinomas.

Hidradenoma Papilliferum of the Perianal Skin

Hidradenomas papilliferum of the perianal skin is believed to derive from perianal sweat gland and contains well-circumscribed complex papillary structures composed of two layers of epithelial cells. The outer layer cells are myoepithelial in nature.

Squamous Cell Carcinoma with Prominent Mucinous Features (Mucoepidermoid Carcinoma)

Squamous cell carcinomas with prominent mucinous features contain a squamous cell component in addition to mucinous microcysts. It seems that the squamous component is biologically closer to adenocarcinoma than to anal squamous cell carcinomas [109].

Key Morphological Features of Well-Differentiated Anal Squamous Cell Carcinoma

• Dyskeratotic squamous proliferation with infiltrative or pushing border

• Or Complex papillary structure (Fig. 7.26)

  Fig. 7.26

  

  Well-differentiated anal squamous cell carcinoma (Surgical Pathology of the GI tract, Liver, Biliary Tract and Pancreas, Elsevier/Saunders, 2009 with permission)

Discussion

Squamous cell carcinomas of the anus are etiologically similar to their cervical counterparts. The diagnostic criteria for esophagus apply to both of them (see esophagus section for more discussion). Two locally invasive variants are to be recognized. The giant condyloma acuminatum of Buschke–Lowenstein normally are large (>10 cm in diameter) complex papillary structures with focal invasion identified in only 50 % of reported case series. Verrucous carcinomas have characteristic pushing border front and crater-like keratinization.

Differential Diagnosis

Condyloma

Condylomas are usually less bulky and have shorter papillae and less epithelial atypia than giant condyloma acuminatum. They also lack locally destructive growth pattern of the latter.

Bowenoid Papulosis

Bowenoid papulosis occurs mainly in young adults and is characterized by its circumscription and low-grade epithelial atypia with surface maturation. It lacks complex structures and dermal involvement.

Bowenoid papulosis should not be confused with Bowen’s disease which is a variant of squamous cell carcinoma in situ in an older population. The latter shows greater cytological atypia with surface maturation disturbance and occasional involvement of adnexal structures.

Squamous Dysplasia Involving Anal Ducts

Squamous dysplasia involving anal ducts manifests a smooth rather than ragged contour. Comparison to adjacent uninvolved ductal structures helps with the appreciation of the smooth outlines of the involved. The nuclear features are the same as those of the dysplastic surface epithelium.

Gastrointestinal Tract Stroma

Key Morphological Features of High-Risk Gastrointestinal Stromal Tumor (GIST)

• Spindle and/or epithelial proliferation in the submucosa

• Mitotic activity > 5/50HPF (Fig. 7.27)

  Fig. 7.27

  

  Gastrointestinal stromal tumor. The different histocytological presentations have no prognostic significance

Discussion

The older scheme for separating GISTs into benign and malignant categories has been replaced by a stratification system in which the risk of aggressive clinical behavior is predicted based on data from large-scale studies [110, 111]. In the stratification system, hemorrhage, necrosis, and nuclear pleomorphism, tumor size and even infiltrative growth pattern have been excluded. The 2010 AJCC classification uses mitotic rate as the only criterion in separating GISTs into low (grade 1) and high (grade 2) categories. In acknowledgment of the effect of anatomical location on tumor behavior, it recommends different staging criteria for gastric and small intestinal GISTS. The staging criteria for the former also apply to omental GISTs and those for the latter to esophageal, colorectal, mesenteric, and peritoneal GISTs.

Morphologically, most GISTS have a spindle cell pattern with epithelioid, mixed cell patterns accounting for the rest [112, 113]. Typically, the spindle cells are in short fascicles or whorls and contain eosinophilic fibrillary cytoplasm and indistinct cell borders. Epithelioid cells in GISTs are characterized by round cells with eosinophilic to clear cytoplasm arranged in nests or sheets. Cytological atypia is more frequently present than in spindle cells. Counterintuitively, scattered bizarre epithelioid cells are more commonly seen in low-grade gastric GISTs than in high-grade ones. As there are many other entities with spindle and epithelioid morphology in the gastrointestinal tract, the importance of microscopic examination of GISTs lies mainly in differentiating them from other spindle and epithelioid tumors and choosing appropriate fields for mitotic counting [112, 113].

As the database on GISTS expands, future studies might bring into the picture additional stratifying criteria, such as tumor rupture and status of surgical margins. Furthermore, high-grade small bowel GISTs are composed of long fascicles of spindles cells and contain less stromal skeinoid fibers than their benign counterparts. A tightly packed epithelioid appearance has been associated with an adverse clinical outcome in gastric GISTS. The current recommendation is that the presence of such morphological features should prompt at least a more meticulous evaluation of mitotic activity [110].

Differential Diagnosis

For Spindle Cell GISTs

Reactive Nodular Fibrous Pseudotumor and Pseudosarcomatous Proliferation

Reactive nodular fibrous pseudotumors occur mainly in the outer layer of the gut in patients with a previous history of abdominal surgery or trauma. Transmural extension, however, is possible. The hypocellular bland spindle and stellar cells are arranged haphazardly or in short fascicles.

Pseudosarcomatous proliferation contains granulation tissue with associated ulceration or polyps. The stromal cells, endothelial cells, and adjacent epithelial cells usually show marked cytological atypia. Overall low cellularity and a prominent inflammatory infiltrate are noticeable.

Leiomyoma

Leiomyomas have characteristic intersecting fascicles composed of cells with abundant eosinophilic cytoplasm, blunt end nuclei, and distinctive cell borders. Relative to GISTs, they have less cellularity. The tumor cells are diffusely negative for CD117 and CD34.

Schwannoma

Gastrointestinal schwannomas occur most frequently in the stomach, and they typically lack or contain inconspicuous trademark components of the tumor: Verocay bodies, nuclear palisading, xanthoma cell, and hyalinized vessels. Instead, they acquire an important feature: presence of a rim of lymphoid tissue with follicular center formation. The spindle cells have elongated, tapering, and often buckled nuclei and are arranged in trabeculae or even sheets. To further confound the matter, gastric and anorectal GISTs are commonly associated with fascicles of spindle cells with prominent nuclear palisading.

Thus accurate distinction between the two entities depends heavily on immunostainings. The tumor cells of the former stain are strongly positive for S100 (both nuclei and cytoplasm) and negative for CD117 and CD34.

Inflammatory Myofibroblastic Tumor

Inflammatory myofibroblastic tumors occur predominantly in the mesentery and omentum of children and young adults. The compact spindle cell variant resembles GISTs. However, the tumors contain a prominent component of inflammatory cells with significant numbers of plasma cells. Tumor cells are positive for ALK-1 and negative for CD117.

Inflammatory Fibroid Polyp

Inflammatory fibroid polyps contain loosely collagenous- or granulation-type stroma, with CD34 + fibroblasts distributed in a patternless pattern. Characteristic onion-skin cuffs of perivascular spindle cells and inflammatory infiltration (eosinophils as the prominent component) set them apart from GISTs. The tumor cells are positive for PDGFR and negative for CD117.

Desmoid Fibromatosis

Desmoid fibromatosis is a predominantly mesenteric tumor with possible infiltration of the gut wall. It is characterized by long sweeping fascicles of spindle cells and collagenous matrix (sometimes keloid-like collagen fibers). It lacks high cellularity, nuclear palisading, skeinoid fibers, and epithelioid cell components. Other characteristic features of the tumor include small muscular arteries and thin-walled and often ectatic veins with scant perivascular lymphocytes and scattered mast cells. The tumor cells commonly express beta-catenin and infrequently CD117.

Solitary Fibrous Tumor

Solitary fibrous tumors are located mainly in the peritoneum and retroperitoneum with possible serosal involvement. Characteristic features include a patternless pattern of the spindle cells, alternating hypercellularity and hypocellularity, ropy keloid collagen fibers, and hemangio-pericytoma-like vasculature. The tumor cells are CD34 positive and CD117 negative.

Spindle Tumors with Malignant Cytology

The differential diagnosis of spindle GISTs includes melanoma, sarcomatoid carcinoma, leiomyosarcoma, malignant peripheral nerve sheath tumor, clear cell sarcoma, and other rare entities. A detailed discussion of them is out of the scope of this book. Several excellent review papers are available for reference.

For Epithelioid GISTs

Neuroendocrine Tumor

Low-grade neuroendocrine tumors might exhibit both spindle and epithelioid cell patterns. Their characteristic chromatin and growth patterns usually point to the right diagnosis.

PEComa and Glomus Tumor

PEComas are characterized by a perivascular epithelioid cell proliferation which forms sheets or nests. Occasional CD117-positive cases have been reported. Therefore, in difficult cases myomelanocytic markers (HMB-45 or Melan A) should be included.

Glomus tumor cells have a uniform round shape distinctive cell borders and are closely associated with ectatic vessels. They are positive for SMA and negative for CD117.

Paraganglioma

Paragangliomas predominantly involve the duodenum and consist of three types of cells: spindle, epithelioid, and ganglion-like cells. The first two form the so-called Zellballen structure. Interestingly, the spindle cells are S100 positive and the ganglion-like cells stain for synaptophysin. All three of them are positive for NSE.

Epithelioid Tumors with Malignant Cytology

The differential diagnosis of epithelioid GISTs includes melanoma, poorly differentiated carcinoma and neuroendocrine tumors, epithelioid leiomyosarcoma, and other rare entities. A detailed discussion of them is out of the scope of this book. Several excellent review papers are available for reference.

Caution: Variable expression of CD117 has been reported in melanoma, angiosarcomas, and PEComas.

The Gastrointestinal Neuroendocrine Tissue

Key Features of Well-Differentiated Gastrointestinal Neuroendocrine Carcinoma (Net GII)

• Ki67 index of 3 to 20 % or mitotic counter 2 to 20/10 HPF (Fig. 7.28)

  Fig. 7.28

  

  Gastrointestinal neuroendocrine tumor. As for gastrointestinal stromal tumor, the different histological manifestations of the tumor carry no clinical significance. Mitotic index is the sole index in the grading (Surgical Pathology of the GI tract, Liver, Biliary Tract and Pancreas, Elsevier/Saunders, 2009 with permission)

Discussion

The 2010 WHO classification replaces the term well-differentiated neuroendocrine carcinoma with neuroendocrine tumor grade 2 (NET GII) [86]. It uses mitotic count as the sole index in the three-tier tumor grading system for the gastrointestinal tract. This is in contrast to the four-tier system for the pulmonary system in which tumor grading is based on both mitotic count and necrosis. Importantly, cytological atypia is left out in both systems. Analogous to pulmonary neuroendocrine tumors, the gastrointestinal neuroendocrine tumors are a heterogeneous population of tumors which most likely can also be divided into two molecular and biological distinct categories with carcinoid (NET G1) and atypical carcinoid (NET G2) tumors manifesting similar genetic changes [114–116]. The two categories have remarkable differences in histopathologic and cytological features which allow their easy separation.

Information on tumor size, location, depth of tissue involvement, and even nodal metastasis has been incorporated into the staging scheme. In acknowledgement of their functional diversity and nonrandom distribution of the various cell types in the gastrointestinal system, a slightly different staging system has been adopted for the foregut, midgut, and hindgut, respectively [117].

Differential Diagnosis

Adenocarcinoma

NET G1 and G2 tumors have their characteristic trabecular, nest-like, or glandular patterns composed of bland-looking cells with uniform central nuclei with salt and pepper chromatin pattern. Therefore, a diagnosis is usually straightforward for typical cases.

Duodenal NET G1 and G2 tumors can have a prominent tumor acinar or glandular pattern with frequent intraluminal psammoma bodies [116]. Cursory low power examination can lead to an erroneous diagnosis of well-differentiated adenocarcinoma.

Appendiceal duodenal NET G1 and G2 tumors can show goblet cell and Paneth cell differentiation and focal glandular formation. The so-called tubular type simulates invasive adenocarcinoma even more in that it presents as teardrop-like tubules in a loosely fibrotic stroma [116]. The tumor cells are negative for chromogranin A (rectal neuroendocrine tumors are negative for chromogranin A).

Glomus Tumor

Glomus tumors are composed of uniform small round cells with lumpy chromatin pattern, and their close association with ectatic vessels is evident. The tumor cells are positive for SMA and negative for chromogranin and synaptophysin.

Lymphoma, Melanoma, and Poorly Differentiated Tumors

Lymphomas, melanomas, or poorly differentiated tumors can present in a nest pattern. However, attention to their cytological and other histological features avoids an erroneous diagnosis. In difficult cases, immunostainings are required.