Am J Surg Pathol

Fibroepithelial polyps of the anus: a histologic, immunohistochemical, and ultrastructural study, including comparison with the normal anal subepithelial layer.

Groisman GM. Polak-Charcon S.
Department of Pathology, Hillel-Yaffe Medical Center, Hadera, Israel.
Fibroepithelial polyps of the anus (FEPA) are relatively common lesions that have attracted little attention. A series of 40 FEPA, together with sections from normal anal mucosa, were studied histologically, histochemically, immunohistochemically, and ultrastructurally. The polyps consisted of myxoid or collagenous stroma covered by squamous epithelium. Stromal cells with two or more nuclei were found in 30 polyps (80%). In five cases (12%) these cells showed atypical nuclear features. All the polyps harboring atypical cells were of large size. Mast cells were frequently present and sometimes intimately related to the stromal cells. Stromal cells stained positive for vimentin and negative for actin. Desmin was expressed in 30% of the cases. Electron microscopic examination confirmed the fibroblastic and myofibroblastic nature of the stromal cells. Examination of the subepithelial connective tissue from the normal anal mucosa showed bizarre multinucleated cells and mast cell infiltration. It is concluded that FEPA are benign lesions characterized by the presence of mononucleated and multinucleated, sometimes atypical stromal cells showing fibroblastic and myofibroblastic differentiation. The morphologic similarity between FEPA and normal anal mucosa supports the hypothesis that FEPA may represent a reactive hyperplasia of the subepithelial connective tissue of the anal mucosa. Mast cells, by means of their fibrogenic, fibrolytic, and angiogenic activities may play an important role in the pathogenesis of FEPA.

Classification of primary gastric lymphomas according to histologic features.

Hsi ED. Eisbruch A. Greenson JK. Singleton TP. Ross CW. Schnitzer B.
Department of Pathology, University of Michigan Medical School, Ann Arbor, USA.
Histologic features of low-grade gastric lymphomas of mucosa-associated lymphoid tissue (MALT) have been extensively described, and transformation to a large cell (high-grade) lymphoma can occur. We characterize high-grade gastric lymphoma histologically in an attempt to distinguish between MALT-type and non-MALT-type lesions. We studied a series of 60 gastric lymphomas and characterized them clinically, histopathologically, and immunophenotypically. Low-grade gastric lymphomas were classified according to established criteria. High-grade lymphomas were classified in three groups based on the presence or absence of a low-grade component and lymphoepithelial lesions (LELs): 1) high-grade MALT lymphomas appearing in low-grade MALT lymphomas (LG/HG MALT lymphoma); 2) large cell lymphoma with LELs composed of large cells (high-grade LELs) but without a low-grade component (HG MALT lymphoma); and 3) diffuse large cell lymphoma without a low-grade MALT lymphoma component or LELs (DLCL). Twenty-two lymphomas were classified as low-grade MALT lymphomas, 16 as LG/HG MALT lymphomas, 10 as HG MALT lymphomas, and 12 as DLCL. B-cell immunophenotype was confirmed in all 55 cases in which immunophenotyping was performed. Low-grade LELs were seen in all low-grade MALT lymphomas, and CD20(L26) expression confirmed B-cell phenotype in the LELs in 20 of 20 cases. Clinical follow-up was available for 56 patients (range, 1-264 months; mean, 57 months). Actuarial analysis of disease-specific survival and relapse-free survival showed that clinical stage was highly statistically significant (P < 0.0001), whereas histologic type and grade approached statistical significance. Multivariate analysis showed that clinical stage was the only significant factor in relapse-free and disease-specific survival.

Chronic liver allograft rejection: a National Institute of Diabetes and Digestive and Kidney Diseases interinstitutional study analyzing the reliability of current criteria and proposal of an expanded definition. National Institute of Diabetes and Dige

Demetris AJ. Seaberg EC. Batts KP. Ferrell L. Lee RG. Markin R. Detre KM.
Thomas E. Starzl Transplantation Institute, Department of Pathology, University of Pittsburgh, Pennsylvania 15215, USA. demetris+@pitt.edu
A study was conducted to assess the inter and intrarater agreement for the histopathologic features and diagnosis of chronic rejection (CR) and several other important causes of late liver allograft dysfunction. On two occasions, five pathologists, experienced with liver transplantation, reviewed a set of 49 slides representing a range of diagnoses, without knowledge of the clinical history or liver injury test results. The readings were correlated with the original histopathologic diagnosis, liver injury tests, and clinicopathologic follow-up. Assessment of biopsy adequacy (kappa = 0.69) and portal tract counts (kappa = 0.79) showed good to excellent intrarater agreement, whereas interrater agreement for these variables was moderate to good, respectively (kappa = 0.44 and 0.65). Likewise, the intrarater agreement for the diagnosis of CR (kappa = 0.68), hepatitis (kappa = 0.77), and obstructive cholangiopathy (kappa = 0.55) showed good to excellent agreement, whereas the interrater agreement for these same diagnoses ranged from fair to good (kappa = 0.58, 0.46, and 0.25, respectively). In 18 specimens, there was a near unanimous diagnosis of CR across both readings. These biopsies were obtained at a median of 7.1 months (range, 42 days to 4.9 years) after transplantation, and the average number of portal tracts was 8.4 (range, 4-15). Interestingly, only 13 of these 18 specimens showed bile duct loss in >50% of the portal triads; the remaining cases showed atrophy/pyknosis of the biliary epithelium in a majority of small bile ducts. Clinicopathologic correlation showed that these 18 biopsies were obtained from 16 grafts from 15 patients, 14 of whom ultimately required retransplantation or died of or with CR, whereas two of the grafts/patients recovered. A high rate of sensitivity (92%) and a somewhat lower, but acceptable, rate of specificity (71% to 80%) was found for the diagnosis of CR. Chronic rejection and other causes of late liver allograft dysfunction can be diagnosed reliably by a group of pathologists experienced with liver transplantation, and the diagnosis of CR correlates with clinical course and liver function abnormalities. Expanded criteria for the diagnosis of CR are presented, and potential problem areas for practicing pathologists are discussed.

Multinucleated epithelial giant cell changes in esophagitis: a clinicopathologic study of 14 cases.

Singh SP. Odze RD.
Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
We describe the clinical and pathologic features of a hitherto unreported finding in patients with esophagitis: the presence of multinucleated squamous epithelial giant cells simulating viral cytopathic effect and/or dysplasia. Routinely processed hematoxylin and eosin (H&E)-stained slides of esophageal mucosal biopsies from 14 patients with both active esophagitis and multinucleated epithelial giant cells were evaluated for a variety of inflammatory and epithelial features. Clinical, endoscopic, and follow-up data were collected and correlated with the histologic findings. Immunostaining (ABC method) for cytokeratin AE1/AE3, S-100, MIB-1, herpes simplex virus 1 and 2 (HSV), cytomegalovirus (CMV), as well as DNA in situ hybridization for human papilloma virus (HPV-ISH) was performed in all cases. Electron microscopic evaluation for viral particles was performed in three cases. The study group consisted of nine men and five women (mean age 59 years; range 23-87 years; 12 white, one black, one Hispanic). Patients presented with dysphagia or odynophagia (n = 5), upper gastrointestinal bleeding (n = 5), heartburn (n = 2), or abdominal pain (n = 2). The etiology of esophagitis was attributed to gastroesophageal reflux in 10, radiotherapy in one, Candida infection in one, drug-induced (alendronate) in one, and unknown in 1. Endoscopically, seven patients had an ulcer or erosion, four erythema, two stricture formation, and one white mucosal plaques. Microscopically, all cases showed multiple multinucleated (mean three nuclei per cell, range two to nine) squamous epithelial cells (range 2 to 11 cells per biopsy) confined to the basal zone in nine of 14 cases and involving the basal and superficial epithelium in the remainder. The nuclei contained a single or multiple eosinophilic nucleoli with a perinucleolar halo, but no inclusions, hyperchromaticity, or atypical mitoses. All cases showed associated nonspecific features of active esophagitis such as ulceration, neutrophilic and eosinophilic inflammation, basal cell hyperplasia, and elongation of the lamina propria papillae. The multinucleated giant cells, in all cases, were strongly positive for cytokeratin AE1/AE3 and were negative for S-100, HSV I and II, CMV, and HPV-ISH. MIB-1 positivity was observed in all basally located multinucleated giant cells, whereas those in the more superficial layers were negative. Electron microscopy failed to show viral particles in three of three cases. After treatment, all patients demonstrated clinical improvement. Three patients in whom follow-up biopsies were performed showed no evidence of esophagitis, epithelial cell multinucleation, or dysplasia. Multinucleated epithelial giant cell changes may rarely be seen in patients with esophagitis of varying etiology and probably represent a regenerative response to injury. This feature is important to distinguish from either viral cytopathic effect or dysplasia.

Clear cell sarcoma of the ileum: the crucial role of cytogenetics for the diagnosis.

Donner LR. Trompler RA. Dobin S.
Department of Pathology, Scott & White Clinic, Texas A & M University Health Science Center, College of Medicine, Temple 76508, USA.
We report a case of clear cell sarcoma that arose in the ileum and metastasized to the liver. The tumor cells did not contain melanin or glycogen; expressed S-100 protein, but not HMB45; and contained possible atypical melanosomes when examined by electron microscopy. They carried a clonal chromosomal rearrangement: 50,XY,t(2;7)(q37;q22),+8,+8,+9,+11, t(12;22)(q13;q12). The diagnosis was greatly facilitated by the cytogenetic analysis. The translocation t(12;22)(q13;q12-13) has been reported as specific for clear cell sarcomas.

Malignant tumors in the rectum simulating solitary rectal ulcer syndrome in endoscopic biopsy specimens.

Li SC. Hamilton SR.
Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205-2196, USA.
Patients with solitary rectal ulcer syndrome (SRUS) frequently present with a mass that can be misinterpreted as cancer. In contrast, the occurrence and characteristics of SRUS-like histopathology produced by underlying malignancy have not been reported in detail. We report seven patients whose rectal mass that was induced by infiltrating carcinoma showed only histopathologic changes of SRUS on initial mucosal biopsy specimens. Carcinoma was evident in subsequent specimens after one to five repeat biopsies with delay in diagnosis from 1 week to 18 months in six patients. In one patient, infiltrating carcinoma was suggested on the first biopsy specimen by immunohistochemistry for cytokeratin. Three of the patients had primary rectal adenocarcinoma, two had metastatic carcinoma from stomach or ovary, and two had direct invasion of anal squamous cell carcinoma or prostatic adenocarcinoma. We conclude that the histopathology of SRUS may occasionally represent a characteristic but nonspecific mucosal reactive change to a deeper seated malignancy. The terminology "solitary rectal ulcer syndrome/mucosal prolapse changes" with a cautionary note may be useful for reporting biopsy results to emphasize the possibility of underlying primary or metastatic malignancy in the differential diagnosis.

Progression of pancreatic intraductal neoplasias to infiltrating adenocarcinoma of the pancreas.

Year 1998
Brat DJ. Lillemoe KD. Yeo CJ. Warfield PB. Hruban RH.
Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-6971, USA.
Pancreata with cancer also frequently have intraductal proliferative lesions, suggesting an association between pancreatic cancer and these lesions. We present three cases in which atypical papillary hyperplasia of the pancreas was documented 17 months to 10 years before the development of an infiltrating adenocarcinoma of the pancreas. The first patient was a 70-year-old woman who underwent pancreaticoduodenectomy for adenocarcinoma of the pancreas. Atypical papillary duct hyperplasia extended to the pancreatic neck margin of resection, but the margin was negative for infiltrating carcinoma. Nine years later, an infiltrating adenocarcinoma developed in the remaining pancreas. The second patient was a 58-year-old man who underwent distal pancreatectomy for chronic pancreatitis with pseudocyst. Histologic examination showed chronic pancreatitis and multiple foci of atypical papillary duct hyperplasia. Ten years later, the patient underwent a Whipple procedure for infiltrating adenocarcinoma of the pancreas. The third patient was a 46-year-old woman with recurrent pancreatitis who underwent a Whipple procedure. Histologic examination showed atypical papillary duct hyperplasia and chronic pancreatitis but no infiltrating carcinoma. At the time of surgery, the tail of the pancreas was grossly and radiographically normal. Seventeen months later, a malignant pleural effusion developed, and postmortem examination showed infiltrating adenocarcinoma in the tail of the pancreas. In the cases presented, atypical papillary hyperplasia was documented 17 months, 9 years, and 10 years before the development of infiltrating adenocarcinoma of the pancreas, supporting the concept that there is a progression from intraductal hyperplasia to infiltrating carcinoma of the pancreas, just as there is a progression from adenoma to infiltrating carcinoma in the colorectum. Based on evidence that these intraductal lesions are precursor lesions to infiltrating adenocarcinoma of the pancreas, we suggest that the term "hyperplasia" be replaced by the more specific term "pancreatic intraepithelial neoplasia."

Perianal Pagets disease: a histologic and immunohistochemical study of 11 cases with and without associated rectal adenocarcinoma.

Year 1998
Goldblum JR. Hart WR.
Department of Anatomic Pathology, The Cleveland Clinic Foundation, Ohio 44195, USA.
Perianal Paget's disease is rare, and its relationship to an associated internal regional cancer has been ill defined. We analyzed the histologic and immunohistochemical features of perianal Paget's disease in 11 patients to determine the frequency and relationship of associated regional internal carcinoma and to gain insight into its histogenesis. Of five patients with documented rectal adenocarcinoma, it was discovered synchronously with the Paget's disease in four and, subsequently, in one. Paget's cells of signet ring type predominated in four cases. Intraepithelial glands with intraluminal dirty necrosis were present in four cases. The immunophenotype in four cases studied was cytokeratin (CK)7+/CK20+/gross cystic disease fluid protein- (GCDFP) in both the intraepithelial Paget's cells and the invasive rectal adenocarcinoma. Six patients did not have documented rectal carcinoma. The Paget's cells in four were CK7+/CK20-/GCDFP15+. Three of these had purely intraepithelial Paget's disease, and invasive or metastatic disease developed in none after wide local excision. Bilateral inguinal lymph node metastases developed in the fourth patient, and the patient died 8 months after diagnosis of Paget's disease. In two patients, the Paget's cells were CK7+/CK20+/GCDFP15-. Recurrent intraepithelial perianal Paget's disease developed in one patient at 7 months; the patient was alive without disease at 24 months, and the other patient had several intraepithelial recurrences of perianal Paget's disease, and, subsequently, a large perianal tumor of uncertain cell type developed at 108 months, which led to the patient's death. We conclude that there are two types of perianal Paget's disease. One type has endodermal differentiation with gastrointestinal-type glands containing intraluminal dirty necrosis, numerous signet ring cells, CK20 positivity, and GCDFP15 negativity. Such cases are especially likely to be associated with synchronous or metachronous rectal adenocarcinoma. The other type is a primary cutaneous intraepithelial neoplasm in which the Paget's cells display sweat gland differentiation, including GCDFP15 positivity; it generally lacks gastrointestinal-type glands, intraluminal dirty necrosis, and CK20 positivity. The CK7 is a sensitive, albeit nonspecific, marker for Paget's cells.

The histopathology of treated Barretts esophagus: squamous reepithelialization after acid suppression and laser and photodynamic therapy.

Year 1998
Biddlestone LR. Barham CP. Wilkinson SP. Barr H. Shepherd NA.
Gloucestershire Royal and Cranfield University Institute of Medical Sciences, Gloucestershire Royal Hospital, England.
Columnar metaplasia of the lower esophageal epithelium (Barrett's esophagus) occurs in response to acid reflux, and its most important long-term complication is malignancy. In view of this, techniques are being explored for the eradication of Barrett's esophagus, and histopathologists will increasingly be required to assess response to these therapies in esophageal biopsy samples. The histopathologic features before and after treatment were studied in biopsy samples from 16 patients receiving omeprazole only, 10 treated by KTP laser photoablation, and five who underwent photodynamic therapy. All the treatment modalities resulted in histologic changes with at least partial squamous reepithelialization of the metaplastic columnar epithelium. The histologic findings suggest three main mechanisms for this: encroachment of adjacent squamous epithelium at the squamocolumnar junction, extension of epithelium from the submucosal gland duct to form squamous islands, and squamous metaplasia within the Barrett's columnar mucosa itself. The latter mechanism implies the existence of pluripotential stem cells within Barrett's mucosa. A relatively common finding was residual glandular mucosa, nonneoplastic and dysplastic, beneath squamous epithelium indicating the requirement for histologic confirmation of endoscopically suspected complete squamous reepithelialization with sufficiently deep biopsies.

Pigmented (black) extraadrenal paraganglioma.

Year 1998
Lack EE. Kim H. Reed K.
Department of Pathology, Georgetown University School of Medicine, Washington, DC 20007, USA.
A pigmented ("black") extraadrenal paraganglioma was discovered incidentally in a 57-year-old woman during ultrasonography. The tumor was located in the retroperitoneum near the superior border of the right kidney. Results of preoperative fine-needle aspiration and intraoperative frozen sectioning of the resected jet-black tumor (13 cm in diameter, 225 g) were both interpreted as suspicious for malignant melanoma. Histomorphology and immunohistochemistry were diagnostic for paraganglioma. Electron microscopy showed numerous dense-core neurosecretory-type granules, as well as abundant, larger pleomorphic electron-dense granules; most were consistent with lipofuscin or neuromelanin. No melanosomes or premelanosomes were identified. Histochemical stains showed that the pigment most likely is neuromelanin, a nonenzymatic or oxidative waste product of catecholamine metabolism. Eighteen other examples of pigmented paragangliomas have been reported in various sites in the English literature during the last 12 years; most indicate the presence of melanosomes or premelanosomes using electron microscopy, whereas in a minority of cases the pigment has not been characterized rigorously. Common embryogenesis from neural crest may help explain the overlapping phenotype of melanocytes and cells of paraganglioma.

Polypoid dysplasia and adenomas in inflammatory bowel disease: a clinical, pathologic, and follow-up study of 89 polyps from 59 patients.

Year 1998
Torres C. Antonioli D. Odze RD.
Department of Pathology, Brigham and Women's Hospital, Boston, Massachsetts 02115, USA.
Dysplasia in inflammatory bowel disease (IBD) is categorized as either flat or associated with a raised lesion or mass (dysplasia-associated lesion or mass [DALM]). One specific subtype of a dysplasia-associated lesion or mass consists of isolated discrete nodules or polyps that are difficult to distinguish from sporadic adenomas. Because the clinical management of these two lesions is different, we performed this study to (1) evaluate the clinical presentation, pathologic features, and natural history of polypoid dysplastic lesions and sporadic adenomas in patients with IBD and (2) determine whether there are clinical, endoscopic, or pathologic findings useful in differentiating between these two lesions. The morphologic features of 89 benign polypoid epithelial neoplasms from 59 patients with IBD (51 with ulcerative colitis, 8 with Crohn's colitis) were evaluated and correlated with the clinical, endoscopic, and follow-up data. In a separate analysis, patients were categorized arbitrarily as having (1) a probable sporadic adenoma if the polypoid epithelial neoplasm was not located within areas of histologically proven colitis, (2) a probable IBD-associated polypoid dysplasia if the lesion developed within an area of colitis, and associated flat dysplasia or an adenocarcinoma was detected during follow-up evaluation or (3) an indeterminate polyp, which was seen in the remainder of the cases. The clinical, endoscopic, and histologic data were compared among these three patient and polyp subgroups. There were 35 males and 24 females (median age, 57 years; range, 27-85 years). Median duration of disease was 10 years. Forty-nine percent of the patients had pancolitis; 66% had histologically active disease at the time of presentation. Nearly 70% of patients had only one polyp; the majority occurred in either the left colon or the rectum (66%). Most polyps were described as a sessile nodule, whereas only 7 (7.8%) were pedunculated. Polyps ranged from 2 mm to 50 mm (median, 5 mm); most had a tubular architecture (84.3%) and contained low-grade dysplasia (64%). In addition, most polyps had mildly increased lamina propria and intraepithelial neutrophilic and mononuclear inflammation. At follow-up evaluation (40 patients; median follow-up time, 13 months; range, 1-78 months), a further neoplastic lesion developed in 20%; low-grade flat dysplasia was seen in 5 (12.5%), and adenocarcinoma developed in 3 (7.5%). However, dysplasia or adenocarcinoma did not develop in the patients who had polyps located outside of areas of histologically proven colitis. In addition, at least one more benign polypoid epithelial neoplasm developed in 15 of 40 patients (37.5%). Patients with probable IBD-associated polypoid dysplasia had a statistically significant (p < 0.05), longer disease duration than patients with probable sporadic adenoma. A statistically significant, higher proportion of polyps with tubullovillous or villous architecture, an admixture of normal and dysplastic epithelium at the surface of the polyps, and increased lamina propria mononuclear inflammation was noted in probable IBD-associated polypoid dysplastic lesions compared with those considered to be sporadic adenomas. Several clinical and pathologic features may be useful to help categorize a polypoid dysplastic lesion as a sporadic adenoma or an IBD-related neoplasm in a patient with IBD. This distinction is important because the natural history of these two lesions (as shown by the results of this study) and their subsequent management are quite different.

Dysplasia and dysregulation of proliferation in foveolar and surface epithelia of fundic gland polyps from patients with familial adenomatous polyposis.

Year 1998
Wu TT. Kornacki S. Rashid A. Yardley JH. Hamilton SR.
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Fundic gland polyps (FGPs) of the stomach are regarded as hamartomatous or hyperplastic/functional polyps that occur sporadically but at increased frequency in patients with familial adenomatous polyposis syndrome (FAP).There is controversy about the histopathology of FGPs, including occurrence of dysplasia. We, therefore, studied dysplasia in 270 sporadic FGPs from 216 patients and 49 FGPs from 24 patients with FAP. We evaluated dysregulation of epithelial proliferation manifested by loss of the normal inverse topographic distribution of Ki-67 proliferation marker and the cyclin-dependent kinase inhibitor p21(WAF1/CIP1) using immunohistochemistry in 27 sporadic FGPs and in 22 FGPs from patients with FAP. Dysplasia in foveolar and surface epithelia occurred in 12 of 49 (25%) FGPs in patients with FAP but in only 3 of 270 (1%) of sporadic FGPs (p < 0.000001). Fourteen of 49 (29%) of FGPs from patients with FAP were indefinite for dysplasia, as contrasted with 8 of 270 (3%) sporadic FGPs (p < 0.00001). The normal inverse topographic distribution of Ki-67 and p21(WAF1/CIP1) was maintained in 20 of 22 (91%) of FGPs negative for dysplasia but was lost in all (8 of 8) FGPs with dysplasia and in 11 of 19 (58%) FGPs that were indefinite for dysplasia (p = 0.00001). The results indicate that dysplasia can occur in foveolar and surface epithelia of FGPs, especially in patients with FAP, and often is preceded by dysregulation of epithelial proliferation when the morphologic abnormalities are indefinite for dysplasia.

Benign hepatocellular tumor of the placenta.

Year 1998
Vesoulis Z. Agamanolis D.
Akron City Hospital, Summa Health Systems, Ohio 44309, USA.
Neoplasms of the placenta, other than trophoblastic tumors and chorangiomas, are exceedingly rare and predominantly include teratomas and metastatic maternal tumors. There has been a single case report of a hepatocellular adenoma-like neoplasm of the placenta that was characterized as most likely representing a specialized monodermal teratoma. We report a second apparent case of a hepatocellular adenoma-like lesion occurring in a preterm placenta with compelling morphologic, immunohistochemical, and ultrastructural validation of tissue hepatic in origin. It remains inconclusive that this lesion represents a neoplasm rather than a rare ectopic or heterotopic occurrence.

Multihormone-producing islet cell tumor of the pancreas associated with somatostatin-immunoreactive amyloid: immunohistochemical and immunoelectron microscopic studies.

Year 1998
Takahashi M. Hoshii Y. Kawano H. Setoguchi M. Gondo T. Yamashita Y. Nakayasu K. Kamei T. Ishihara T.
Department of Surgical Pathology, Yamaguchi University School of Medicine, Ube, Japan.
Pancreatic islet cell tumors, especially insulinomas, are often associated with amyloid deposition in the tumor tissue. Biochemical analysis has demonstrated that the amyloid protein from insulinoma is derived from islet amyloid polypeptide (or amylin) that is produced by tumor cells originating from beta cells of the islet of Langerhans. We examined a case of malignant pancreatic islet cell tumor with amyloid deposition in the tumor tissue using immunohistochemistry and double-labeling immunogold electron microscopy. The tumors were composed of cells producing multiple hormones, including somatostatin, gastrin, amylin, insulin, calcitonin gene-related polypeptide, and calcitonin. Amyloid deposits reacted with antisomatostatin antiserum but not with other antisera, including antiamylin. The present study demonstrated for the first time that amyloid associated with islet cell tumors is not always derived from amylin and can come from somatostatin.

Coexistence of hereditary hemorrhagic telangiectasia and fibropolycystic liver disease.

Year 1998
Saxena R. Hytiroglou P. Atillasoy EO. Cakaloglu Y. Emre S. Thung SN.
Lillian and Henry M. Stratton-Hans Popper Department of Pathology, Mount Sinai Medical Center of the City University of New York, New York 10029, USA.
This is a case report of a 43-year-old woman who received a transplant for end-stage liver disease due to hereditary hemorrhagic telangiectasia and fibropolycystic liver disease. This is an uncommon association of two autosomal-dominant conditions with defined genetic and molecular defects. The liver showed extensive vascular malformations of arteries and veins as well as telangiectasia and fibrosis. In addition, there were cystically dilated ducts containing inspissated bile and extensive von Meyenburg complexes. This case raises interesting questions about the possible relationship of these genes and their gene products, both of which are related to cell-matrix interactions and are strongly associated with blood vessels, one of them being expressed on endothelial cells and the other being developmentally important in blood vessels.

Histology of the stomach and duodenum in Crohns disease.

Year 1998
Wright CL. Riddell RH.
Department of Pathology, McMaster University Medical Centre, Hamilton, Ontario, Canada.
Crohn's disease (CD) not uncommonly affects the stomach and duodenum, but its histologic appearance is not well described beyond the identification of granulomas. We retrospectively identified 209 upper gastrointestinal biopsy samples from 80 sets of biopsies from 49 patients with CD. Age- and sex-matched control biopsies were selected from recent cases of Helicobacter pylori gastritis (73 biopsy samples from 34 patients), from patients with a known history of nonsteroidal antiinflammatory drug use (18 biopsy samples from 12 patients), and from three patients with ulcerative colitis. Architectural and inflammatory changes were evaluated and compared. Over three fourths of the patients with CD had abnormal biopsy results. Fifty-six percent of patients with CD had acute inflammation, but only 10% of the patients were infected with H pylori. Focal acute inflammation was a characteristic of H pylori-negative CD (stomach, 31%; duodenum, 40%), which was much less common in the non-CD group (stomach, 2%; duodenum, 8%). Surface intraepithelial neutrophils of the duodenum were more common in H pylori-negative patients with CD (25%) than in those who did not have CD (4%), and deep acute inflammation of the duodenum was more likely in H pylori-negative patients with CD (19% vs. 0%). Granulomas were found in only 9% of the CD group. Focal acute inflammation of the gastroduodenum, especially in a background of noninflamed mucosa, is strong evidence for CD in the appropriate clinical context, but the stomach and duodenum must be properly sampled and carefully examined for any evidence of H pylori.

Inflammatory myofibroblastic tumor of the pancreaticobiliary region: morphologic and immunocytochemical study of three cases.

Year 1998
Walsh SV. Evangelista F. Khettry U.
Harvard Medical School, and Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
Inflammatory myofibroblastic tumor (IMT) is a rare tumor of the pancreaticobiliary region. The etiology and biologic behavior of IMTs at this site are unknown. We present three patients with IMT of the pancreaticobiliary region, each with long-term follow-up. In all three cases a second tumor developed. Grossly these tumors mimicked a malignant process. Microscopically, all were composed of an admixture of spindle cells and chronic inflammatory cells, including plasma cells, lymphocytes, eosinophils, and macrophages. The spindle cells stained positively for smooth muscle actin and vimentin but were negative for S-100, cytokeratin, CD35, and latent membrane protein. Results of in situ hybridization with EBER probes were negative in all cases. In addition to carcinoma, the differential diagnosis of these tumors includes follicular dendritic cell tumor and inflammatory fibrosarcoma. The importance of extensive pathologic examination to prevent misdiagnosis and the need for long-term follow-up are emphasized. This subset of IMT does not appear to be related to Epstein-Barr virus.

High proportion of granzyme B-positive (activated) intraepithelial and lamina propria lymphocytes in lymphocytic gastritis.

Year 1998
Oberhuber G. Bodingbauer M. Mosberger I. Stolte M. Vogelsang H.
Department of Clinical Pathology, University of Vienna, Medical School, Austria.
Intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LpLs) have not been well studied in gastric mucosa, particularly in lymphocytic gastritis. Therefore, they were immunohistologically characterized with antibodies recognizing CD3, CD8, CD57, T cell-restricted intracellular antigen (TIA-1), and granzyme B (GrB). The TIA-1 labels cytotoxic granules of resting and activated T-cells, whereas GrB decorates activated cytotoxic T cells. Thirty patients with celiac disease, including 20 taking gluten and 10 on a gluten-free diet, 15 patients with nonceliac disease-associated lymphocytic gastritis, and 20 controls were studied. Stained cells were counted and results were given as IELs/100 epithelial cells or percentage of lamina propria cells. Sixty percent to 90% of CD3+ IELs and up to 12% of lamina propria cells contained TIA-1-positive cytotoxic granules. The number of GrB+ IELs and LpLs was increased in Helicobacter pylori-positive controls (p < 0.03 vs. H pylori-negative controls) and celiac disease patients taking gluten (p < 0.05 vs. controls). The highest number of GrB+ IELs and LpLs was found in nonceliac disease-associated lymphocytic gastritis (p < 0.009 vs. controls, p < 0.05 vs. celiac disease). This study shows that a high proportion of gastric IELs and LpLs is potentially cytotoxic in nature. Through stimuli not yet identified, a proportion of them becomes activated after H pylori infestation and in lymphocytic gastritis.

Neoangiogenesis and sinusoidal capillarization in dysplastic nodules of the liver.

Year 1998
Park YN. Yang CP. Fernandez GJ. Cubukcu O. Thung SN. Theise ND.
Department of Pathology, Yonsei Medical Center, Seoul, Korea.
The blood supply of hepatocellular carcinoma (HCC) is primarily arterial. Recent studies reported differences of vascular, especially arterial, supply among low- and high-grade dysplastic nodules and HCC. We assessed arterialization using monoclonal antibody specific for smooth muscle actin as well as simultaneous changes in sinusoidal capillarization in cirrhotic nodules, dysplastic nodules, and HCC. We immunohistochemically stained 56 cirrhotic nodules, 20 low-grade dysplastic nodules, 27 high-grade dysplastic nodules, and 20 HCCs for alpha smooth muscle actin (to identify unpaired arteries (i.e., arteries not accompanied by bile ducts) and CD34 (indicating sinusoidal capillarization). Distribution and number of unpaired arteries and distribution of sinusoidal capillarization were graded semiquantitatively. Unpaired arteries were rare in cirrhotic nodules, significantly more common in dysplastic nodules of both types (p < 0.00001), and most common in HCC. Sinusoidal capillarization was least common in cirrhotic nodules, significantly more common in dysplastic nodules (p < 0.0035), and most common in HCC. No topographic relationship between unpaired arteries and sinusoidal capillarization was identified. These findings showed that (1) distributions of sinusoidal capillarization and unpaired arteries in dysplastic nodules are intermediate between those in cirrhotic nodules and HCC, supporting dysplastic nodules as premalignant lesions; (2) unpaired arteries are histologically useful for distinguishing dysplastic nodules from large cirrhotic nodules; and (3) areas of sinusoidal capillarization within dysplastic nodules are unrelated to location of arterialization.

Development of gastrointestinal beta2-microglobulin amyloidosis correlates with time on dialysis.

Year 1998
Jimenez RE. Price DA. Pinkus GS. Owen WF Jr. Lazarus JM. Kay J. Turner JR.
Harper Hospital and Wayne State University, Detroit, Michigan 48202, USA.
Dialysis-associated beta2-microglobulin (beta2m) amyloidosis affects predominantly musculoskeletal tissue, but visceral involvement also occurs. To evaluate the clinical significance and prevalence of gastrointestinal beta2m amyloidosis, we studied hemodialysis patients admitted for gastrointestinal-related complaints. Hemodialysis patients (excluding those with non-beta2m amyloidosis) who were admitted with gastrointestinal complaints from 1984 to 1994 were identified. Gastrointestinal tissues from patients with available autopsy or surgical specimens were examined using hematoxylin and eosin stain, Congo red stain, and beta2m immunostain. Each case was evaluated independently by two pathologists and scored for quantity and location of beta2m amyloid and associated pathology. Of 24 patients, eight (four men and 4 women) had beta2m amyloid deposits within the gastrointestinal tract. Acute clinical presentation ranged from abdominal pain to gastrointestinal bleeding and was not significantly different for patients with or without gastrointestinal beta2m amyloid deposits. However, the mean time on dialysis of 15.3 +/- 5.7 years (range 6-24 years) for patients with gastrointestinal beta2m amyloidosis was significantly greater than that of patients without gastrointestinal beta2m amyloidosis (10.5 +/- 7.0 years, range

Liver carcinoma in PiZ alpha-1-antitrypsin deficiency.

Year 1998
Zhou H. Fischer HP.
Department of Pathology, University Bonn, Federal Republic of Germany.
One hundred sixty-four consecutive cases of primary liver carcinoma were evaluated for tumor type, (i.e., hepatocellular carcinoma [HCC], cholangiocarcinoma [CC], and combined hepatocholangiocarcinoma [CHCC]), and for signs of alpha-1-antitrypsin deficiency (AATD) in the surrounding liver tissue. Hepatocellular globular alpha-1-antitrypsin deposits, as detected by a monoclonal antibody to the mutant PiZ alpha-1-antitrypsin (AAT), were seen in 13 cases (7.9%). With regard to tumor type, 4 of 111 HCC cases (3.5%), but 4 of 37 CC cases (10.5%), and even 5 of 16 CHCC cases (30%) were positive for this antitrypsin variant. In all but 1 of 13 cases of alpha-1-antitrypsin deficiency, the carcinoma developed in noncirrhotic liver tissue of elderly people (mean age, 62.9 years). In three patients, a heterozygous state of ATT (PiMZ) could be revealed using isoelectric focusing or direct genetic analysis. We conclude from our findings that CHCC and CC especially might be associated with PiZ alpha-1-antitrypsin deficiency. Primary liver carcinoma might develop even in a heterozygote state of PiZ alpha-1-antitrypsin deficiency without concurrent liver disease. Furthermore, liver cirrhosis is not a precondition for these tumors.

Lesions described as nodular mesothelial hyperplasia are primarily composed of histiocytes.

Year 1998
Ordonez NG. Ro JY. Ayala AG.
University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
It is known that, on occasion, histiocytic proliferations can be confused with reactive mesothelial cell hyperplasia or with a malignant process. We report four cases of histiocytic proliferation, two occurring in the pleura in a 23-year-old woman and a 78-year-old woman, respectively, one in a hernial sac of a 2-year-old boy, and one in the lamina propria of the bladder of a 74-year-old man with a noninvasive papillary transitional cell carcinoma. The morphologic features of the pleural lesion of the 23-year-old woman and of the hernial sac lesion of the 2-year-old boy, as well as the bladder lesion, were similar to those reported in cases of the so-called nodular mesothelial hyperplasia. The pleural lesion in the 78-year-old woman consisted of a proliferation of cells with a signet ring-like morphology that was originally interpreted as either an unusual form of mesothelial hyperplasia or a metastatic signet ring cell adenocarcinoma. Because of mitotic activity and some cellular atypia in the bladder lesion, the possibility of invasive transitional cell carcinoma into the lamina propria was considered before immunohistochemical studies were performed. Staining for keratin showed only a few positive cells in the hernial sac and pleural lesions, whereas most cells reacted for the histiocytic marker CD68. Immunohistochemical studies on the bladder lesion also demonstrated strong staining for CD68, but no reactivity for keratin was observed. Based on these results, it is concluded that all of the lesions are primarily reactive histiocytic proliferations and because they may occur in other locations aside from the serosal membranes, the designation "nodular histiocytic hyperplasia" appears to be more appropriate than that of nodular mesothelial hyperplasia. It is important that the reactive nature of these lesions be recognized because on occasion they may present high mitotic activity or may show signet ring-like morphology and thus they can be confused with a malignancy.