The many faces of acinic cell carcinomas of the salivary glands: a study of 40 cases relating histological and immunohistological subtypes to clinical parameters and prognosis.

AIMS: To study the morphological heterogeneity of acinic cell carcinoma (ACC) in correlation with clinicopathological parameters. METHODS AND RESULTS: Forty well-characterized ACCs were classified as solid (n = 20), microcystic (n = 15), papillary-cystic (n = 4) or follicular (n = 1), based on the dominant architectural growth pattern. Fourteen tumours exhibited eosinophilic/clear cell morphology and 18 tumours were rich in zymogen granules (so-called blue dot tumours). High-grade morphology occurred in five tumours. Based on cytokeratin (CK) 7 staining and in analogy to CK7 expression in normal salivary gland epithelia, three distinct histogenetic subtypes were recognized: acinar (CK7-negative; n = 13), ductular (diffuse CK7-positive; n = 11) and mixed ductulo-acinar (10-66% CK7-positive cells; n = 16). Most papillary-cystic tumours displayed ductular differentiation (P = 0.015), whereas blue dot tumours never did (P < 0.001). Analysis of relapse-free survival (RFS) revealed that Stage I tumours had the best prognosis without any relapse in 18 years follow-up (P = 0.06). High-grade tumours were associated with shorter RFS (P = 0.028). Concerning the histogenetic types, monophasic (pure acinar or ductular) tumours were associated with a significantly better RFS than mixed ductulo-acinar tumours (P = 0.008). CONCLUSION: The results underscore the great histological diversity of ACC, and the value of histogenetic subtyping as an additional prognostic factor regarding RFS.

Pancreatic-type acinar cell carcinoma of the liver: a clinicopathologic study of four patients.

Acinar cell carcinoma of pancreatic type rarely occurs at extra-pancreatic sites. We report four primary liver tumors with features of pancreatic acinar cell carcinoma. The patients were two males and two females with a mean age of 65 years (range, 49-72 years). They had upper abdominal pain, weight loss and/or an incidentally discovered liver mass. None had evidence of a primary pancreatic tumor. Grossly, the tumors were large (mean size, 12 cm), well circumscribed and showed a lobulated cut surface. Histologically, they showed a predominantly microacinar pattern, with occasional trabecular, solid and microcystic areas. Cellular atypia and mitotic activity varied within the same tumor and from tumor to tumor. Immunohistochemically, the tumor cells were positive for cytokeratin 18 and at least one acinar cell marker (ie, trypsin, amylase or lipase), but were negative for cytokeratins 7, 19 and 20, HepPar-1, AFP, CD10, carcinoembryonic antigen, CD56, Islet-1 and CDX2. Two tumors stained focally for synaptophysin and chromogranin A. Adjacent liver parenchyma displayed no evidence of cirrhosis. During a mean follow-up of 22 months (range, 3-38 months) no metastases occurred, but one patient developed local recurrence. Our study demonstrates that acinar cell carcinoma of pancreatic type may also originate from the liver and can be readily distinguished from other primary liver neoplasms by its distinct histological and immunohistochemical features. Because our cases were observed within a rather short period, it is likely that this tumor type is so far underrecognized and has been mistaken as a variant of hepatocellular carcinoma, cholangiocarcinoma or any other liver tumor.

IL-10 expression by primary tumor cells correlates with melanoma progression from radial to vertical growth phase and development of metastatic competence.

Downregulation of the immune system facilitates tumor progression at different stages of cutaneous melanoma. Sentinel nodes, the first lymph nodes on lymphatics draining directly from a primary melanoma, are immune downregulated by tumor-generated immunosuppressive cytokines, including interleukin-10 (IL-10). To better understand the kinetics of sentinel node suppression, we investigated IL-10 expression by melanoma cells and tumor-associated macrophages and lymphocytes at different stages of primary melanoma evolution. We used reverse-transcriptase in situ PCR to identify the cellular sources of IL-10 mRNA in 39 melanomas. IL-10 mRNA was identified in tumor cells of 2 of 6 melanomas in situ (33%), of 17 of 21 invasive melanomas (81%) and of 11 of 12 metastatic melanomas (92%). Higher IL-10 expression correlates with tumor progression, with differences between melanoma in situ, invasive melanoma and metastatic melanoma. In primary melanomas, the IL-10 mRNA content of tumor cells correlates with Clark's level. There was significantly more IL-10 mRNA in vertical growth-phase melanoma cells than in radial growth-phase cells. In a logistic regression model, moderate-to-high IL-10 mRNA expression by tumor cells was significantly associated with vertical growth-phase melanoma. IL-10 mRNA was detected in melanoma-associated macrophages and lymphocytes. In invasive melanomas, IL-10 mRNA reactivity of macrophages decreased as Clark's level increased. Alterations of immunity by IL-10 derived from melanoma cells and melanoma-associated macrophages and lymphocytes potentially facilitate evolution of the primary melanoma and render regional lymph nodes susceptible to metastases.

Distinct biphasic histomorphological pattern in gastrointestinal stromal tumours (GISTs) with common primary mutations but divergent molecular cytogenetic progression.

AIMS: The morphological diversity of gastrointestinal stromal tumours (GISTs) is well appreciated. The aim of this study was to shed light on the molecular pathogenesis of GISTs displaying a distinct biphasic histomorphological pattern, which is poorly understood. METHODS AND RESULTS: Six biphasic gastric GISTs (four high, one intermediate and one low risk for aggressive behaviour) were studied by histological, immunohistochemical, molecular and comparative genomic hybridization methods. The different tumour components were designated as primary and secondary compartments, based on cellularity and mitotic index. In addition, metastases from two patients were analysed separately. According to the classification of Miettinen et al., four biphasic histomorphological patterns were seen: (i) sclerosing spindle cell/dyscohesive or paraganglioma-like epithelioid (n = 2); (ii) sarcomatous spindle cell/pleomorphic sarcomatous spindle cell (n = 1); (iii) sarcomatous spindle cell/sarcomatous epithelioid (n = 2); and (iv) sclerosing epithelioid/hypercellular epithelioid/sarcomatous epithelioid (n = 1) morphology. In each case, both tumour compartments revealed the same KIT (n = 5) or platelet-derived growth factor receptor-alpha (n = 1) mutation, as well as common chromosomal imbalances reflecting their common clonal origin. Additional chromosomal imbalances were detected in the secondary tumour compartments and their respective metastases. CONCLUSIONS: Our results indicate that the intratumoral phenotypic diversity in GIST reflects histomorphological progression, which is associated with higher chromosomal instability, irrespective of the primary mutation.

Lymph node metastasis in gastrointestinal stromal tumours (GIST) occurs preferentially in young patients < or = 40 years: an overview based on our case material and the literature.

PURPOSE: Data on the clinicopathological and biological profiles of gastrointestinal stromal tumours (GISTs) at higher risk for nodal metastasis are lacking. MATERIALS AND METHODS: We reviewed our own case material and the relevant English literature. RESULTS: Regional node metastasis was detected in two of 210 GISTs in our case material (1%) corresponding to 6% of 33 patients with nodal dissection (mean, 11 nodes) and 25% of those < or = 40 years of age. The two patients had a mean age of 32 years, contrasting with a mean age of 65 years for the whole cohort. One of them had incomplete Carney triad with pulmonary chondromas. The literature disclosed a comparable frequency of lymphatic spread among paediatric patients and young adults (approximately 20%), irrespective of the features of the Carney triad. Although a wider age range was reported in isolated reports, a majority (66%) of patients with lymph node metastasis were women < or = 40 years with gastric epithelioid/mixed type ulcerated endoluminal GIST presenting with GI bleeding. CONCLUSION: Contrasting GISTs in elderly patients, lymphatic spread represents a common route of initial spread in patients < or = 40 with gastric GISTs, suggesting the need for node sampling in this particular subset of GIST patients. The prognostic significance of nodal metastasis in GIST patients remains to be further clarified.

Minute gastric sclerosing stromal tumors (GIST tumorlets) are common in adults and frequently show c-KIT mutations.

Multifocal hyperplasia of interstitial cells of Cajal (ICC hyperplasia) is a precursor of hereditary gastrointestinal stromal tumors (GISTs) in patients with germline mutations of c-KIT or PDGFRA, but precursor lesions of sporadic GISTs have not been defined yet. Small hyalinizing stromal tumors of the proximal stomach (referred to in this study as GIST tumorlets) were collected prospectively from 98 consecutive autopsies and additional cases were retrieved from surgical pathology files (total n=57). GIST tumorlets were grossly detectable in 22.5% consecutive autopsies performed in individuals older than 50 years. All lesions were located in the cardia, fundus, or proximal body, and ranged in size from 1 to 10 mm (4 mm). Similar lesions were not detected in the antrum, duodenum, and the remainder of the bowel. Histologically, the spindle cell subtype comprised all cases, with hyalinization and calcification in 57% of cases. The spindle cells were immunohistochemically positive for vimentin, CD117, and CD34. Twenty-four cases yielded sufficient DNA for subsequent molecular analysis, which showed c-KIT mutations in 11 cases (46%) and PDGFRA mutations in 1 case (4%). Sporadic GIST tumorlets of the proximal stomach are common in the general population over the age of 50 years and frequently show somatic c-KIT mutations. GIST tumorlets probably represent the grossly recognizable counterpart of sporadic ICC hyperplasia caused by somatic c-KIT or PDGFRA mutations. Early hyalinization and calcification seems to confer limited growth potential, and complete regression of such lesions is common. GIST tumorlets likely represent preclinical (preneoplastic) lesions that need additional stimuli to evolve into clinical GISTs, raising the possibility of a hyperplasia-neoplasia sequence in the development of sporadic GISTs.

Primary and metastatic high-grade pleomorphic sarcoma/malignant fibrous histiocytoma of the gastrointestinal tract: an approach to the differential diagnosis in a series of five cases with emphasis on myofibroblastic differentiation.

Primary and metastatic so-called malignant fibrous histiocytoma/undifferentiated high-grade pleomorphic sarcoma (MFH) is rare in the gastrointestinal (GI) tract with approximately 50 primary and five metastatic cases reported so far. We evaluated two primary gastric and three metastatic intestinal high-grade pleomorphic sarcomas with features of storiform-pleomorphic MFH. Gastric tumours occurred in a 79-year-old man and a 68-year-old woman. One patient died post-operatively, and the other was disease-free at 6 months. Three patients presented with GI metastasis 24, 60 and 0 months after diagnosis of MFH of the heart (n = 1) and the thigh (n = 2). Metastases were located in the small (n = 1) and large bowel (n = 2) and were characteristically pedunculated and polypoid with oedematous haemorrhagic stroma. Concurrent metastases (brain, lung, bone) were present in all three cases. Tumours expressed alpha-smooth muscle actin (four of five), platelet-derived growth factor receptor (PDGFR) alpha (three of three) and PDGFRbeta (two of three) but were negative for CD117, CD34 and other lineage-specific markers. Ultrastructural examination revealed myo/fibroblastic features. Both gastric MFH were wild type for KIT and PDGFRalpha. In conclusion, primary and metastatic MFH of the GI tract commonly express PDGFRalpha and show a myo/fibroblastic phenotype. They should be distinguished from a variety of primary and metastatic pleomorphic neoplasms, in particular high-grade sarcomatous GI stromal tumours (GIST), pleomorphic leiomyosarcoma, sarcomatoid carcinoma and other mimics.

Epithelioid gastric stromal tumours of the antrum in young females with the Carney triad: a report of three new cases with mutational analysis and comparative genomic hybridization.

Carney triad is a rare non-hereditary condition affecting young females and characterized by metachronous or synchronous occurrence of epithelioid gastrointestinal stromal tumours (GISTs), pulmonary chondroma and extra-adrenal paraganglioma. The genetic alterations in Carney triad-related GISTs have not been well studied. We evaluated GISTs from three females with incomplete Carney triad for KIT and PDGFRA mutations and studied the DNA by comparative genomic hybridization (CGH). All GISTs originated in the antrum and had a monotonous epithelioid morphology. Two patients had GISTs and pulmonary chondroma and one had GISTs and paraganglioma. Initial manifestation was GIST (n=1), pulmonary chondroma (n=1) and bladder paraganglioma (n=1). Time to the second component was 2-13 years. Two patients were alive at 108 and 168 months (one with metastases) and one died of the disease 3 years later. All cases were wild-type for KIT exons 9, 11, 13, 17 and PDGFRA exons 12 and 18. CGH revealed 14 aberrations (mean, 4.7/tumour) including 11 gains (X, 1q, 5p, 8q, 9p, 12p, 13q, 18p, 19q), 2 amplifications (1q, 19p) and one loss (13q). Carney triad-related GISTs do not only lack conventional KIT and PDGFRA mutations, but they also lack the non-random loss of 14q and 22q characteristic of their sporadic counterparts, suggesting an origin through a distinct pathogenetic pathway.

Collision Tumor Composed of Meningioma and Cavernoma.

A true collision tumor is a rare entity composed of two histologically distinct neoplasms coinciding in the same organ. This paper reports a unique case of cerebral collision tumor consisting of two benign components. On the first hand, meningioma which is usually a benign lesion arising from the meningothelial cell in the arachnoidal membrane. On the other, cerebral cavernoma which is a well-circumscribed, benign vascular hamartoma within the brain. To our knowledge, there is no previously documented case of cerebral collision tumor consisting of two benign components. A 56-year-old Caucasian male suffered in 2002 from an atypical meningioma WHO II° located in the left lateral ventricle. Three years after the tumor extirpation, the patient suffered from a hematoma in the fourth ventricle due to a recurrently haemorrhaged cavernoma. In 2008, a recurrence of the tumor in the left lateral ventricle was discovered. Additionally, another tumor located in the quadrigeminal lamina was detected. After surgical resection of the tumor in the left lateral ventricle, the pathological examination confirmed the diagnosis of a collision tumor consisting of components of a meningioma WHO II° and a cavernoma. Postoperatively, no adjuvant treatment was needed and no tumor recurrence is discovered up to the present. A possible explanation for the collision of those two different tumors may be migration of tumor cells mediated by the cerebrospinal fluid. After 5-years of follow-up, there is no sign of any tumor recurrence; therefore, surgical tumor removal without adjuvant therapy seems to be the treatment of choice.

Sporadic Cajal cell hyperplasia is common in resection specimens for distal oesophageal carcinoma. A retrospective review of 77 consecutive surgical resection specimens.

Interstitial cell of Cajal (ICC) hyperplasia has been documented in conditions associated with multiple gastrointestinal stromal tumours (GISTs) (familial GIST syndromes, Carney's triad and von Recklinghausen's disease) and rarely in the vicinity of sporadic GISTs. The incidence of sporadic ICC hyperplasia and the so-called seedling leiomyoma (SLM) of the lower oesophagus has not been studied in the KIT era. In a retrospective review of 77 consecutive, routinely processed oesophagogastric resection specimens for distal oesophageal carcinoma, we found foci of ICC hyperplasia in 7 of 77 (9.1%) cases and foci of SLM in 17 of 77 (22%) cases. Two types of ICC hyperplasia were recognized: a non-circumscribed type and a nodular expansile type with peripherally compressed myenteric neural tissues. All cases of ICC hyperplasia were vimentin+/CD34+/CD117+. SLMs were desmin+/vimentin(-)/CD34(-)/CD117(-), similar to smooth muscles of the gut wall. In a prospective study of 32 non-carcinomatous specimens from age-matched patients (mostly autopsy cases), we found SLMs in only one case, but we were unable to detect ICC hyperplasia in any of the cases. We concluded that sporadic KIT-positive spindle-cell hyperplasia and SLMs were unexpectedly common in distal oesophageal specimens harbouring carcinomas. The possible mechanisms leading to the development of these putative precursor lesions will be discussed.

Epithelioid and sarcomatoid malignant pleural mesothelioma in endoscopic gastric biopsies: a diagnostic pitfall.

Pleural malignant mesothelioma (MM) usually presents with chest pain, pleural effusion, or cough in middle-aged and elderly individuals with a history of asbestos exposure, but may rarely present at unusual metastatic sites. The luminal gastrointestinal (GI) tract is only rarely involved in patients with wide-spread disease at autopsy. Encountering MM in endoscopic GI biopsies is an exceptionally rare event in surgical pathology practice and may therefore pose great diagnostic challenges if not considered, in particular if the clinical history is not informative or the GI symptoms are the presenting signs of the disease. To our knowledge, only three cases of epithelioid mesothelioma (EM) involving the luminal GI tract (intestine) have been reported so far, but no case of sarcomatoid MM (SM) involving the GI mucosa has been described. We herein present the first two cases of MM (one each of EM and SM) of the pleura, presenting in endoscopic gastric biopsies as small polypoid lesions and poorly healing ulcers 30 and 35 months after the initial diagnosis of pleural MM, respectively. The major differential diagnoses encompass primary or metastatic adenocarcinoma in case one and cytokeratin-positive (KIT negative!) GI stromal tumors (GISTs) and sarcomatoid carcinoma in case two, as well as other rare entities.

Follicular dendritic cell tumor of the gastrointestinal tract: Report of a rare neoplasm and literature review.

Follicular dendritic cell (FDC) tumor is a rare neoplasm of the accessory immune system showing FDC differentiation. Histologically, a conventional type and an inflammatory pseudotumor (IPT-like) type are recognized. The etiology of FDC tumor is unknown. While rare FDC tumors were associated with hyaline-vascular Castleman's disease (HVCD), hepatosplenic IPT-like FDC tumors consistently harbor EBV infection. FDC tumors of the gastrointestinal (GI) tract and mesentery/omentum are exceedingly rare, with only 17 cases reported so far. We report an additional case of an IPT-like FDC tumor of the ileum and mesentery in a 52-year-old schizophrenic man. The tumor consisted of highly atypical multinucleated giant cells in a background of intense lymphoid infiltrate with prominent eosinophilia reminiscent of Hodgkin's lymphoma. Tumor cells were immunoreactive for vimentin, CD21, CD35, fascin, smooth muscle actin and CD68, but were negative for all lineage-specific lymphoreticular, myeloid, mesenchymal and epithelial markers. Immunostaining for HHV-8 and in situ hybridization for EBV-encoded RNA (EBER) were negative. Some mesenteric lymph nodes showed HVCD-like changes. The differential diagnostic considerations of this unusual and rare neoplasm, mainly lymphocyte-rich GI stromal tumor (GIST), malignant lymphoma and inflammatory neoplasia of diverse histogenetic types, will be discussed together with a literature review on gastrointestinal FDC tumors.

Occurrence of other malignancies in patients with gastrointestinal stromal tumors.

Almost one-third of gastrointestinal stromal tumors (GISTs) are discovered incidentally during investigative or therapeutic procedures for unrelated diseases. In this regard, GISTs may coexist with different types of cancer, either synchronously or metachronously. The frequency of this association and the spectrum of neoplasms involved have not been sufficiently analyzed. We conducted a review of the literature and our own records for cases with sporadic GISTs and other malignancies, with emphasis on solid tumors. Neurofibromatosis 1 and Carney triad-associated tumors were excluded. Based on these data, there were 518 cancers in 486 GIST patients among 4813 cases with informative data. The overall frequency of second tumors in different series varied from 4.5% to 33% (mean, 13%). A total of 29 patients had multiple malignancies. GISTs of gastric location were most commonly involved with other neoplasms, reflecting their overall high frequency (60%) of all GISTs. The major types of GIST-associated cancers were gastrointestinal carcinomas (n=228; 47%), lymphoma/leukemia, (n=36; 7%), and carcinomas of prostate (n=43; 9%), breast (n=34; 7%), kidney (n=27; 6%), lung (n=26; 5%), female genital tract (n=25; 5%), and carcinoid tumors (n=13; 3%). Other cancers included soft tissue and bone sarcomas (n=15; 3%), malignant melanoma (n=12; 2%), and seminoma (n=6; 1%). Occurrence of collision tumors and metastases of carcinoma or sarcoma into a GIST (the latter noted in 4 cases) can be challenging diagnostic problems. The potential nonrandom association and causal relationship between GIST and other neoplasms remain to be investigated.

Lack of association between the functional CX3CR1 polymorphism V249I and hepatocellular carcinoma.

Chemokine production by cancer cells constitutes a duality. Leukocyte recruitment under the pressure of chemokines may be beneficial for the host or for the tumor. Recently, the chemokine fractalkine and its receptor CX3CR1 have been shown to be expressed in hepatocytes in vivo and in a human hepatocarcinoma cell line in vitro. Therefore, the aim of this study was to analyze the expression of CX3CR1 in hepatocellular carcinoma (HCC) in vivo and to investigate the prevalence of the genetic CX3CR1 polymorphism V249I in HCC patients since this polymorphism has been associated with reduced number of fractalkine binding sites, reduced cell-cell adhesion and decreased signaling and chemotaxis. Genotyping was performed in 183 patients with histologically proven HCC and 99 healthy controls by RFLP-analysis. The frequency of the individual genotypes was similar in HCC patients and controls. The V249I polymorphism revealed no association with tumor grade and stage, the presence of extrahepatic metastasis or the degree of fibrosis in non-tumorous tissue. In addition to genotyping, CX3CR1 mRNA expression was analyzed by quantitative PCR in 9 HCC specimens and in 6 cases in corresponding non-tumorous liver tissues. CX3CR1 mRNA expression levels in HCC showed high variation between individual patients. Similarly, expression in HCC compared to non-tumorous liver varied, from strong downregulation to remarkable upregulation. CX3CR1 mRNA expression levels showed no correlation to the V249I polymorphism. In summary, these results suggest that the patho-physiological role of individual chemokines in carcinogenesis may vary and that the functional CX3CR1 polymorphism V249I is no genetic risk factor for HCC. However, additional independent studies in HCC patients with different ethnic background will be needed to confirm the present study and to elucidate the functional role of CX3CR1 and its polymorphism V249I in chronic liver disease and hepatocarcinogenesis.

Superiority of combined chemo-embolization and portal infusion with 5-fluorouracil over locoregional infusion concepts in Novikoff hepatoma-bearing rats.

The aim of this study was to investigate experimentally whether there is a superior effect of the combination of hepatic artery chemo-embolization with portal vein infusion over either of the two treatment modalities alone. Novikoff hepatoma cells transplanted under the liver capsule of Sprague Dawley rats were used as a model. Tumor growth was assessed at 7 and 21 days after tumor inoculation. The prolamine solution Ethibloc was employed for embolization, and 5-fluorouracil was used as a chemotherapeutic agent for both infusion and chemo-embolization. All arterial treatment modalities were administered in a super-selective manner. There was no intolerable toxicity after dosages of 55 to 125 mg 5-fluorouracil/kg body weight. With regard to therapeutic efficacy the results show that embolization is an effective therapeutic means for inducing tumor necrosis in selected liver areas. As a consequence, the ranking of all treatment modalities was based on the combined evaluation of tumor size and extent of tumor necrosis. According to this evaluation, hepatic artery chemo-embolization was superior to the respective type of infusion (P<0.01). In addition, the combination of both modalities in the form of hepatic artery chemo-embolization and portal vein infusion was effective in destroying more than 97% of vital tumor tissue (P<0.01). These results suggest the need for a comparative clinical study.

Impact of serosal involvement/extramural growth on the risk of synchronous and metachronous peritoneal spread in gastrointestinal stromal tumors: proposal for a macroscopic classification of GIST.

BACKGROUND: Peritoneal and hepatic metastases are the main routes of spread of gastrointestinal stromal tumors (GIST). However, criteria to predict the site and pattern of recurrence in individual cases are still lacking. PATIENTS: We retrospectively analyzed 67 consecutive GISTs with complete gross descriptions to correlate macroscopic patterns with clinical course. Primary endpoint was the appearance of synchronous or metachronous peritoneal disease. Tumors were classified into type I (luminal/intramural) and type II (extramural) based on the macroscopic/histologic presence or absence of normal tissue between deeper tumor border and serosa, respectively. RESULTS: Patients were 35 men and 32 women (mean age, 64 yrs) with gastric (n=32), small bowel (n=30) and large bowel (n=5) GISTs. Based on the above proposal, 22 tumors were classified as type I and 45 as type II. Type I tumors were predominantly gastric (18/22; P<0.001) and frequently had very low/low risk (14/22; P<0.001) whereas type II tumors were predominantly intestinal (31/45; P<0.001) and often of intermediate/high risk (36/45; P<0.001). Ten patients had synchronous peritoneal spread and 6/30 patients with a mean follow-up of 29 months developed metachronous peritoneal spread at a mean of 27 months. Tumor rupture was seen in 2 patients (3%). Thus, 16/40 patients (40%) had synchronous or metachronous peritoneal progression. Taken by gross type, peritoneal progression was seen in 15/30 type II compared to 1/10 type I tumors (p=0.032). CONCLUSION: this study points to extramural growth as a predictor of peritoneal recurrence in GIST, probably as a consequence of tumor rupture or due to microscopic serosal penetration. This study aimed at alerting surgical pathologists to the importance of careful gross and microscopic assessment of resection specimen harboring GIST to allow for reliable prospective evaluation of serosal involvement as an adverse prognostic factor in GIST.

Effect of EpCAM, CD44, CD133 and CD166 expression on patient survival in tumours of the ampulla of Vater.

BACKGROUND: Carcinomas of the Vaterian system are rare and presumably arise from pre-existing adenomas. According to the cancer stem cell (CSC) hypothesis, only a small subset of tumor cells has the ability to initiate and develop tumor growth. In colorectal cancer, CD44, CD133, CD166 and EpCAM have been proposed to represent CSC marker proteins and their expression has been shown to correlate with patient survival. AIMS: To evaluate a potential role of these CSC proteins in tumors of the ampulla of Vater, we investigated their expression in 175 carcinoma, 111 adenoma and 152 normal mucosa specimens arranged in a Tissue Microarray format. MATERIALS AND METHODS: Membranous immunoreactivity for each protein marker was scored semi-quantitatively by evaluating the number of positive tumor cells over the total number of tumor cells. Median protein expression levels were used as cut-off scores to define protein marker positivity. Clinical data including survival time were obtained by retrospective analysis of medical records, tumor registries or direct contact. RESULTS: The expression of all evaluated marker proteins differed significantly between normal mucosa, adenoma and carcinoma samples. In all markers, we found a tendency towards more constant expression from normal to neoplastic tissue. EpCAM expression was significantly correlated with better patient survival. The increased expression of CD44s, CD166 and CD133 from normal mucosa samples to adenoma and carcinoma was linked to tumor progression. However, there was no statistically significant correlation with survival. CONCLUSION: Our findings indicate, that in ampullary carcinomas, loss of expression of EpCAM may be linked to a more aggressive tumor phenotype.

Adenomatoid tumors of the female and male genital tract. A comparative clinicopathologic and immunohistochemical analysis of 47 cases emphasizing their site-specific morphologic diversity.

Adenomatoid tumors (ATs) are uncommon benign mesothelial tumors with a predilection for the genital tract. We reviewed 47 ATs diagnosed at our institutions during 10-year period. Thirty tumors (64%) originated in the female (21 uterine, 8 tubal, and 1 ovarian) and 17 (36%) in the male (9 epididymal and 8 testicular) genital tract. The median age for females and males was 47.5 and 51 years, respectively. While 83% of tumors in females were incidental findings in resections for unrelated diseases, 94% of male lesions presented as clinical masses leading to surgery. The median size was 2, 1, and 0.5 cm for uterine, epididymo-testicular, and tubo-ovarian lesions, respectively. Architecturally, the microcystic/angiomatoid pattern was the most frequent (32/47; 68%), followed by combined microcystic/trabecular (26/47; 55%) and retiform/adenoid (15/47; 32%) pattern. The trabecular/solid (6%) and macrocystic (4%) patterns were uncommon. However, 57% of cases revealed ≥2 growth patterns. Taken by anatomic site, 20 of 21 uterine cases were at least focally microcystic but none was retiform. In contrast, the retiform pattern dominated in male genital tract tumors (12/17; 71%). Immunohistochemistry showed expression of calretinin (36/36) and D2-40 (30/30) and lack of CD34 (0/30) and PAX8 (0/32). GLUT-1 was expressed in 11/11 male genital tract tumors but in none of the microcystic uterine lesions. Estrogen and progesterone receptor expression was weak and focal (two and three uterine cases, respectively). None stained for the androgen receptor. Our study illustrates the great site-specific morphological diversity of ATs emphasizing their wide site-dependent differential diagnosis.