Issue 4 - August 2010 - Pacini Editore

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lectures The EC patients with abnormal IHC results are referred for a genetic evaluation including MSI analysis, if indicated a methylation test and mutational analysis of the screened genes. references Garg K, Leitao M, Kauff N, et al. Selection of endometrial carcinomas for DNA mismatch repair protein immunohistochemistry using patient age ansd tumor morphology enhances detection of mismatch repair abnormalities. Am J Surg Pathol 2009;33:925-33. Garg K, Soslow RA. Lynch Syndrome (hereditary non-polyposis colorectal cancer) and endometrial carcinoma. J Clin Pathol 2009;62 679- 84. Karamurzin Y, Rutgers KL. DNA Mismatch Repair Deficiency in endometrial carcinoma. Int J Gynecol Pathol 2009;28,3;239-52. Resnick K, Straughn JM, Backes F, et al. Lynch Syndrome screening strategies among newly diagnosed endometrial cancer patients. Obstet Gynecol 2009;114:530-6. lynch syndrome and new model of individualized gynaecological cancer prevention M.G. Tibiletti U.O. Anatomia Patologica Ospedale di Circolo, Università dell’Insubria Varese Lynch syndrome (LS), or hereditary non-polyposis colorectal cancer (HNPCC), is an autosomal dominant syndrome (MIM) that predisposes its carriers to multiple malignancies including colorectal cancer (CRC), endometrial cancer (EC), ovarian cancer (OC), and cancer of the renal pelvis and ureter, stomach, pancreas, small bowel and brain. Traditionally Lynch syndrome has been perceived as a CRC dominated syndrome. However, in women with Lynch syndrome, the incidence of EC equals or exceeds that of CRC, and in more than 50% of cases, these women present a gynaecological cancer as their first malignancy. LS is caused by a germline mutation in one of the DNA mismatch repair genes: MLH1, MSH2, MSH6, and PMS2. Deficient mismatch repair protein activity leads to DNA microsatellite instability (MSI) and absent immunoistochemical protein expression in tumour tissue. This pattern of abnormal staining provides guidance as to which of the MMR genes is likely to harbour a germline mutation. 143 The initial (1991) and revised (1998) Amsterdam criteria were developed to identify families at high risk for LS. These criteria required colorectal or other LS-associated cancers in three first- degree relatives, occurring in at least two successive generations, and in one individual under the age of 50 years. These criteria were recognized to have poor sensitivity in identifying individuals carrying an LS gene mutation. Therefore, the Bethesda guidelines were introduced to broaden testing recommendations and to identify a greater proportion of affected individuals. The Bethesda guidelines recommended molecular testing for LS in different groups of patients including two gynaecologic cancer populations: patients with endometrial cancer diagnosed before 45 years of age and those with two LS-related cancers. In 2006 an European group of experts in LS established guidelines for the clinical management of LS (Mallorca guidelines J Med Genet 2007) in order to improve the identification and the care of these families. Identification of LS in affected individuals has important implications for screening in individuals as well as family members, as close screening and surveillance has been shown to reduce the mortality of colorectal cancer by over 60%. The frequency of germline DNA mismatch repair gene mutations among unselected patients with EC has been found to be 1.8% to 2.1% which is similar to the frequency of LS in colorectal carcinoma. In patients younger than 50 years, the incidence is increased up to 9%. The identification of these patients is important for several reasons. Affected patients are at risk for multiple synchronous and metachronous tumors. These individuals would therefore benefit from surveillance measures to detect other LS associated tumours; their family members may benefit from genetic testing to determine carrier status and to have adequate surveillance measures. references Meyer LA, et al. Endometrial cancer and Lynch Syndrome: Clinical and pathological considerations. Cancer Control 2009;16:14-22. Vasen H, et al. Guidelines for the clinical management of Lynch syndrome (HNPCC). J Med Genet 2007;44;353-62. Walsh CS, et al. Lynch syndrome among gynecologic oncology patients meeting Bethesda guidelines for screening. Gynecon Oncol <strong>2010</strong>;116:516-21. Pathologica symposium: new frontiers in immunohistochemistry Immunoprofile of renal tumors D. Segala, M. Brunelli, G. Martignoni Department of diagnostic pathology, University of Verona, Verona, Italy The WHO 2004 classification of renal cell neoplasms includes numerous entities characterized by different prognosis and the correct subtyping is an important procedures to predict the behavior of these tumors. Among major renal histotypes, oncocytoma has the best prognosis followed by chromophobe, papillary, clear cell and collecting duct renal cell carcinomas (RCCs) 1-4 . The overlapping morphological features and the increasing description of novel potential entities determine the difficulties of some histologic distinctions. That is why traditional histology needs today the support of more specific markers that should be consistently detected also on small biopsies. In fact, new minimal invasive forms of therapies, such as criotherapy and diathermocoagulation will require a pre-operative diagnosis 5 6 . Moreover, reliable predictive factors are essential for the stratification of patients into clinically meaningful categories. Staging has recently improved with the development of integrated systems 7 8 , however the information obtained by molecular tumor markers are expected to revolutionize the staging of RCC. Immunohistochemistry is the most easily available and not expensive ancillary technique used by pathologists, therefore it is the most important field to be improved. Diagnostic immunohistochemical markers Clear cell renal cell carcinoma. Clear cell RCC is immmunohistochemically characterized by a high positive rate for CD10 (82%) 9-11 . In our experience also CD13 is a good immunohistochemical marker of clear cell renal cell carcinoma being positive in 81% 12 . Most clear cell RCCs typically show
144 a restricted expression pattern of cytokeratins (CK) with limited cases expressing CK7, CK8, CK19, high weight CKs and a large portion of cases positive for CK18 13 14 . Parvalbumin was found to be constantly absent 10 . Alpha-methylacyl-CoA racemase (AMACR) positivity has been detected in 25% whereas S100A1 immmunostaining has been observed in 75% of the cases 15 16 . Around more than a half of the clear cell RCCs reveals immunoreactivities for vimentin, RCC Marker and Epithelial Membrane Antigen (EMA) 9 14 17 . Papillary renal cell carcinoma. Papillary RCCs typically express CK7 (87%), 8, 18 and 19, Vimentin (90%) and they constantly show AMACR immunostain 14 15 18 . CK7 expression is more frequently observed in type 1 (87-100%) than type 2 (20-50%) 18 such as EMA (type 1 ranging from 72 to 100% and type 2 from 13 to 17%) 17 19 whereas E-cadherin is reported predominantly in type 2 17 . An high incidence of positivity for CD10 (59-90%), BerEP4, EMA and RCC Marker is reported 10 20 . S100A1 is reported in 92% of papillary RCCs 16 which occasionally express high molecular weight CKs (26%) 11 . Chromophobe renal cell carcinoma. Chromophobe RCCs is strongly positive for parvalbumin in all primary and metastatic tumors 21-23 . Chromophobe RCCs are also positive for CK7 in 73-100% of the samples 13 14 . CD10 expression has been found in 26% of chromophobe RCCs, five of the seven (71%) showing aggressive features 10 . CKs 8, 18, EMA and E-cadherin are frequently positive whereas chromophobe RCCs do not usually express vimentin 13 14 17 24 . Immunohistochemical membrane expression of c-KIT is frequently found in chromophobe RCC however c-kit mutation has not been found 25 . AMACR is usually not expressed and only 4% of chromophobe RCCs are positive for S100A1 15 16 . Collecting duct carcinoma. The immunohistochemical profile of these carcinomas shows high molecular weight CKs, EMA, vimentin, lectin Ulex europaeus agglutinin and peanut lectin agglutinin (Arachis hypogaea) immunostain 26 . Oncocytoma Most of oncocytomas are immunoreactive for CKs (86%), EMA (86%), E-cadherin (71%), parvalbumin (70%) and c- KIT (100%) 13 14 17 21 27 28 . Vimentin and RCC marker are usually not expressed 14 . Althought contrasting results have been reported for CK7 in renal oncocytoma, it actually seems that only a focal immunoreactivity of a few cells can be found 29 30 . S100A1 is expressed in 92% of this neoplasm 16 . Renal mucinous tubular and spindle cell carcinoma. This histotype immunostains for CKs (CK5/6, 7, 8, 13, 14, 17, 18, 19, 20), high molecular weight CKs 1, 5, 10, 14, E-cadherin and vimentin, but CD10 and RCC marker are usually not expressed 31-33 . Immunoreactivity for AMACR (93%), CK7 (81%) and EMA (95%) have also been reported 33 . TFE-family translocation renal cell carcinomas. TFE-family translocation renal cell carcinomas bear specific translocations that results in overexpression of TFE3 or TFEB, genes that are strictly related to microphtalmia transctiption factor (MiTF). Different translocations involving chromosome Xp11.2 bring TFE3 fusion gene product overexpression, whereas TFEB overexpression is the result of the specific translocation t(6;11)(p21;q12). Immunohistochemistry for TFE3 and TFEB is the most reliable test able to distinguish TFE-family translocation renal cell carcinomas from formalin-fixed and paraffin-embedded archive tissue, but sometimes troubles using these antibodies have been reported. These tumors were also consistently im- 5 th triennial congress of the italian society of anatomic Pathology and diagnostic cytoPathology munoreactive for the RCC antigen and CD10 and negative or focally positive for citokeratins 34-37 . Our group have recently described the immunohistochemical expression of Cathepsin-K, a protein described in osteoclasts to be modulated by the expression of MiTF, in 17 cytogenetically demonstrated TFE3 and TFEB renal cell carcinomas and in a large group of renal tumors 38 . Cathepsin-K was positive in all TFEB renal cell carcinoma and in 60% of TFE3 renal cell carcinomas, whereas all other renal tumors were negative. Therefore cathepsin-K could be a useful marker alternative to TFE3 and TFEB. End-stage renal disease associated tumors. Tumors arising in kidneys with end-stage renal disease include those resembling sporadic renal tumors such and tumors distinct from them that Tickoo at al named “acquired cystic diseaseassociated renal cell carcinoma” and “clear cell papillary renal cell carcinoma of the end-stage renal kidneys” 39 . This last neoplasms seem to display distinctive histologic features not easily referable to the histotypes described in the WHO 2004 classification system. Clear-cell papillary renal cell carcinoma of the end-stage kidney, unlike papillary RCC, were costantly negative for AMACR, but unlike clear-cell RCC all tumors tested showed strong immunoexpression for CK7 39 . Gobbo et al. found similar tumors in normal kidneys 40 . They also observed the lack of immunoexpression of CD10. Tumors with a strict related immunohistochemical pattern and similar morphological features have also been recently described and called RCC with prominent angioleiomyomatous proliferation 41 . This tumors are characterized by a various grade of stromal proliferation beside the epithelial structures. To date the correlation between these two entities is not already demonstrated. Prognostic molecular markers Nomograms assigning numerical scores to various clinical and pathological prognostic indicators, excluding molecular markers, has been proposed, however a wide variety of molecular markers have been examined and some seem promising to legitimize further research to prove their value as prognostic tools. Among tumour suppressor genes p53 overexpression has been described as a significant molecular predictor of tumor recurrence, especially in clear cell RCC and the loss of p27/kip1 expression is described as a possible prognostic and diagnostic marker of tumor development and/or progression 42-44 . Ki-67 proliferation index has been shown to be a prognostic factor in both univariate and multivariate analysis, although conflicting evidence has challenged these findings 45 46 . COX-2 expression in patients with renal cell carcinoma is associated with several clinicopathological factors, and appeared to play an important role in tumor cell proliferation, but is not a significant prognostic factor 47 48 . The adipose differentiation-related protein (ADFP) is a lipid storage droplet-associated protein and its transcription is considered to be regulated by the von Hippel-Lindau/hypoxia-inducible factor pathway. ADFP expression status may provide useful prognostic information as a biomolecular marker in patients with clear cell RCC 49 . Decreased carbonic anhydrase IX (CAIX) levels are independently associated with poor survival in advanced RCC. CAIX reflects significant changes in tumor biology, which should be used to predict clinical outcome and identify high-risk patients in need for adjuvant immunotherapy and CAIX-targeted therapies 50 .
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lectures Azienda sanitaria dell’A
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lectures The Convention on Human Ri
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lectures Case n. 1 Aggressive psamm
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lectures of benign or malignant sub
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lectures Deficit of DNA mismatch re
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238 ultrastructural features. Lung
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240 Dideoxysequencing. The DNA to b
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242 of error. Nevertheless, the num
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244 Background. In cases of breast
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246 Background. TNM stage I CRC is
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248 Background. We evaluated the ex
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250 Armstrong C (eds). Myology. Thi
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252 to report the occurrence of the
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254 ovarian SCC HC-type showed nucl
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256 predisposition for Eastern and
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258 and prominent nucleoli. Areas o
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260 sarcoma in a young lady which w
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262 Methods. p-AKT (Ser473) and p-m
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264 cell cycle during G1-S. Additio
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266 up: the patient was given cours
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268 The mosaic pattern of INI1/SMAr
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270 Incidence of O6-methylguanine D
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272 leiomyomas are usually found bo
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274 drial disorder which involves t
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276 CLDN5 is claimed to be specific
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278 Results 1 st year (179 nodules)
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280 6)Anatomia Patologica Ed Oncolo
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282 Udine, Italy 6)Department of On
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284 Aberrant S-100 protein expressi
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286 phy white respect to lesion int
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288 a bulk of wt tumor could impact
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290 to the primary OSCC and develop
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292 peared to be encapsulated. On c
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294 ate intensity. Lack of EGFR and
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296 Analysis of microsatellite inst
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298 IDH-1/IDH-2, TP53, and C-MYC/N-
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300 Thus, it is possible that the h
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302 feasibility of fluorescence in
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304 sina, Italia 4)Dipartimento Di
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306 The histological analysis highl
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308 demonstrated no significative r
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310 rhage, acute tubular necrosis,
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312 performed in order to exclude t
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314 use of IGK gene rearrangement a
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316 evaluation of DNA ploidy in car
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318 is considered to be normal. To
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320 Conclusioni. Dall’analisi del
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322 Pelvic epidermal cyst of the ro
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324 sive recent hemorrhage was seen
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326 expression of HMlH1 and HMSH2 i
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328 Kaushik D, Gulamjat SM, Thangja
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330 Results. The gastric lesion (7
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332 Methods. Macroscopically, left
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334 Spontaneous cutaneous cholester
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336 leptogenesis 3 but this possibi
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338 Complete cytoreduction and hype
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340 alternative NFKB pathways. On t
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342 Primary synovial sarcoma of kid
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344 Solitary extramedullary plasmac
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346 type (p < 0.05), with a prevale
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348 Squamous metaplasia was weakly
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350 in 3.3%). P63 gene gain was fou
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352 BCl10 expression in peripheral
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354 Breast lump in a male, first ma
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356 blastema compared to the neopla
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358 lack fat and are associated wit
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360 neuroendocrine tumors arising i
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362 latory cytokine/chemokine gene
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364 references 1 Capella C, Solcia
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366 Methods. Gastric biopsy routine
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368 sential prerequisite to make an
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370 nodule (DN)”, is commonly bel
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372 Summary of results. By studying
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374 (C5) was 60%, because C4 cases,
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376 composed of ammonium acid urate
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378 Background. Spindle cell lipoma
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380 TCl1A and MNDA expression in sp
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382 Methods. Immunohistochemistry w
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Pathologica 2010;102:385-390 AuTHOr
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author indeX Faquin W., 310 Faralli
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author indeX Pandolfi P.P., 370 Pan
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Issue 4 - August 2010 - Pacini Editore

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