Virchows Archiv

Mazzucchelli, Roberta; Barbisan, Francesca; Tagliabracci, Adriano; Lopez-Beltran, Antonio; Cheng, Liang; Scarpelli, Marina; Montironi, Rodolfo

doi: 10.1007/s00428-007-0367-xpmid: 17285325

Reported incidence of no residual prostate cancer (i.e. pathological stage pT0) on radical prostatectomy ranges from 0.07 to 4.2%. The incidence is higher after neoadjuvant endocrine treatment. The aim of this study was to search for residual cancer on radical prostatectomy (RP) specimens when an initial sampling failed to find the cancer in patients with positive biopsy. Our database of 1,328 consecutive patients whose biopsies and RP specimen were both examined at the Polytechnic University-United Hospitals of the Marche Region between March 1995 and June 2006 was reviewed. The radical prostatectomies were grossly completely sampled and examined with the whole mount technique. We identified eight patients (i.e. 0.6%; three untreated and five hormonally treated preoperatively, i.e. 0.3 and 0.8%, respectively, of the total number of RPs included in the study) with positive biopsy and with no residual cancer in the initial routine histological examination of the RP. The RP of this group of eight was subjected to additional sectioning and evaluation of the paraffin blocks of the prostatectomy, also after block-flipping, immunostaining with an antibody against CAM 5.2, p63, PSA, and alpha-methylacyl-CoA racemase, and DNA specimen identity analysis. There were no cases with a false positive biopsy diagnosis, and cancer was not overlooked or missed in the initial routine histological examination of any of the 8 pT0 RPs. A minute focus of cancer (the diameter was always below 2.0 mm) was found on the additional sections in five. In particular, cancer was found after block-flipping in one of them. In an additional case, cancer was eventually discovered after immunostaining tissue sections for cytokeratin CAM 5.2, for p63 and PSA. In the remaining two cases (one untreated and the other hormonally treated), cancer was not found (0.15% of the 1,328 RPs included in the study); the review of the description of the macroscopic appearance of the RP and of its slides revealed that part of the peripheral zone corresponding to the site of the positive biopsy was missing, i.e. not removed from the patient at the time of the operation at least in one of the two. DNA specimen analysis confirmed the identity of the biopsy and prostatectomy in both. An extensive search for residual cancer reduces the number of pT0 RPs after a positive biopsy from 0.6 to 0.15%. It is recommended to have the needle biopsy reviewed, carefully look again at the radical prostatectomy, do deeper sections and then flip certain paraffin blocks. In addition, atypical foci should be stained for basal cell markers and often AMACR, especially in hormone-treated cases. If a block is missing part of the peripheral zone (capsular incision), this should be commented on. DNA analysis for tissue identity should be performed when the other steps have been taken without finding cancer.

Pinto, Mafalda; Soares, Maria; Cerveira, Nuno; Henrique, Rui; Ribeiro, Franclim; Oliveira, Jorge; Jerónimo, Carmen; Teixeira, Manuel

doi: 10.1007/s00428-007-0386-7pmid: 17333263

Papillary and chromophobe renal cell carcinomas are characterized by multiple trisomies and monosomies, respectively, but the molecular mechanisms behind the acquisition of these numerical chromosome changes are unknown. To evaluate the role of mitotic checkpoint defects for the karyotypic patterns characteristic of these two renal cell cancer subtypes, we analyzed the messenger RNA expression levels of the major mitotic checkpoint genes of the budding uninhibited by benzimidazole family (BUB1, BUBR1, BUB3) and of the mitotic arrest deficiency family (MAD1, MAD2L1, MAD2L2) by real-time quantitative polymerase chain reaction in 30 renal cell cancer samples (11 chromophobe and 19 papillary) and 36 normal kidney tissue samples. MAD1, MAD2L1, and MAD2L2 showed significant expression differences in tumor tissue compared to controls. Chromophobe tumors presented underexpression of MAD1, and MAD2L2, whereas papillary tumors showed overexpression of MAD2L1. The expression level of the BUB gene family did not differ significantly from that of normal kidney. We conclude that expression changes in mitotic arrest deficiency genes (MAD1, MAD2L1, and MAD2L2) play a role in renal carcinogenesis characterized by multiple numerical chromosome abnormalities.

Woenckhaus, Joachim; Steger, Klaus; Sturm, Klaus; Münstedt, Karsten; Franke, Folker; Fenic, Irina

doi: 10.1007/s00428-006-0358-3pmid: 17377809

Disrupted phosphatidylinositol 3-kinase (PI3K) activity and its effect on the downstream target AKT plays an important role in malignant diseases. Gain and/or amplification of PIK3CA gene, encoding the catalytic subunit of phosphatidylinositol 3-kinase (p110α) and its increased expression are associated with enhanced PI3K activity in ovarian cancer cell lines. In this study, ovarian carcinomas with documented clinical outcome were assessed for genetic aberrations at the 3q26.3 locus, including PIK3CA, by fluorescence in situ hybridization. PIK3CA amplification was evaluated by quantitative real-time PCR with respect to a control gene situated at 3q13. The expression of p110α, phosphorylated AKT (pAKT) and the proliferation marker Ki-67 were immunohistochemically investigated. PIK3CA amplification and Ki-67 index were strong predictors for an early tumour-associated death. p110α expression correlated with 3q26.3 gain and Ki-67 index but not with the patient outcome. No relationship could be observed between p110α and pAKT or between pAKT and disease outcome. It is interesting to note that cases with a nuclear pAKT immunoreactivity showed a trend of improved overall survival. Our results underline the prognostic significance of PIK3CA in ovarian carcinoma and argue against a simple linear model of PIK3CA gain/amplification followed by PI3K activation and consecutive AKT phosphorylation in ovarian carcinoma.

Kasashima, Satomi; Kawashima, Atsuhiro; Zen, Yoh; Ozaki, Satoru; Kobayashi, Masako; Tsujibata, Akihiko; Minato, Hiroshi

doi: 10.1007/s00428-007-0381-zpmid: 17333267

The clinicopathological profiles of histiocytoid carcinoma of the breast have not been well examined because of their rarity and heterogenous groups of ductal and lobular origin. A large foamy or granular cytoplasm of histiocytoid carcinoma was characterized by abundant mucin, but the properties of mucin in histiocytoid carcinoma have also not been well investigated. We selected eight cases of histiocytoid features of invasive lobular carcinoma (HLC) and compared with 14 age- and tumor size-matched cases of classical invasive lobular carcinoma (CLC). Mucin profiles were significantly different between the two groups: a fair number of HLC cases were immunopositive for MUC2 and MUC5AC (75 and 50%, respectively); in contrast, almost all CLC cases showed both as negative. Both groups were immunopositive for MUC1 and negative for MUC4 and MUC6. The prognosis of HLC was significantly worse than CLC; HLC showed shorter disease-free time than CLC (p = 0.0262). In particular, HLC with MUC2 and MUC5AC expressions showed significantly shorter disease-free time and survival time than lobular carcinoma without the expressions of MUC2 and MUC5AC (p = 0.0055 and p = 0.0060, respectively). Therefore, the expression of ‘non-mammary mucins’, such as MUC2 and MUC5AC in HLC, is characteristic and indicates the more malignant transformation of tumor cells and poorer prognosis.

Peron, Jean-Marie; Danjoux, Marie; Kamar, Nassim; Missoury, Réda; Poirson, Hélène; Vinel, Jean-Pierre; Mansuy, Jean-Michel; Bureau, Christophe; Izopet, Jacques; Brousset, Pierre; Selves, Janick

doi: 10.1007/s00428-007-0382-y

Musso, Carlos; Castelo, Jane; Tsanaclis, Ana; Pereira, Fausto

doi: 10.1007/s00428-007-0388-5pmid: 17333262

The aim of this investigation was to study the frequency of visceral larva migrans (VLM) granulomas in autopsies at a Children’s Reference Hospital in Vitoria, ES Brazil, where anti-Toxocara antibodies are frequently detected in the serum of children admitted at the hospital. Two liver fragments from 310 autopsies of children aged between 1 and 15 years were paraffin embedded, and sections were stained with hematoxylin and eosin and submitted to detection of Toxocara antigens using a rabbit anti-Toxocara serum. Among the 24 cases with granulomatous lesions, ten had eosinophil-rich granulomas positively stained with the anti-Toxocara serum. Some were typical epithelioid granulomas, with a positive reaction in multinucleated giant cells, epithelioid cells, or necrotic debris. The results showed that VLM granulomas are the most frequent granulomatous hepatitis in children in our county. This agrees with the high prevalence of anti-Toxocara antibodies in the serum of children admitted to the Children’s Reference Hospital. The 3.2% frequency of liver VLM granulomas in autopsies is less than the 30–39% frequency of positive serology in these children, probably reflecting the low larval burden in infected children.

Compérat, E.; Camparo, P.; Haus, R.; Chartier-Kastler, E.; Radenen, B.; Richard, F.; Capron, F.; Paradis, V.

doi: 10.1007/s00428-007-0383-xpmid: 17333265

Aurora-A, a member of serine/threonine kinase, is implied in mitosis and centrosome maturation. Increasing levels of Aurora-A have been shown to be present in several malignancies and especially in bladder cancer. No immunohistochemical marker has shown to be able to predict the clinical outcome of patients with superficial bladder cancer, except MIB-1, as a predictive marker of relapse and progression. The aim was to investigate the expression of Aurora-A and MIB-1 in tissue micro arrays of superficial bladder cancer representative of pTa papillary urothelial neoplasm with different degrees of aggressiveness (low malignant potential [PUNLMP], non-invasive papillary urothelial carcinoma low grade [NILGC], non-invasive papillary urothelial carcinoma high grade [NIHGC] and carcinoma in situ). We analysed predictive values of both markers, their specificity and sensitivity in tumor recurrence. Aurora-A was a sensitive marker to predict tumor recurrence especially for pTa (PUNLMP, NILGC; PUNLMP p < 0.001, NILGC p < 0.001) with statistical significant correlation between immunohistochemical staining and clinical outcome. MIB-1 expression displayed statistical difference p = 0.002 in the PUNLMP group and p = 0.03 in the NILGC group. Aurora-A is a more sensitive marker than MIB-1 to predict relapse in pTa bladder neoplasias. The combination of both markers seems to have a very powerful predictive value of recurrence (p < 0.001).

Verdorfer, I.; Höllrigl, A.; Strasser, U.; Susani, M.; Hartmann, A.; Rogatsch, H.; Mikuz, G.

doi: 10.1007/s00428-007-0385-8pmid: 17333264

Sertoli cell tumours (SCT) are rare and poorly explored neoplasias, and the genetic features of these uncommon tumours are largely unknown. Data about chromosomal aberrations in human SCT of the testis are very rare. We present in this paper the first molecular-cytogenetic study of SCT of the testis. DNA was isolated from paraffin-embedded tumour material from 11 patients with unilateral SCT. We used comparative genomic hybridisation to investigate changes in DNA copy number. The detected DNA imbalances showed variation from case to case, indicating a high genetic heterogeneity. Chromosomal aberrations were detected in 9 of the 11 tumours evaluated, with 13 losses versus 14 gains. The most frequent aberrations detected were gain of chromosome X (5 of 11 cases) followed by losses of entire or part of chromosomes 2 and 19 in three cases. This study suggests a high variability in histomorphological and genetic patterns. Only gain of the entire chromosome X seems to be a frequent aberration in these tumours. Further studies of these tumour types are necessary to clarify the significance of chromosomal alterations in carcinogenesis of SCT.

Bléchet, Claire; Lecomte, Pierre; Calan, Loïc; Beutter, Patrice; Guyétant, Serge

doi: 10.1007/s00428-007-0379-6pmid: 17333268

Previous studies have shown that C cells are twice as numerous in male than in female thyroids and that C cell hyperplasia (CCH) is much more frequent in men. These findings suggest regulation involving sex steroid hormones through the expression of sex steroid hormone receptors on C cells. To investigate this hypothesis, we performed an immunohistochemical study of estrogen receptors α (ERα) and β (ERβ), progesterone receptors (PR), and androgen receptors (AR) on specimens from a series of 40 patients operated on for a medullary thyroid carcinoma (MTC; n = 28; female 18, male 10) and/or CCH (n = 19; female 6, male 13). ERβ was the only receptor to be consistently expressed in CCH (100%) and MTC (96.5%), whereas ERα was never expressed. PR and AR were rarely expressed in MTC (7 and 14%, respectively). AR was expressed in half the CCH cases (53%), with a trend to male predominance (61% in men vs 33% in women). Our study is the first to describe ERβ expression in CCH. In addition, our findings suggest that CCH, and possibly MTC, might be influenced by sex steroid hormones, namely, estrogens and androgens, through the expression of ERβ and AR on C cells.

Carbonnelle, Amélie; Martin-Garcia, Nadine; Ortonne, Nicolas; Laroche, Liliane; Bagot, Martine; Molinier-Frenkel, Valérie; Wechsler, Janine

doi: 10.1007/s00428-007-0372-0pmid: 17377810

Distinguishing between low-grade primary cutaneous B-cell lymphoma (LG-pCBCL) and cutaneous lymphoid hyperplasia (CLH) based on histological features is often difficult. CLH lesions contain numerous reactive cells of the histiocyte lineage [Langerhans cells (LC), dermal dendritic cells (DDC), and macrophages], which are also often present in CBCL. The aim of this study was to determine whether immunohistochemical detection of those cells could help differentiate between CLH and LG-pCBCL. We determined the percentages of those histiocytic cells in the dermal infiltrates of 45 cases of cutaneous lymphoproliferations comprising 16 CLH and 29 LG-pCBCL (19 follicle-center cell lymphomas and 10 marginal zone lymphomas) by immunohistochemical labeling with antibodies to CD1a, FXIIIa, and CD68 to respectively detect LC, DDC, and macrophages. To avoid observer-dependent bias, an automated morphometric analysis method was used to recognize immunoreactive cells and calculate their percentages within the infiltrate. FXIIIa+ cells were significatively more frequent in CLH than in LG-pCBCL, whereas CD1a+ and CD68+ cell frequencies were comparable in the two groups. The results of our study suggest that DDC might play an important role in the genesis of cutaneous lymphomas.