[Microvascular density in lymphomas - evaluation methods and clinical impact]. / Mikrovaskulární denzita v lymfomech - hodnocení a klinický význam.

In recent years antiangiogenic therapy has become a part of treatment protocols of solid tumors as well as of lymphomas. This is why tumor vascularization has been explored, the most important parameters to describe it being the microvascular density and immunohistochemical assessment of the expression of VEGF (vascular endothelial growth factor) and of its receptors. This review summarizes various methods of assessment of the microvascular density and the prognostic impact of microvascular density in lymphomas.

Aggressive and nonaggressive translocation t(6;11) renal cell carcinoma: comparative study of 6 cases and review of the literature.

UNLABELLED: t(6;11) renal cell carcinoma (RCC) has been recognized as a rare and mostly nonaggressive tumor (NAT). The criteria for distinguishing aggressive tumors (AT) from NATs are not well established. A total of 6 cases were selected for the study. Five cases of t(6;11) RCCs behaved nonaggressively, and 1 was carcinoma with aggressive behavior. The tumors were analyzed morphologically using immunohistochemistry and by molecular-genetic methods. The specimen of aggressive t(6;11) RCC was from a 77-year-old woman who died of the disease 2.5 months after diagnosis. The specimens of nonaggressive t(6;11) RCCs were from 3 women and 2 men whose ages range between 15 and 54 years. Follow-up was available in all cases (2.5 months-8 years). The tumor size ranged from 3 to 14 cm in nonaggressive t(6;11) RCC. In the aggressive carcinoma, the tumor size was 12 cm. All tumors (6/6) were well circumscribed. Aggressive t(6;11) RCC was widely necrotic. Six (100%) of 6 all tumors displayed a solid/alveolar architecture with occasional tubules and pseudorosettes. Pseudopapillary formations lined by bizarre polymorphic cells were found focally in the aggressive t(6;11) RCC case. Mitoses, though rare, were found as well. All cases (AT and NAT) were positive for HMB-45, Melan-A, Cathepsin K, and cytokeratins. CD117 positivity was seen in 4 of 5 NATs, as well as in the primary and metastatic lesions of the AT. mTOR was positive in 2 of 5 NATs and vimentin in 4 of 5 NATs. Vimentin was negative in the primary lesion of the AT, as well as in the metastasis found in the adrenal gland. Translocation t(6;11)(Alpha-TFEB) or TFEB break was detected in 4 of 5 NATs and in the AT case. Aggressive tumor showed amplification of TFEB locus. Losses of part of chromosome 1 and chromosome 22 were found in 1 of 5 NATs and in the AT. CONCLUSIONS: (1) Aggressive t(6;11) RCCs generally occur in the older population in comparison with their indolent counterparts. (2) In regard to the histologic findings in ATs, 3 of 5 so far published cases were morphologically not typical for t(6;11) RCC. Of the 3 cases, 2 cases lacked a small cell component and 1 closely mimicked clear cell-type RCC. (3) Necroses were only present in aggressive t(6;11) RCC. (4) Amplification of TFEB locus was also found only in the aggressive t(6;11) RCC.

Renal cell carcinoma with leiomyomatous stroma--further immunohistochemical and molecular genetic characteristics of unusual entity.

UNLABELLED: Renal cell carcinoma (RCC) with leiomyomatous stroma (RCCLS) is a recently recognized entity with indolent biological behavior. The diagnostic implication of absence/presence of VHL gene mutation, VHL hypermethylation, or/and loss of heterozygosity of chromosome 3p (LOH 3p) is widely discussed. Criteria for establishing a diagnosis of RCCLS are still lacking. Fifteen RCCLSs were retrieved from our registry. The cases were studied with consideration to the morphology, immunohistochemistry, and molecular genetics. All cases were composed of low-grade epithelial cells with clear cytoplasm arranged in nests intermingled with abundant leiomyomatous stroma. Age range of the patients was 33 to 78 years. The tumor size ranged from 1.5 to 11 cm. Six of the patients were males, and 9, females. Of the 15 tumors sent for molecular genetic testing, only 12 cases were analyzable. All cases were analyzable immunohistochemically. Of 12 of these cases, 5 showed complete absence of VHL gene mutation, VHL hypermethylation, and LOH 3p. Of these 5 cases, 3 were positive for cytokeratin 7 (CK 7). All of the 5 cases were positive for carbonic anhydrase 9, vimentin, and CD10. The remaining 7 of 12 genetically analyzable cases were found to have had VHL hypermethylation, LOH 3p, VHL gene mutation, or a combination of the former 2 characteristics. These 7 cases were positive for vimentin. Variable reactivity was found for CK 7, carbonic anhydrase 9, α-methylacyl-CoA racemase, and CD10. In 1 of these 7 cases, gains on chromosomes 7 and 17 as well as hypermethylation of VHL gene were found. This case was considered as clear cell RCC with aberrant status of chromosomes 7 and 17. CONCLUSIONS: (1) Leiomyomatous stroma is not specific for the so called RCCLS. It can be seen also in otherwise typical clear cell RCCs. (2) There are no characteristic morphological/immunohistochemical features unique for "RCCLS." (3) Our results indicate that only tumors with the absence of the VHL gene mutation, hypermethylation, and LOH 3p can be diagnosed as RCCLS. (4) Relation of RCCs with a prominent smooth muscle stroma to the renal angiomyoadenomatous tumor/clear cell papillary (tubopapillary) RCC is not clearly evident from our study and has to be further analyzed on larger cohort of the patients.

Cystic Renal Oncocytoma and Tubulocystic Renal Cell Carcinoma: Morphologic and Immunohistochemical Comparative Study.

Renal oncocytoma (RO) may present with a tubulocystic growth in 3% to 7% of cases, and in such cases its morphology may significantly overlap with tubulocystic renal cell carcinoma (TCRCC). We compared the morphologic and immunohistochemical characteristics of these tumors, aiming to clarify the differential diagnostic criteria, which facilitate the discrimination of RO from TCRCC. Twenty-four cystic ROs and 15 TCRCCs were selected and analyzed for: architectural growth patterns, stromal features, cytomorphology, ISUP nucleolar grade, necrosis, and mitotic activity. Immunohistochemical panel included various cytokeratins (AE1-AE3, OSCAR, CAM5.2, CK7), vimentin, CD10, CD117, AMACR, CA-IX, antimitochondrial antigen (MIA), EMA, and Ki-67. The presence of at least focal solid growth and islands of tumor cells interspersed with loose stroma, lower ISUP nucleolar grade, absence of necrosis, and absence of mitotic figures were strongly suggestive of a cystic RO. In contrast, the absence of solid and island growth patterns and presence of more compact, fibrous stroma, accompanied by higher ISUP nucleolar grade, focal necrosis, and mitotic figures were all associated with TCRCC. TCRCC marked more frequently for vimentin, CD10, AMACR, and CK7 and had a higher proliferative index by Ki-67 (>15%). CD117 was negative in 14/15 cases. One case was weakly CD117 reactive with cytoplasmic positivity. All cystic RO cases were strongly positive for CD117. The remaining markers (AE1-AE3, CAM5.2, OSCAR, CA-IX, MIA, EMA) were of limited utility. Presence of tumor cell islands and solid growth areas and the type of stroma may be major morphologic criteria in differentiating cystic RO from TCRCC. In difficult cases, or when a limited tissue precludes full morphologic assessment, immunohistochemical pattern of vimentin, CD10, CD117, AMACR, CK7, and Ki-67 could help in establishing the correct diagnosis.

Molecular-genetic analysis is essential for accurate classification of renal carcinoma resembling Xp11.2 translocation carcinoma.

Xp11.2-translocation renal carcinoma (TRCC) is suspected when a renal carcinoma occurs in young patients, patients with a prior history of exposure to chemotherapy and when the neoplasm has morphological features suggestive of that entity. We retrieved 20 renal tumours (from 17,500 archival cases) of which morphology arose suspicion for TRCC. In nine cases, TFE3 translocation was confirmed by fluorescence in situ hybridisation analysis. In 9 of the remaining 11 TRCC-like cases (7 male, 4 female, aged 22-84 years), material was available for further study. The morphological spectrum was diverse. Six tumours showed a mixture of cells with eosinophilic or clear cytoplasm in tubular, acinar and papillary architecture. One case was high grade with epithelioid, spindle cell and sarcomatoid areas. Another showed tubular, solid, and papillary areas and foci containing spindle cells reminiscent of mucinous tubular and spindle cell carcinoma. The third showed dyscohesive nests of large epithelioid and histiocytoid cells in a background of dense lymphoplasmacytic infiltrate. By immunohistochemistry, keratin AE1/AE3 was diffusely positive in three tumours, while CK7 strongly stained one tumour and another focally and weakly. CD10 and Pax8 were expressed by eight, AMACR and vimentin by seven, CA-IX by four and TFE3 and cathepsin K by two tumours. Of the two TFE3-positive tumours, one showed polysomy of chromosome 7 and the other of 17; they were VHL normal and diagnosed as unclassifiable RCC. Of the seven TFE3-negative tumours, three showed polysomy of 7/17 and VHL abnormality and were diagnosed as combined clear cell RCC/papillary RCC. One TFE3-negative tumour with normal 7/17 but LOH 3p (VHL abnormality) was diagnosed as clear cell RCC. One TFE3-negative tumour with polysomy 7/17 but normal VHL was diagnosed as papillary RCC, and two with normal chromosomes 7/17 and VHL gene were considered unclassifiable. As morphological features and IHC are heterogeneous, TRCC-like renal tumours can only be sub-classified accurately by multi-parameter molecular-genetic analysis.

Microvessel density of mantle cell lymphoma. A retrospective study of its prognostic role and the correlation with the Ki-67 and the mantle cell lymphoma international prognostic index in 177 cases.

The clinical course and therapy of mantle cell lymphoma (MCL) are heterogeneous and often unsatisfactory. Prognostic factors are needed to stratify the patients. Microvessel density (MVD) has prognostic significance in some malignancies. There is little information about the vasculature of MCL, although some antiangiogenic drugs are in use. We studied MVD using systematic uniform random sampling and unbiased counting frames in immunohistochemical reactions with anti-CD34 antibody in pre-therapeutic extramedullary MCL samples of 177 patients. We analyzed the relationship of MVD to overall survival (OS) and progression-free survival (PFS), as well as to proliferative activity (Ki-67), mantle cell lymphoma prognostic index (MIPI), morphological variant, pattern of growth, and localization. MVD varied widely: range 54.6-503.6 vessels/mm(2), median 158.2 vessels/mm(2). Higher MVD was associated with bone marrow infiltration at the time of diagnosis (P = 0.001). High MVD was associated with significantly worse OS (P = 0.04) only in patients treated with non-intensive (conventional) therapy. MVD correlated positively with MIPI scores but not with the proliferation, morphological variant, growth pattern, or localization. Univariate analysis identified a prognostic influence of morphological variant, MIPI, and proliferative activity on OS and PFS and a prognostic influence of bone marrow infiltration at the time of diagnosis on PFS. Multivariate analysis showed prognostic influence of MIPI and proliferative activity on OS and PFS only. In conclusion, this is the first clinicopathological study of MVD of MCL with long-term follow-up showing negative prognostic trends of high MVD in MCL and positive correlation of MVD and MIPI.

Retrospective analysis of 235 unselected patients with mantle cell lymphoma confirms prognostic relevance of Mantle Cell Lymphoma International Prognostic Index and Ki-67 in the era of rituximab: long-term data from the Czech Lymphoma Project Database.

Although a prognostic model (MIPI, Mantle Cell Lymphoma International Prognostic Index) for patients with mantle cell lymphoma (MCL) has been established, its clinical significance for daily practice in the rituximab era remains controversial. Data of 235 unselected patients with MCL from the Czech Lymphoma Project Database were analyzed. MIPI, simplified MIPI (s-MIPI) and Ki-67 proliferation index were assessed for all patients and for a subgroup of 155 rituximab-treated (RT) patients. MIPI divided all patients into subgroups of low-risk (22%), intermediate-risk (29%) and high-risk (49%), with median overall survival 105.8 vs. 54.1 vs. 24.6 months, respectively (p < 0.001). s-MIPI revealed similar results. The validity of both indexes was confirmed in RT patients. We confirmed the Ki-67 index to be a powerful single prognostic factor for overall survival (64.4 vs. 20.1 months, p < 0.001) for all patients and for the RT subset. Our results confirm the clinical relevance of MIPI, s-MIPI and Ki-67 for risk stratification in MCL also in the rituximab era.