Assia Bassarova

Genomic aberrations in mucinous tubular and spindle cell renal cell carcinomas.

Mucinous tubular and spindle cell carcinoma of the kidney is a new diagnostic entity. We present the pathologic and genomic characteristics of three such low-malignant tumors. Two of the tumors were found in women aged 19 and 52 years, the third tumor was found in an 80-year-old man, and the tumor stages were pT2N0MX, pT2NXMX, and pT1NXMX, respectively. Findings by immunohistochemistry were similar but not identical for the three cases; markers for both proximal and distal parts of the nephron were expressed in each tumor, a finding that is in agreement with data from previous studies. The Ki-67-labeling index was below 5 in all three cases. Two of the tumors were predominantly hypodiploid (DNA-indexes 0.77 and 0.80), whereas the third tumor was hypertriploid (1.57) as measured by DNA-image cytometry. From the latter tumor live cells were available making it possible to establish its karyotype: 62-70,XXX,+del(X)(q11),−1,+2,+4,−5,−6,+7,−8,−9,−10,−11,+12,−13,−14,−15,+16,+17,+18,−19,+20,+21,−22[cp15]. Interphase fluorescence in situ hybridization analyses with centromere-specific probes for chromosomes 1, 3, 4, 6, 7, 9, 10, 17, 18, 20, and X showed that the two hypodiploid tumors had disomic and monosomic chromosome populations, whereas the karyotyped, near-triploid tumor was dominated by trisomic chromosome populations. Comparative genomic hybridization analysis was normal for the karyotyped tumor but abnormal for the two others. We conclude that multiple numerical chromosome aberrations may be a feature of mucinous tubular and spindle cell carcinomas of the kidney, but beyond that no clear-cut karyotypic aberration pattern is so far discernible.

D2-40 is not a specific marker for cells of mesothelial origin in serous effusions.

The presence of effusion in a patient with a history of primary malignant tumor elsewhere in the body is generally accepted as a clinical manifestation of metastatic disease. Even in those cases, it is sometimes difficult to differentiate reactive mesothelial cells from carcinoma cells. Another challenging issue especially in the field of serous effusions is the differential diagnosis between malignant mesothelioma and metastatic adenocarcinoma. The aim of this study was to evaluate the potential use of the D2-40 antibody detecting the M2A oncofetal antigen in the diagnosis of malignant serous effusions. Two hundred and ninety effusion specimens (169 ovarian carcinomas, 44 breast carcinomas, 32 malignant mesotheliomas, 6 lung carcinomas, 8 reactive specimens, and 31 tumors of other origin) were assessed. Expression in reactive mesothelial cells was additionally assessed on 145 malignant effusions. Immunohistochemical analysis using the EnVision system was performed. M2A antigen was expressed in malignant mesotheliomas and reactive mesothelial cells in all specimens. Positive membranous staining was observed in 58% of ovarian carcinomas, 33% of lung carcinomas, and 30% of breast carcinomas. Pulmonary, breast, and nonovarian gynecologic tumors usually showed weak focal membranous staining, whereas the ovarian adenocarcinomas showed an expression pattern more similar to mesotheliomas.The results from the present study suggest low specificity for D2-40 as a mesothelial marker, especially in the context of differentiating mesothelial cells from ovarian carcinoma, and argue against its inclusion in the diagnostic panel of serous effusions.

Vascularization in primary breast carcinomas: Its prognostic significance and relationship with tumor cell dissemination

Purpose: The interaction between tumor cells, stroma, and endothelial cells is important for the dissemination of tumor cells. The aim of the present study is to examine vascularity in primary breast carcinomas and its prognostic significance and relationship with tumor cell dissemination. Experimental Design: A total of 498 invasive breast carcinomas were analyzed. Representative tumor sections were stained for CD34 and CD105, and vascularity was quantified by the Chalkley method. The relationship between Chalkley counts, vascular invasion, disseminated tumor cells (DTC) in the bone marrow, other clinicopathologic variables, and clinical outcome was evaluated. Results: High vascular grades determined by Chalkley counts were significantly associated with shorter distant disease–free survival and breast cancer–specific survival in all patients (P < 0.001, log-rank) and in node-negative patients not receiving adjuvant systemic therapy (P < 0.05). In multivariate analysis, both CD34 and CD105 Chalkley counts showed prognostic significance for distant disease–free survival (P = 0.014 and P = 0.026), whereas CD34 also showed prognostic significance for breast cancer–specific survival (P = 0.007). Vascular invasion and DTCs in the bone marrow showed independent prognostic significance. DTC did not discriminate survival for CD34 low Chalkley counts, whereas a very poor prognosis was observed for DTC-positive patients with high CD34 counts. In node-negative patients not receiving systemic chemotherapy, high CD34 and high CD105 counts in combination identified patients with unfavorable outcome, as opposed to all other CD34/CD105 combinations. Conclusions: Improved identification of risk groups could be obtained by adding CD34 and CD105 vascular analysis to DTC, vascular invasion, and other primary tumor factors. This may facilitate the selection of candidates for adjuvant systemic therapy.

Clinical and Histopathological Features of Folliculotropic Mycosis Fungoides: a Norwegian Patient Series

Folliculotropic mycosis fungoides is a variant of cutaneous T-cell lymphoma with distinct clinicopathological features. We describe here the clinical presentation, pathology findings and treatment outcome in 15 Norwegian patients. All patients were diagnosed between 1997 and 2010 at Oslo University Hospital. A spectrum of skin lesions, both typical and atypical, such as leonine facies, acneiform lesions, psoriasiform plaques, purulent ulcerations and cystic milia-like lesions for mycosis fungoides, were seen. Histological examination revealed characteristic infiltration of hair follicles with neoplastic T cells associated with partial destruction of the former. A CD4+ immunophenotype of the neoplastic T cells with loss of one or more T-cell markers was demonstrated. In general, the patients were given more aggressive therapeutic regimens than those with conventional mycosis fungoides, and showed a trend towards more rapid disease progression. In conclusion, this case series confirms the distinct clinical and histological features of folliculotropic mycosis fungoides.

Pilomatrix carcinoma with lymph node metastases.

Pilomatrix carcinoma is a rare skin tumor with an origin from hair matrix cells. The tumor is locally aggressive with a great tendency for recurrence, but the metastatic potential is limited. A pilomatrix carcinoma in 76‐year‐old female with lymph node metastases is presented. In addition to classical histopathological criteria and DNA ploidy analysis, a broad panel of antibodies was used for evaluation of the metastatic potential. Both primary tumor and lymph node metastasis revealed extremely high proliferation and apoptotic rates. High constant expressions of CD44v6 and P‐cadherin were also observed. In the metastasis, significant reduction of E‐cadherin and β‐catenin was detected. The best approach for assessment of metastatic potential of pilomatrix carcinoma seems to be the complex evaluation of routine histological criteria like vessel invasion, mitotic index, apoptotic count, and new molecular markers of cell death and adhesion.

Expression of vascular endothelial growth factor and vascular endothelial growth factor receptors 1 and 2 in invasive breast carcinoma: prognostic significance and relationship with markers for aggressiveness.

Dhakal H P, Naume B, Synnestvedt M, Borgen E, Kaaresen R, Schlichting E, Wiedswang G, Bassarova A, Holm R, Giercksky K‐E & Nesland J M 
(2012) Histopathology 61, 350–364

Mantle cell lymphoma with partial involvement of the mantle zone: an early infiltration pattern of mantle cell lymphoma?

Most patients with mantle cell lymphoma present with a diffuse or nodular infiltration of the involved organs at diagnosis. We present two patients with a rare morphological variant, displaying a partial involvement of the mantle zone. Patient 1 presented with an enlarged inguinal lymph node, which showed marked follicular hyperplasia with singly spread Cyclin D1+ small lymphoid cells in the mantle zones. An additional lymph node biopsy taken 3 months later showed the same pattern. Patient 2 presented with a classical mantle cell lymphoma with lymph node, bone marrow and gastro-intestinal involvement. However, revision of an appendectomy specimen taken 4 years earlier showed pronounced follicular hyperplasia with singly spread Cyclin D1+ small lymphoid cells in the mantle zones. Mantle cell lymphoma with partial involvement of the mantle zone has rarely been reported and many represent an early manifestation of mantle cell lymphoma. Our cases also illustrate that the inclusion of an anti-cyclin D1 antibody in the diagnostic panel of antibodies to study unexplained follicular hyperplasia, might be advised.

Real-Time PCR Quantification of c-erbB-2 Gene is an Alternative for FISH in the Clinical Management of Breast Carcinoma Patients

Evaluation of gene amplification and protein expression of the c-erbB-2/neu in breast carcinomas has been an important task in breast cancer management. Although immunohistochemistry is widely applied, fluorescence in situ hybridization (FISH) technology shows its advantage in discriminating tumors in an objective manner. More recently, development of LightCycler technology permits evaluation of gene amplification with a small volume of DNA run in a 20 µL glass capillary. In this study, a series of 87 breast carcinomas were chosen for evaluation of c-erbB-2/neu gene amplification detected by both LightCycler technology and FISH. Real-time polymerase chain reaction (PCR) was performed in LightCycler capillaries with 10 ng sample DNA. By using LightCycler Relative Quantification Software version 1 (Light-Cycler, Roche, Mannheim, Germany), the amount of c-erbB-2 DNA was calculated as a ratio of c-erbB-2/reference gene quantity in a sample, and then the ratio was divided by the ratio of c-erbB-2 gene/reference gene quantities of a calibrator DNA (a standard DNA provided in the kit), which was run with each sample reaction in parallel. Dualcolor FISH was performed on sections of the formalin-fixed, paraffin-embedded tissue array samples using the DAKO HER2 FISH pharmDX™ kit (DAKO A/S, Glostrup, Danmark) according to the manufacturer’s instructions. Furthermore, immunohistochemistry was performed in parallel, with both the NCL-CB11 and HercepTest antibodies. Both the FISH technology and the LightCycler-PCR identified a similar percentage of tumors with c-erbB-2 gene amplification in our present study, 16% (14/87) and 15% (13/87), respectively, whereas immunohistochemistry demonstrated 32% and 34% c-erbB-2 overexpression with the NCL-CB11 and HercepTest antibodies, respectively. In addition, FISH and PCR were highly correlated in detecting tumors mainly with 3+++ c-erbB-2 protein expression by immunohistochemistry, indicating that LightCycler real-time quantification of c-erbB-2 gene may be an alternative to FISH in breast cancer clinical application.

Transformation of B cell lymphoma to histiocytic sarcoma: Somatic mutations of PAX-5 gene with loss of expression cannot explain transdifferentiation

Transdifferentiation of B cell lymphoma of germinal center cell origin to histiocytic sarcoma has recently been described but is a rare occurrence. The cause for loss of B cell differentiation in these lymphomas is unknown. We investigated whether somatic hypermutation of the PAX-5 gene, a transcription factor that is important for maintaining B cell identity and is frequently mutated in B cell lymphomas of germinal center cell origin, might be a cause for loss of PAX-5 expression and thus B cell phenotype. However, no somatic hypermutation of the PAX-5 gene was detected in the two cases we studied. The molecular basis for transdifferentiation of B cell lymphoma to histiocytic sarcoma remains therefore unresolved.

Simultaneous Bilateral Breast Carcinomas: A Category with Frequent Coexpression of HER-2 and ER-α, High Ki-67 and bcl-2, and Low p53

The aim of this study was to evaluate clinicopathological characteristics and immunophenotypes of simultaneous bilateral adenocarcinomas of the breast and their axillary metastases. Immunohistochemical analysis and in situ hybridization were performed using formalin-fixed/paraffin-embedded tissues. In total, 15 primary and 9 metastatic tumors from 8 patients were evaluated. The expression of estrogen receptor-alpha (ER-α), progesterone receptor (PR), Ki 67, p53, bcl-2, and bax were evaluated by immunohistochemistry. Her2 gene amplification was evaluated by chromogenic in situ hybridization (CISH). Four patients were younger that 40 years of age (mean 47 years). Six patients had pleomorphic lobular carcinoma in 1 breast. Four of these had invasive ductal carcinoma in the contralateral breast. One patient had atypical medullary carcinoma in both breasts and 1 patient had atypical medullary carcinoma in 1 breast and pleomorphic lobular carcinoma in the other. The phenotype of the primary tumors and corresponding metastatic tumors was similar for the expression of ER-α (p=0.001), PR (p=0.03), and HER-2 (p=0.018). While strong coexpression of HER-2 and ER-α is exceptional in hereditary breast carcinoma and sporadic breast carcinoma, 6/8 (75%) patients in this study had tumors with strong coexpression of HER-2 and ER-α. P53 protein expression was found in only 2/15 (13%) primary tumors, which is in contrast to BRCA1-related hereditary bilateral breast carcinomas, which often express p53 protein. Most of the patients presented with axillary metastases and had very aggressive course. Characteristically, the tumors showed high levels of expression of ER-α and Her2 amplification, were bcl-2 positive, and had high Ki-67 fraction. However, in patients with atypical medullary carcinoma there was no expression of ER-α or amplification of Her-2.