Incidence and prognostic impact of secondary cytogenetic aberrations in a series of 145 patients with mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with an aggressive behavior, characterized by the t(11;14)(q13;q32). Several secondary genetic abnormalities with a potential role in the oncogenic process have been described. Studies of large MCL series using conventional cytogenetics, and correlating with proliferation and survival, are scarce. We selected 145 MCL cases at diagnosis, displaying an aberrant karyotype, from centers belonging to the Spanish Cooperative Group for Hematological Cytogenetics. Histological subtype, proliferative index and survival data were ascertained. Combined cytogenetic and molecular analyses detected CCND1 translocations in all cases, mostly t(11;14)(q13;q32). Secondary aberrations were present in 58% of patients, the most frequent being deletions of 1p, 13q and 17p, 10p alterations and 3q gains. The most recurrent breakpoints were identified at 1p31-32, 1p21-22, 17p13, and 1p36. Aggressive blastoid/pleomorphic variants displayed a higher karyotypic complexity, a higher frequency of 1p and 17p deletions and 10p alterations, a higher proliferation index and poor survival. Gains of 3q and 13q and 17p13 losses were associated with reduced survival times. Interestingly, gains of 3q and 17p losses added prognostic significance to the morphology in a multivariate analysis. Our findings confirm previous observations indicating that proliferation index, morphology and several secondary genetic alterations (3q gains and 13q and 17p losses) have prognostic value in patients with MCL. Additionally, we observed that 3q gains and 17p losses detected by conventional cytogenetics are proliferation-independent prognostic markers indicating poor outcome.

Local recurrence of a parosteal osteosarcoma 21 years after incomplete resection.

Parosteal osteosarcoma (POS) is the most common form of surface osteosarcoma. Its symptoms are insidious and its duration prior to diagnosis is considerably longer than that of other types of osteosarcoma. We report a case of POS with a growing mass but no evidence of metastasis. This tumor, which was diagnosed as calcified hematoma with benign characteristics, was incompletely resected in our hospital 21 years before the diagnosis of recurrence. The patient underwent a wide en bloc resection in our hospital and was free of symptoms, with no signs of tumor recurrence or metastasis during a 53-month follow-up.

Positive VEGF immunostaining independently predicts poor prognosis in curatively resected gastric cancer patients: results of a study assessing a panel of angiogenic markers.

Angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF) contribute to gastric cancer aggressiveness by up-regulating the expression of proteases. We evaluated the expression and the prognostic significance of angiogenic factors and proteases in 148 patients with R0-resected gastric cancer. Expression of VEGF, Ang-2, cyclooxygenase-2 (COX-2), urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1, matrix metalloproteinases (MMP)-1 and -9 were assayed by immunohistochemistry. After a mean of 63 +/- 4 months, 81 out of 148 patients had died due to disease. The probability of being free of recurrence was 62, 48, and 42% at 2, 5, and 10 years, respectively. Single bivariate analysis identified VEGF, Ang-2, COX-2, PAI-1, and MMP-9 expression, along with several clinicopathological parameters (grade of curability, lymph node ratio, pTNM, pT, pN), as variables associated with both decreased disease-specific survival and recurrence. On multivariate analysis, after adjusting for significant clinical covariables, positive VEGF immunostaining was the primary prognostic factor, and no other tumor marker variable could add any significant improvement for the prediction, for both disease-specific survival (p = 0.001; HR, 3.27; 95% CI, 1.76 to 6.10) and tumor recurrence (p = 0.002; HR, 2.81; 95% CI, 1.48 to 5.35). Our study suggests that VEGF alone may be clinically useful for establishing therapeutic decisions in gastric cancer patients.

Epstein-Barr virus negative clonal plasma cell proliferations and lymphomas in peripheral T-cell lymphomas: a phenomenon with distinctive clinicopathologic features.

Clonal B-cell populations have been described in peripheral T-cell lymphomas (PTCL) as secondary Epstein-Barr virus (EBV) driven B-cell expansions that may evolve to an overt B-cell lymphoma. EBV-negative B-cell proliferations associated with T-cell lymphomas are uncommon and not well characterized. We studied 15 patients who developed an EBV-negative B-cell proliferation or malignant lymphoma associated with PTCL. The T-cell tumors were 8 PTCL, not otherwise specified, 4 angioimmunoblastic T-cell lymphomas, and 3 cutaneous PTCL. The B-cell component was intermingled with the PTCL in all patients and it was classified as clonal/monotypic plasma cell proliferation in 8 lesions, clonal/monotypic large B-cell proliferation in 4 patients, and B-cell lymphoma with plasmacytic/plasmablastic differentiation in 3 patients. Two patients had 2 clonally unrelated plasma cell proliferations associated with the same PTCL. All cases showed cytoplasmic Ig light chain restriction. Clonal IgH and T-cell receptor rearrangements were detected in 11/12 and 11/13 cases examined, respectively. EBV, cytomegalovirus, and HHV-8 were not observed in any of the examined cases. Sequential samples in 7 patients showed persistence of the PTCL and the B-cell component in 4, the PTCL without the B-cell lymphoma in 2, and progression of the B-cell neoplasm in 1. Patients followed an aggressive clinical course similar to conventional PTCL. In conclusion, EBV-negative clonal or mononotypic B-cell proliferations in patients with PTCL present with a spectrum of lesions ranging from plasma cell proliferations to overt lymphomas with plasmacytic/plasmablastic features. The distinctive features of these patients suggest that these lesions represent a specific phenomenon in PTCL.

Duodenal-content reflux into the esophagus leads to expression of Cdx2 and Muc2 in areas of squamous epithelium in rats.

The molecular events responsible for the transdifferentiation of epithelial cells of the esophagus to a columnar cell type are not well understood. Cdx2 has been detected in Barrett's esophagus, so we sought evidence of Cdx2 expression during the process of transdifferentiation of the esophageal squamous epithelium into a glandular phenotype. Thirty-two rats underwent an esophago-jejunostomy to produce esophagitis of 20, 25, 30, or 35 weeks of duration. The spectrum of esophageal lesions induced by chronic reflux was examined for expression of Cdx2 and Muc2 by immunohistochemistry. Five animals developed glandular metaplasia and adenosquamous carcinoma, two developed only glandular metaplasia, and two had adenosquamous carcinoma alone. Nuclear Cdx2 expression was detected in 57% (four of seven) and 43% (three of seven) of foci of glandular metaplasia and adenosquamous carcinomas, respectively. Cdx2 staining was detectable in some squamous and some mucus secreting cells. Perinuclear and perivacuolar staining of Muc2 was detected focally in 71% (five of seven) and 57% (four of seven) of areas with glandular metaplasia and adenosquamous carcinoma, respectively. We show that duodenal-content reflux into the esophagus switches on the expression of Cdx2 protein in esophageal keratinocytic cells, promoting a mucinous transdifferentiation process with secretion of intestinal mucin Muc2.

Development and clinical implementation of a new template for MRI-based intracavitary/interstitial gynecologic brachytherapy for locally advanced cervical cancer: from CT-based MUPIT to the MRI compatible Template Benidorm. Ten years of experience.

PURPOSE: To study outcome and toxicity in 59 patients with locally advanced cervix carcinoma treated with computed tomography (CT)-based Martinez universal perineal interstitial template (MUPIT) and the new magnetic resonance imaging (MRI)-compatible template Benidorm (TB). MATERIAL AND METHODS: From December 2005 to October 2015, we retrospectively analyzed 34 patients treated with MUPIT and 25 treated with the TB. Six 4 Gy fractions were prescribed to the clinical target volume (CTV) combined with external beam radiotherapy (EBRT). The organs at risk (OARs) and the CTV were delineated by CT scan in the MUPIT implants and by MRI in the TB implants. Dosimetry was CT-based for MUPIT and exclusively MRI-based for TB. Dose values were biologically normalized to equivalent doses in 2 Gy fractions (EQD2). RESULTS: Median CTV volumes were 163.5 cm3 for CT-based MUPIT (range 81.8-329.4 cm3) and 91.9 cm3 for MRI-based TB (range 26.2-161 cm3). Median D90 CTV (EBRT + BT) was 75.8 Gy for CT-based MUPIT (range 69-82 Gy) and 78.6 Gy for MRI-based TB (range 62.5-84.2 Gy). Median D2cm3 for the rectum was 75.3 Gy for CT-based MUPIT (range 69.8-132.1 Gy) and 69.9 Gy for MRI-based TB (range 58.3-83.7 Gy). Median D2cm3 for the bladder was 79.8 Gy for CT-based MUPIT (range 71.2-121.1 Gy) and 77.1 Gy for MRI-based TB (range 60.5-90.8 Gy). Local control (LC) was 88%. Overall survival (OS), disease free survival (DFS), and LC were not statistically significant in either group. Patients treated with CT-based MUPIT had a significantly higher percentage of rectal bleeding G3 (p = 0.040) than those treated with MRI-based TB, 13% vs. 2%. CONCLUSIONS: Template Benidorm treatment using MRI-based dosimetry provides advantages of MRI volume definition, and allows definition of smaller volumes that result in statistically significant decreased rectal toxicity compared to that seen with CT-based MUPIT treatment.

Carcinosarcoma of the prostate: two cases with distinctive morphologic and immunohistochemical findings.

Carcinosarcomas (CS) of the prostate are very uncommon neoplasms defined by the admixture of malignant epithelial and mesenchymal components. We describe here two new examples of CS in two patients aged 66 and 77 years, the first without previous history of prostate adenocarcinoma and the second with a 5-year history of acinar type prostate adenocarcinoma. The diagnosis of CS was made on the cystoprostatectomy specimen in the first case and transurethral resection in the second case. Both biphasic tumours exhibited papillary areas of ductal differentiation and conventional adenocarcinoma in the epithelial component, as well as malignant fibrous histiocytoma and angiosarcomatous areas in the first case and solid, poorly differentiated epithelial areas with neuroendocrine features in the second case. Immunohistochemistry revealed over-expression of c-erb B2 in the papillary epithelial component of both cases, whereas the solid undifferentiated epithelial areas in the second patient expressed c-kit, CD10 and synaptophysin, thus conforming a very undifferentiated cell population. The angiosarcomatous component of the first case expressed CD31 and CD10. The clinical course of the cases was divergent; the first patient is free of disease after radical surgery and adjuvant therapy and the other died 5 months after the diagnosis of CS, having already developed liver metastases.

A new template for MRI-based intracavitary/interstitial gynecologic brachytherapy: design and clinical implementation.

PURPOSE: To describe the potential clinical use of a new brachytherapy applicator for gynecological tumors, with special attention to locally advanced cervical carcinoma. This device allows the combination of intracavitary radiotherapy and MRI-compatible transperineal interstitial needles. The design of this template addresses the disadvantages of currently commercially available templates: the inability of the intracavitary component to reach deep into the cervix (MUPIT), and the MRI-incompatibility of these templates (MUPIT and Syed), which necessitates use of CT imaging for the dosimetry. MATERIAL AND METHODS: The newly developed Benidorm Template applicator allows titanium needles in a template with straight and angled holes to provide different angles of divergence to be used with currently existing MRI-compatible intrauterine tubes. It can provide total coverage of the craniocaudal and lateral extension of the tumor (intrautherus, parametrial, and paravaginal). This method is mainly indicated in advanced cervical carcinoma with bulky parametrial invasion (medial or distal), with bulky primary disease that responds poorly to external beam radiotherapy extensive paravaginal involvement (tumor thickness greater than 0.5 cm) extending to the middle or lower third of the vagina, or for disease that has invaded the bladder or rectum (stage IVA). RESULTS: Between April 2013 until December 2014, we treated 15 patients with locally advanced cervical carcinoma employing the Benidorm Template. The median dose at D90 for the CTV was 79.8 Gy (71.5-89.9 Gy), at D2cc for the bladder it was 77.6 Gy (69.8-90.8 Gy), and at D2cc for the rectum it was 71.9 Gy (58.3-83.7 Gy). Values expressed in EQD2, assuming α/ß of 10 for CTV and 3 for OAR. CONCLUSIONS: This new applicator allows the use of MRI-based dosimetry, thus providing the advantages of MRI volume definition. As such, it facilitates determination of complete intracavitary and interstitial CTV coverage and the sparing of normal tissues.

CD10 expression in epithelial tissues and tumors of the gynecologic tract: a useful marker in the diagnosis of mesonephric, trophoblastic, and clear cell tumors.

We tested 417 cases of formalin-fixed, paraffin-embedded normal or hyperplastic gynecologic tissues as well as neoplasms involving the gynecologic tract with a monoclonal antibody against CD10 (clone 56C6), with special emphasis on epithelial and epithelial-like structures and tumors. CD10 was always expressed in mesonephric remnants (mesonephric remnants of the uterine cervix, epoophoron, rete ovarii) and tumors (mesonephric adenocarcinoma of the uterine cervix, tumors of wolffian origin of the broad ligament and ovary). CD10 was also positive in the syncytiotrophoblast, cytotrophoblast, and intermediate trophoblast of normal gestations, partial and complete moles, choriocarcinoma, and placental site trophoblastic tumors. Finally, CD10 was positive in several metastatic neoplasms to the gynecologic tract (100% in metastatic renal clear cell and intestinal carcinomas and melanomas). In contrast, CD10 was almost invariably negative in müllerian epithelia of the female genital tract and in their corresponding tumors, with the exception of focal expression found in squamous epithelia and tumors with squamous differentiation. Thus, the expression of CD10 may be useful in the establishing the diagnosis of mesonephric and trophoblastic tumors and in the differential diagnosis between gynecologic clear cell carcinoma (always negative) and metastatic clear cell carcinoma of renal origin.

[Erdheim-Chester disease: study of 12 cases]. / Enfermedad de Erdheim-Chester: estudio de 12 casos.

BACKGROUND AND OBJECTIVE: Erdheim-Chester disease (EC) is a rare form of non-Langerhans' cell histiocytosis. It is characterized by the xanthomatous infiltration of tissues with foamy CD68+/CD1a- histiocytes. We report a series of 12 patients diagnosed with EC. PATIENTS AND METHODS: We reviewed the clinical, pathological and therapeutic aspects of 12 cases diagnosed with EC at 7 tertiary teaching hospitals in Spain. Patients were included if tissue infiltration by histiocytes CD68+/CD1a- could be demonstrated in an appropriate clinical setting. RESULTS: Twelve patients (7 male) were included. Median follow-up was 36 months (IQR: 20-84). The median age at the time of clinical onset and pathological diagnosis was 49 (IQR: 28-61) and 56 years (IQR: 37-62), respectively. In 6 cases multiples biopsies were performed (skin, muscle, testicular) previous to diagnosis, which was confirmed in 3 cases after a carefully review of pathological tissues. Neurological involvement was independently associated with mortality (P<.05). Characteristic long bone osteosclerosis was detected in 9 patients. CONCLUSION: EC is a multisystemic and heterogeneous clinicopathological condition. A high index of suspicion and fluent communication between clinicians and pathologists is necessary to achieve a correct diagnosis.

Conventional cancer screening versus PET/CT in dermatomyositis/polymyositis.

OBJECTIVE: To determine the value of whole-body [(18)F] fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for diagnosing occult malignant disease in patients with myositis compared with broad conventional cancer screening. METHODS: We prospectively studied 55 consecutive patients with a recent diagnosis of myositis in 3 teaching hospitals over a 3-year period by whole-body FDG-PET/CT and compared the results with those of conventional cancer screening, which included thoracoabdominal CT, mammography, gynecologic examination, ultrasonography, and tumor marker analysis. Comparisons were made using predictive values and their 95% confidence intervals. RESULTS: A total of 9 of 55 patients were diagnosed with paraneoplastic myositis. FDG uptake was positive in 7 patients (1 false-positive), negative in 44 patients (3 false-negative), and inconclusive in 4 patients. Positive and negative predictive values of FDG-PET/CT for the diagnosis of cancer were 85.7% and 93.8%, respectively. Conventional screening was cancer-positive in 9 patients (2 false-positive) and negative in the remaining 46 patients (2 false-negative). Positive and negative predictive values were 77.8% and 95.7%, respectively. The overall predictive value of broad conventional screening was the same as that of FDG-PET/CT (92.7 vs 92.7). CONCLUSION: The performance of FDG-PET/CT, a single imaging study, for diagnosing occult malignant disease in patients with myositis was comparable to that of broad conventional screening, which includes multiple tests.

Distinct synovial immunopathology in Behçet disease and psoriatic arthritis.

INTRODUCTION: The aim of the study was to investigate synovial immunopathology differences between early Behçet disease (BD) and psoriatic arthritis (PsA). METHODS: Needle arthroscopy of an inflamed knee joint was performed in patients with early untreated BD (n = 8) and PsA (n = 9). Synovial fluid (SF) was collected for cytokines, perforin, and granzyme analysis. Eight synovial biopsies per patient were obtained for immunohistochemical analysis of the cellular infiltrate (T cells, natural killer cells, macrophages, B cells, plasma cells, mast cells, and neutrophils), blood vessels as well as expression of perforin and granzyme. The stained slides were evaluated by digital image analysis. RESULTS: The global degree of synovial inflammation was similar in the two types of arthritis. In the analysis of the innate immune cell infiltration, there was a striking neutrophilic inflammation in BD synovitis whereas PsA displayed significantly higher numbers of cells positive for c-kit, a marker of mast cells. As for lymphocytes, CD3+ T cells, but neither CD20+ B cells nor CD138+ plasma cells, were significantly increased in BD versus PsA. Further analysis of the T-lymphocyte population showed no clear shift in CD4/CD8 ratio or Th1/Th2/Th17 profile. The SF levels of perforin, an effector molecule of cytotoxic cells, displayed a significant four- to fivefold increase in BD. CONCLUSIONS: This systematic comparative analysis of early untreated synovitis identifies neutrophils and T lymphocytes as important infiltrating cell populations in BD. Increased levels of perforin in BD suggest the relevance of cytotoxicity in this disease.

Diagnostic efficacy of bone scintigraphy, magnetic resonance imaging, and positron emission tomography in bone metastases of myxoid liposarcoma.

Myxoid liposarcomas (MLS) have a tendency to metastasize to unusual sites. We report an unusual case of bone metastases not detected by bone scan and neither by fluorodeoxyglucose positron emission tomography (PET-FDG) and successfully identified with magnetic resonance imaging (MRI) in a patient with metachronic MLS. Histopathological examination of the primary tumor evidenced a tumor with unfavorable prognostic markers, and the biopsy of an iliac bone lesion confirmed the diagnosis of metastatic disease. On histological grounds, the tumor showed features of a more differentiated neoplasm without foci of round cells or necrosis in the latter. MRI allowed the identification of disseminated disease compared to computed tomography (CT) and PET scans. Thus, because of the heterogeneous histological features of MLS and the biological behavior of the disease, a combined approach of FDGPET-CT and MRI, may allow a more accurate staging of soft tissue sarcomas.

Ectopic lymphoid neogenesis in psoriatic arthritis.

BACKGROUND: Ectopic lymphoid neogenesis (LN) occurs in rheumatoid synovium, where it is thought to drive local antigen-dependent B cell development and autoantibody production. This process involves the expression of specific homing chemokines and the development of high endothelial venules (HEV). OBJECTIVE: To investigate whether these mechanisms occur in psoriatic arthritis (PsA) synovium, where autoantibodies have not been described and the organisation and function of B cells is not clear, and to analyse their clinical correlates. METHODS: Arthroscopic synovial biopsy specimens from patients with PsA before and after tumour necrosis factor alpha blockade were characterised by immunohistochemical analysis for T/B cell segregation, peripheral lymph node addressin (PNAd)-positive HEV, and the expression of CXCL13, CCL21 and CXCL12 chemokines in relation to the size of lymphoid aggregates. RESULTS: Lymphoid aggregates of variable sizes were observed in 25 of 27 PsA synovial tissues. T/B cell segregation was often observed, and was correlated with the size of lymphoid aggregates. A close relationship between the presence of large and highly organised aggregates, the development of PNAd+ HEV, and the expression of CXCL13 and CCL21 was found. Large organised aggregates with all LN features were found in 13 of 27 tissues. LN in PsA synovitis was not related to the duration, pattern or severity of the disease. The synovial LN pattern remained stable over time in persistent synovitis, but a complete response to treatment was associated with a regression of the LN features. CONCLUSIONS: LN occurs frequently in inflamed PsA synovial tissues. Highly organised follicles display the characteristic features of PNAd+ HEV and CXCL13 and CCL21 expression, demonstrating that the microanatomical bases for germinal centre formation are present in PsA. The regression of LN on effective treatment indicates that the pathogenic and clinical relevance of these structures in PsA merits further investigation.

Uterine (CD56+) natural killer cells recruitment: association with decidual reaction rather than embryo implantation.

PROBLEM: Whether decidual leukocyte recruitment and/or increase is primarily hormonally regulated or induced mainly by blastocyst implantation is a matter of debate. Thus, this study investigated the number and distribution of leukocyte populations, with emphasis on natural killer (NK) cells of uterine and peripheral type, within decidual tissue from women with decidualized endometrium both related and unrelated to pregnancy and those with ectopic decidua associated with intrauterine pregnancy, as well as in tubal implantation sites. METHOD OF STUDY: Immunohistochemical characterization of immune cells using antibodies to CD3, CD4, CD8, CD20, CD68, CD16, CD56, CD57, in formalin-fixed, paraffin-embedded tissue, and a quantitative analysis of these subpopulations was conducted in tissue blocks from four groups of patients: (i) 20 women with decidualized endometrium due to progestin therapy (i.e. not associated with gestation) (group Prog-D); (ii) 20 women with intrauterine pregnancy-associated ectopic decidua (seven in the Fallopian tube, five in the ovary, five in the uterine cervix, and three in the omentum) (group Ect-D); (iii) 20 women with spontaneous abortion who had an histologic sample of the decidua at the uterine implantation site (group Uter-D); and (iv) 20 consecutive patients who had had an ectopic tubal pregnancy (group Tub-Preg). Twenty gynecologic specimens with marked inflammatory reaction were used as controls (group Con). RESULTS: CD3+, CD4+, CD8+, CD68+ cells were detected in all tissue samples investigated. In contrast, CD20+ cells were detected in all samples in group Con, but only in 75%, 25%, 55% and 70% of groups Prog-D, Ect-D, Uter-D and Tub-Preg, respectively. In all tissue samples investigated, CD57+ and CD16+ cells were detected. Conversely, CD56+ cells were completely absent in 15 of 40 cases (37.5%) lacking decidual reaction (group Tub-Preg, 7/20; group Con, 8/20) but were present in all cases showing decidual reaction. In contrast with CD56+ cells, CD57+ NK cells were more abundant in group Con than in the four study groups. CONCLUSIONS: CD56+ NK cells are closely related to decidua irrespective of its eutopic or ectopic location rather than to the implantation site. This suggests that the recruitment and/or increase of uterine NK cells into the uterus is not dependent on the physical presence of an implanting embryo but instead is controlled hormonally.

A practical approach to intraoperative evaluation of sentinel lymph node biopsy in breast carcinoma and review of the current methods.

BACKGROUND: Sentinel lymph node (SLN) biopsy is increasingly becoming an alternative method for assessing axillary status in breast carcinoma patients. Intraoperative SLN evaluation can potentially select patients for immediate axillary clearance and spare most of them a second surgical procedure. Nevertheless, no standard protocol for intraoperative SLN evaluation has been developed. The aims of this study were to establish the reliability of SLN intraoperative evaluation in breast carcinoma staging, to review the published methods currently used, and to propose a standard protocol. METHODS: One hundred fifty-two SLNs were collected from 86 patients. Lymphoscintigraphy, blue dye, and gamma camera intraoperative controls were used for localization. Each SLN was sliced 2 mm thick and was intraoperatively evaluated by using the combination of frozen section and imprint cytology. The final examination included standard hematoxylin and eosin staining, and, in case of persistent negativity, further sectioning, including hematoxylin and eosin combined with immunohistochemistry (CAM5.2 cytokeratin), was performed. RESULTS: The combination of frozen section and imprint cytology for intraoperative SLN evaluation yielded an intraoperative sensitivity of 78% and a specificity of 100%. All macrometastases (>2 mm) were detected during surgery, as were 2 micrometastases. Final examination detected seven more micrometastases, six of which consisted of isolated tumor cells. CONCLUSIONS: We propose a fast, cost-effective, and accurate procedure for SLN evaluation that is useful for making intraoperative decisions, feasible for most institutions, and reliable because of its high sensitivity (100% for macrometastases) and specificity.

C-kit expression in sarcomatoid renal cell carcinoma: potential therapy with imatinib.

PURPOSE: Sarcomatoid (S) renal cell carcinoma (RCC) is an uncommon subtype of RCC with a poor prognosis because of its local aggressiveness and high metastatic rate. Currently, there is no specific, effective treatment for it. A relatively nontoxic tyrosine kinase inhibitor, imatinib (STI-571) has been approved as a target therapy in neoplasms that express c-Kit. We investigated c-Kit expression in this type of tumor, which to our knowledge has not been previously described. MATERIALS AND METHODS: We reviewed 215 cases of RCC diagnosed at our department from 1995 to 2002. Of the cases 20 (9.3%) were SRCC. Formalin fixed, paraffin embedded material was available in 19 cases. We performed immunohistochemical staining against c-Kit using rabbit polyclonal antihuman antibody (CD117, Dako Corp., Carpinteria, California), diluted 1:100. Its expression was evaluated in the epithelial and the spindle components. RESULTS: Two of the 20 SRCC cases (10%) showed no epithelial differentiation. The epithelial component was conventional RCC in 10 cases (50%), papillary RCC in 5 (25%) and chromophobe RCC in 3 (15%). A total of 16 cases (80%) presented at an advanced stage at diagnosis, namely T3 or T4 and/or metastatic disease. Immunohistochemical study showed positivity in the epithelial component only in the 3 chromophobe SRCCs. The sarcomatoid component was positive for c-Kit in 18 cases (94.7%). CONCLUSIONS: High c-Kit expression in SRCC in our series and the existence of a target therapy, imatinib (STI-571), against cells that express this receptor open the possibility of using this treatment for these tumors, especially in cases of advanced disease.

Ultrastructural and molecular heterogeneity in non-small cell lung carcinomas: study of 110 cases and review of the literature.

The authors reviewed a series of 110 surgical specimens of primary non-small cell lung carcinomas from the Department of Pathology at the Hospital Clinic, University of Barcelona Medical School, between 1987 and 1997. The sample included 25 squamous cell carcinomas, 60 adenocarcinomas, 14 large cell carcinomas, and 11 neuroendocrine tumors. Electron microscopic subcellular characteristics of the lung cancer cells were studied to define the squamous, adenoid, or neuroendocrine differentiation in each tumor. An immunohistochemical study for Cyclin D1 was performed in 96 cases. In 71 cases (65%) the author found a single ultrastructural differentiation, and in 30 cases (27%) ultrastructural differentiation was double: 25 adenosquamous and 5 adeno-neuroendocrine. In 3 cases a triple adeno-squamous-neuroendocrine differentiation was found. There were no cases of squamous-neuroendocrine differentiation. In 6 cases no differentiation of any kind could be found. Cyclin D1 overexpression was found in 58% of all tumors. The positive expression rates in squamous cell carcinoma and adenocarcinoma were 72% and 62%, respectively. In purely adenoid-differentiated tumors there was a strong association between high Cyclin D1 overexpression and differentiation (p=.006). In bronchioloalveolar carcinoma the positivity rate was 70%; all were heavy expressers, compared with 25% of heavy expressers in adenocarcinomas as a whole (p<.005). In purely squamous tumors differentiated ultrastructurally no relationship was found between high Cyclin D1 expression and degree of differentiation (p=.08). Lung cancers are morphologically and molecularly heterogeneous, and certain molecular alterations are related to specific subcellular characteristics.