Prognostic impact of histologic subtyping of adult renal epithelial neoplasms: an experience of 405 cases

Just two and a half decades ago adult renal cell neoplasms, i.e., those arising from the renal tubules or collecting duct epithelium, were subdivided into two major subtypes: "clear cell carcinoma" and "granular cell carcinoma." Subsequent detailed morphologic and/or cytogenetic studies have resulted in the recognition of several distinctive subtypes of adult renal epithelial neoplasms, which has led to the promulgation of a refined contemporary histologic classification of these tumors. This study examines the prognostic significance of histologic subtyping in accordance with the new classification in a consecutive series of 405 cases treated at a single institution. Cases were histologically classified into 28 (7%) benign tumors [27 (6.7%) renal oncocytomas, 1 (0.2%) metanephric adenoma] and 377 (93%) malignant tumors [255 (63%) conventional (clear cell) renal cell carcinoma, 75 (18.5%) papillary renal cell carcinoma, 24 (5.9%) chromophobe renal cell carcinoma, and 23 (5.7%) renal cell carcinoma, unclassified]. A total of 25 (6.6%) malignant tumors showed evidence of sarcomatoid change. Kaplan-Meier survival analysis with log-rank test showed histologic type (p = 0.002), Fuhrman's nuclear grade (p = 0.001), TNM stage (p = 0.001), vascular invasion (p = 0.001), and necrosis (p = 0.001) to be significantly associated with disease-specific survival and progression-free survival, based on follow-up of 368 patients (mean 64.5 months, median 56 months). The 5-year disease-specific survival for chromophobe renal cell carcinoma, papillary renal cell carcinoma, conventional (clear cell) renal cell carcinoma, and renal cell carcinoma, unclassified was 100%, 86%, 76%, and 24%, respectively; no patient with a benign tumor diagnosis progressed or died of disease. The 5-year progression-free survival for chromophobe renal cell carcinoma, papillary renal cell carcinoma, conventional (clear cell) renal cell carcinoma, and renal cell carcinoma, unclassified was 94%, 88%, 70%, and 18%, respectively. Malignant tumors with sarcomatoid change had a 35% and 27%, 5-year disease-specific and progression-free survival, respectively. Cox proportional hazards regression analysis showed TNM stage (p = 0.001), nuclear grade (p = 0.01), and necrosis (p = 0.05) to be significant predictors of disease-specific survival. In conclusion, our study shows that the histologic categorization of adult renal epithelial neoplasms performed by routine light microscopic hematoxylin and eosin-based examination in accordance with the contemporary classification scheme has prognostic utility.     

Immunohistochemical p53 expression patterns in sarcomatoid carcinomas of the upper respiratory tract

Sarcomatoid carcinoma of the upper respiratory tract is a phenotypically complex neoplasm that has triggered much thoughtful discussion regarding histogenic origin and morphologic classification. In particular, its putative epithelial lineage and distinction from a pseudosarcomatous reaction are sometimes questioned. Little is known about the genetic alterations underlying sarcomatoid carcinoma. Although about 45% of conventional squamous cell carcinomas of the upper respiratory tract harbor p53 mutations, the p53 status of sarcomatoid carcinomas is not well established. p53 immunohistochemical analysis using the monoclonal antibody D07 was performed on 23 sarcomatoid carcinomas of the upper respiratory tract. Twenty tumors were biphasic, having dual epithelial and spindled components. In four of these biphasic tumors, the epithelial and spindled components were separately analyzed for p53 gene mutations by sequence analysis. p53 immunohistochemistry was also performed on 19 cases of postradiation stromal atypia. Strong and diffuse p53 staining was detected in 18 (78%) of the 23 sarcomatoid carcinomas. When the spindled component was compared with its corresponding epithelial component, identical patterns of p53 protein expression were noted in 19 (95%) of the 20 biphasic tumors. Weak p53 staining was observed in one (5%) of the 19 cases of postradiation stromal atypia. In the four biphasic tumors evaluated by DNA sequence analysis, p53 status was always the same in the paired epithelial and spindle cell components. These findings help further dispel the notion that sarcomatoid carcinoma represents a reactive spindle cell proliferation (pseudosarcoma) or a collision between a carcinoma and a sarcoma (collision tumor). Instead, the epithelial and spindled components share a common pathway of tumorigenesis despite their conspicuous divergence at the phenotypic level.     

Sarcomatoid renal cell carcinoma: an examination of underlying histologic subtype and an analysis of associations with patient outcome

A sarcomatoid component can occur in all histologic subtypes of renal cell carcinoma (RCC) and indicates an aggressive tumor. We studied 2381 patients treated with radical nephrectomy for RCC between 1970 and 2000. A urologic pathologist reviewed the microscopic slides from all tumor specimens for the presence of a sarcomatoid component, defined as a RCC with any malignant spindle cell component. All tumors with a sarcomatoid component were classified as nuclear grade 4. A total of 120 (5.0%) patients had RCC with a sarcomatoid component, including 94 who died of RCC at a mean of 1.4 years following nephrectomy (median 8 months; range 44 days to 10 years). Cancer-specific survival rates at 2 and 5 years following nephrectomy were 33.3% and 14.5%, respectively. The presence of distant metastases at the radical nephrectomy and histologic tumor necrosis were significantly associated with death from RCC among patients with sarcomatoid RCC. Patients with clear cell (conventional) RCC and chromophobe RCC were more likely to have tumors with a sarcomatoid component (5.2% and 8.7%, respectively) compared with patients with papillary RCC (1.9%). The presence of a sarcomatoid component was significantly associated with death from RCC for all three subtypes (P < 0.001). Even among patients with grade 4 clear cell RCC, the presence of a sarcomatoid component was significantly associated with outcome, both univariately (risk ratio 1.59; P = 0.010) and after adjusting for TNM stage, tumor size, and histologic tumor necrosis (risk ratio 1.46; P = 0.037).     

Flow cytometric analysis of DNA ploidy, cell cycle and cytomorphometry in sarcomatoid renal cell carcinoma.

In 5 patients with sarcomatoid renal cell carcinoma, the nuclear DNA content and size were determined by flow cytometry (FCM), and the prognostic value of DNA ploidy, the percentage of S-phase cells (SPF), and the ratio of modal nuclear size with clinicopathologic behavior was analyzed. Age and clinical stage have been shown to have a strong correlation with prognosis. Older patients with a high stage of cancer had poor outcome with a shorter survival time. In all 60% of the tumors were aneuploid. Tumor invasiveness was related to DNA ploidy. With increasing stage, the overall incidence of aneuploid rises. One alive patient had diploid DNA while 75% of the patients who died of sarcomatoid renal cell carcinomas had aneuploid DNA. Diploid sarcomatoid renal cell carcinomas show significantly lower SPF than aneuploid tumors. There was no significant association between the modal nuclear size and the invasiveness of tumors or survival time. This study suggests that FCM analysis of tumor DNA content and cell cycle could be regarded as an additional prognostic determinant of sarcomatoid renal cell carcinoma.     

Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma

Our objective was to compare cancer-specific survival and to examine associations with outcome among the histologic subtypes of renal cell carcinoma (RCC). We studied 2385 patients whose first surgery between 1970 and 2000 was a radical nephrectomy for sporadic, unilateral RCC. All RCC tumors were classified following the 1997 Union Internationale Contre le Cancer and American Joint Committee on Cancer guidelines. There were 1985 (83.2%) patients with clear cell, 270 (11.3%) with papillary, 102 (4.3%) with chromophobe, 6 (0.3%) with collecting duct, 5 (0.3%) with purely sarcomatoid RCC and no underlying histologic subtype, and 17 (0.7%) with RCC, not otherwise specified. Cancer-specific survival rates at 5 years for patients with clear cell, papillary, and chromophobe RCC were 68.9%, 87.4%, and 86.7%, respectively. Patients with clear cell RCC had a poorer prognosis compared with patients with papillary and chromophobe RCC (p <0.001). This difference in outcome was observed even after stratifying by 1997 tumor stage and nuclear grade. There was no significant difference in cancer-specific survival between patients with papillary and chromophobe RCC (p = 0.918). The 1997 TNM stage, tumor size, presence of a sarcomatoid component, and nuclear grade were significantly associated with death from clear cell, papillary, and chromophobe RCC. Histologic tumor necrosis was significantly associated with death from clear cell and chromophobe RCC, but not with death from papillary RCC. Our results demonstrate that there are significant differences in outcome and associations with outcome for the different histologic subtypes of RCC, highlighting the need for accurate subtyping.     

An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage,size, grade and necrosis: the SSIGN score

PURPOSE: Currently outcome prediction in renal cell carcinoma is largely based on pathological stage and tumor grade. We developed an outcome prediction model for patients treated with radical nephrectomy for clear cell renal cell carcinoma, which was based on all available clinical and pathological features significantly associated with death from renal cell carcinoma. MATERIALS AND METHODS: We identified 1,801 adult patients with unilateral clear cell renal cell carcinoma treated with radical nephrectomy between 1970 and 1998. Clinical features examined included age, sex, smoking history, and signs and symptoms at presentation. Pathological features examined included 1997 TNM stage, tumor size, nuclear grade, histological tumor necrosis, sarcomatoid component, cystic architecture, multifocality and surgical margin status. Cancer specific survival was estimated using the Kaplan-Meier method. Cox proportional hazards regression models were used to test associations between features studied and outcome. The selection of features included in the multivariate model was validated using bootstrap methodology. RESULTS: Mean followup was 9.7 years (range 0.1 to 31). Estimated cancer specific survival rates at 1, 3, 5, 7 and 10 years were 86.6%, 74.0%, 68.7%, 63.8% and 60.0%, respectively. Several features were multivariately associated with death from clear cell renal cell carcinoma, including 1997 TNM stage (p <0.001), tumor size 5 cm. or greater (p <0.001), nuclear grade (p <0.001) and histological tumor necrosis (p <0.001). CONCLUSIONS: In patients with clear cell renal cell carcinoma 1997 TNM stage, tumor size, nuclear grade and histological tumor necrosis were significantly associated with cancer specific survival. We present a scoring system based on these features that can be used to predict outcome.     

Spindle cell (sarcomatoid) carcinoma of the breast: a clinicopathologic and immunohistochemical analysis of 29 cases

Spindle cell (sarcomatoid) carcinoma of the breast is a rare variant of breast cancer that has been classified under the broad rubric of metaplastic carcinoma. Because the term "metaplastic carcinoma" comprises a heterogeneous group of tumors, it has been difficult to reliably predict biologic potential or to determine optimal therapy. To better characterize the spindle cell subset of metaplastic breast carcinomas, we reviewed 29 cases. All patients were adult females ranging from 40 to 96 years of age (median, 68 years). Tumor size ranged from 1.5 to 15 cm (median, 4 cm). Treatment was by excision and/or mastectomy with axillary node evaluation in most cases, often combined with postoperative radiation and/or chemotherapy. All cases were clinically of breast origin, showed >or=80% spindled/sarcomatoid morphology, and demonstrated keratin positivity and/or close association with ductal carcinoma in situ. Immunohistochemical studies showed evidence suggesting myoepithelial differentiation as exhibited by immunoreactivity for smooth muscle actin, cytokeratin 14, and p63 in a subset of cases (39%). Twenty-seven cases exhibited pure spindled or sarcomatoid morphology of variable appearance and nuclear grade, whereas 2 contained high-grade invasive ductal carcinoma comprising 相似文献   

Expression of hypoxia inducible factor-1α and 2α in conventional renal cell carcinoma with or without sarcomatoid differentiation

Objectives

Expressions of hypoxia inducible factor (HIF)-1α and HIF-2α in epithelial and sarcomatoid components from the same patients with clear cell renal cell carcinoma (RCC) are lacking. We performed this study to define better the correlations among these molecules in RCC tissues.

Materials and methods

Immunohistochemical staining of paraffin sections for HIF-1α and HIF-2α was performed in 24 cases of RCC with sarcomatoid differentiation using a streptavidin-peroxidase procedure. Control samples were collected from 58 patients with no sarcomatoid differentiation matched to cases by age, gender, and TNM stage.

Results

HIF-1α was more expressed within the epithelial component of clear cell RCC with no sarcomatoid differentiation (82.8%) than within that with sarcomatoid differentiation (66.7%). HIF-2α was expressed in most of the epithelial component, regardless of the sarcomatoid differentiation. However, HIF-1α and HIF-2α were not expressed in the sarcomatoid component in about 50.0% of clear cell RCC regardless of the sarcomatoid differentiation. Multivariate Cox proportional hazards model analysis showed that HIF-1α expression was an independent predictor of cancer-specific survival in clear cell RCC with sarcomatoid differentiation (P = 0.029).

Conclusions

HIF-1α and HIF-2α are not expressed in the sarcomatoid component in about a half of clear cell RCC with sarcomatoid differentiation, while HIF-2α was consistently overexpressed in the epithelial component in a majority of the tumors. Only HIF-1α expression regardless of tumor component is an independent prognostic factor in clear cell RCC with sarcomatoid differentiation.     

Carcinosarcomas of the lung: a clinicopathologic study of 66 patients

Carcinosarcoma is a malignant tumor having a mixture of carcinoma and sarcoma containing differentiated mesenchymal elements, such as malignant cartilage, bone, and skeletal muscle. These tumors have been linked histogenetically to pleomorphic carcinomas; it is unclear whether their clinical behavior is significantly different. To investigate this issue, we studied 66 cases of carcinosarcomas of the lung and compared them with cases from a previously published series of pleomorphic carcinomas. Carcinosarcomas show a male-to-female ratio of 7.25:1, with a mean and median age of 65 years. They most often present as solitary masses in the upper lobes and average 7 cm in diameter. Most (62%) were endobronchial or central tumors, whereas 38% were described as peripheral. The most frequent epithelial component was squamous cell carcinoma (46%), followed by adenocarcinoma (31%) and adenosquamous carcinoma (19%), whereas sarcomatous elements most frequently included rhabdomyosarcoma, chondrosarcoma, osteosarcoma, or combinations of these elements. Survival of patients with carcinosarcomas of lung was poor, with a 5-year survival rate of 21.3%. Of several clinical and pathologic parameters, only increased tumor size (with 6 cm as the optimal cutoff point) appeared to be related to reduced survival (p = 0.0195). In comparison with patients with pleomorphic carcinoma, patients with carcinosarcomas had no significant difference in the size of their tumors (p = 1.0), stage at presentation (p = 0.883), location in the lung (p = 0.073), or their overall survival (21.3% vs 15.0%) (p = 0.1038). A significantly greater proportion of patients with carcinosarcoma had squamous cell (p = 0.004) or adenosquamous (p = 0.016) carcinoma, whereas patients who had pleomorphic carcinoma showed a significantly greater frequency of adenocarcinoma (p = 0.029) and large cell carcinoma. The histologic differences between these two types of tumor suggest that they may be different entities with similar behavior, but additional studies are warranted to investigate this hypothesis.     

Pleomorphic carcinoma of the lung: clinicopathologic characteristics of 70 cases

Pleomorphic carcinoma (PC) of the lung is rare, and it is classified as a subtype of sarcomatoid carcinoma of the lung in the World Health Organization histologic classification of lung tumors. In this study, 70 cases of PC surgically resected were reviewed to identify its clinicopathologic characteristics. There were 57 men and 13 women, and their mean age was 66 years (range: 29 to 80 y). Sixty-eight tumors contained identifiable epithelial components, and the other 2 consisted of spindle cells and giant cells alone. An adenocarcinoma component was found in 34 cases, a squamous cell carcinoma component in 13, and a large cell carcinoma component in 40. The overall survival rate and disease-free survival rate were 36.6% and 40.7%, respectively, and both rates were significantly lower than for other nonsmall cell lung carcinomas. When the PC patients were divided into 3 groups according to the predominant epithelial component, an adenocarcinoma group, squamous cell carcinoma group, and large cell carcinoma group, there were no significant differences in the overall survival rate and median survival time between the 3 groups. Univariate analysis revealed that advanced stage (stage III), mediastinal lymph node metastasis, lymphatic permeation, and histologically diagnosed massive coagulation necrosis (>25% of the tumor) predicted poorer disease-free survival. Multivariate analysis showed that massive necrosis alone was an independent prognostic factor. We concluded that PC should be considered as an aggressive disease and massive necrosis should be routinely reported and used as a factor in clinical assessments.     

影响肾癌预后的因素

目的探讨影响肾癌预后的因素。方法对401例’肾癌患者,就20项临床病理因素作Kaplan—Meier单因素分析和COX多因素分析,所有数据用SPSS11．5统计软件处理。结果单因素分析,年龄、性别、病理类型等12项因素对生存率有影响（P〈0．01）。COX多因素分析,仅有年龄、肉瘤样变等7项因素是影响肾癌预后的独立因素（P〈0．05）。赔论老龄、有肉瘤样变、全身症状、腔静脉瘤拴、淋巴结转移、远处转移、TNM高分期。肾癌病人预后差。     

Mucinous tubular and spindle cell carcinoma of the kidney with sarcomatoid change

Sarcomatoid change has been well documented in the various subtypes of renal cell carcinoma (RCC) and its presence is known to portend a worse prognosis in RCC. Mucinous tubular and spindle cell carcinoma is a RCC subtype, which is defined as polymorphous histology wherein the spindled epithelial cell is an inherent carcinomatous component. Many of these putatively low-grade tumors have been previously misdiagnosed as unclassified or sarcomatoid papillary RCC. We present 2 examples of hitherto undescribed sarcomatoid change in mucinous tubular and spindle cell carcinoma in a 71-year-old woman and an 80-year-old man who both underwent a radical nephrectomy procedure. In addition to the classic mucinous tubular and spindle cell carcinoma morphology, both cases had a sarcomatoid component characterized by predominantly high-grade spindle cells, solid pleomorphic epithelioid cells, and malignant fibrous histiocytoma-like storiform patterns. Sarcomatoid change comprised 60% and 20% of the tumors, respectively. Unlike the spindle sarcomatoid cells, the inherent spindle cell elements of mucinous tubular and spindle cell carcinoma had distinctively low-grade cytology and occasionally blended with tubular structures and variable mucinous stroma. The sarcomatoid cells were associated with significant necrosis, marked nuclear pleomorphism, mitoses of up to 5/10 high power field, higher proliferation fraction (MIB1), and loss of alpha-methylacyl-CoA racemase or cytokeratin 7 expression. Cytogenetic analysis in 1 tumor showed loss of chromosomes 14 and 15 and gains of chromosomes 2, 5, 7, 9, 10, 12, 17, 19, 20, 22, and X. Widespread metastasis to lymph nodes, bones and lungs occurred in one patient who succumbed 9 months after nephrectomy. Helpful features in distinguishing spindle cells of sarcomatoid component versus that of the native tumor include the presence of high-grade cytology, expansile growth with loss of typical imperceptible blending with the tubulo-papillary component, extensive necrosis, high mitotic activity, high proliferation fraction, and loss of expression of alpha-methylacyl-CoA racemase that contrasted the classic areas. Distinction of the sarcomatoid histology from inherent spindle cell component of mucinous tubular and spindle cell carcinoma is important because of its unfavorable prognostic implication.     

Immunohistochemical expression of hypoxia inducible factor-1alpha and its downstream molecules in sarcomatoid renal cell carcinoma

PURPOSE: Sarcomatoid renal cell carcinomas, highly aggressive variants of renal cell carcinoma subtypes, often present with or develop metastases soon after the primary diagnosis. Most metastatic cases do not respond to immunotherapy or aggressive chemotherapy. Recently targeted therapies, particularly those targeting hypoxia inducible pathway molecules, have been tested clinically on metastatic clear cell renal cell carcinoma with promising initial results. No such studies are available on sarcomatoid renal cell carcinoma. We investigated the hypoxia inducible pathway marker immunohistochemical expression profile, and any potential therapeutic implications that such expression may have, in these tumors. MATERIALS AND METHODS: Immunohistochemical staining for hypoxia inducible factor-1alpha, glucose transporter 1, carbonic anhydrase IX and vascular endothelial growth factor was performed in 22 clear cell and 12 nonclear cell sarcomatoid renal cell carcinomas. The immunoreactivity in the tumors was graded from 0 to 3+ (0-no staining, 1+-1% to 25% cells positive, 2+-26% to 50% cells positive and 3+-greater than 50% cells positive). The results were then compared with various clinical parameters to assess for associations. RESULTS: Most clear cell renal cell carcinomas over expressed (2+ or 3+) hypoxia inducible factor-1alpha (in 59%), carbonic anhydrase IX (95%), glucose transporter 1 (91%) and vascular endothelial growth factor (95%). None of the nonclear cell sarcomatoid renal cell carcinomas showed 2+ or 3+ expression of hypoxia inducible factor-1alpha, carbonic anhydrase IX or glucose transporter 1, but 92% showed diffuse positivity for vascular endothelial growth factor. Over expression of carbonic anhydrase IX showed no association with survival, unlike that reported in (nonsarcomatoid) clear cell renal cell carcinoma. There was significant discordance in the staining grades among hypoxia inducible factor-1alpha, carbonic anhydrase IX and glucose transporter 1 in clear cell renal cell carcinoma, suggesting that mechanisms other than hypoxia inducible pathway may be involved in some sarcomatoid clear cell renal cell carcinoma. CONCLUSIONS: Hypoxia inducible pathway markers continue to be over expressed in sarcomatoid clear cell renal cell carcinoma, and can be of diagnostic usefulness in such high grade tumors. Over expression of vascular endothelial growth factor in the clear and nonclear cell groups raises the possibility that vascular endothelial growth factor targeted therapies may have a role in the management of sarcomatoid renal cell carcinoma, and deserve further investigation.     

Renal cell carcinoma invading the urinary collecting system: implications for staging

PURPOSE: Current TNM staging of renal cell carcinoma is based on the tumor propensity for local extension (T), nodal involvement (N) and metastatic spread (M). Locally advanced renal cell carcinoma may involve the perirenal fat, adrenal glands, renal vein, vena cava and/or urinary collecting system. The existing TNM classification does not reflect the ability of renal cell carcinoma to invade the urothelium. We evaluated the incidence and characteristics as well as overall and cancer specific survival of renal cell carcinoma invading the urinary collecting system. METHODS AND MATERIALS: We reviewed pathological findings in 504 kidneys from 475 patients with renal cell carcinoma who presented to our institution in a 3-year period. Urothelial involvement required evidence of gross or histological invasion of the renal calices, infundibulum, pelvis or ureter. Demographic and survival data were obtained from medical records and an institutional cancer registry for tumors invading the urothelium. Stage specific survival data were then compared with tumors not involving the urinary collecting system. RESULTS: Definitive urothelial involvement by the primary tumor was interpretable in 426 of 504 kidneys. Invasion of the collecting system was identified in 61 of 426 cases (14%). Mean diameter of the invading lesions was 10.2 cm. (range 3 to 26). The majority of cases showed clear cell and sarcomatoid histology. Invasion by a papillary lesion was rare. Involvement of the collecting system was most common at the renal poles. Of 61 lesions invading the collecting system 48 (79%) were stage pT3 or greater, while only 13 (21%) were pathologically localized stage pT2 or less. Vascular invasion was identified in 38 renal cell carcinoma cases (62%) with urothelial involvement. A total of 16 cases (26%) were associated with vena caval thrombus. Invading tumors were high Fuhrman grade III or IV in 43 cases (70%). Overall disease specific survival was poor with a median of 19 months. In patients with localized stage pT1 or pT2N0M0 disease and urothelial invasion median disease specific survival was 46 months. CONCLUSIONS: Renal cell carcinoma lesions involving the renal collecting system are characteristically large, high grade and high stage. Clear cell carcinoma most commonly invades, while invasion by papillary tumors is rare. Overall the prognosis for high stage lesions with urothelial involvement is poor and does not appear significantly different from the reported disease specific survival of patients with high stage lesions without urothelial invasion. Localized tumors 4 cm. or less, which are amenable to elective nephron sparing surgery, rarely invade the urothelium. However, when a low stage pT2 or less renal lesion involves the urinary space, survival appears worse than equivalently staged renal cell carcinoma without invasion. Including urothelial invasion into current TNM staging systems for renal cell carcinoma is unlikely to provide significant additional prognostic or therapeutic information.     

Down-regulation of HLA class I antigen is an independent prognostic factor for clear cell renal cell carcinoma

PURPOSE: We determined the prognostic impact of human leukocyte antigen class I on the survival of patients with clear cell renal cell carcinoma. MATERIALS AND METHODS: Immunohistochemical staining for HLA class I was performed on specimens from 45 patients with clear cell renal cell carcinoma. We performed univariate and multivariate analyses of various factors affecting cause specific survival including HLA class I, Fuhrman grade, TNM stage and tumor size. Furthermore, we compared the survival of patients with HLA class I positive renal cell carcinoma to that of those with down-regulated HLA class I using the Kaplan-Meier method and log rank test. RESULTS: HLA class I was immunohistochemically down-regulated in 17 (37.8%) clear cell renal cell carcinomas. The down-regulation had no correlation with other clinicopathological parameters such as tumor size, perirenal fat invasion, tumor thrombus, TNM stage or nuclear grade. Univariate and multivariate analyses revealed that HLA class I expression, tumor grade and TNM stage were significant factors influencing the disease specific survival of patients with renal cell carcinoma. Patients with HLA class I positive renal cell carcinoma had longer recurrence-free survival than those with down-regulated expression at 5-year followup (95.5% and 61.1%, respectively). CONCLUSIONS: Our data demonstrate that down-regulation of HLA class I on tumor cells is an independent prognostic factor for clear cell renal cell carcinoma. This finding suggests that HLA class I restricted cytotoxic T lymphocytes have an important role in the suppression of renal cell carcinoma.     

Endometriosis does not confer improved prognosis in ovarian carcinoma of uniform cell type

The role of endometriosis in ovarian cancer, disease progression, and survival is a subject of active investigation. A series of 144 ovarian cancers with clear cell or endometrioid histology or associated endometriosis, all classified on the basis of strict histologic criteria, was evaluated to further explore the relationship between endometriosis-associated ovarian cancer and age at presentation, FIGO stage, histology, presence of synchronous primary disease elsewhere in the mullerian tract, and survival. Patients with endometrioid carcinomas were significantly younger (mean, 52 y) in comparison with patients with either clear cell carcinoma (mean, 55 y) or mixed tumors (mean, 59 y; P=0.002). Clear cell carcinoma presented as low-stage disease (FIGO I) in 33% of cases compared with endometrioid carcinomas in 97% of cases and mixed carcinomas in 27% of cases. Endometriosis was associated with 53% of clear cell carcinomas, 33% of endometrioid carcinomas, and 45% of mixed tumors (P<0.001). Synchronous primary tumors, observed in 31% of endometrioid tumors, 5% of mixed tumors, and in 2% of clear cell tumors (P<0.001), were unlikely to be associated with endometriosis (P=0.04). Univariate analysis of the aggregate cohort demonstrated that the single best overall predictor of disease-free survival was FIGO stage at presentation (P<0.001), followed by histologic subtype (P=0.003). Endometriosis did not have a significant relationship with disease-free survival (P=0.7). We conclude that the link between endometriosis and ovarian cancer is much stronger for clear cell carcinoma than for other histologic subtypes (P<0.001). Furthermore, when uniform histologic criteria are applied, true mixed endometrioid and clear cell carcinomas are uncommon; most endometriosis-associated mixed tumors are heterogenous mixtures of endometrioid, mucinous, and serous histology with areas of clear cell cytoplasm. Endometriosis per se does not appear to predict prognosis in clear cell and endometrioid tumors, with the possible exception of tumors with mixed histology. Until more data are collected, pathologists should classify ovarian tumors with mixed histology as a separate and potentially unique biological and prognostic group.     

Chromophobe renal cell carcinoma: the impact of tumor grade on outcome

It has been reported that Fuhrman grading is not appropriate for chromophobe renal cell carcinoma (RCC). The objective of this study was to determine whether nucleolar grading and the recently described chromophobe RCC grading system by Paner and colleagues provide prognostic information. Pathologic features of 185 patients with chromophobe RCC treated surgically between 1970 and 2006 were reviewed, including nucleolar grade, chromophobe RCC grade, the 2010 TNM groupings, sarcomatoid differentiation, and coagulative tumor necrosis. Cancer-specific (CS) survival was estimated using the Kaplan-Meier method, and associations with CS survival were evaluated using Cox proportional hazard regression models. Twenty-three patients died from RCC at a mean of 3.0 years after surgery (median 1.3; range 0 to 16) with estimated CS rates (95% confidence interval) of 89% (84 to 94), 86% (81 to 92), and 85% (78 to 91) at 5, 10, and 15 years after surgery. Univariate associations with CS survival included the 2010 TNM stage groupings, sarcomatoid differentiation, coagulative tumor necrosis, chromophobe RCC grade, and nucleolar grade (all P<0.001). These last 4 features remained significantly associated with CS survival after adjusting for the 2010 TNM stage groupings. When the analysis was restricted to the 155 patients with nonsarcomatoid TNM stage groupings I and II chromophobe RCC, only stage grouping (I vs. II) was significantly associated with CS survival (P=0.03). Although the chromophobe RCC grading system described by Paner and colleagues and nucleolar grade are associated with CS survival in chromophobe RCC, they add no additional prognostic information once TNM stage and sarcomatoid differentiation are assessed.     

Cytoreductive nephrectomy for metastatic renal cell carcinoma with nonclear cell histology

PURPOSE: To our knowledge the benefit of cytoreductive surgery for patients with metastatic renal cell carcinoma with nonclear cell histology is unknown. In this retrospective study we report our experience with cytoreductive nephrectomy for nonclear cell metastatic renal cell carcinoma at M. D. Anderson Cancer Center. We compared the outcomes with those in patients with clear cell metastatic renal cell carcinoma. MATERIALS AND METHODS: From 1991 to 2006, 606 patients with metastatic renal cell carcinoma underwent cytoreductive nephrectomy and they formed the basis of this report. Of these patients 92 had nonclear cell metastatic renal cell carcinoma. The remaining 514 patients had clear cell metastatic renal cell carcinoma and they formed a comparative group. Multivariate Cox regression analysis was performed to evaluate the relationship between clinical variables and histology (clear cell vs nonclear cell) on disease specific survival. RESULTS: Compared with patients with clear cell histology those with nonclear cell metastatic renal cell carcinoma were younger (p = 0.0001), and more likely to have nodal metastases (p <0.0001) and sarcomatoid features (23% vs 13%, p = 0.026). On multivariate analysis median disease specific survival in patients with nonclear cell histology was significantly worse than that in patients with clear cell metastatic renal cell carcinoma (9.7 vs 20.3 months, p = 0.0003) even after adjusting for T stage, grade, performance status, age and sarcomatoid features. Sarcomatoid features were a predictor of poor outcome in cases of clear and nonclear cell histology, although even in the absence of sarcomatoid features nonclear cell histology was associated with worse disease specific survival (p = 0.017). Interestingly although there was a significantly higher incidence of positive nodes in patients with nonclear histology (p <0.0001), this phenotype was not associated with a worse disease specific survival, as it was in those with clear cell histology (p = 0.0001). In fact, patients with node negative disease with nonclear cell histology had the worst prognosis overall in the entire group. CONCLUSIONS: Patients with nonclear cell metastatic renal cell carcinoma were younger and had a higher incidence of nodal metastases, a higher incidence of sarcomatoid features and a worse prognosis than those with clear cell histology who underwent cytoreductive surgery.     

Biological significance of c-met over expression in papillary renal cell carcinoma

PURPOSE: Hereditary papillary renal cell carcinoma is associated with mutations of the c-met proto-oncogene. Similar aberrations have been described at a molecular level in up to 13% of sporadic papillary renal cell carcinomas. We assessed c-met expression in papillary renal cell carcinomas and evaluated the prognostic significance of c-met expression in patients with this tumor. MATERIALS AND METHODS: We performed immunohistochemical testing to identify c-met expression in archival specimens of 55 papillary renal cell carcinomas in 51 patients. Only 1 patient reported a family history of renal malignancy. RESULTS: We identified c-met protein expression in the cytoplasm and cell membrane of 80% and 56% of these tumors, respectively. c-met expression significantly correlated with higher stage tumors (p = 0.004) but it was not associated with Fuhrman nuclear grade (p = 0.157). A trend toward a higher overall survival rate was noted in patients in whom tumors did not express c-met but this association failed to achieve statistical significance (p = 0.07). CONCLUSIONS: Our study indicates that c-met over expression may be associated with an aggressive phenotype in these tumors.