The prognostic value of DNA ploidy in small renal cell carcinoma

The objective was to study the prognostic value of Deoxyribonucleic Acid (DNA) ploidy status in small renal cell carcinomas (RCC). The nuclear DNA content of renal cell carcinoma tissues from patients who underwent radical or partial nephrectomy has been analyzed by flow cytometry. The results of the DNA ploidy have been correlated to the size of tumors and disease progression. Of the 50 patients with RCC studied, 8 (16%) progressed. Tumors with non-diploid DNA patterns were found in 24 (48%) of the 50 patients and in 4 of the 8 patients who progressed. Overall the median tumor size in our series was 50 mm. A tumor diameter of 50 mm or less was measured in 26 patients (group I) and above 50 mm in 24 (group II). Non-diploid DNA patterns were found in 11 (42.3%) and 13 (54.2%) patients in groups I and II, respectively. This difference between the groups was not significant. Only one patient in group I (3.8%) developed metastatic disease and died 72 months after the operation. In group II, 7 patients (29.2%) presented tumor progression and 5 died of metastatic disease. The survival probability in group I was 95% at 5 and 8 years (95% CI 70% to 99%) and for group II 94% at 5 years (95% CI 67%-99%) and 67% at 8 years (95% CI 39%-83%). DNA ploidy is an inaccurate predictor of tumor behavior in patients with RCC, even in small tumors. Tumor size is a more significant predictor of outcome.     

Flow cytometric analysis of the DNA profile of renal cell carcinoma

DNA flow cytometry was applied to one hundred consecutive renal cell carcinomas from years 1974-1979. Single cell suspensions were prepared from paraffin-embedded tissue. From 96 evaluable tumours 34 were considered diploid and 62 aneuploid. Ploidy did not correlate statistically significantly with local growth, venous invasion, nodal or distant metastatic spread, or nuclear grade of renal cell carcinomas. Also the survival of the patients with diploid and aneuploid tumours was not significantly different, but, excluding patients with distant metastases at the time of extrafascial nephrectomy, 83% of the patients with diploid tumour survived for five years, while only 57% of the patients with aneuploid tumour were alive after the same time interval. The difference between survival curves is statistically almost significant (p less than 0.05). The cytologic nuclear grade predicted the prognosis more significantly (p less than 0.01), and the combination of these methods is recommended for the prognostication of renal cell carcinoma.     

MET expression in sporadic renal cell carcinomas

Although germline mutations of met proto-oncogene on human chromosome 7q31-34 have been known as useful molecular markers of hereditary papillary renal cell carcinoma (RCC), the expression of MET, a product of met proto-oncogene, has not been fully studied in sporadic RCC, along with its clinical significance. We investigated the expression of MET by immunohistochemistry in 182 cases of renal neoplasm encompassing 145 RCC, 25 urothelial carcinomas of renal pelvis, and 12 oncocytomas. MET was diffusely and strongly expressed in 90% of papillary RCC, all collecting duct carcinomas, and 92% of urothelial carcinomas of renal pelvis. On the contrary, clear cell RCC, chromophobe RCC, and oncocytomas were negative or focally positive for MET expression. In clear cell RCC, MET expression was positively correlated with high nuclear grade, presence of infiltrative growth, tumoral necrosis, papillary architecture, sarcomatoid component, tumoral involvement of the renal pelvis or ureter, involvement of the calyx, and lymphatic invasion. In conclusion, diffuse and strong expression of MET in papillary RCC and collecting duct carcinoma might be helpful in discriminating from the other subtypes of RCC with tubular or papillary growth. In case of MET expression observed in clear cell RCC, it might correlate with those clinicopathological parameters implying aggressive behavior.     

Expression of topoisomerase II and Ki-67 in cervical carcinoma--clinicopathological study using immunohistochemistry

AIM: To study the correlation between the expression of topoisomerase II and Ki-67 antigen and disease outcome in cervical squamous cell carcinomas. EXPERIMENTAL DESIGN: Forty-nine cervical carcinomas, 10 cases of high-grade cervical intraepithelial neoplasia (CIN II-III) and 5 control cervices were stained by monoclonal antibodies for topoisomerase II and Ki-67 (MIB-1 clone). Nuclear counts were correlated with patient age, tumor stage, histological grade and survival. RESULTS: Thirteen patients died of disease, 35 remained free of disease, and one patient was lost to follow up. Ki-67 counts were higher in CIN lesions, when compared to both invasive carcinomas and control cervices. Topoisomerase II counts were comparable for CIN and invasive tumors. No immunoreactivity for topoisomerase was detected in control cases. Neither stage nor grade was associated with nuclear counts using either marker. In multivariate survival analysis, stage (p=0.001), grade (p=0.03) and older patient age (p=0.02) predicted poor survival. Ki-67 counts predicted survival with borderline significance (p=0.07), while topoisomerase II counts were not related to survival. CONCLUSION: Ki-67 and topoisomerase II counts do not appear to have a significant role in the prediction of survival in cervical squamous cell carcinoma.     

Primary breast carcinomas with neuroendocrine features: Clinicopathological features and analysis of tumor growth patterns in 36 cases

Primary breast carcinoma with neuroendocrine features (NEBC) is an uncommon tumor. In the classification of WHO 2012, these tumors were categorized as: 1- neuroendocrine tumor, well-differentiated; 2- neuroendocrine carcinoma, poorly differentiated/small cell carcinoma; and 3- invasive breast carcinoma with neuroendocrine differentiation. In this study, we reviewed NEBC except poorly differentiated/small cell carcinoma variant in order to define the morphological growth patterns and cytonuclear details of these tumors. All breast surgical excision materials between 2007 and 2016 were re-evaluated in terms of neuroendocrine differentiation. Thirty-six cases showing positive staining for synaptophysin and/or chromogranin A in ≥50% of tumor cells were included in the study. All cases were female with a mean age of 67.4. Mean tumor diameter was 26 mm. Multifocality was noted in 5 cases. Grossly, they were mostly infiltrative mass lesions. T stages, identified in 34 cases, were as follows: 13 cases with pT1; 19 pT2 and 2 pT3. We described schematically 4 types of patterns depending on predominant growth pattern, except one case: 1) Large-sized solid cohesive groups (6 cases), 2) Small- to medium-sized solid cohesive groups with trabeculae/ribbons and glandular structures (6 cases), 3) Mixed growth patterns (20 cases), 4) Invasive tumor with prominent extracellular and/or intracellular mucin (3 cases). The tumor cells were mostly polygonal-oval with eosinophilic/eosinophilic-granular cytoplasm. The nuclei of tumor cells were mostly round to oval with evenly distributed chromatin. Only 5 cases showed high grade nuclear and histological features. Molecular subtypes of the cases were as follows: 33 luminal A, 2 luminal B, and 1 triple negative. NEBC should come to mind when a tumor display one of the morphological patterns described above, composed of monotonous cells with mild to moderate nuclear pleomorphism and abundant eosinophilic/eosinophilic granular or clear cytoplasm, especially in elderly patients.     

Tubular carcinoma of the breast and associated intra-epithelial lesions: a comparative study with invasive low-grade ductal carcinomas

Ductal intra-epithelial lesions of the breast are associated with invasive neoplasms and comprise a large spectrum of histological patterns. We have examined 23 cases of pure tubular carcinomas (TCs) of the breast and 53 cases of invasive ductal low-grade carcinomas to determine the relationship and distribution of intra-epithelial lesions, mainly of ductal in situ carcinoma type, but including also lobular intra-epithelial neoplasia (LIN) in both entities. Eleven cases of TC showed flat epithelial atypia (FEA) (47.8%), and, in 14 and 6 cases, micropapillary and cribriform low-grade ductal carcinoma in situ (DCIS) were present (60.7 and 26.1%, respectively). On the opposite, in ductal grade I invasive carcinomas, the most frequent architectural pattern was low-grade DCIS growing in arcades in 26 cases (49%). While absent in TCs, low-grade DCIS of solid type was found in five (9.4%) cases of ductal invasive carcinomas, where FEA were present in seven (13.2%) cases. LIN lesions were present in four (17.4%) cases of TC, whereas they represented 7.5%, as reported by Carstens et al. (Am J Clin Pathol 58:231–238, 1972), of cases of low-grade carcinomas. These results suggest that invasive pure TC and low-grade ductal carcinomas of the breast are different lesions, and support the fact that TC, of low histopathological grade, is a particular distinct tumoural entity.     

Ductal carcinoma of the breast. An analysis of proportions of intraductal and invasive components

One hundred and ninety patients with mammary ductal carcinoma were studied to evaluate the correlation of proportions of intraductal and invasive tumor growth to histologic and immunohistochemical features. Initially, attempts were made to divide the cases into 6 groups according to the proportion of extraductal invasive areas within the whole tumor. It has been found that ductal carcinoma could be divided, on this criterion, into 2 groups. One comprised tumors in which invasive areas made up less than 20% of the tumor, the other included those with invasive areas exceeding 20%. In the former, intraductal and invasive components exhibited a lower grade of nuclear and tumor component and a higher incidence of cells with CEA immune positivity. The latter manifested higher grades in both intraductal and invasive components and a lower incidence of CEA positive cells. Many of the latter tumors had a solid or comedo-like growing pattern of the intraductal component. There was a significant difference in the prognosis between the two categories. We conclude that like intraductal carcinomas, invasive ductal carcinomas with a predominant intraductal component should be considered a lower grade malignancy.     

Comparison of standardized and nonstandardized nuclear grade of renal cell carcinoma to predict outcome among 2,042 patients

We compared the ability of original nuclear grades from surgical pathology reports and grades reviewed by a urologic pathologist to predict death due to renal cell carcinoma (RCC) for 2,042 patients treated with radical nephrectomy between January 1970 and December 1998. Reviewed grade I tumors had small, round nuclei with inconspicuous nucleoli visible at x400; grade 2 contained round to slightly irregular nuclei with mildly enlarged nucleoli visible at x200; grade 3 had round to irregular nuclei with prominent nucleoli visible at x100; grade 4 contained enlarged pleomorphic or giant cells. Predictive abilities were compared using R2 values from Cox proportional hazards models. There were 1,733 (84.87%) clear cell, 222 (10.87%) papillary, and 87 (4.26%) chromophobe tumors. Reviewed grades were more predictive of death due to RCC than original grades for clear cell (R2, 21% vs 16%), papillary (R2, 16% vs 13%), and chromophobe (R2, 39% vs 27%) RCC. Among patients with clear cell and papillary RCC, this difference was apparent even after adjusting for the 1997 TNM stage. Standardized nuclear grades were more predictive of death due to RCC than nonstandardized grades for all subtypes studied.     

Types of tumor lymphoid response and sinus histiocytosis. Relationship to five-year, disease-free survival in patients with breast cancer

Diffuse (D), perivascular (PV), and a combination form (DPV) of lymphoid infiltrates were found in 95% of invasive breast cancers. The DPV and D patterns were associated with tumor necrosis, and the D pattern with cancers of nuclear grade 3 (most anaplastic) and histologic grade 3 (most malignant). An absent cell reaction was significantly related to absent nodal metastases. Life-table analyses disclosed a higher incidence of patients' being disease free for five years when no cell reaction was encountered. There was no significant association between the presence or absence of any particular type of sinus histiocytosis (SH) of regional lymph nodes and five-year, disease-free survival. It is uncertain whether lymphoid reactions and SH represent immunologic host responses, but if they do, they appear to be biologically ineffectual and, in the former instance, perhaps even detrimental.     

Fine-needle aspiration of renal masses in adults: analysis of results and diagnostic problems in 108 cases.

Fine-needle aspiration (FNA) biopsy of the kidney has a traditionally well-defined role in the diagnosis and treatment of renal lesions. Recent improvements in renal imaging techniques have also brought renal FNA to the forefront, since small and asymptomatic renal masses are increasingly being detected. Before the physician institutes a treatment plan, such lesions usually require a definitive diagnosis that is best provided by FNA. To assess various aspects of renal FNA, including specimen adequacy, questionable cytologic patterns, and diagnostic pitfalls, we retrospectively evaluate our experience with 108 FNA biopsies performed for the evaluation of renal masses in adults. For each case, the smears were reviewed and correlated with tissue sections from cell blocks, surgical specimens, or autopsy material, when available. The cytologic diagnoses were confirmed by cell block (59 cases), nephrectomy or autopsy (35 cases), or clinical follow-up. Of the 108 FNA biopsy samples, 17 showed evidence of blood, soft tissue, necrotic material, glomeruli, or tubular cells and were classified as unsatisfactory. The following diagnostic categories were noted in the 91 satisfactory aspirates: renal abscess (four cases), benign cyst (30 cases), suspicious lesions (11 cases), and malignant lesions (46 cases). In four cases of renal abscess, FNA found abundant clusters of neutrophils. For the 30 cases interpreted on cytologic evidence as benign cysts, the diagnosis was confirmed in 28 cases; the two remaining cases were acquired cystic kidney and cystic renal-cell carcinoma, respectively. Among the 11 suspicious lesions, the final diagnoses were one benign simple cyst, one angiomyolipoma, two multilocular cystic nephromas, two adult polycystic kidneys, one acquired cystic kidney, three cystic papillary renal-cell carcinomas, and one solid renal-cell carcinoma. Cases classified as suspicious shared characteristic cytologic patterns that distinguished them from simple benign cysts and from classic renal-cell carcinoma. Among the 46 malignant lesions, as evidenced on cytologic examination, 27 were renal-cell carcinomas, five were transitional-cell carcinomas, four were lymphomas, one was a small-cell undifferentiated carcinoma, and nine were metastatic carcinomas. False-positive or false-negative cases were not encountered in this category. In conclusion, FNA is an excellent method to diagnose space-occupying lesions of the kidney. For cystic lesions, cytologic-radiographic correlation is needed to avoid misinterpretation. Our study defines a spectrum of suspicious patterns characteristic of a group of renal lesions that are distinct from both benign simple cyst and straightforward renal malignancy.     

Extra copies of chromosomes 16 and X in invasive breast carcinomas are related to aggressive phenotype and poor prognosis

BACKGROUND: Breast cancer is a genetically complex disease, which involves the accumulation of various structural and numerical chromosomal aberrations. AIM: To assess the numerical status of chromosomes 16 and X by interphase cytogenetics, in 114 women with primary invasive breast carcinomas, in relation to clinicopathological parameters, patients' overall survival and indices of cell growth (c-erbB-2, topoisomerase IIalpha (topoIIalpha)) and cell survival (caspase-3, bcl-2). Experimental design: Chromogenic in situ hybridisation with pericentromeric probes was performed for molecular analysis, while oestrogen and progesterone receptors, cerbB-2, topoIIalpha, caspase-3 and bcl-2 expression was immunohistochemically detected (ABC/HRP). The results were statistically assessed by univariate and multivariate analyses. RESULTS: Polysomy of chromosomes 16 and X was detected as the predominant aberration (73.7% and 57.9%, respectively). Gain of chromosome 16 copies was associated with high nuclear grade (p = 0.009), increased tumour size (p = 0.041), advanced stage (p = 0.002), the expression of topoIIalpha (p = 0.005) and worse overall survival by multivariate analysis (p = 0.032). Chromosome X polysomy was increased in ductal carcinomas of high histological grade (p = 0.008), in high nuclear grade tumours (p = 0.001), and was associated with the expression of topoIIalpha (p = 0.005), loss of caspase-3 (p = 0.036) and impaired prognosis of ductal carcinomas (p = 0.041). CONCLUSIONS: Polysomy of chromosomes 16 and X was reported as the predominant alteration in phenotypically aggressive breast tumours, characterised by poor differentiation, increased growth potential and impaired prognosis, whereas gain of chromosome X in particular is probably implicated in cell survival.     

Aberrant expression of beta-catenin and mutation of exon 3 of the beta-catenin gene in renal and urothelial carcinomas

The present study attempted to clarify the significance of aberrant expression of beta-catenin protein and mutation of exon 3 of the beta-catenin gene in renal and urothelial carcinogenesis. beta-Catenin expression was examined immunohistochemically and mutation of the beta-catenin gene was analyzed by polymerase chain reaction-single strand conformation polymorphism (SSCP) and direct sequencing. beta-Catenin immunoreactivity was observed at the cell membrane in all 30 renal cell carcinomas (RCC) examined, and no RCC showed a mobility-shifted SSCP band. Of 46 transitional cell carcinomas (TCC) examined, there was reduced expression of beta-catenin, as compared with its expression in non-cancerous transitional epithelium, in 22 cases (48%) and beta-catenin accumulation in the nucleus in five cases (11%). Of four renal pelvis TCC examined, point mutation of exon 3 of the beta-catenin gene at codon 45 resulting in amino acid substitution (Ser to Phe) was detected in one (25%). The incidence of reduced expression of beta-catenin correlated significantly with the growth pattern (superficial type vs invasive type) of TCC (P < 0.05). These data indicate that: (1) aberrant beta-catenin expression may be at least partly involved in urothelial carcinogenesis, but less significantly so in renal carcinogenesis, and (2) it may be associated with the progression of TCC showing invasive growth.     

The expression of insulin-like growth factor-I receptor correlates with Fuhrman grading of renal cell carcinomas

Recent reports have shown significant correlation between Fuhrman nuclear grade of renal cell carcinoma (RCC) and patient survival. However, no one specific gene alteration has yet been described to account for this correlation. This study investigated the expression of the insulin-like growth factor-I receptor (IGF-IR) in RCC and correlated the results to the tumor Fuhrman nuclear grade. Formalin-fixed, paraffin-embedded sections from 68 cases of RCC were stained using the immunohistochemical avidin-biotin-peroxidase method. An anti-human IGF-IR rabbit polyclonal antibody was used. The stains were semiquantitatively evaluated using the Allred score system, assessing intensity of stain and percentage of positive tumor cells. Statistical analysis was performed using the Kruskal-Wallis test. Strong and diffuse cytoplasmic IGF-IR stain (Allred score 7 to 8) was identified in 25 of 25 (100%) of grade 3 and 4 RCCs. Grade 2 RCCs had a median IGF-IR Allred score of 4. Ten of 10 (100%) grade 1 RCCs were negative. Even in the positive high-nuclear-grade tumors, areas of low nuclear grade, when present, were IGF-IR negative. Statistical analysis using the Kruskal-Wallis test demonstrated significant correlation between increasing Fuhrman nuclear grade and increasing IGF-IR Allred score (P <0.0001). Thus we report the novel finding of significant statistical correlation between IGF-IR protein expression and Fuhrman nuclear grade of RCC, and consequentially with patient survival.     

Renal cell carcinoma with mixed features of papillary and clear cell cytomorphology: a fluorescent in situ hybridization study

We performed fluorescent in situ hybridization (FISH) to investigate the numeric change of chromosomes 7, 17, and Y and loss of chromosome 3p in “papillary renal cell carcinomas (RCC) with extensive clear cell changes (CCC).” Consecutive cases of RCC over a 12-year period were reviewed to identify “papillary RCC with extensive CCC.” Immunostaining for cytokeratin 7 and alpha-methylacyl-CoA racemase (AMACR) and FISH for chromosomes 7, 17, Y, and 3p were applied. Of the total of 521 RCC retrieved, there were 49 RCC with papillary architecture and clear cell areas that could be divided into: Group 1 (12 cases), typical clear cell RCC with focal areas of papillary formation; Group 2 (28 cases), focal typical papillary RCC having papillary architecture with extensive CCC; and Group 3 (nine cases), RCC with an admixture of eosinophilic/clear cytoplasm and solid/papillary architecture. Group 1 showed negative immunoreactivity for CK7 and AMACR and absence of numeric chromosomal gain or loss of chromosomes 7/17 and Y. Groups 2 and 3 showed variable reactivity for CK7 and AMACR. Tumors in group 2 and five in group 3 showed trisomies of chromosomes 7 and/or 17 with or without loss of chromosome Y. Loss of small arm 3p was observed in groups 1 and 3 but not in group 2 tumors. In conclusion, papillary RCC may show phenotypical CCC mimicking clear cell RCC. In a small number of cases with mixed histopathological features, FISH is helpful in subtyping RCC.     

Oncocytic papillary renal cell carcinoma with solid architecture: mimic of renal oncocytoma

Papillary renal cell carcinoma (PRCC) can display extensive areas of solid and non-papillary architecture and extensive areas with oncocytic cytoplasm. Eleven oncocytic renal cell neoplasms (ORCN) with histopathological features posing a diagnostic problem between renal cell carcinoma (RCC) with oncocytic features and renal oncocytoma (RO) were identified. The neoplasms were well circumscribed or encapsulated tumors with solid and diffuse growth pattern. Very occasional papillae were seen in four and tumoral necrosis in two of 11. Six ORCN displayed a CD117+/progesterone receptor (PR)+ immunophenotype (feature shared by RO) and five tumors displayed a CD117–/PR– immunophenotype (feature shared by RCC). The CD117–/PR– ORCN also displayed α-methylacyl-coenzyme A racemase and RCC antigen reactivity as well as varying reactivity for cytokeratin 7, vimentin and CD10 (features of oncocytic PRCC). These five cases had tumor sizes ranging from 1 to 6 cm. Two patients in the latter group developed progression of the disease with metastases. In conclusion, oncocytic PRCC with solid architecture is a rare type of RCC. The carcinoma often poses differential diagnostic problems with RO and has similar immunohistochemical properties to the common type of PRCC. Cytogenetic and molecular studies have not been performed yet for this variant of RCC.     

Clinicopathologic analysis of invasive micropapillary differentiation in breast carcinoma.

Invasive micropapillary carcinoma (IMPCa) of breast is histologically characterized by growth of cohesive tumor cell clusters within prominent clear spaces resembling dilated angiolymphatic vessels. In this study, eighty three breast carcinomas with IMPCa differentiation were identified by review of the invasive carcinoma cases in our institution and correlated retrospectively with standard clinicopathologic parameters and survival status relative to a control series of cases (mean follow up 7 years). IMPCa growth pattern was present in 6% of all breast carcinomas; it was generally a focal component in otherwise typical invasive ductal carcinoma. It comprised more than 80% of the total neoplasm in only 10 cases (12%), 50-80% of the neoplasm in 7 cases (8%), 20-50% of the neoplasm in 22 cases (26%) and less than 20% in 44 cases (53%). The mean tumor size was 4 cm, 22% invaded skin, and 58% were poorly differentiated, but 71% were ER positive. Axillary node metastases were present in 77% of cases, were typically multiple (51% had three or more positive), and usually contained an IMPCa component (81% of the cases). There was no significant difference in node status, ER status, size, tumor grade, or peritumoral angiolymphatic invasion between tumors with predominant (more than 50%) v/s focal IMPCa components. In both groups 46% of the patients died from their disease (mean interval to death = 36m). Skin involvement and nodal status were the only parameters which predicted poor survival (P =.01). The outcome of patients with IMPCa did not differ significantly from infiltrating ductal carcinomas of similar node status. In conclusion, our results suggest that IMPCa growth pattern may be a manifestation of aggressive behavior, as shown by frequent skin invasion and extensive nodal involvement. However, clinicopathologic features and outcome of IMPCa are not strongly dependent on the relative amount of micropapillary component.     

Immunophenotypic markers in renal cell carcinoma.

We studied immunophenotypic and tumor cell markers in renal cell carcinoma (RCC) to determine if there are patterns of expression which may correlate with biologic behavior and response to therapy. Fourteen RCCs from 13 patients were stained by the immunoperoxidase technique using primary antibodies to Leu 4, Leu 14, Leu 2a, Leu 3a and b, lysozyme, dendritic reticulum cell (DRC), S-100, HLA-DR, epithelial membrane antigen (EMA) and beta-2-microglobulin (B2-MG). Staining was correlated with tumor stage, nuclear grade, histologic patterns, degree of cellular infiltrate, and clinical followup. Four RCCs were stage T1, four T2, five T3, and one T4. Most tumors were clear or granular cell type, with a solid or tubular growth pattern. The number of infiltrating lymphocytes and monocytes correlated with tumor grade and stage. Tumor-infiltrating lymphocytes (TILs) were predominantly Leu 3-positive (T-helper phenotype). B-cell markers were negative. Dendritic cells were rare. HLA-DR was present on endothelial cells in 11 tumors and on tumor cells in ten. HLA-DR expression increased with tumor grade. Tumor cells expressed EMA in 12 cases; B2-MG in four cases. Two patients, stages 3 and 4, died at 2 and 6 mo. Conclusions: (a) T-helper cells and monocytes infiltrate RCCs. Their numbers increase with tumor grade and stage. (b) HLA-DR expression by tumor cells tends to correlate with increasing stage and grade. (c) Dendritic cells are infrequent in RCCs.     

A major solid undifferentiated carcinoma pattern correlates with tumour progression in locally advanced prostatic carcinoma

Solid undifferentiated carcinoma was the major microscopic pattern in 24 prostatic carcinomas, 12 of which were clinically recurrent. Tumour cells were uniform, with moderately hyperchromatic nuclei and indistinct cytoplasm, and were arranged in solid or focally irregular aggregates. In areas, the tumour cells were large with vesicular nuclei, nucleoli and more abundant cytoplasm. In previous specimens, solid undifferentiated carcinoma was absent or was a minor pattern. Twenty of 23 cases showed prostate specific antigen and prostatic acid phosphatase immunoreactivity, and nine of 17 cases contained scattered argyrophilic or chromogranin-immunoreactive cells. On proliferating cell nuclear antigen immunostaining of 12 specimens, the mean tumour proliferative fraction in solid undifferentiated carcinoma (range: 10.5-18%) was greater than in areas of grade 3 prostatic carcinoma (range: 3-6%). In all 22 stage C and D cases, there was a close correlation with clinical evidence of tumour progression, and the overall 2-year survival rate was only 16.7%. It is concluded that a major solid undifferentiated pattern correlates with increased biological aggressiveness and a poor prognosis in locally advanced prostatic carcinoma.