A multiinstitutional review of 3778 patients with a primary malignancy of the urinary bladder revealed 18 cases (0.48%) of small cell carcinoma which were histologically and morphometrically identical to pulmonary small cell undifferentiated carcinoma. Age, sex, and symptoms at first presentation were comparable to that known in transitional cell carcinoma. Sixteen patients (89%) developed metastatic disease, with most frequent involvement of regional lymph nodes, liver, skeleton, and abdominal cavity. The unfavorable clinical outcome was worse as compared with that reported in advanced stage poorly differentiated transitional cell carcinoma, and was similar to the rapidly fatal outcome of pulmonary small cell undifferentiated carcinoma. Fourteen patients (78%) died by tumor at a mean follow‐up period of 9.4 months, and only one patient was free of recurrent disease more than 5 years after cystectomy. This apparent aggressive tumor behavior was independent of the presence of neuroendocrine differentiation characteristics at immunohistochemical (13 cases, 72%) or electron microscopic study (eight cases, 44%). The prolonged survival periods (15‐‐38 months) of the five patients who received combination chemotherapy suggested that, just as in small cell lung carcinoma, chemotherapy may be profitable. A unified concept of histogenesis of bladder cancer with a common origin from a multipotent mucosal stem cell is proposed.

In 80 patients with primary superficial bladder carcinoma Tumor Nodes Metastasis (TNM classification: stages Ta and T1) with adequate follow-up of at least four years, the value of selective nuclear morphometry and DNA flow cytometry on paraffin-embedded material in addition to classic prognosticators was assessed. Only the quantitative techniques appeared to be valuable predictors of new tumor occurrence. The recurrence rate in patients with large nuclei (mean nuclear area greater than 95 micron 2; n = 29) and in aneuploid cases (n = 30) was significantly higher (Wilcoxon: P = 0.05 and P = 0.0001) than in those with small nuclei (mean nuclear area less than = 95 micron 2; n = 51) and diploid cases (n = 50). The prevalence of large nuclei and aneuploidy also appeared useful to predict progressive recurrence, i.e., grade 3 or/and muscle invasive carcinoma (TNM classification: stages T2-T4) (chi-square: P less than 0.0001). Clinical follow-up showed that only 62.1% of the cases with large nuclei remained free of progressive recurrence, compared with 92.2% of those with small nuclei (Mantel-Cox: P less than 0.0001). For the aneuploid and diploid cases, these figures came to 53.3% and 98% (Mantel-Cox: P less than 0.0001). By multivariate analysis DNA ploidy was selected as the best discriminator. None of the classic prognosticators, including histologic grade, had additional prognostic value. Also, morphometry did not add to the prognosis prediction, which can be explained by the considerable overlapping between the prevalence of large nuclei and aneuploidy (24 of 29 and 30 cases, respectively). These findings practically suggest that patients presenting with superficial carcinoma with large nuclei (mean nuclear area greater than 95 microns 2) or aneuploid DNA values should be treated more aggressively.

Purpose For optimal management of ductal carcinoma in situ (DCIS), reproducible histopathological assessment is essential to distinguish low-risk from high-risk DCIS. Therefore, we analyzed interrater reliability of histopathological DCIS features and assessed their associations with subsequent ipsilateral invasive breast cancer (iIBC) risk. Methods Using a case-cohort design, reliability was assessed in a population-based, nationwide cohort of 2767 women with screen-detected DCIS diagnosed between 1993 and 2004, treated by breast-conserving surgery with/without radiotherapy (BCS ± RT) using Krippendorff’s alpha (KA) and Gwet’s AC2 (GAC2). Thirty-eight raters scored histopathological DCIS features including grade (2-tiered and 3-tiered), growth pattern, mitotic activity, periductal fibrosis, and lymphocytic infiltrate in 342 women. Using majority opinion-based scores for each feature, their association with subsequent iIBC risk was assessed using Cox regression. Results Interrater reliability of grade using various classifications was fair to moderate, and only substantial for grade 1 versus 2 + 3 when using GAC2 (0.78). Reliability for growth pattern (KA 0.44, GAC2 0.78), calcifications (KA 0.49, GAC2 0.70) and necrosis (KA 0.47, GAC2 0.70) was moderate using KA and substantial using GAC2; for (type of) periductal fibrosis and lymphocytic infiltrate fair to moderate estimates were found and for mitotic activity reliability was substantial using GAC2 (0.70). Only in patients treated with BCS-RT, high mitotic activity was associated with a higher iIBC risk in univariable analysis (Hazard Ratio (HR) 2.53, 95% Confidence Interval (95% CI) 1.05–6.11); grade 3 versus 1 + 2 (HR 2.64, 95% CI 1.35–5.14) and a cribriform/solid versus flat epithelial atypia/clinging/(micro)papillary growth pattern (HR 3.70, 95% CI 1.34–10.23) were independently associated with a higher iIBC risk. Conclusions Using majority opinion-based scores, DCIS grade, growth pattern, and mitotic activity are associated with iIBC risk in patients treated with BCS-RT, but interrater variability is substantial. Semi-quantitative grading, incorporating and separately evaluating nuclear pleomorphism, growth pattern, and mitotic activity, may improve the reliability and prognostic value of these features.

The prognostic value of nuclear morphometry and DNA flow cytometry of paraffin embedded material of 58 patients with primary and untreated transitional cell carcinoma of the bladder was compared with that of histological grade (WHO-system), tumour stage (TNM-classification), tumour size, multiplicity and ulceration. Small nuclear size (mean nuclear area less than or equal to 95 microns2) (n = 25) and DNA diploidy (n = 28) indicated a favourable outcome (5-year survival 95.8% and 92.2%); large nuclei (mean nuclear area greater than 95 microns2) (n = 33) and DNA aneuploidy (n = 30) indicated a worse prognosis (5-year survival 61.4% and 62.5%) (Mantel-Cox; p = 0.002 and p = 0.007). The quantitative techniques had the advantage over subjective histological grading that distinguishment of an intermediate patient group (WHO-system: grade 2; n = 32) with heterogeneous outcome (5-year survival 78%) was avoided. Multivariate analysis showed tumour stage as the most important prognosticator of survival. Neither the quantitative techniques, nor the other classic features added significantly to the prediction. The additional value of the quantitative techniques was however shown in superficial carcinoma (TNM-classification: stage Ta and T1; n = 37); large nuclei (mean nuclear area greater than 95 microns2) (n = 15) and aneuploid DNA peaks (n = 13) were associated with progressive recurrent tumour (n = 7) (Mantel-Cox: p = 0.03 and p = 0.0004). The quantitative methods thus indicate which patients are at risk for progression and may enable more appropriate treatment at an earlier stage of disease.

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