Feulgen-DNA-values in transitional cell carcinoma of the human urinary bladder.

Feulgen-stained imprint smears from 24 biopsy specimens from transitional cell carcinoma of the human urinary bladder were examined by means of scanning cytophotometry. One hundred randomly selected nuclei were measured from each biopsy specimen and the results compared with analogous measurements of nuclei from normal urinary transitional cell epithelium (13 cases in the control group). 97% of the nuclei in the control group were diploid. Well differentiated transitional cell carcinoma of the bladder mainly had a diploid DNA-stemline comprising 85% or more of the cells. One case of a well differentiated bladder cancer with a tetraploid DNA-stemline was found. The different cases of moderately differentiated bladder cancer showed diploid, triploid, tetraploid and hexaploid DNA-stemlines, while 4 out of 5 poorly differentiated tumours had a diploid DNA-stemline. The fifth extremely de-differentiated bladder carcinoma did not have any DNA-stemline at all. Together with these changes of the ploidy of the DNA-stemlines, increasing undifferentiation of the tumour tissue was combined with a reduced number of cells belonging to the tumour DNA-stemline, and increasingly scattered distribution of cells not contributing to the DNA-stemline. This indicates increased proliferative activity and/or chromosomal instability of the poorly differentiated cell population. Predominance of cells in the diploid, tetraploid and or octoploid intervals without marked frequency of DNA-values in the intermediary classes seemed to be a sign of clinical more "benign" bladder tumours, while a clinically more "malignant" tumour is characterized by increase of DNA-values in the triploid and hexaploid classes.     

The relevance of ultrastructural examination in the classification of primary lung tumours

Biopsies from 50 primary lung tumours were classified according to the World Health Organisation's Histological Typing of Lung Tumours. They were also subjected to electron microscopic examination. Comparison of the diagnoses made by these separate methods showed that many poorly differentiated squamous cell carcinomas had been incorrectly classified. Agreement was good in the diagnosis of adenocarcinoma whilst ultrastructural examination of small anaplastic carcinomas disclosed a neuroendocrine tumour with a combination of squamous and glandular elements. Large cell anaplastic carcinoma proved to be a 'waste-basket' containing tumours which displayed ultrastructural characteristics of poorly differentiated squamous cell carcinoma, poorly differentiated adenocarcinoma or neuroendocrine carcinoma. Electron microscopy was also valuable in characterization of other pulmonary tumours whose identity could not be resolved at the light microscopic level. Ultrastructural examination may provide a better understanding of the histogenesis and derivation of lung tumours, as well as their behaviour and therapeutic response.     

Small cell neuroendocrine carcinoma of the urinary bladder

Summary Small cell carcinoma with the histological appearance of pulmonary small cell carcinoma is a rare tumour in the urinary bladder. In previous case reports the neuroendocrine nature of small cell bladder carcinoma has been accepted, but on review the evidence for true neuroendocrine differentiation appears unsatisfactory. In this study the histological, immunohistochemical and ultrastructural characteristics of three cases of small cell carcinoma of the urinary bladder are described. Ultrastructurally, the cytoplasm of all three tumours contained neurosecretory-type granules and each of the tumours demonstrated positive immunoreaction for two or more neuroendocrine markers, from a panel including neuron-specific enolase, chromogranin A, Leu-7, bombesin and synaptophysin. Although the combination of ultrastructural and immunohistochemical examination obviously offers the strongest evidence in establishing neuroendocrine differentiation, it is argued that immunohistochemistry alone may also yield important information in demonstrating a neuroendocrine nature, provided that at least neuron-specific enolase and synaptophysin are included as markers. The clinical relevance of identifying neuroendocrine differentiation in small cell bladder carcinoma is suggested by the favourable response to combination chemotherapy in two of our cases.     

An ultrastructural classification of carcinomas of the lung]

For the purpose of providing more accurate histological typing of lung carcinoma, it is necessary to classify carcinomas of the lung by electron microscopy. One hundred and fifty cases of resected lung carcinoma were examined under electron microscope. The results of ultrastructural typing of lung carcinoma were as follows: 1. carcinomas showed differentiated features of glandular and squamous epithelium, including squamous cell carcinoma (28 cases), adenocarcinoma (35 cases), and adenosquamous carcinoma (29 cases). Among them, some cases were associated with neuroendocrine differentiation. In addition, solid mucinous cell carcinoma (4 cases) and adenoid cystic carcinoma (2 cases) were seen. 2. Carcinomas showed differentiated features of bronchioloalveolar epithelium, subdividing into clara cell (9 cases), type II pneumocyte (3 cases), mucinous cell (5 cases) and mixed type (4 cases). 3. Carcinomas showed differentiated features of neuroendocrine cell (Kulchitsky cell), including well differentiated (carcinoid, 13 cases), intermediately differentiated (atypical carcinoid, 12 cases), and poorly differentiated (small cell carcinoma, 6 cases). Among them, some cases were associated with squamous differentiation. The ultrastructural classification was compared with histological classification of lung carcinomas and the differences between them are discussed.     

Cell Kinetic and morphological studies of human cholangiocellular carcinoma

We investigated the cell kinetics and morphologies of cholangiocellular carcinoma (CCC) using 48 autopsied or surgically resected cases (47 were adenocarcinoma and the remaining adenosquamous cell carcinoma), all of which were formalin-fixed and paraffin-embedded. Cell kinetics were analyzed by counting the number of argyrophilic nucleolar organizer regions (AgNOR) using immunostaining of proliferating cell nuclear antigens (PCNA) and flow cytometric DNA analysis. Dedifferentiation of CCC was positively correlated with AgNOR number (2.22 ± 0.21 in well differentiated, 3.66 ± 0.85 in moderately differentiated and 4.17 ± 0.49 in poorly differentiated adenocarcinomas, respectively). In 22 cases, the labeling index (LI) of PCNA was higher in moderately and poorly differentiated adenocarcinomas (24.0 ± 2.35 and 26.0 ± 4.89, respectively) than in well differentiated ones (10.8 ± 2.14). A majority of well differentiated ones were diploid, while aneuploidy prevailed in moderately to poorly differentiated ones. These data suggest that cell proliferative indices and nuclear DNA analysis of CCC accurately reflect their histological grading. The anatomical location of CCC along the biliary tree had no relation to either of the cell kinetic data. In autopsy cases, the patients with organ and lymph node metastases tended to show a higher DNA index and aneuploidy. This study implies that a combination of several cell kinetic data is valuable for the evaluation of the biological behaviors of CCC, and also supports further studies of cell kinetics of CCC using small-sized biopsy specimens, as a prognostic indicator.     

膀胱小细胞神经内分泌复合癌1例报道及文献复习

目的：研究膀胱小细胞神经内分泌复合癌（ＳＣＮＥＣＣ）的临床病理特征及生物学行为。方法：采用光镜、电和免疫细胞对１例膀胱ＳＣＮＥＣＣ进行观察及行随访。结果本例肿瘤组织由小细胞神经内分泌癌，移行细胞癌及腺中闾民分构成。电镜下在小细胞癌人可找见神经内分泌颗粒，免疫组化ＮＳＥ阳性。术后３个月发生肝与肩胛骨转移，１３个月死于肝功能衰竭。结论：ＳＣＮＥＣＣ是一罕见高度恶性肿瘤，有独特的病理形态，早期即可发生侵     

Transitional cell carcinoma of the urinary bladder with osteoclast-type giant cells: a report of two cases and review of the literature

We report two transitional cell carcinomas of the urinary bladder containing numerous osteoclast-type giant cells that stained for vimentin and acid phosphatase (with and without tartrate) and were negative for cytokeratin and lysozyme. One tumour, in a 65-year-old man, was composed of papillary transitional cell carcinoma, invasive poorly differentiated carcinoma with a prominent spindle cell component and numerous osteoclast-type giant cells; repeat curettage 2 months later showed no residual tumour. The second tumour occurred in a 75-year-old woman who underwent a radical cystectomy for a deeply invasive transitional cell carcinoma with a spindle and anaplastic giant cell component and areas containing numerous osteoclast-type giant cells. Osteoclast-type giant cells, which appear to be reactive, should be distinguished from the neoplastic giant cells of giant cell carcinoma.     

Lymphoepithelioma-like carcinoma of the urinary bladder: a clinicopathologic study of 13 cases

Lymphoepithelioma-like carcinoma (LELCA) of the urinary bladder is a rare variant of bladder cancer characterized by a malignant epithelial component densely infiltrated by lymphoid cells. It is characterized by indistinct cytoplasmic borders and a syncytial growth pattern. These neoplasms deserve recognition and attention, chiefly because they may be responsive to chemotherapy. We report on the clinicopathologic features of 13 cases of LELCA recorded since 1981. The chief complaint in all 13 patients was hematuria. Their ages ranged from 58 years to 82 years. All tumors were muscle invasive. A significant lymphocytic reaction was present in all of these tumors. There were three pure LELCA and six predominant LELCA with a concurrent transitional cell carcinoma (TCC). The remainder four cases had a focal LELCA component admixed with TCC. Immunohistochemistry showed LELCA to be reactive against epithelial membrane antigen and several cytokeratins (CKs; AE1/AE3, AE1, AE3, CK7, and CK8). CK20 and CD44v6 stained focally. The lymphocytic component was composed of a mixture of T and B cells intermingled with some dendritic cells and histiocytes. Latent membrane protein 1 (LMP1) immunostaining and in situ hybridization for Epstein-Barr virus were negative in all 13 cases. DNA ploidy of these tumors gave DNA histograms with diploid peaks (n=7) or non-diploid peaks (aneuploid or tetraploid; n=6). All patients with pure and 66% with predominant LELCA were alive, while all patients having focal LELCA died of disease. Our data suggest that pure and predominant LELCA of the bladder appear to be morphologically and clinically different from other bladder (undifferentiated and poorly differentiated conventional TCC) carcinomas and should be recognized as separate clinicopathological variants of TCC with heavy lymphocytic reaction relevant in patient management.     

Retrospective study of prognostic importance of DNA flow cytometry of urinary bladder carcinoma.

Cellular DNA content was determined by flow cytometry on routinely processed paraffin sections of 61 primary and untreated transitional cell carcinomas of the urinary bladder, and correlated with tumour grade and stage and clinical follow up. All 16 (25%) grade 1 carcinomas were diploid and all 11 (20%) grade 3 tumours were aneuploid. The 34 (55%) grade 2 carcinomas comprised 13 (40%) diploid and 21 (60%) aneuploid cases. Among the 37 superficial carcinomas (stage Ta and T1), 25 (65%) were diploid; 20 (85%) of the 24 advanced tumours (stage T2 to T4) had aneuploid tracings. Ploidy was a significant prognostic indicator (p: 0.006) of five year survival. The initial presence of aneuploidy in superficial bladder carcinoma (stage Ta and T1) is a strong argument for more aggressive treatment than is customary.     

Pulmonary neuroendocrine carcinomas. A review of 234 cases and a statistical analysis of 50 cases treated at one institution using a simple clinicopathologic classification

CONTEXT: Primary pulmonary neuroendocrine tumors are traditionally classified into 3 major types: typical carcinoid (TC), atypical carcinoid (AC), and large cell neuroendocrine carcinoma (LC) or small cell neuroendocrine carcinoma (SC). Confusion arises frequently regarding the malignant nature of TC and the morphologic differentiation between AC and LC or SC. OBJECTIVE: To provide clinicopathologic evidence to streamline and clarify the histomorphologic criteria for this group of tumors, emphasizing the prognostic implications. PATIENTS: To minimize variability in diagnostic criteria and treatment plans, we analyzed a group of patients whose diagnosis and treatment occurred at a single institution. We reviewed 234 cases of primary pulmonary neuroendocrine tumors and thoroughly studied 50 cases of resected tumors from 1986 to 1995. RESULTS: On the basis of morphologic characteristics and biologic behaviors of the tumors, we agree with many previous investigators that these tumors are all malignant and potentially aggressive. Based on our accumulated data, we have modified Gould criteria and reclassified these tumors into 5 types: (1) well-differentiated neuroendocrine carcinoma (otherwise called TC) (14 cases, with less than 1 mitosis per 10 high-power fields [HPF] with or without minimal necrosis); (2) moderately differentiated neuroendocrine carcinoma (otherwise called low-grade AC) (6 cases, with less than 10 mitoses per 10 HPF and necrosis evident at high magnification); (3) poorly differentiated neuroendocrine carcinoma (otherwise called high-grade AC) (10 cases, with more than 10 mitoses per 10 HPF and necrosis evident at low-power magnification); (4) undifferentiated LC (5 cases, with more than 30 mitoses per 10 HPF and marked necrosis); and (5) undifferentiated SC (15 cases, with more than 30 mitoses per 10 HPF and marked necrosis). The 5-year survival rates were 93%, 83%, 70%, 60%, and 40% for well, moderately, and poorly differentiated, and undifferentiated large cell and small cell neuroendocrine carcinomas, respectively. We found nodal metastasis in 28% of TC in this retrospective review, a figure higher than previously recorded. CONCLUSION: Using a grading system and terms comparable to those used for many years and used for neuroendocrine tumors elsewhere in the body, we found that classification of pulmonary neuroendocrine carcinomas as well, moderately, poorly differentiated, or undifferentiated provides prognostic information and avoids misleading terms and concepts. This facilitates communication between pathologists and clinicians and thereby improves diagnosis and management of the patient.     

DNA aneuploidy in invasive carcinoma of the uterine cervix

Forty cases of squamous cell carcinoma and twenty cases of adenocarcinoma of the cervix were subjected to DNA ploidy analysis to find out the frequency of aneuploid DNA pattern in different types of invasive carcinoma of the uterine cervix and their possible correlation with the clinical stage and age of the patients. From the DNA analysis an increasing trend of DNA aneuploidy was observed from well differentiated (63.6%) to moderately differentiated (70.8%) to poorly differentiated squamous cell carcinoma (83.3%). However, 85% adenocarcinomas of endocervix showed aneuploid DNA pattern. It indicates that aneuploidy increases with tumour dedifferentiation and further confirms the importance of DNA ploidy as a high risk indicator.     

Small cell carcinoma of urinary bladder is differentiated from urothelial carcinoma by chromogranin expression, absence of CD44 variant 6 expression, a unique pattern of cytokeratin expression, and more intense γ-enolase expression

AIMS: Small cell (neuroendocrine) carcinoma of the urinary bladder is clinically more aggressive than urothelial (transitional cell) carcinoma. We have investigated the immunohistochemical markers most useful in diagnosing small cell carcinoma in bladder. METHODS AND RESULTS: We evaluated the expression of chromogranin A, CD44 variant 6 (CD44v6), cytokeratin (CAM 5.2), gamma-enolase, synaptophysin, and CD45 in 46 small cell carcinomas of the bladder. Small cell and urothelial carcinoma were mixed in 21 (46%) cases. The two immunohistochemical markers with best ability to discriminate between small cell and urothelial carcinoma were chromogranin A and CD44v6. Chromogranin A had 97% specificity for small cell carcinoma, staining 65% of cases with 2+/3+ mean intensity; only one case (5%) of urothelial carcinoma was weakly (1+/3+) positive. CD44v6 was 80% specific for urothelial carcinoma, with immunoreactivity in 60% of cases, compared with 7% of small cell carcinoma cases. In cases positive for CD44v6, the mean percentage of reactive urothelial carcinoma cells was 75% (range 10-100%), greater than the 12% of cells in three cases of small cell carcinoma (P = 0.31); further, the pattern of immunoreactivity was membranous vs. focal cytoplasmic, respectively. All small cell carcinomas stained with one of the three neuroendocrine markers tested; 76% of cases were reactive for synaptophysin and 93% for gamma-enolase, with specificities of 86% and 73% in comparison to urothelial carcinoma. gamma-enolase staining of small cell carcinoma was more intense (P = 0.01) than for urothelial carcinoma. Cytokeratin CAM 5.2 stained a mean 47% of cells in small cell carcinoma, always in a punctate perinuclear pattern, and 75% in urothelial carcinoma, in a membranous pattern. CONCLUSIONS: CD44v6, chromogranin A, and possibly gamma-enolase and cytokeratin (CAM 5.2) help differentiate small cell carcinoma from urothelial carcinoma.     

Variable sex chromatin pattern in an early carcinoma of the bladder

Sex chromatin studies on squash preparations of a well differentiated transitional cell carcinoma of the bladder without evidence of invasion from a female aged 63 revealed a single body in some regions, but two to four bodies in others. All regions were near diploid according to DNA estimations. Previous observations on a variety of invasive tumours of females showed that the presence of more than one sex chromatin body is generally associated with a high chromosome number. The pattern of two or more bodies in near-diploid cells seen in this non-invasive tumour may therefore characterize an intermediate stage of clonal evolution, eventually resulting in malignancy, when the cell line has not yet achieved the ability to invade or metastasize.     

Malignant tumors of the small intestine: a histopathologic study of 41 cases among 1,312 consecutive specimens of small intestine

There are few comprehensive studies of small intestinal malignancies. The author retrospectively reviewed 1,312 archival pathologic specimens of the small intestine in the last 10 years in our pathologic laboratory in search for malignant tumors of the small intestine. There were 22 cases (1.7%) of primary adenocarcinoma, 3 cases (0.2%) of primary squamous cell carcinoma, 6 cases (0.5%) of metastatic carcinoma, 6 cases (0.5%) of malignant lymphoma, 3 cases (0.2%) of carcinoid tumor, and 1 case (0.08%) of gastrointestinal stromal tumor (GIST). Of the 25 cases of primary adenocarcinoma and squamous cell carcinoma, 24 cases were located in the duodenum and 1 case in the ileum. The 22 cases of adenocarcinoma were classified into 7 well differentiated, 7 moderately differentiated, and 8 poorly differentiated adenocarcinomas. All the three squamous cell carcinomas were moderately differentiated ones with keratinization and intercellular bridges. In the 25 cases of carcinoma, immunoreactive p53 protein was present in 23 cases, and the Ki-67 labeling ranged from 40% to 95% with a mean of 76%. In the 6 cases of metastatic adenocarcinoma, the origin was ovary in 1 case, pancreas in 2 cases, gall bladder in 1 case, lung in 1 case, and colon in 1 case. In the 6 cases of lymphoma, 4 cases were diffuse large B-cell lymphomas and 2 cases were peripheral T-cell lymphomas. In the 3 cases of carcinoid tumor, all were typical carcinoids and immunohistochemically positive for at least one of neuroendocrine markers (chromogranin, synaptophysin, neuron specific enolase, and CD56). In the 1 case of GIST, the cell type is spindle and GIST cells were immunohistochemically positive for KIT and CD34. The histological risk was intermediate. Forty-one cases of small intestinal malignancies were reviewed histopathologically.     

Mixed mesonephric adenocarcinoma and transitional cell carcinoma of the bladder

Mesonephric type adenocarcinoma is a very rare tumour in the bladder and bears a resemblance to nephrogenic adenoma. We report (to the best of our knowledge), the first case where the tumour was partly composed of mesonephric and partly of poorly differentiated transitional cell carcinoma. Staining for alpha 1-antitrypsin and carcino-embryonic antigen were positive in the mesonephric component but negative in the transitional cell carcinoma.     

Combined small and transitional cell carcinoma of the urinary bladder with CA19-9 production

It is well known that extrapulmonary small cell carcinoma, which exhibits morphological features similar to those observed in the lung, occurs in various organs. Clinically, most cases manifest aggressive biological behavior. A case of small cell carcinoma of the urinary bladder producing a high level of serum carbohydrate antigen (CA) 19-9, in which expression was confirmed in cancer cells of small as well as transitional cell carcinoma in the same tumor mass by immunostaining is reported. This paper documents combined small and transitional cell carcinoma of the urinary bladder with CA19-9 production, although it has already been reported that adenocarcinoma or transitional cell carcinoma in various organs frequently expresses CA19-9. Observations suggest that the histogenesis of some cases of combined small and transitional cell carcinoma in the urinary bladder may be the same, as both can produce CA19-9.     

Histopathologic study of the rectum in 1,464 consecutive rectal specimens in a single Japanese hospital: II. malignant lesions

The author investigated histopathology of 1,464 consecutive rectal specimens in of our pathology laboratory in Japan. A review of pathological reports was done by computer. Observation of histological slides was performed, when appropriate. The rectal specimens were composed of 1,041 benign lesions and 423 malignant lesions. The 423 malignant lesions were composed of 367 cases of primary rectal carcinoma, 41 cases of carcinoma in adenoma, 7 cases of neuroendocrine tumor, 3 cases of malignant lymphoma, 2 cases of gastrointestinal stromal tumors (GIST), and 3 cases of metastatic carcinoma. Of the 367 cases of primary rectal carcinoma, 37 cases were early carcinomas whose invasion was limited up to the submucosa (early rectal carcinoma). The remaining 330 cases were advanced carcinoma invading beyond the proper muscle layer. The histological types were well differentiated adenocarcinoma in 197 cases, moderately differentiated adenocarcinoma in 129 cases, poorly differentiated adenocarcinoma in 10 cases, mucinous adenocarcinoma in 24 cases, signet ring cell carcinoma in 6 cases, squamous cell carcinoma in 1 case In the 41 cases of carcinoma in adenoma, the carcinoma was well to moderately differentiated adenocarcinoma, and all cases were early carcinomas without invasion or with little invasions to subserosa. The size of carcinoma in adenoma was as follows: < 10 mm, 5 cases; 10-15 mm, 8 cases; 15-20 mm, 23 cases; > 20mm, 5 cases. The background adenoma was as follows: tubular adenoma (n=15), tubulo-villous adenoma (n=14), and villous adenoma (n=12). The 7 cases of neuroendocrine carcinoma consisted of 6 low grade neuroendocrine tumors (carcinoids) and 1 high grade neuroendocrine carcinoma (small cell carcinoma). All were submucosal lesions. Immunohistochemically, the tumor cells were positive for two or more of synaptophysin, chromogranin, neuron-specific enolase, CD56. In small cell carcinoma, KIT and PDGFRA were consistently positive. The 3 cases of malignant lymphoma were diffuse large B-cell lymphomas positive for CD20 and CD79a and negative for NK/T cell markers. The two cases of GIST was spindle cell type, and the risk was intermediate. Kit mutations were recognized in both GISTs. No PDGFRA mutations were seen. Of the 3 metastatic carcinomas, one was a metastasis from prostatic adenocarcinoma, and the remaining two was adenocarcinoma of unknown primary sites.     

The immunocytochemical demonstration of basement membrane deposition in transitional cell carcinoma of bladder

Summary We assessed the staining characteristics of the basement membrane of transitional cell carcinoma of bladder using a monoclonal antibody to type IV collagen. Basement membranes were clearly stained at the stromal/carcinoma interface. As transitional cell carcinoma became less well differentiated and the depth of invasion increased interruptions to basement membrane staining became more extensive and these findings are comparable to those described in similar series of transitional cell carcinoma using polyclonal antibodies to type IV collagen. The defects in basement membrane staining may be related to the degree and direction of tumour cell differentiation or may be explained by increased degradation compared to synthesis of basement membrane components. Demonstration of the basement membrane may be of value in diagnostic histopathology as a marker of the biological behaviour of transitional cell carcinoma of bladder.     

Urinary cytology of a canine bladder carcinoma

This is a study of a case of transitional cell carcinoma of the urinary bladder in a dog. Clinical and radiological signs were inconclusive. The morphology of cells exfoliated from the tumour was very similar to that of cells exfoliated from transitional cell carcinomas in human patients. On the basis of this information a diagnosis was made which was confirmed at post-mortem examination. The findings in this case report demonstrate the usefulness of this technique in the diagnosis of poorly differentiated transitional cell carcinoma.