Cryobiopsy increases the diagnostic yield of endobronchial biopsy: a multicentre trial.

Forceps, brushes or needles are currently the standard tools used during flexible bronchoscopy when diagnosing endobronchial malignancies. The new biopsy technique of cryobiopsy appears to provide better diagnostic samples. The aim of this study was to evaluate cryobiopsy over conventional endobronchial sampling. A total of 600 patients in eight centres with suspected endobronchial tumours were included in a prospective, randomised, single-blinded multicentre study. Patients were randomised to either sampling using forceps or the cryoprobe. After obtaining biopsy samples, a blinded histological evaluation was performed. According to the definitive clinical diagnosis, the diagnostic yield for malignancy was evaluated by a Chi-squared test. A total of 593 patients were randomised, of whom 563 had a final diagnosis of cancer. 281 patients were randomised to receive endobronchial biopsies using forceps and 282 had biopsies performed using a flexible cryoprobe. A definitive diagnosis was achieved in 85.1% of patients randomised to conventional forceps biopsy and 95.0% of patients who underwent cryobiopsy (p<0.001). Importantly, there was no difference in the incidence of significant bleeding. Endobronchial cryobiopsy is a safe technique with superior diagnostic yield in comparison with conventional forceps biopsy.

[CT-guided cutting needle biopsies of thoracic lesions in patients with negative bronchoscopic findings]. / CT-gesteuerte Stanzbiopsien thorakaler Läsionen bei Patienten mit bronchoskopisch negativen Voruntersuchungen.

PURPOSE: The usefulness and the complication rate of CT-guided core biopsies for obtaining specimens for histopathological examinations in patients with uncertain thoracic lesions were evaluated. MATERIALS AND METHODS: Under local anesthesia CT-guided core biopsies were performed in 121 patients using tru-cut systems (14-18 gauge). Prior to CT all patients underwent bronchoscopy without obtaining sufficient material for a definite histopathological diagnosis. The following areas were punctured: lungs 84 (69%), pleura, chest-wall, ribs 24 (20%) and mediastinum 13 (11%). The diameter of the punctured lesion averaged 4.3 cm. RESULTS: Using CT-guided puncture techniques specimens could be obtained in 118 (97.5%) out of 121 patients. Of these 118 specimens 3 (2.5%) showed marked artifacts and necrosis, which obscured a definite histopathological opinion. In the end the biopsies from 115 (95.0%) out of 121 patients could be used whereby 84 (73.0%) were classified as malignant and 31 (27.0%) as benign. Due to further operations or bronchoscopic procedures in 35 patients additional material was obtained for histopathological tests. In 3 (8.6%) of those 35 patients newly malignant disease was diagnosed, therefore these specimens showed a relevant discrepancy as compared to the result of the CT-guided biopsy. Obviously the vital central part of the tumor was not biopsied due to poor delineation caused by peritumoral infiltration. A small pneumothorax or haemoptysis was seen in 17 (14.3%) out of 121 patients. CONCLUSIONS: Despite negative bronchoscopic findings CT-guided core biopsies will deliver sufficient specimens for histopathological tests in 95% of patients with uncertain thoracic lesions. Infiltrations surrounding the vital part of the tumor may obscure the correct targeting and lead to false negative results in a few patients. Severe complications were not seen in this study, although they might happen in rare cases according to reports in the literature. Therefore CT-guided core biopsies represent an efficient and safe procedure in patients with thoracic lesions.

Extended radical lymphadenectomy in patients with urothelial bladder cancer: results of a prospective multicenter study.

PURPOSE: Previous studies demonstrate a positive correlation between postoperative survival and the extent of pelvic lymphadenectomies in patients with bladder cancer. However, the distribution of nodal metastases has not been examined in sufficient detail. Therefore, we conducted a comprehensive prospective analysis of lymph node metastases to obtain precise knowledge about the pattern of lymphatic tumor spread. MATERIALS AND METHODS: Between 1999 and 2002 we performed 290 radical cystectomies and extended lymphadenectomies. Cranial border of the lymphadenectomy was the level of the inferior mesenteric artery, lateral border was the genitofemoral nerve and caudal border was the pelvic floor. We made every effort to excise and examine microscopically all lymph nodes from 12 well-defined anatomical locations. RESULTS: Mean total number and standard deviation of lymph nodes removed was 43.1 +/- 16.1. Nodal metastases were present in 27.9% of patients. The percentage of metastases at different sites ranged from 14.1% (right obturator nodes) to 2.9% (right paracaval nodes above the aortic bifurcation). By studying cases of unilateral primary tumors or with only 1 metastasis we observed a preferred pattern of metastatic spread. However, there were many exceptions to the rule and we did not identify a well-defined sentinel lymph node. CONCLUSIONS: We strongly recommend extended radical lymphadenectomy to all patients undergoing radical cystectomy for bladder cancer to remove all metastatic tumor deposits completely. The operation can be conducted in routine clinical practice and our data may serve as a guideline for future standardization and quality control of the procedure.

DNA cytophotometry and prognosis in typical and atypical bronchopulmonary carcinoids. A clinicomorphologic study of 100 neuroendocrine lung tumors.

Surgical material obtained from 100 patients with typical carcinoids (TC) and atypical carcinoids (AC) of the lung (including 100 primary, four residual tumors, and four lymph node or distant metastases) was investigated by conventional histology and scanning DNA cytophotometry. Of the 60 TC (96%), 58 exhibited euploid DNA histograms compared with only 20 (50%) of the 40 AC. The morphologic findings were related to the patients' survival (median observation period, 9 years). Statistical analyses disclosed the histologic type of disease (TC versus AC) and the DNA content of tumors (euploid versus aneuploid) to affect prognosis significantly (p < 0.001). Deaths resulting from tumor were exclusively observed among patients with atypical (eight of 40) or DNA aneuploid carcinoids (eight of 22). Six patients were alive with persistent tumor manifestations 3 to 20 years after initial diagnosis, four with DNA diploid primary carcinoids. The presence of lymph node metastases alone was not associated with poor prognosis as long as the primary tumor or the related metastases showed a diploid DNA content. DNA cytophotometry thus might be regarded as an adjunctive prognostic criterion in individual carcinoid cases.

Absence of RET proto-oncogene point mutations in sporadic hyperplastic and neoplastic lesions of the parathyroid gland.

We investigated the possible role of RET proto-oncogene mutations in the development of sporadic hyperplastic, benign, and malignant parathyroid lesions. DNA extracted from paraffin-embedded specimens of forty parathyroid lesions was screened for RET proto-oncogene point mutations in exons 10, 11, and 16 by nonisotopic polymerase chain reaction-based single-strand conformation polymorphism and heteroduplex gel electrophoresis. The nucleotide sequence of samples with aberrant band patterns was identified by nonisotopic direct sequencing of polymerase chain reaction-amplified DNA. Parathyroids of seven patients with multiple endocrine neoplasia type 2A (MEN 2A) and MEN 2B served as positive controls. None of the eight hyperplastic lesions, three cases of parathyromatosis, ten parathyroid adenomas, eleven carcinomas or one normal parathyroid gland contained mutations in each of the three RET exons tested. Six MEN-2A-associated hyperplastic glands exhibited identical band shifts in the polymerase chain reaction single-strand conformation polymorphism analysis of exon 11, which corresponded to a Cys 634-->Arg substitution in the nucleotide sequence analysis (TGC-->CGC), whereas in the MEN 2B parathyroid specimen a point mutation was found at codon 918 of exon 16 (ATG-->ACG), causing a Met 918-->Thr substitution. Our data indicate that RET mutations of the MEN 2 loci in exons 10, 11, and 16 are not involved in the development of sporadically occurring benign or malignant parathyroid lesions. Furthermore, our results are in accordance with the observation that MEN 2A patients with Cys 634-->Arg (germline) mutations have a higher risk of developing parathyroid disease than those with other mutations at codon 634.

[MR tomography in prostatic carcinoma: comparison of conventional and endorectal MRT]. / MR-Tomographie des Prostatakarzinoms--Vergleich konventionelle und endorektale MRT.

In a prospective study an attempt was made to determine the value of conventional MRI (354 patients) and MRI using the endorectal surface coil (ESC) (36 patients) in the preoperative staging of prostatic carcinoma. Local preoperative staging with conventional MRI was correct in 83.9% and 88.9% with ESC-MRI. Compared to conventional MRI, ESC-MRI was better in the delineation of the prostatic capsule and early detection of infiltration into the neurovascular bundle. Lymph node staging with MRI showed a sensitivity of 54.4% in detecting pelvic lymph node metastasis. MRI is as limited as CT in assessing pelvic lymph node metastasis.

Cytogenetic survey of 32 cancers of the prostate.

Cytogenetic studies after short-term culture were performed on 32 adenocarcinomas of the prostate from patients without prior treatment. The tumor specimens, ranging from stage B1 to D1, were obtained by radical prostatectomy or diagnostic biopsies. Fourteen tumors showed a normal diploid chromosome complement in all metaphases examined. Clonal chromosomal alterations were detected in 16 tumor samples and the remaining two cases contained double minute (dmin) chromosomes in some cells. The most frequent numerical changes included loss the Y chromosome and trisomy 7, both found in four cases. The only recurrent structural aberration was del(10)(q24), seen in three cases both as a sole anomaly and within multiple rearrangements. Six patients showed cytogenetically unrelated clones. The occurrence of the chromosomal changes found in this study shows no relationship to certain histopathologic characteristics of the tumors. The recurrent finding of del(10)(q24) as sole anomaly and the evidence for clonal evolution in one patient demonstrates that this change is an early karyotypic event which may be important for the pathogenesis in at least a subset of prostatic cancers.

[Pathology of prostatic carcinoma: new approaches to its development and biological significance]. / Die Pathologie des Prostatakarzinoms: Neue Wege zum Verständnis seiner Entwicklung und biologischen Wertigkeit.

The common prostatic carcinoma consists of two different types with respect to development, spread, histopathology, morphogenesis and prognosis. These are the carcinoma of the dorso-peripheral zone and the tumor which is located in the antero-central zone. The first one corresponds to the clinically manifest prostatic carcinoma, the latter is identical to the prostatic carcinoma incidentally found by the pathologist examining unsuspicious prostatic tissue from transurethral resection or simple prostatectomy. The antero-central tumor growths to the ventral area and infiltrates the apex and bladder neck frequently. It is biologically not as important as the tumor of the dorso-peripheral zone showing a lower grade of malignancy in the majority of cases. In 2 of 3 cases, however, there are one or more coexisting carcinomas in other, frequently dorso-peripheral zones. Therefore the risk of the individual patient can not precisely be estimated. The carcinoma of the dorso-peripheral zone does predominate by frequency and biological potency. The incidence of positive lymph nodes strongly increases when seminal vesicle invasion is found. The disturbance of the epithelial-stromal interaction is the starting point of carcinogenesis. In the first step, PIN results of an intraductal proliferation of atypical epithelial cells, whereas atypical hyperplasia develops from an overwhelming proliferation of tubular glands with progressive decrease of basal cells. Based on the topographical and histological relationships the role of PIN as a precursor lesion of the dorso-peripheral prostatic carcinoma is considered, whereas atypical hyperplasia is thought to represent the preneoplastic state of the incidental and antero-central prostatic carcinoma, respectively.

[Signet ring carcinoma in the urinary tract. Primary tumor or metastases of an occult neoplasm?]. / Das Siegelringzellkarzinom im Harntrakt. Primärtumor oder Metastase eines okkulten Neoplasmas?

Between 26/2/88 and 23/6/88 we treated four patients with signet ring cell carcinoma of the urinary tract. There was no conformity in clinical development, results of laboratory investigations, histomorphology or symptoms. For the first time, DNA cytophotometry was used to examine histological preparations of urinary signet ring cell carcinoma. This method provides information about the prognosis of the malignant disease, as it reveals the DNA distribution in the tumor cells. In three cases there was a clearly pathologic so-called an-euploid DNA distribution, indicating the high malignant potency of this tumor entity.

Immunocytochemical differential diagnosis of diffuse malignant pleural mesotheliomas--a clinicomorphological study of 158 cases.

Formalin-fixed paraffin-embedded material of 158 diffuse malignant pleural mesotheliomas (DMPMs) was used in order to determine the differential diagnostic value of immunocytochemical probes against 9 different antigens. While vimentin expression was found in only 50% of cases, regardless of their histological subtype all tumours were found to be cytokeratin-positive when an antibody with broad-spectrum cytokeratin reactivity was used. Conversely, none of the cases was immunostained by antisera against carcinoembryonic antigen (CEA), Leu-M1 antigen, chromogranin, S-100 protein, lysozyme and a T-cell associated antigen. The density of inflammatory cell infiltrates reactive with antisera against the three latter antigens was not associated with the clinical behaviour of the neoplasms examined. Eight DMPM cases showed immunoreactivity with HEA-antibodies against Egp 34, an antigen previously supposed only to be expressed by carcinomas. On the basis of these findings, the consistent cytokeratin reactivity, also of the sarcomatous type of DMPM, may help to exclude metastatic involvement of the pleura by a mesenchymal neoplasm of other origin. CEA and Leu-M1 staining of a given pleural tumour, on the other hand, is indicative of a carcinoma secondarily afflicting the pleura, thus making the diagnosis of primary DMPM unlikely.

Diffuse sclerosing variant of papillary thyroid carcinoma. S-100 protein immunocytochemistry and prognosis.

The recently published second edition of the WHO classification of thyroid tumours describes the diffuse sclerosing papillary carcinoma (DSPC) as a specific variant of papillary thyroid cancer (PC). Besides several histological hallmarks, this rare tumour is characterized by its occurrence in young individuals and is thought to have a less favourable prognosis than PC in general. The observations on two examples of this tumour presented herein, however, are at variance at this assumption. The neoplasms occurred in a 10 year old girl and a 34 year old woman. Each time, diffuse involvement of both thyroid lobes and bilateral cervical lymphadenopathy were seen. In one case, the carcinoma extended into the cervical soft tissue. Follow-up disclosed both patients to be without evidence of disease 2 and 13 years, respectively, after thyroid surgery. Immunocytochemically, both thyroid primaries as well as 7 other cases of DSPC reported in the literature showed dense accumulations of S-100 protein positive dendritic/Langerhans cells. Such infiltrations have been demonstrated to be correlated with a benign clinical course of PC. It is thus suggested that DSPC behaves similarly or even less aggressively than PC in general, at least if prominent Langerhans cell infiltration is present.

Prognostic factors in medullary thyroid carcinomas. Survival in relation to age, sex, stage, histology, immunocytochemistry, and DNA content.

Patients with medullary thyroid carcinomas (MTC) were analyzed according to age, sex, and tumor stage. In addition, the MTC were screened for the predominant histologic pattern, immunocytochemical spectrum (60 tumors), and DNA content (DNA cytophotometry and DNA flow cytometry, 25 tumors). These findings were correlated with follow-up data available for 45 of these patients. Forty-eight percent of the tumors revealed a polygonal cell pattern, whereas 22% showed spindle-cell predominance. All tumors contained cytokeratin, chromogranin A, and calcitonin (CT). Calcitonin gene-related peptide (CGRP) was present in 92%, carcinoembryonic antigen (CEA) in 77%, neuron-specific enolase (NSE) in 75%, and vimentin in 53% of cases. Positivity for neurotensin, somatostatin, neurofilaments, bombesin, and alpha human chorionic gonadotropin (a-hCG) and serotonin ranged between 3% and 27%. All MTC were negative for substance P, adrenocorticotropic hormone (ACTH), thyroglobulin (TG), or S-100 protein. Local recurrences and regional lymph node metastases revealed identical staining patterns as the primaries. Prognosis of MTC was found not to be related to histologic features (dominant architectural pattern, cellular shape, presence of amyloid deposits) or immunocytochemical pattern. Instead, survival was significantly correlated to age, sex, and stage of disease. The best prognosis was seen in women younger than 40 years and revealing an early stage of disease. DNA measurements added valuable information in assessing the prognosis of MTC.

Quantitative assessment of endogenous testicular and adrenal sex steroids and of steroid metabolizing enzymes in untreated human prostatic cancerous tissue.

Total tissue content and subcellular distribution of DHEA sulfate, DHEA, androst-5-ene-3 beta,17 beta-diol, androst-4-ene-3,17-dione, testosterone, 5 alpha-DHT, and 5 alpha-androstane-3 alpha,17 beta-diol as well as the activities of steroid sulfate-sulfatase, 17 beta-hydroxysteroid dehydrogenase, 5 alpha-reductase, 3 alpha/beta-hydroxysteroid dehydrogenase, and creatine kinase were quantified in 12 untreated primary tumors of prostatic cancer. Samples were obtained by radical prostatectomy and serial sections, and were alternately used for either biochemical or morphological evaluation. The results were compared with values determined in benign parts of the same prostates. Qualitatively, all enzymes and steroids found in the benign tissues could also be demonstrated in the cancers. Steroid patterns showed individual quantitative variation but no general differences between the carcinomas and the benign tissues. Enzymes showed a tendency to lower activities in the cancers, particularly when expressed per DNA. Substantial diminutions of creatine kinase and 5 alpha-reductase activity, the latter being often accompanied by an increased testosterone/DHT ratio, were the most striking differences seen in most of the cases between malignant and nonmalignant tissues. Some interesting individual parallels of morphological and biochemical aspects were seen, but there was no obvious general parallelism between the histological picture and endocrinological characteristics.

Androgens, adrenal androgen precursors, and their metabolism in untreated primary tumors and lymph node metastases of human prostatic cancer.

Activities of several steroid metabolizing enzymes (steroid sulfate-sulfatase, 17 beta-hydroxysteroid dehydrogenase, 5 alpha-reductase, and 3 alpha beta-hydroxysteroid dehydrogenase) as well as total tissue content and subcellular distribution (nuclear-extranuclear) of several androgen precursors, active androgens, and androgen deactivation products (DHEA sulfate, DHEA, 5-androstenediol, 4-androstenedione, testosterone, DHT, and 3 alpha-androstanediol) were quantified in primary tumors and lymph node metastases of human prostatic cancer obtained from patients without previous endocrine manipulation. Primary tumors were compared to benign parts of the same prostates, and the metastases were compared to their primary tumors. All enzymes and steroids found in benign prostatic tissues could also be detected in the malignant tissues. Even the capacity to accumulate active androgens in the nuclei was found to be unchanged in nearly all of the samples. Lower activities of hormone-dependent enzymes were observed in the cancers, suggesting a less efficient utilization of hormonal stimuli. Most striking changes found in the malignant tissues were a subtotal loss of 5 alpha-reductase activity and a metabolic shift to testosterone, which was more pronounced in samples from metastatic disease as compared to samples from non-metastatic disease. In conclusion, primary tumors and metastases of prostatic cancers not treated by endocrine manipulations retain their androgen receptor system and possess the same capacity to metabolize adrenal androgen precursors along the pathway to DHT as benign prostatic tissue. Consequently, they should be able to use at least androstenedione for production of active androgens directly in the target tissue.

[Occult papillary thyroid carcinoma. Clinical significance and morphology of a common tumor]. / Das okkulte papilläre Schilddrüsenkarzinom. Klinische Bedeutung und Morphologie eines häufigen Tumors.

In a systematic analysis of surgical specimens of 388 carcinomas of the thyroid 34 occult papillary tumours were revealed. In 18 of the 34 patients cervical lymph-node metastases were demonstrated, which in 16 had been the indication for operation. In 15 patients the tumour was a chance finding in a thyroid resected for other reasons. Postoperative follow-up over an average of ten years demonstrated a uniformly favourable course in all, regardless of tumour size or type, age, sex or lymph-node status. There were no local recurrences or metastases beyond those known at time of thyroidectomy.

Intermediate-filament expression in thyroid gland carcinomas.

Paraffin-embedded specimens of 200 primary thyroid carcinomas were examined immunohistologically for the expression of intermediate-filament (IF) protein of the cytokeratin, vimentin and neurofilament type. In 36 cases, snap-frozen tissue was available, and double label immunofluorescence microscopy was performed in 23 of them. Cytokeratin reactivity was found in all cells of all follicular, papillary and medullary carcinoma cases examined. Using a monoclonal vimentin antibody, positive staining was found in many, though not all cells of the papillary tumours and in approximately 50% of the follicular and the medullary carcinomas. Among anaplastic carcinomas, some tumours were positive for cytokeratins, with or without coexpression of vimentin. Neurofilaments could only be demonstrated in approximately 13% of medullary tumours which in general also exhibited vimentin positivity. The differences of IF expression in follicle and C-cell thyroid carcinomas and the broad variation of cytokeratin and vimentin immunoreactivity among anaplastic tumours of this organ is discussed in relation to the possible intrinsic heterogeneity of these tumours and the diagnostic value of these markers.

[Classification, histologic and cytologic grading and regression grading of prostate cancer]. / Klassifikation, histologisches und zytologisches Grading sowie Regressionsgrading des Prostatakarzinoms.

The submitted recommendation of the pathologic- urologic team "prostatic carcinoma" is the result of several meetings, in order to provide a basis for a uniform nomenclature in diagnosis, therapy, and prognosis of prostatic carcinoma to urologists and pathologists in practice.