College of American Pathologists Conference XXVI on clinical relevance of prognostic markers in solid tumors. Summary. Members of the Cancer Committee.
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Biomarkers, Tumor↗
Biomedical subjects
D J Grignon
Publications and source records attributed to D J Grignon.
College of American Pathologists Conference XXVI on clinical relevance of prognostic markers in solid tumors. Report of the Prostate Cancer Working Group.
Critical analysis of the evidence supporting the use of prognostic markers is needed for these to be used most appropriately in patient management. The College of American Pathologists recently sponsored a national conference to review the status of tumor markers for carcinomas of the breast, colon, and prostate gland. The conclusions of the Prostate Cancer Working Group are presented in this report. Currently, the TNM (Tumor, Lymph Node, Metastasis) staging system, histologic grading (Gleason system), and serum prostate-specific antigen are recommended for general use as prognostic markers in prostate cancer. Data support the use of DNA ploidy analysis in specific clinical settings, although general use is not currently recommended. The Working Group concluded that other markers do not have sufficient support in the literature to recommend routine use at the present time.
Biomarkers, Tumor↗
Inflammatory and other conditions that can mimic carcinoma in the urinary bladder.
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Adenoma↗
Prognostic significance of cellular proliferation in renal cell carcinoma: a comparison of synthesis-phase fraction and proliferating cell nuclear antigen index.
DNA aneuploidy has repeatedly been shown to be a significant prognostic indicator in renal cell carcinoma; however, few studies have emphasized the importance of measurements of cellular proliferation. This study evaluated 55 patients treated by radical nephrectomy and for whom clinical follow-up was available. There were 36 men and 19 women with a mean age of 61 yr. Robson stage distribution was I, 38 cases; II, five cases; and III, 12 cases. Flow cytometric analysis in 44 cases revealed 29 DNA diploid and 15 DNA aneuploid tumors with a median synthesis-phase fraction (SPF) of 4.4% (range 1.0 to 31.4%). The median proliferating cell nuclear antigen index was 3.9% (range 0.1 to 58.0%). There was a significant correlation between SPF and proliferating cell nuclear antigen index (R = 0.769) in the 33 cases in which both were available. Cellular proliferation, as determined by SPF, was a significant prognostic indicator (P < 0.02), but proliferating cell nuclear antigen index did not correlate with outcome (P > 0.05). Other significant predictors in this study were Robson stage (P = 0.03) and nuclear grade (P = 0.0003). DNA ploidy did not correlate with outcome (P > 0.05). We conclude that cellular proliferation, as measured by SPF analysis, is a significant predictor of outcome for renal cell carcinoma. Although the proliferating cell nuclear antigen index correlated with SPF, it did not achieve statistical significance as a prognostic indicator.
Adult↗
Allelic loss in locally metastatic, multisampled prostate cancer.
In order to determine whether retention or loss of potential tumor suppressor loci that map to 8p, 10q, or 16q reflect genetic relationships among prostatic intraepithelial neoplasias (PINs), multicentric primary prostatic cancers, and regional lymph node metastases or are associated with the metastatic phenotype, we analyzed 19 cases of locally metastatic prostate carcinoma (stage D1) utilizing polymerase chain reaction techniques. In each case, tissue samples from metastatic tumor, the (dominant) primary tumor, and nonneoplastic prostatic tissue were examined. In selected cases, allelic loss in additional tumor foci, separate from the dominant tumor nodule, and areas of PIN were examined. Allelic loss of sequences on 8p, 10q, and 16q were observed in 20-29% of PINs, 18-42% of primary tumors, and 8-25% of metastatic tumors. Discrepancies in sequence dosage between histological components were most pronounced for 8p sequences, especially between the dominant tumor nodule and metastatic deposits in cases in which > or = 3 separate tumor foci/gland were identified. These results suggest that putative premalignant lesions, moderately or poorly differentiated, geographically separate primary tumor foci, and metastases within morphologically "complex" prostates (those with > or = 3 foci/gland) are likely to be more discordant for sequence dosage at 8p than those within "simpler" glands (< 3 foci/gland). Also, our results suggest that lymph node metastases may be genetically related to either the dominant or additional primary tumor foci in more complex prostates and that accumulation of genetic aberration may differ in primary and metastatic lesions.
Alleles↗
Prostate inhibin peptide (PIP) in prostate cancer: a comparative immunohistochemical study with prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP).
Prostate inhibin peptide (PIP) is a polypeptide synthesized by the prostate gland that is involved in prostatic growth and differentiation. The objective of this study was to evaluate PIP as an immunocytochemical marker for prostatic adenocarcinoma (PCA) by comparing it with PSA and PAP. A total of 71 cases of primary PCA and 5 cases of metastatic PCA were studied. Primary tumors were specially selected to include a disproportionate number of high-grade tumors. The distribution of cases by Gleason score was 2-5, 14 cases; 6-7, 24 cases; and 8-10, 33 cases. Four metastases were to bone (decalcified tissue) and one to soft tissue. All 71 cases of primary PCA stained positively for the three antibodies tested, with none demonstrating obvious superiority, although individual case variability was seen. In one bone metastasis, staining for PSA was negative, with both PAP and PIP giving positive results. All non-prostatic carcinomas tested were negative. These results indicate that PIP is as sensitive and specific an immunohistochemical marker as PSA and PAP in untreated prostate adenocarcinomas. Further, the androgen-independent nature of PIP may give it an advantage over PSA/PAP in tumors exposed to androgen ablating agents.
Acid Phosphatase↗
Comparative analysis of epidermal growth factor receptor gene expression and protein product in benign, premalignant, and malignant prostate tissue.
In order to more clearly define the status of epidermal growth factor receptor (EGFR) in prostate cancer, expression of EGFR transcript and protein was analyzed in paired samples of benign and malignant tissues from 30 radical prostatectomy specimens. Prostate tumors and high grade prostatic intraepithelial neoplasias (PINs) expressed significantly less EGFR protein than benign tissues or low grade PINs (P < 0.001). Expression of EGFR mRNA was analyzed in a subset of the same samples, and was higher in more prostate tumors than benign specimens (P < 0.05). However, differences in mean mRNA expression between malignant and benign tissues were not significant. EGFR mRNA was expressed at moderate or low levels in equivalent numbers of PIN lesions. These results suggest that, although EGFR mRNA expression is somewhat elevated in prostate tumors, EGFR protein expression may be down-regulated in the same malignant tissues. Furthermore, our data demonstrate phenotypic similarity between prostate tumors and high grade PIN at the level of EGFR protein expression.
Aged↗
DNA content in cervical carcinoma: a flow cytometric assessment of DNA heterogeneity.
The degree of DNA heterogeneity varies between tumors arising in different body sites. Any substantial degree of variability within a given tumor can give rise to significant problems in the interpretation of DNA flow cytometric (FCM) studies. This study was undertaken to evaluate the degree of DNA heterogeneity in cervical carcinomas. A total of 100 3-mm punch biopsies were evaluated from single large cases in 10 sections of cervical carcinoma. Of the 10 tumors, 6 were squamous carcinoma, 1 was an adenocarcinoma, 1 was a mixed small cell and squamous carcinoma, 1 was an adenosquamous cancer, and 1 was a small cell carcinoma with a small area of adenocarcinoma. Adequate histograms were available for 95 (95%) of the samples. Of the 10 cases studied, 9 (90%) revealed homogeneity in the DNA pattern. A solitary case demonstrated heterogeneity in one histogram (nine samples DNA diploid and one sample DNA aneuploid). This case was predominantly small cell undifferentiated carcinoma with focal adenocarcinoma. The area of adenocarcinoma was probably the area that contributed to the heterogeneous FCM pattern. From this study we conclude that for most cervical carcinomas of a specific histologic type there is DNA homogeneity. However, for carcinomas with a mixed morphology, DNA heterogeneity is possible and this must be taken into account in any DNA ploidy studies that include mixed or combined tumors.
Adenocarcinoma↗
Zonal origin of prostatic adenocarcinoma: are there biologic differences between transition zone and peripheral zone adenocarcinomas of the prostate gland?
Prostatic adenocarcinomas predominantly arise in the peripheral zone (PZ) of the organ; however, a significant subset of tumors (approximately 20%) originate in the transition zone (TZ). These tumors exhibit morphologic and growth pattern features suggestive of a lower degree of biologic aggressiveness. From our surgical pathology files, we identified 39 consecutive radical prostatectomy specimens in which discrete adenocarcinomas of both peripheral and transition zone origin were present. All specimens had been entirely embedded, step-sectioned, and reviewed by two urologic pathologists. DNA content was determined by image analysis of Feulgen-stained tissue sections, and cellular proliferation was evaluated by immunohistochemical staining with MIB-1. The mean Gleason score for the PZ and TZ tumors was 6.7 and 5.6, respectively (p < 0.001). Of 15 cases analyzed to date, 8 PZ tumors and 2 TZ tumors were aneuploid (p = 0.055). The proliferation indices for the PZ and TZ tumors were 5.0% and 1.6%, respectively (p < 0.05). These findings confirm other reports, supporting the concept of biological differences between carcinomas of peripheral and transitional zone origin.
Adenocarcinoma↗
The association of human papillomavirus with Schneiderian papillomas: a DNA in situ hybridization study.
Human papillomavirus has been identified with DNA hybridization techniques in Schneiderian papillomas, though results reported in the literature have been conflicting. This study investigated 33 cases of Schneiderian papilloma (26 inverted papillomas, seven fungiform papillomas). In situ hybridization using a cocktail of human papillomavirus (HPV) probes 6/11, 16/18, 31/33/35 failed to identify HPV genome in any of the inverted papillomas. This is contrasted by the detection of HPV 6/11 in six of seven fungiform papillomas. Of the 26 cases of inverted papilloma, 10 had recurrences, five were associated with dysplasia, and two were associated with squamous cell carcinoma. Of the seven cases of fungiform papillomas, two had recurrences, and two were associated with dysplasia, but not malignancy was found. This study supports the concept that fungiform papilloma and inverted papilloma are two distinct lesions: the former is associated with HPV 6/11.
DNA, Viral↗
Glutathione S-transferase expression in renal cell carcinoma: a new marker of differentiation.
Expression of two GST isoenzymes (alpha and pi) was assessed immunohistochemically in 46 cases of renal cell carcinoma (RCC) for which clinical follow-up was available. In the normal kidney GST alpha stained most intensely in the proximal convoluted tubules and GST pi in distal tubules/collecting ducts. All 46 tumors studied stained positively for GST alpha with most demonstrating strong cytoplasmic and nuclear reactivity. GST pi immunostaining was positive in 35/46 cases (76%). Five-year survival for patients with GST pi positive tumors was 88% versus 50% for those with GST pi negative tumors (P < 0.008). Loss of GST mRNA has been reported in RCC and it has been suggested that this may represent a dedifferentiation program in RCC. These data support this hypothesis and further indicate a potential value for GST pi as a prognostic indicator in RCC.
Adult↗
DNA heterogeneity in prostatic adenocarcinoma. A DNA flow cytometric mapping study with whole organ sections of prostate.
BACKGROUND: The degree of DNA heterogeneity varies between tumors arising at different sites. The presence of a significant degree of variability within a given tumor may result in problems in the interpretation of DNA flow cytometric findings. This study evaluated the degree of DNA heterogeneity in prostatic adenocarcinoma. METHODS: A total of 122 3-mm punch biopsy specimens were evaluated from single representative whole organ sections from nine cases of prostate cancer (range, 4-18 samples per case; mean, 12 samples; median, 14 samples). Individual punch biopsy specimens were graded and reviewed to confirm the presence of carcinoma and processed for DNA ploidy analysis. RESULTS: Assessable histograms, defined as having a coefficient of variation of the diploid G0/G1 peak of 7.5% or less, were available for 111 (91%) of the samples. Of the nine cases studied, five (56%) showed heterogeneity in the DNA pattern (diploid plus aneuploid, n = 1; diploid plus tetraploid, n = 2; and diploid plus tetraploid plus aneuploid, n = 2). All four cases having a homogeneous DNA content were DNA diploid in all samples. In those cases with a heterogeneous pattern, the areas having abnormal DNA patterns could not be predicted by histologic pattern or grade. CONCLUSIONS: From this study, the authors conclude that a significant degree of DNA heterogeneity exists within individual cases of prostatic adenocarcinoma, and this may be an important confounding factor in DNA ploidy studies.
Adenocarcinoma↗
Transitional cell carcinoma of the renal pelvis with choriocarcinomatous differentiation. Immunohistochemical and immunoelectron microscopic assessment of human chorionic gonadotropin production by transitional cell carcinoma of the urinary bladder.
BACKGROUND: There have been 12 documented cases of choriocarcinoma arising in the urinary bladder, either alone or in combination with other epithelial tumors. It has been shown that some high-grade transitional cell carcinomas (TCC), without obvious syncytiotrophoblastic elements, can produce human chorionic gonadotrophins (HCG). METHODS: A case of choriocarcinoma, in association with high-grade TCC of the renal pelvis, was encountered in an 80-year-old man. For additional evaluation of HCG production by TCC, 25 consecutive cases of invasive high-grade TCC of the bladder were stained with an anti-HCG antibody. Immunogold staining also was performed in two of the cases studied. RESULTS: Immunoperoxidase staining of the renal pelvis tumor showed focal positivity for HCG within the TCC and a more intense reaction as the tumor cells differentiated into choriocarcinoma elements. Seven of the 25 cases (28%) displayed varying degrees of reactivity within individual cells or groups of cells. In an additional case, typical syncytiotrophoblastic giant cells without cytotrophoblasts were seen in a high-grade TCC. Immunogold studies demonstrated positive labeling in the cytoplasm of carcinoma cells in a case of TCC without syncytiotrophoblasts and in the syncytiotrophoblastic giant cells in the one case in which these were present. CONCLUSIONS: The findings support a metaplastic origin of cases of choriocarcinoma arising primarily in the urothelial tract.
Aged↗
Malignant paraganglioma with skeletal metastases and spinal cord compression: response and palliation with chemotherapy.
Paragangliomas (carotid body tumours, chemodectomas) may arise in any area of the body where sympathetic ganglia are present, including chemoreceptors, the adrenal medulla and retroperitoneal ganglia. Increasing numbers of patients are being reported with vertebral metastases and spinal cord compression for which either decompression laminectomy or external beam radiotherapy, or both, are required. Patients with vertebral metastases may develop progression of disease after radiation therapy. There is little published information on the use of chemotherapy in this clinical situation. We report a case of metastatic paraganglioma complicated by spinal cord compression showing evidence of clinical benefit from chemotherapy after progressive disease and symptoms developed in a region previously treated by radiation therapy.
Adult↗
Mucinous metaplasia in the prostate gland.
The prostate gland normally secretes neutral mucosubstances that can be detected within the lumina of acini and ducts; adenocarcinomas often produce both acidic and neutral mucins, a feature that has been suggested to be of some diagnostic use. The presence of mucin-filled cells is not, however, a feature of the normal prostate. Over the last few years, we have observed tall, columnar, mucin-secreting cells in a variety of conditions in 12 benign prostates. All cases were stained histochemically for mucin with Mayers' mucicarmine, alcian blue (pH 2.7), and periodic-acid-Schiff with diastase digestion. In four cases, immunoperoxidase stains for prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP) were performed. Mucin-secreting cells were found in the foci of sclerotic atrophy (n = 5), transitional cell metaplasia (n = 3), basal cell hyperplasia (n = 2), prostatrophic hyperplasia (n = 1), and nodular hyperplasia (n = 1). In all examples, the cells stained intensely with PAS, mucicarmine, and alcian blue. The cells were nonreactive for PSA and PAP in the cases studied. To our knowledge, the presence of tall, columnar, mucin-secreting cells has not been previously described in atrophy or basal cell hyperplasia. These observations expand our appreciation of the histologies that may be seen in the prostate gland; in addition, the recognition of acidic mucin-secreting cells in benign lesions points to the nonspecificity of this finding in the diagnosis of malignancy.
Acid Phosphatase↗
Sarcomatoid renal cell carcinoma. An immunohistochemical study of 18 cases.
Malignant spindle cell neoplasms are a diagnostic challenge regardless of their location. In the retroperitoneum a major consideration in the differential diagnosis is sarcomatoid renal cell carcinoma; if an epithelial component cannot be recognized histologically, special studies may be required to reach the correct diagnosis. In an attempt to better characterize this entity, 23 cases of sarcomatoid renal cell carcinoma (6.3%) were identified from a review of 363 renal cell carcinomas. Blocks were available for immunohistochemical analysis in 18 cases. The epithelial and sarcomatoid portions were studied with a panel of antibodies directed against cytokeratin (AE1/AE3, CAM 5.2, and 34 beta E12), epithelial membrane antigen, Leu-M1, muscle-specific actin, S100 protein, desmin, and vimentin. The epithelial nature of the spindle cell component was best demonstrated by positive reactivity with the anti-cytokeratin AE1/AE3 (in 17 [94%] of the 18 cases). The other epithelial markers stained the spindle cell component less frequently: cytokeratin CAM 5.2 in seven cases (39%); epithelial membrane antigen in nine cases (50%); and high-molecular-weight cytokeratin 34 beta E12 in no cases (0%). In 10 cases (56%) vimentin positivity and in six cases (33%) actin positivity was seen in the spindled areas. The spindle cell component stained for Leu-M1 in four cases (22%) and for S100 protein in one case (6%) and did not react for desmin in any case. From this study we conclude that in the majority of sarcomatoid renal cell carcinomas the epithelial nature of the spindle cells, as indicated by cytokeratin expression, can be documented using immunohistochemical methods.
Carcinoma, Renal Cell↗
Sarcomatoid carcinoma of the prostate. A clinicopathologic study of 12 patients.
Sarcomatoid carcinoma of the prostate is a rare tumor that can be difficult to distinguish from a true sarcoma. The authors report 12 patients in whom the typical light microscopic appearance of prostatic adenocarcinoma was accompanied by the appearance of spindled or pleomorphic sarcomatoid areas within the same specimen or in subsequent accessions. Immunostaining or electron microscopic study demonstrated epithelial differentiation within the sarcomatoid area(s) in 6 of the 11 patients in whom special studies were performed. All nine patients for whom follow-up data were available died of disease within 3 to 48 months (median time until death, 12.0 months) after the appearance of the sarcomatoid carcinoma, and the clinical course in each instance was characterized by aggressive local recurrence. Our experience confirms that sarcomatoid carcinoma of the prostate is an aggressive variant of prostatic adenocarcinoma.
Aged↗
Small cell carcinoma of the urinary bladder. A clinicopathologic analysis of 22 cases.
Small cell carcinoma of the urinary bladder is an uncommon tumor. The authors report the clinicopathologic findings in a series of 22 cases. Fifteen men and 7 women were studied; their ages ranged from 51 to 87 years (mean, 62.4 years). The most frequent presentation was hematuria (94.4%). At diagnosis, three patients had Stage B disease, six had Stage C, and ten had Stage D (unknown stage in three). Histologically, 6 were oat cell type tumors, 11 were of intermediate cell type, and 5 were of combined cell type. Immunohistochemical studies demonstrated positivity for neuron-specific enolase in ten of ten cases, cytokeratin in seven of ten cases, chromogranin in eight of nine cases, serotonin in seven of nine cases, and S-100 protein in four of ten cases. Neuroendocrine differentiation was seen in five of seven cases examined by electron microscopy. Treatment and follow-up data were available for 19 patients: 10 (52.6%) were dead of disease, 5 (26.3%) were alive and well, 3 (15.8%) were alive with disease, and 1 (5.3%) died of an unrelated cause. The 2-year survival rate was 50% for patients with Stage B, 25% for patients with Stage C, and 33% for patients with Stage D disease. Although overall survival was poor, some cases responded well to therapy. Based on the authors' experience, radical cystectomy with adjuvant chemotherapy appears to be the treatment of choice.
Aged↗