Prognostic factors in prostate cancer. College of American Pathologists Consensus Statement 1999.

BACKGROUND: Under the auspices of the College of American Pathologists, a multidisciplinary group of clinicians, pathologists, and statisticians considered prognostic and predictive factors in prostate cancer and stratified them into categories reflecting the strength of published evidence and taking into account the expert opinions of the Prostate Working Group members. MATERIALS AND METHODS: Factors were ranked according to the previous College of American Pathologists categorical rankings: category I, factors proven to be of prognostic importance and useful in clinical patient management; category II, factors that have been extensively studied biologically and clinically but whose importance remains to be validated in statistically robust studies; and category III, all other factors not sufficiently studied to demonstrate their prognostic value. Factors in categories I and II were considered with respect to variations in methods of analysis, interpretation of findings, reporting of data, and statistical evaluation. For each factor, detailed recommendations for improvement were made. Recommendations were based on the following aims: (1) increasing uniformity and completeness of pathologic evaluation of tumor specimens, (2) enhancing the quality of data collected pertaining to existing prognostic factors, and (3) improving patient care. RESULTS AND CONCLUSIONS: Factors ranked in category I included preoperative serum prostate-specific antigen level, TNM stage grouping, histologic grade as Gleason score, and surgical margin status. Category II factors included tumor volume, histologic type, and DNA ploidy. Factors in category III included perineural invasion, neuroendocrine differentiation, microvessel density, nuclear roundness, chromatin texture, other karyometric factors, proliferation markers, prostate-specific antigen derivatives, and other factors (oncogenes, tumor suppressor genes, apoptosis genes, etc).

American Joint Committee on Cancer prognostic factors consensus conference.

BACKGROUND: The American Joint Committee on Cancer (AJCC) published the 1st edition of the Cancer Staging Manual in 1977 and began using T (tumor extent), N (regional lymph node status), and M (the presence or absence of distant metastasis) in an organized staging scheme to express the extent of disease in a number of cancer sites. The goal of this program has been to provide physicians and others with a useful methodology to plan treatment, project prognosis, and measure outcome end results. Until recent years, this system has incorporated only elements of anatomic extent of the tumors determined by clinical and pathologic methods. At the present time an increasing number of nonanatomic cancer prognostic factors are being identified and studied. Some of these factors currently are being used for outcome predictions and treatment decisions. METHODS: To begin the process of identifying and validating these prognostic factors to refine the present TNM system, the AJCC convened a Prognostic Factors Consensus Conference to evaluate the roles of biologic, genetic, molecular, and other nonanatomic factors in staging cancer. Working groups were appointed for carcinomas of the breast, colorectum, prostate, and ovary and experts in each of these areas were invited to participate. Emphasis was placed on evaluating existing data and the correlation of these data with survival. RESULTS: None of the groups believed that there were sufficient data at the present time to merit incorporation of serum markers into the TNM system for the four tumors under consideration, although this soon might become possible in prostate carcinoma after the evaluation of survival data from multiple institutions. Recommendations were made regarding the emerging sentinel lymph node technique, the need for an increased use of histopathology in the staging of breast and ovarian carcinomas, and the use of additional histologic staining techniques for the detection of "micrometastases" in lymph nodes. A number of additional recommendations were made for changes to the TNM system that did not involve serum markers and other nonanatomic cancer prognostic factors. CONCLUSIONS: These recommendations are presented for the purpose of discussion and evaluation and do not yet represent formal proposals for a change in the AJCC TNM system of staging.

Vascular toxicity associated with chemotherapy and hormonotherapy.

Vascular complications associated with chemotherapy and hormonotherapy are being reported with increasing frequency. Such vascular toxicity is clinically heterogenous, ranging from asymptomatic venous lesions to fatal hepatic venoocclusive disease of the liver. Putative mechanisms for such toxicity include drug-induced endothelial cell damage, perturbation of the clotting cascade, platelet activation and aggregation, alteration of thromboxane-prostacyclin homeostasis, and dysregulation of cytokines. Better documentation of the incidence and types of vascular toxicity and studies to help elucidate the pathogenesis and management of such toxicity are needed.

Modified nucleosides in human serum.

Methylated purines and pyrimidines derived from the degradation of transfer ribonucleic acid have been shown to be excreted in abnormal amounts in the urine of patients with cancer. Recent technology developed by Gehrke and Kuo has allowed the separation and quantification of modified nucleosides in serum using reversed-phase high-performance liquid chromatography with diode-array measurement. Serum levels of ten modified nucleosides were measured in 37 normal healthy adults to establish normal values and to correlate activity with age and sex. In addition, serum levels of patients with several malignancies were measured to determine activity in these diseases. Levels of modified nucleosides in normal individuals were consistently reproducible and showed no significant variation among males versus females or with age. Patients with malignant diseases showed consistent elevations and these were highest in patients with more advanced disease. The evidence of no significant differences in the mean levels of modified nucleosides in serum with age or sex in normal adults and elevations in patients with malignancies demonstrate the potential value of modified nucleosides as cancer biomarkers.

Vascular toxicity associated with antineoplastic agents.

It is apparent that a variety of vascular disorders have been reported after the administration of antineoplastic agents. However, it is not clear whether all of these entities are related to cytotoxic drugs, the malignancy itself, or some other unrelated factor. Nonetheless, there does appear to be a cause-effect relationship between cisplatin, bleomycin, velban chemotherapy, and Raynaud's phenomenon. In addition, painful acral erythema may occur in association with several drugs, especially protracted infusions of 5-fluorouracil and high-dose cytosine arabinoside. Mitomycin is the most common cause of the thrombotic microangiopathic syndrome, and in the majority of cases it is a lethal event. Unfortunately, HVOD is a major toxic effect of many preparatory bone marrow transplantation protocols and ways to prevent this potentially life-threatening complication should be avidly pursued. In this regard, pentoxifylline and low-dose heparin have recently been reported to be effective in preventing HVOD. Although recent reports have documented thromboses and thromboembolic events in patients with breast cancer treated with cytoxan, methotrexate, and 5-fluorouracil-based protocols, only one study had a no-treatment control arm. Future breast cancer studies should evaluate this problem prospectively. More studies are needed to help elucidate the pathogenesis of vascular toxicity associated with chemotherapy.

Mechanism of action of hydroxyurea.

Hydroxyurea is well absorbed after oral administration, converted to a free radical nitroxide in vivo, and transported by diffusion into cells where it quenches the tyrosyl free radical at the active site of the M2 protein subunit of ribonucleotide reductase, inactivating the enzyme. The entire replitase complex, including ribonucleotide reductase, is inactivated and DNA synthesis is selectively inhibited, producing cell death in S phase and synchronization of the fraction of cells that survive. Repair of DNA damaged by chemicals or irradiation is also inhibited by hydroxyurea, offering potential synergy between hydroxyurea and radiation or alkylating agents. Hydroxyurea renders cells sensitive to bleomycin because the quenched tyrosyl free radical no longer stabilizes the adjacent iron center, making it more susceptible to the chelating properties of bleomycin, which then produces active oxygen. Synergy has also been observed between hydroxyurea and a number of other chemotherapeutic agents, including cytarabine and etoposide. Recently, two new effects of hydroxyurea have been observed: hydroxyurea increases the level of fetal hemoglobin, leading to a reduction in the incidence of vasoocclusive crises in sickle cell anemia, and hydroxyurea selectively reduces the level of episomal DNA and thus potentially may reduce drug resistance associated with duplicated genes retained as episomes. Further exploration of the efficacy of hydroxyurea in combination with other therapeutic agents is warranted.

Oncogenes and cancer suppressor genes.

Cancer is caused by the malfunction of genes that regulate cell proliferation. Two kinds of regulatory genes have been discovered in the search for cancer genes: those that promote growth, called oncogenes, and those that suppress growth, called anti-oncogenes or cancer suppressor genes. The retroviruses that cause animal cancers contain oncogenes coding for growth-promoting signals. These retroviruses rarely cause human cancer but study of their oncogenes has allowed identification of many human cancer genes. These genes code for growth factors, growth factor receptors, cytoplasmic proteins, and nuclear proteins. The complete sequence of cellular growth control begins when a growth factor binds to its receptor and acts directly or indirectly through a G protein and second messenger to induce phosphorylation (activation) of an intracellular protein that ultimately alters the expression of the genes necessary to initiate cell division. At each step in the complex sequence that up-regulates cell division, there is an opposite down-regulating activity produced by the protein products of anti-oncogenes or cancer suppressor genes. These proteins do this by binding to and inactivating transcription factors that initiate DNA synthesis or by directly inactivating the molecules activated by the oncogene products. When this carefully orchestrated and regulated cell control process goes awry because one or more of the proteins in the sequence has been altered by a mutated gene, the cell divides in an uncontrolled manner and malignancy results. It is thought that most human cancers result from a combination of genetic changes that must include both the absence of the protein products of cancer suppressor genes and the presence of abnormal products of oncogenes. The work of Volgelstein and coworkers at Johns Hopkins University has provided the best insight so far into the complex pathogenesis of a common tumor, colon cancer. Carcinogenesis in colon cancer requires a sequence of events that involves more than five genes. Understanding of these pathogenic mechanisms should improve cancer diagnosis and treatment.

Immunotherapy of cancer with lymphokines and lymphokine-activated killer cells.

Our expanding knowledge of the immune system has provided a basis of rationality for immunotherapy. Some non-specific immunotherapy has achieved the status of standard treatment: interferon in hairy cell leukemia and chronic myelogenous leukemia, BCG in bladder cancer, and levamisole in colon cancer adjuvant therapy. Tumor infiltrating lymphocytes, moreover, offer a level of specificity heretofore unknown. Combined with the newly available synthetic cytokines that regulate the normal immune system there is the potential for a major breakthrough in biotherapeutics. Problems remain. We have yet to identify tumor antigens with the precision necessary for effective immunotherapy. Indeed, we have no assurance that tumors will regularly synthesize new antigens. In the broad spectrum of immune deficiency syndromes, we have yet to see an increase in the common epithelial tumors that account for the great bulk of human cancer. This suggests that we still have a great deal more to learn.

Changing cancer care in the 1990s and the cost.

Progress in cancer research in the 1980s has led to predictions of a technologic explosion in the 1990s. Yet, with this progress there has been a groundswell of protest at the rapidly escalating costs of health care. More than $600 billion was spent on health care in 1989 and estimates of $1.5 trillion are made for the year 2000. Repeated attempts at cost containment have failed. It has been suggested that only by retarding technologic advances will we be able to control costs. Many observers believe that rationing of health care is the only solution, but new technology not only improves cancer care, it often decreases cost. It is not rational to retard advances that may later reduce costs, nor is it humane to retard advances that improve care, even if they cost more. In identifying priorities we should begin with the principle that treatments be restricted to clinical trials unless they have been demonstrated to prolong survival or improve the quality of life. If the payers reimburse procedures in an investigative setting, they will be on firm ground when they deny support for those same procedures outside an investigative setting. This is both an ethical and a fiscally responsible position for the third parties to take. It will not be easy for the profession or for the payers to deal with these problems. Public education and patient education will be key elements of any solution. Shifting the blame from politician to payer to professional will only make the problems worse.

Assessment of physician perceptions on the fatality of cancer.

A questionnaire was developed to evaluate internists' perceptions about patients' survival of cancer as compared with other diseases. The questionnaire consisted of four pairs of survival-matched cancer and non-cancer diseases. The questionnaire was administered to 42 faculty members and 37 resident physicians in the Department of Medicine at the University of Missouri-Columbia. Physicians rated patients' survival of cancer to be significantly lower than patients' survival of comparable non-cancer diseases (p less than 0.001). Resident physicians estimated patients' survival of breast cancer to be significantly lower (p less than 0.007) and estimated the survival of lung cancer to be significantly higher than the faculty members' estimate (p less than 0.003). These physicians' perceptions could adversely affect the quality of care and the degree of consideration given to both cancer and non-cancer patients. The differences observed in faculty members' and resident physicians' responses were attributed to the greater knowledge and clinical experience of faculty rather than differences in attitudes toward cancer.

National survey of the pattern of care for carcinoma of the lung.

A national survey of the patterns of care for carcinoma of the lung sponsored by the Commission on Cancer of the American College of Surgeons has documented continuing changes in epidemiology, treatment, and outcome. The project consisted of a long-term study of 15,219 patients whose diagnosis was made in 1981 and a short-term study of 19,074 patients whose diagnosis was made in 1986. The male/female incidence ratios have continued to decrease and the decrease has moved into the older age groups. Although the percentage of adenocarcinoma is increasing at the expense of squamous carcinoma, the latter is still the most prevalent histologic type. The accuracy of percutaneous needle biopsy and transbronchial biopsy of lung nodules reported from this group of 941 hospitals was high and equal to that reported by single institutions. The percentage of patients having a resection did not increase from 1981 to 1986, but for smaller lesions a move was apparent toward more lung-sparing resections. Little change has occurred in the use of adjuvant radiotherapy, particularly in stage III disease, where approximately 50% of the patients received postoperative irradiation. An improvement in the overall 5-year survival when compared with Surveillance, Epidemiology, and End Results data was noted. Whether this is a true improvement in survival or is the result of selection because of an unrecognized change in the pattern of care for patients with a carcinoma of the lung is unknown.

Corticosteroid treatment of hemolytic anemia associated with Mycoplasma pneumoniae pneumonia.

We have described a 35-year-old man with M pneumoniae pneumonia who had severe hemolytic anemia that appeared to respond well to high-dose corticosteroid therapy. Whether corticosteroids have value in decreasing the severity of hemolytic anemia due to cold agglutinin and other protean extrapulmonary manifestations with M pneumoniae infection needs further controlled study. Our experience suggests that corticosteroids may be beneficial.

Epidural spinal cord compression as the presenting manifestation of tumor of unknown origin.

Epidural spinal cord compression is a common complication of malignancy. In the majority of cases, the primary site is known at diagnosis or is evident following limited investigation. During the period January 1975 to December 1987 we encountered seven cases of tumor of unknown origin presenting as cord compression. Myelography detected the site of cord involvement in six cases, and computed tomography of the spine was utilized in one case. All seven patients underwent laminectomy. Histologic diagnosis was adenocarcinoma in four cases, squamous in one case, and large cell undifferentiated carcinoma in two cases. Evaluation for a primary site was unrewarding. Prognosis was poor, with a median survival of 10 weeks. Only one patient had a satisfactory response to treatment.

Acanthocytosis associated with myelodysplasia.

Dysplastic hematopoiesis associated with erythrocyte macrocytosis is a morphologic hallmark of myelodysplasia. We report the cases of six patients with myelodysplasia in which acanthocytosis was the predominant red blood cell (RBC) abnormality. In each case acanthocytes represented 5% to 10% of circulating RBC forms and was the primary reason for referral in two cases. None of the patients had comorbid conditions known to be associated with acanthocyte formation. Myelodysplasia should be considered in the differential diagnosis of acanthocytosis, particularly in the anemic, elderly individual. Acanthocytosis may be a harbinger of an unrecognized, hematologic stem-cell disorder.

Malignant ascites of unknown origin.

To determine the clinical characteristics of patients presenting with malignant ascites, as well as means of evaluating the outcome of patients with the disease, a retrospective review was conducted of all cases of malignant peritoneal effusions diagnosed from 1978 to 1987 at a University Hospital and a Veterans Administration Hospital. Of 65 patients with malignant ascites (40 women; 25 men), the primary site was known in 51 cases (80%). Common sites in women were the ovaries, endometrium, and cervix; in men, common sites were the colon, rectum, and stomach. For five women and nine men the primary site was unknown. Median survival from diagnosis was 7.5 days (mean, 43 days; range 1-256 days). Chest radiograph and abdominal computed tomography (CT) scan did not disclose the occult primary. An occult primary was detected while the patient was alive in only two cases and at autopsy in two other patients. Due to the poor prognosis for this disease, we do not recommend an aggressive approach to malignant ascites of unknown origin, except perhaps in women, in whom ovarian cancer should be suspected.