Panel Of Pathologists Research Articles

Primary extranodal and nodal non-Hodgkin's lymphoma: A survey of a population-based registry

In a population-based registry, there were 580 patients with non-Hodgkin's lymphoma (NHL); 236 had primary extranodal lymphoma ( 41%). The initial localization of the primary extranodal lymphomas varied markedly, although 36% were primary gastrointestinal lymphomas. Histological classification was performed by a regional panel of pathologists according to the Kiel Classification and the International Working Formulation. Twelve per cent of the patients with nodal NHL had a localized disease in contrast to 40% with primary extranodal NHL. Low grade lymphomas were encountered in 30 and 10% of the patients with primary nodal and extranodal NHL, respectively. Recurrence-free survival rate for patients with localized low-grade malignancy and disseminated intermediate grade NHL is significantly better for extranodal lymphoma than for nodal NHL. Patients with disseminated high-grade extranodal NHL had the worst prognosis of all. We conclude that primary nodal and primary extranodal lymphomas should be considered as distinctive and separate entities.

Pathologic analysis of advanced adult soft tissue sarcomas, bone sarcomas, and mesotheliomas. The Eastern Cooperative Oncology Group (ECOG) experience.

A total of 488 tumors entered in the Eastern Cooperative Oncology Group (ECOG) Study EST 3377 were evaluated histologically by a panel of pathologists from member institutions for quality control purposes. The overall agreement rate between the eligible submitting diagnosis and the pathology review panel's diagnosis was 74% (312/424). In 10% (44/424), the case was excluded because it was deemed to be nonsarcoma. In the other 16%, the disagreement concerned the type of sarcoma. The histologic type with the lowest agreement rate was rhabdomyosarcoma (17%), followed by sarcoma not otherwise specified (NOS) (27%), angiosarcoma (33%), and fibrosarcoma (48%). These figures reflect the significant degree of difficulty in the diagnosis of these tumor types. The treatment response rate of soft tissue sarcomas in the randomized study of Adriamycin (Adria Laboratories, Columbus, OH) regimens was slightly higher for those with lower grade sarcomas, i.e., 25% (four of 16) response rate for Grade 1 lesions; 22% (17/77) for Grade 2, and 21% (35/170) for Grade 3. When adjusted for type of sarcoma, there was no noticeable difference between Grade 1-2 versus 3 in response rate. A statistically significant difference in the percentage of complete responders was noted between Group A tumors (synovial sarcoma, hemangiopericytoma, sarcoma NOS, and Ewing's; 12.2%) versus Group B tumors (all other types--mostly spindle cell sarcomas; 3.5%) (P = 0.02).

Combination chemotherapy in malignant non-seminomatous germ-cell tumors: results of a cooperative study of the German Society of Pediatric Oncology (MAKEI 83)

In January 1983, the German Society of Pediatric Oncology started a cooperative trial (MAKEI 83) for non-testicular germ-cell tumors. The pilot phase closed in December 1985. The treatment regimen was stratified according to histology, tumor site and tumor stage. In malignant non-seminomatous germ-cell tumors (mNSGCTs), chemotherapy consisted of four courses of 3 mg/m2 vinblastine, on days 1 and 2 and 15 mg/m2 bleomycin on days 1-3, given by continuous infusion, and 20 mg/m2 cisplatin on days 4-8 with mannitol diuresis. Courses were repeated every 3 weeks. In mNSGCT patients with ovarian FIGO stages III-IV or extragonadal primaries, second-look surgery was carried out, followed by four additional courses of chemotherapy with 100 mg/m2 VP-16 on days 1-3, 1.5 g/m2 ifosfamide on days 1-5 with mesna uroprotection and 20 mg/m2 cisplatin on days 1-5 with mannitol diuresis. In patients with sacrococcygeal germ-cell tumors, en bloc resection of the tumor, including the coccygeal bone, was mandatory. During the registration period, 57 patients with mNSGCTs were entered: 37 protocol patients and 20 follow-up patients. The event-free survival for protocol patients at 57 months was 78% +/- 6% and that for follow-up patients was 40% +/- 10% (Kaplan-Meier): the crude survival for both groups was 83% +/- 6% and 54% +/- 12%, respectively. After a review by a panel of pathologists, the histological diagnoses in 7% of all registered cases of germ-cell tumors were changed. The results of the present studies show that the histological subclassification of mNSGCTs, tumor site and tumor stage no longer had prognostic value.

Expression of the epithelial L1 antigen as an immunohistochemical marker of squamous cell carcinoma of the lung.

The distribution of epithelial L1 antigen was evaluated in 139 bronchogenic carcinomas which had been classified by a panel of pathologists according to the WHO recommendation of 1981. L1 was not found in three large cell and 13 small cell carcinomas, but it was expressed by tumour cells in 67 of 69 squamous cell carcinomas (97%), in three of four adenosquamous carcinomas (75%), and in three of 49 adenocarcinomas (6%). The staining for L1 antigen was more diffusely distributed in the positive adenocarcinomas than in the squamous cell carcinomas. Its expression in squamous cell carcinomas was typically confined to relatively small tumour cell groups and never included a complete specimen. Semi-quantitative estimation of the immunostaining showed no clear relationship to the degree of differentiation and scores for proliferation, but L1 expression was negatively related to nuclear aberration (P less than 0.025) and malignancy scores (P less than 0.002). The good agreement between morphological classification and expression of L1 makes this a valuable marker in the diagnosis of lung carcinomas.

Histopathological classification of childhood rhabdomyosarcoma: A report from the international society of pediatric oncology pathology panel

Five hundred thirteen soft tissue tumours of childhood referred to the International Society of Pediatric Oncology (SIOP) Rhabdomyosarcoma study have been reviewed. The period covered was from January 1975 to December 1983. Three hundred thirty-nine neoplasms were regarded as embryonal rhabdomyosarcoma. The histological diagnosis of all referred tumours is given, and a classification of rhabdomyosarcomas developed during the course of the study is described. The relationship between histological subtypes and aspects of clinical behaviour is presented. The classification is thought to be helpful in diagnosis and also in assessment of the likelihood of recurrence and/or metastasis of childhood rhabdomyosarcoma.

Evaluation of pathology review of malignant lymphomas and Hodgkin's disease in cooperative clinical trials. The Eastern Cooperative Oncology Group experience.

Although central expert pathology review for quality assurance in cooperative clinical trials involving malignant lymphomas and Hodgkin's disease was put in place by the NCI two decades ago, its impact upon patient eligibility for given treatment protocols has never been assessed. We reviewed diagnoses from contributing pathologists, the Eastern Cooperative Oncology Group (ECOG) review pathologists and the Pathology Panel for Lymphoma Clinical Studies in 2019 cases from 14 ECOG protocols. Although we found high rates of disagreements in diagnoses, the vast majority of these represented differences which did not impact on protocol eligibility. A total of 221 cases (10.9%) were excluded from protocols, representing a range of 2.8 to 36.7% of cases per protocol. Eighty-six percent of the exclusions resulted from the initial review by the ECOG hematopathologists. Our data indicate that while central pathology review is mandatory for quality assurance in malignant lymphoma (ML) and Hodgkin's disease (HD) protocols, a two-tier review mechanism is not necessary for adequate quality control.

Mesothelioma of childhood.

Malignant mesothelioma (MM) of childhood is a rare but important neoplasm. Eighty children with a previous diagnosis of MM were identified. Four of the 80 children had exposure to known risk factors (two had history of exposure to asbestos, one had received radiation therapy, and one had been exposed in utero to isoniazid). Tissue slides were available for independent and joint review by a panel of three pathologists in 22 of the cases. Ten were accepted as MM, nine were reclassified as other malignancies, and three were considered tumors of uncertain nature. Six of the ten children with MM were boys, and four were girls. Eight had pleural tumors, and two had peritoneal tumors. Four died at 7, 8, 18, and 48 months after diagnosis; three remained alive at 19, 20, and 59 months; and three had no follow-up. This review suggests that MM of childhood is a valid entity with a grave prognosis. The tissue diagnosis is difficult and is best made by a panel of pathologists. The available evidence does not support a causal relationship between MM and asbestos, radiation, or isoniazid.

Inter- and intra-pathologist variability in histologic diagnoses of lung cancer.

To estimate variability and reliability in histologic diagnosis (Dx) of lung cancers, lung cancer preparations were divided into eight equal sets and diagnosed independently by an eight-man pathology panel. Majority Dx (Dx affirmed by more than 4 panelists) was regarded as the consensus Dx of each cancer. The consensus rate of each panelist ranged from 78.8% to 96.1% with an average of 89.4%. The consensus rates were not significantly different among the panelists. Relatively high inter-pathologist agreement was observed in squamous cell carcinoma, adenocarcinoma, and small cell carcinoma. However, regarding large cell carcinoma, there was occasional disagreement among the panelists. Forty-seven cancers were reexamined by the same panelists, with no preliminary announcement, 7 months after the first examination to study the intra-pathologist agreement. The rate of the intra-pathologist agreement ranged from 76.6% to 93.3%. Dx of large cell carcinoma was the most intra-changeable. It was concluded that the histologic Dx of large cell carcinoma was the most inter- and intra-changeable, and the most frequent dissenting Dx from it was poorly differentiated squamous cell carcinoma.

The New Mexico Melanoma Registry. A model of a statewide cooperative program.

The prevalence of cutaneous melanoma is high among Anglo residents of New Mexico. In order to achieve consistency in diagnosis and pathologic staging, a melanoma registry was established in 1980 in conjunction with the University of New Mexico Cancer Center. The registry functions through pathology panel review of newly diagnosed melanomas combined with collection of clinical data. Reports are submitted gratis to contributing pathologists and dermatologists. The melanoma registry works closely with the population-based New Mexico Tumor Registry. Acceptance of the melanoma registry has been excellent. We believe that in excess of 90% of new melanoma cases in the state are sent spontaneously to the registry. During 1986 approximately 150 melanomas were reviewed together with 450 atypical, benign pigmented lesions such as dysplastic nevi. In addition to pathology consultations, the registry serves an educational function and has potential for a variety of epidemiologic studies.

Gallbladder adenocarcinoma: prognostic significance of tumor acid mucopolysaccharide content.

The gall bladder mucosa is composed of neutral mucopolysaccharide and protein radical containing secretory cells, protein radical containing migratory cells, and neutral and acid mucopolysaccharides plus sialic acid containing goblet cells. The prognostic significance of histologic or histochemical parameters in gall bladder adenocarcinoma (GBA) are unknown. To determine if histochemical acid mucopolysaccharide content in GBA has prognostic value, GBA histologic sections from 26 advanced stage disease patients participating in Eastern Cooperative Oncology Group (ECOG) treatment study EST-2273 were stained with alcian blue at pH. 1.0, assessed by a pathology panel for either high (greater than 50%) or low (less than 50%) acid mucopolysaccharide content, and correlated with patient survival. Initial panel unanimous concurrence rate on acid mucopolysaccharide content was 88.9%. Median survival times from the start of chemotherapy to date of death for high acid mucopolysaccharide content GBA was 14 weeks versus five weeks for the low content GBA (P less than 0.0001). The results indicate that high acid mucopolysaccharide content in GBA significantly improves prognosis. ECOG recommends stratification by acid mucopolysaccharide content in future GBA treatment investigations.

What should be the morphologic criteria for the subdivision of follicular lymphomas?

The members of the Pathology Panel for Lymphoma Clinical Studies undertook a collaborative study with the hope of resolving some of the controversies regarding the criteria and methods for the subclassification of follicular lymphomas (FLs). A group of 105 patients with FL were subclassified by seven hematopathologists according to two methods. In the first method, cases were subclassified according to the Rappaport, Lukes and Collins, and Working Formulation systems. In each of these systems, FLs are subclassified by estimation of the different cell populations, without actual counting of cells. In the second method, precise counts of different cells were made according to the standard and modified Berard methods. With this counting method, diagnoses were independently derived, based on counts provided by the seven pathologists, for large cleaved (LC), small noncleaved (SNC), and large noncleaved (LNC) cells. To ascertain what method and which criteria are most useful in predicting survival, we made clinicopathologic correlations. When the subjective (first method) diagnoses were rendered, and when the consensus diagnoses of the seven pathologists were used, there were no significant differences in survival among patients with the different subtypes. On the other hand, when we used the counting method of Berard (second method) and the cut- off points for the cell counts suggested by him for the subclassification, we were able to divide the patient population into prognostic subgroups. Because the cut-off points proposed by Berard are not derived objectively, we made statistical comparisons of survival curves to determine cut-off points (and thus to establish objective criteria). We found that the patient population could be separated into at least two prognostic groups, for SNC and/or LNC and for SNC + LNC + LC cells. The cut-off points which we derived differed with cell type, however. Until the usefulness of these new cut-off points is established, we recommend that the cut-off points and the counting method of Berard be used for the subclassification of FL. Because the choice of treatment for the different subtypes of FL is totally dependent on the histologic diagnosis, and because of the variability among the diagnoses of pathologists, treatment planning is difficult.

What Should Be the Morphologic Criteria for the Subdivision of Follicular Lymphomas?

The members of the Pathology Panel for Lymphoma Clinical Studies undertook a collaborative study with the hope of resolving some of the controversies regarding the criteria and methods for the subclassification of follicular lymphomas (FLs). A group of 105 patients with FL were subclassified by seven hematopathologists according to two methods. In the first method, cases were subclassified according to the Rappaport, Lukes and Collins, and Working Formulation systems. In each of these systems, FLs are subclassified by estimation of the different cell populations, without actual counting of cells. In the second method, precise counts of different cells were made according to the standard and modified Berard methods. With this counting method, diagnoses were independently derived, based on counts provided by the seven pathologists, for large cleaved (LC), small noncleaved (SNC), and large noncleaved (LNC) cells. To ascertain what method and which criteria are most useful in predicting survival, we made clinicopathologic correlations. When the subjective (first method) diagnoses were rendered, and when the consensus diagnoses of the seven pathologists were used, there were no significant differences in survival among patients with the different subtypes. On the other hand, when we used the counting method of Berard (second method) and the cut-off points for the cell counts suggested by him for the subclassification, we were able to divide the patient population into prognostic subgroups. Because the cut-off points proposed by Berard are not derived objectively, we made statistical comparisons of survival curves to determine cut-off points (and thus to establish objective criteria). We found that the patient population could be separated into at least two prognostic groups, for SNC and/or LNC and for SNC + LNC + LC cells. The cut-off points which we derived differed with cell type, however. Until the usefulness of these new cut-off points is established, we recommend that the cut-off points and the counting method of Berard be used for the subclassification of FL. Because the choice of treatment for the different subtypes of FL is totally dependent on the histologic diagnosis, and because of the variability among the diagnoses of pathologists, treatment planning is difficult.

Myocarditis and Endomyocardial Biopsy

There is little correlation between the clinical and the biopsy tissue diagnoses of myocarditis, and both are prone to false-positive and false-negative interpretations. Perhaps the most common error that leads to a false-positive clinical diagnosis of myocarditis is the preconceived but unproved notion that unexplained heart failure of sudden onset or rapid progression must be due to myocarditis. Therefore, most clinical diagnoses of myocarditis are presumptive and are never proved "beyond all reasonable doubt." False-negative clinical diagnoses may occur in patients with myocarditis in whom signs and symptoms are atypical or absent. The two most common sources of error that result in a false-positive biopsy tissue diagnosis of myocarditis are a failure to recognize how many lymphocytes normally occupy the myocardial interstitium and a misinterpretation of noninflammatory interstitial cells as lymphocytes. Sampling error may be the most common cause of false-negative tissue diagnoses in patients with myocarditis. Myocarditis is characterized histologically by an inflammatory infiltrate and by injury to myocardial cells that is not typical of infarction. Healing may occur by resolution or fibrosis. I believe that quantitative evidence of an interstitial leukocytic infiltrate is currently the best histopathologic criterion for the diagnosis of myocarditis in biopsy tissue. In the setting of clinically suspected myocarditis, the tissue diagnosis of myocarditis in a patient's first biopsy should be designated as present, borderline, or absent. In subsequent biopsies, the myocarditis should be evaluated in a temporal as well as a qualitative or quantitative sense and designated as ongoing, resolving, or resolved. The nature of the inflammatory infiltrate and the extent of fibrosis should also be stated in all such biopsies. The pathologist should render an evaluation that is as accurate and unbiased as possible, since patients with a tissue diagnosis of myocarditis often receive immunosuppressive therapy that may have associated morbidity or even mortality.

Carcinoids: the association of histologic growth pattern and survival.

There are five generally accepted carcinoid histologic growth patterns, i.e., insular, trabecular, glandular, undifferentiated, and mixed. To determine their possible prognostic significance, a panel of pathologists studied the growth patterns of 138 carcinoids collected from an Eastern Cooperative Oncology Group carcinoid advanced stage disease chemotherapy investigation. Survival times were measured from date of initial pathologic diagnosis of carcinoid disease to date of either death or last follow-up. Significant differences were observed in survival times between the five major growth patterns (P less than 0.001). Within the mixed growth pattern group, significant differences in survival time were also observed (P approximately 0.05). In decreasing order of median survival time in years, the growth patterns ranked as follows: mixed insular plus glandular, 4.4; insular, 2.9; trabecular, 2.5; mixed insular plus trabecular, 2.3; three pooled low incidence rate mixed growth patterns, 1.4; glandular, 0.9; and undifferentiated, 0.5. Histologic growth patterns are recommended as a stratification factor in future studies of this disease.

Exogenous Estrogens and Other Risk Factors for Breast Cancer in Women With Benign Breast Diseases<xref ref-type="fn" rid="fn2">2</xref><xref ref-type="fn" rid="fn3">3</xref>

A group of 1,439 white women who were initially treated for biopsy-proved benign breast diseases from 1942 to 1975 in a single private surgery practice were followed through 1976 for development of breast cancer. Information on age, parity, and use of noncontraceptive estrogens was collected on all women at the time of their initial benign lesions. At follow-up, ages at menarche, menopause, and birth of first child were obtained, as was information on use of estrogens after the initial lesion. Slides from the initial lesion were reinterpreted and classified by a panel of pathologists. The influence of gross and microscopic features of the initial benign conditions on subsequent risk of breast cancer was ascertained and reported previously. This paper presents results of additional analyses based largely on Cox's proportional hazards model. Risk of breast cancer was related to nulliparity and ages at menarche and birth of first child and to a lesser extent to age at artificial menopause. Exogenous estrogen taken prior to the initial benign lesion did not alter risk of breast cancer. Subsequent use, primarily of conjugated estrogens, eliminated the protective effect of an artificial menopause and appeared to act synergistically with epithelial hyperplasia or papillomatosis in the initial lesion and calcification of that lesion to increase the risk of breast cancer. A marked increase in risk of breast cancer in succeeding birth cohorts was unexpectedly found that could not be explained by temporal changes in any of the other risk factors considered.

Pathology Panel for Lymphoma Clinical Studies: A Comprehensive Analysis of Cases Accumulated Since Its Inception<xref ref-type="fn" rid="FN2">2</xref>

Pathology Panel for Lymphoma Clinical Studies: A Comprehensive Analysis of Cases Accumulated Since Its Inception<xref ref-type="fn" rid="FN2">2</xref>

Arsenic exposure in a copper smelter as related to histological type of lung cancer.

Tissue samples from lung cancer patients who had worked at a copper smelter and from controls were collected and classified by a panel of pathologists: 38% of the cancers were found to be adenocarcinomas, compared to 12% among the controls, a statistically significant difference (p less than 0.05). The predominance of adenocarcinomas was associated with arsenic exposure. This finding is not consistent with Kreyberg's hypothesis that small-cell undifferentiated and epidermoid carcinomas are the only type that increase in response to inhaled carcinogens [1962].

The evolution of the British National Lymphoma Investigation (report no 5)

This report reviews the evolution of the British National Lymphoma Investigation since its inception in 1970. With the collaboration of colleagues from 35 centres, pathological material from more than 4500 patients has been referred to the Pathology Panel and almost 3000 cases have been included in a number of prospective trials of treatment methods in Hodgkin's disease and the non-Hodgkin's lymphomas. Reference is made to general principles adhered to by the group and to the collection of clinical and pathological material by which these studies have been made possible. This report reviews the evolution of the British National Lymphoma Investigation since its inception in 1970. With the collaboration of colleagues from 35 centres, pathological material from more than 4500 patients has been referred to the Pathology Panel and almost 3000 cases have been included in a number of prospective trials of treatment methods in Hodgkin's disease and the non-Hodgkin's lymphomas. Reference is made to general principles adhered to by the group and to the collection of clinical and pathological material by which these studies have been made possible.

Difficulties encountered in the application of Clark classification and the Breslow thickness measurement in cutaneous malignant melanoma.

The purpose of this study was to analyse the reproducibility of Clark's classification and Breslow's measure of tumor thickness to determine if there is general agreement among pathologists regarding these parameters and whether these pathologists reach consistent conclusions concerning each slide. Three successive workshops including a panel of pathologists were held at Amsterdam, in May 1977; at Villejuif in June 1977, followed by circulation of slides and at Villejuif again, in June 1978, followed by slide projection. This was necessary because of the great divergencies of opinion noted at the first meeting at Amsterdam. These sessions gave a better understanding of the divergencies and finally indicated that general agreement could only be reached by slide presentation followed by discussion. Regarding histogenesis, agreement between pathologists was improved after discussion from 6/11 cases to 11/13 cases. Regarding the level, no initial agreement was reached (Amsterdam). At the second meeting an agreement was obtained in 4/13 cases and finally in 11/13 cases (Villejuif). Clark's classification is more difficult to use than Breslow's because it depends on a discontinuous variable, the choice of the infiltration level. Breslow's classification, on the other hand, is based on a continuous variable. Because of frequent discrepancies, the classification of patients into various therapeutic groups according to Clark's level and Breslow's thickness necessitates that all cases including in therapeutic trials be reviewed by a panel of pathologists.

Angiosarcoma of the liver: a marker tumour for the late effects of Thorotrast in Great Britain.

Monitoring the incidence of angiosarcoma of the liver (ASL) between 1974 and 1977 has led to the confirmation by a panel of pathologists of 7 new cases of ASL in patients who had received intra-arterial Thorotrast for radiological investigations. A cluster of cases has appeared in and around Edinburgh where the use of Thorotrast was pioneered in Britain in 1933-48, and a mortality study of 113 Edinburgg patients has confirmed a significant excess of liver-tumour deaths in recent years. Deaths from cancers of the lung and breast, and from hepatic cirrhosis, were also in excess, but the limitations of the death-certificate data are described in relation to the clinical and pathological findings. Thorotrast was also used in other centres, and an increased incidence in Britain of liver tumours attributable to this agent is indicated.