'Tumour volume' as a predictor of survival after resection of non-small-cell lung cancer (NSCLC)

Many factors have been individually related to outcome in populations of non-small-cell lung cancer (NSCLC) patients. Factors responsible for the outcome of an individual after surgical resection are poorly understood. We have examined the importance of 'tumour volume' in determining prognosis of patients following resection of NSCLC in a multivariate model. Cox's proportional hazard analysis was used to determine the relative prognostic significance of stage, patient age, gender, tumour cell-type, nodal score and estimated 'tumour volume' in 669 cases with NSCLC treated with surgical resection, of which 280 had died. All factors (except tumour cell-type, P = 0.33) were individually related to survival (P < 0.05). When examined together, survival time was significantly and independently related to 'tumour volume' and stage (P < 0.001), and other factors ceased to be significant. In cases with stage I or II tumours, risk of death was found to increase significantly with increasing estimated 'tumour volume' (23.8% relative increase in hazard to death per doubling of 'tumour volume', 95% confidence interval 13.2-35.2%, P < 0.001 stage I; P < 0.006 stage II). In cases with stage IIIa tumours this factor alone was the significant prognostic variable. In conclusion, an estimate of 'tumour volume' significantly improves prediction of prognosis for individual NSCLC patients with UICC stage I or II tumours.

Expression of markers of differentiation in normal bronchial epithelium and bronchial dysplasia.

Bronchial epithelial dysplasia is a non-invasive cellular change often associated with physical or chemical injury and considered a pre-neoplastic lesion in the formation of lung cancer. A series of 39 bronchial dysplasias associated with both neoplastic and non-neoplastic lesions were assessed for expression of markers of differentiation by immunocytochemistry and compared with samples of normal bronchial epithelium. The normal bronchial epithelium studied expressed cytokeratins (CKs) 4, 6, 7, 8, 18, and 19 in all cases; CK 13 in 13 cases; and peanut agglutinin (PNA) in seven cases. Involucrin, CK 10, and CK 14 were not observed in the normal bronchial samples. In the dysplastic bronchial biopsies, epithelial staining was observed with epithelial CKs 7, 8, 18, and 19 in all cases; CK 13 was seen in 26 cases; CK 14 in 13 cases; CK 6 in 11 cases; and CK 10 in five cases. In 13 cases of dysplasia, only simple epithelial antigens were identified. Involucrin expression was observed in 17 dysplastic biopsies and PNA in 12. By Fisher's exact test, a significant association between non-severe histological grade of dysplasia and CK 6 expression (P = 0.018) was found. Comparison of the results using the same analysis showed significant correlations between the loss of CK 6 expression (P < 0.001) and the expression of CK 14 (P = 0.008) and involucrin (P = 0.0018) with bronchial dysplasia. These data show that the pattern of differentiation antigen expression in bronchial dysplasia is significantly different from that of the normal bronchial epithelium, but the phenotypic heterogeneity of these lesions is similar to that of bronchial carcinomas.

Correlates of tumor size, gender, cell type, and metastasis of resected non-small cell lung cancer and age.

The purpose of this retrospective study was to examine the relationship between tumor volume and age in resected non-small cell lung cancer (NSCLC). Differences exist in the behavior, growth rate, and metastatic potential of solid tumors in both aged humans and experimental animal models. Data from 669 cases of NSCLC resected between 1980 and 1992 were reviewed (445 males; 224 females; median age 67 years, range 16-86). Measurements of the resected tumor in-situ were made in three dimensions, and these were multiplied to give an estimate of the tumor volume. Multiple regression analysis was used to examine the relationship between the tumor volume, age, gender, histological cell type, and TNM nodal score. No direct relationship existed between patient age and tumor volume or nodal score. However, there was a significant relationship between patient gender and tumor volume, i.e., smaller volume tumors in female patients (p = .02). Considering all variables, two relational subgroups were identified: younger male patients with large adenocarcinomas and older female patients with small squamous cell carcinomas (p = .05). We conclude that the relationship between tumor volume and age is complex and dependent on patient gender and tumor cell type.

p53 expression in normal and dysplastic bronchial epithelium and in lung carcinomas.

Bronchial epithelial dysplasia is thought to be a premalignant stage in the evolution of lung cancers. Using the CM-1 polyclonal antibody, we have examined the expression of the p53 protein in a larger series of bronchial dysplasias (n = 60) than hitherto investigated. The p53 protein was detected in 14% of mild, 25% of moderate and 59% of severe dysplasias; increased p53 expression correlated with the severity of dysplasia. p53-positive dysplasias had greater PCNA indices than p53-negative dysplasias. p53 expression in dysplastic tissues was compared with that in two groups of histologically normal epithelium: 14 bronchial biopsies from non-cancer patients of which all but one were negative and 32 bronchial margins from resected carcinomas, of which 17 showed infrequent solitary cells with p53-positive nuclei in predominantly basal locations scattered throughout the epithelium. These results for resection margins were confirmed by use of a second antibody, DO-1. Sixty-nine per cent of the corresponding carcinomas were p53 positive, but in 15 cases the p53 reactivity differed from resection margins. No correlation between p53 expression and any of the clinicopathological characteristics of these tumours was found. This study supports the observation that abnormal p53 expression may be an early but not obligatory event in malignant transformation in lung.

Early experience of directional coronary atherectomy: clinical results, complications and histopathological findings.

OBJECTIVE: To report the early experience, clinical results and histopathologic findings of Directional Coronary Atherectomy from a UK centre experienced in coronary angioplasty. DESIGN: Prospective study of the first 45 Directional Coronary Atherectomy (DCA) procedures using the Simpson coronary atherectomy device. RESULTS: Forty-five procedures were performed in 33 male and 5 female patients (mean age, 55.1 years). Directional Coronary Atherectomy was performed to 50 lesions (39 de novo, 11 restenosis; 44 left anterior descending, 3 right, 2 circumflex coronary arteries and 1 saphenous vein graft). Clinical and primary angiographic success was achieved in 43 of 45 cases (95.5%) and in 47 of 50 lesions (94%) after DCA alone. Before DCA the mean diameter stenosis was 88.7% (range, 50-100%) but following DCA (and percutaneous coronary angioplasty (PTCA) if necessary) the mean diameter stenosis was 3.5% (range, 0-15%; P < 0.001). Complications included occlusive dissection requiring coronary artery bypass surgery in two patients; abrupt closure of right coronary artery in one patient successfully reopened by PTCA and thrombolysis, complicated by excessive blood loss; reversible coronary artery spasm due to minor nose-cone trauma in four patients and temporary side branch loss in one patient. There were no coronary artery perforations, guide catheter complications, peripheral vascular trauma or deaths. On average 5.6 specimens (range, 1-18) were removed per case. Histology showed fibrous intimal plaque in 98%, media in 39% and adventitia in 7%. Neo-intimal hyperplasia was found in all restenosis lesions but also in 30% of de novo lesions. CONCLUSIONS: This small initial series indicates that directional coronary atherectomy is an effective and safe procedure for the treatment of obstructive coronary artery disease in carefully selected patients. With care, a high success rate can be achieved even during a learning phase. The technique is particularly effective for morphologically complex lesions that are unfavourable for PTCA. The procedure is unlike PTCA and requires additional training if pitfalls are to be avoided, high success rates achieved and complication rates kept low.

Simple cytokeratins in the serum of patients with lung cancer: relationship to cell death.

An important role in differentiation and proliferation has been demonstrated for the 20 cytokeratin (CK) polypeptides. The serum of 24 patients with biopsy-proven non-small cell lung cancer (NSCLC) and a similar number of controls was examined for evidence of CK8 and CK18. Using enzyme-linked immunosorbent assay (ELISA), all the control sera were negative, but 9 of the 24 patients were positive (mean 2.62 ng/ml; range 1.4-5.8; P = 0.0036). Western blotting confirmed the results of the ELISA in all cases, and indicated full size CK polypeptides. Advanced stage disease patients were more likely to be seropositive (P = 0.00024). Biopsy specimens showed CK8 expression in all 24 cases by immunochemistry and CK18 in 22 cases. This is the first study to demonstrate that a subgroup of NSCLC patients have intact CK8 and CK18 peptides in their serum, and their detection may correlate with advanced disease.

Expression of proliferating cell nuclear antigen (PCNA) in dysplasia of the bronchial epithelium.

Proliferating cell nuclear antigen (PCNA) is expressed in cells in the cell cycle and has been studied as a marker of proliferation in lung and other tumours. We have noted immunocytochemical differences in PCNA expression between normal and neoplastic bronchial cells. As bronchial dysplasia is considered preneoplastic, we have examined PCNA expression in this condition. PCNA staining in 47 cases of bronchial dysplasia and 32 samples of normal bronchial epithelium was compared. Of the dysplasias, three were mild, 11 moderate, and 33 severe. A significant increase in PCNA counts over normal epithelium was seen only in moderate and severe dysplasias. In dysplasia, mitotic indices showed a significant positive correlation with the percentage of PCNA-positive cells. We conclude that in moderate and severe dysplasias there is an increase in the number of cells expressing PCNA and undergoing division, indicating abnormal growth control.

Mucosa associated lymphoma of the lung.

Two cases of mucosa associated lymphoma (pseudolymphoma) of the lung are described which highlight the varied clinical and radiological features of this rare pulmonary condition. Following chemotherapy with prednisolone and chlorambucil, both patients are disease free three years later.

Audit in histopathology: description of an internal quality assessment scheme with analysis of preliminary results.

In the first six months of a formal Internal Quality Assessment Scheme operating in the Department of Histopathology, Broadgreen Hospital, Liverpool, 1005 items of data were gathered, relating to 80 cases. The scheme entails a random 2% sample of biopsy specimens being selected, each case being analysed using a structured proforma, and a numerical scoring system being allocated to all aspects of specimen handling. Technical and secretarial performance was good while the quality of clinical information provided by the requesting clinician was poor. There was a wide variation in reporting times, which related partly to the complexity of the specimen, and partly to the degree of supervision required by the reporting pathologist. Month by month analysis of reporting times showed a significant increase in reporting times associated with rotation of junior staff, but not with periods of annual leave. Pathologist performance scores were good, but close examination of components of the overall score for an individual pathologist indicated occasional areas of weakness (such as the adequacy of the macroscopic report). It is concluded that this scheme is worthwhile and its practice will be continued indefinitely. The comprehensive nature of the analysis allows for the formal identification of areas of work which need improvement, and the allocation of a formal numerical score allows improvement in these areas to be monitored. The monthly meetings provide a means whereby performance scores are fed back to the participating pathologists, and they are also of general educational value regarding histological reporting practice. It is intended that the scheme be extended to include the assessment of special stains, frozen sections, and adequacy of the report delivery service. The system is easily adaptable for use within other histopathology departments.

Syringoacanthoma: an acrosyringeal tumour.

Syringoacanthoma is a rare benign appendage tumour derived from the intraepidermal portion of the acrosyringium. We report its occurrence in 3 women. In each case the tumour clinically most resembled a seborrhoeic keratosis. Its importance histopathologically lies in the need to differentiate it from conditions such as malignant melanoma, squamous cell carcinoma, intraepidermal carcinoma, Paget's disease and metastasis, which may all show intraepidermal spread.

Diagnosis of T-cell lymphoma using beta F1, anti-T-cell receptor beta chain antibody.

The reactivity of a new monoclonal antibody to the T-cell beta chain antigen receptor (beta F1) with routinely processed paraffin sections from patients with T-cell lymphoma is described. Staining of tumour cells was seen in 36/47 cases of T-cell lymphoma. No staining was seen in any cases of B-cell lymphoma (0/21 cases), nine of which had previously been shown to react with other T-cell antibodies (MT1/UCHL1). We conclude that beta F1 is a specific marker for demonstrating a T-cell histogenesis of lymphoma and with advantages over other currently available antibodies reactive with paraffin sections.

Paraffin section immunophenotyping of non-Hodgkin's lymphoma, using a panel of monoclonal antibodies.

The monoclonal antibodies F8-11-13, 4KB5, MB1, and MB2 recognize largely B-cell-restricted antigenic determinants that resist routine processing. Similarly, MT1, MT2, and UCHL1 react with fixation-resistant T-cell-restricted antigens. In order to evaluate the diagnostic potential of these antibodies, the authors have assessed their immunoreactivity with a series of 81 formalin-fixed and paraffin-embedded non-Hodgkin's lymphomas (48 B-cell, 33 T-cell) encompassing a wide variety of histologic subtypes, which had been fully characterized by frozen-section immunophenotyping. Ninety-six percent of B-cell lymphomas reacted with one or more of the B-cell-associated antibodies, whereas 100% of T-cell lymphomas reacted either with MT1, UCHL1, or both antibodies. MT2 was of no value in distinguishing between B- and T-cell lymphomas. None of the antibodies was entirely lineage specific; furthermore, a proportion of cases failed to react with one or more of the B- or T-cell-associated antibodies. Although these antibodies provide useful information in distinguishing between T- and B-cell lymphomas, the authors suggest that a panel of these antibodies is necessary for accurate determination of the histogenesis of these tumors. As with any immunohistochemical marker, interpretation of the immunostaining must be in the context of the morphologic features.

T-cell lymphoma: morphology, immunophenotype and clinical features.

The histology, immunophenotype and clinical presentation of 43 cases of T-cell lymphoma are described. Cases were classified into nine types; T-lymphocytic lymphoma (three), mycosis fungoides (six), Sézary syndrome (two), T-zone lymphoma (13), angioimmunoblastic lymphadenopathy (AIL)-like T-cell lymphoma (five), pleomorphic medium cell (one), large cell immunoblastic (four), large cell polylobated (five) and lymphoblastic (four). The patients comprised 26 males and 17 females aged between 15 and 86 years. The majority showed disseminated disease at the time of diagnosis (18 stage IV, nine stage III, five stage II, eight stage I and three cases not staged). Thirty-one patients showed lymph node involvement. Cutaneous involvement was a common finding (18 cases, 10 cases excluding mycosis fungoides and Sézary syndrome). Details of therapy and clinical follow-up were obtained in 37 cases. With simple chemotherapy only one complete response (7%, 1/16) was obtained. With aggressive therapy 48% (13/27) of patients showed complete responses. Twenty patients died during the follow-up period. Life table analysis showed a 58% probability of surviving 1 year and 36% probability of surviving 3 years. There was a significant difference in survival probability between low/intermediate-grade (lymphocytic, Sézary syndrome, mycosis fungoides and T-zone lymphoma including AIL-type) lymphomas and high-grade (large cell immunoblastic and polylobated and lymphoblastic) lymphomas (P less than 0.025). However, when survival of T-zone and AIL-like T-cell lymphoma was compared with survival of large cell immunoblastic and polylobated lymphomas no significant difference was detected. Age (less than 50 years) and stage I or II disease were associated with significantly better survival (P less than 0.005 and P less than 0.05).

Malignant melanoma of penis.

We report a case of malignant melanoma of the penis. Appropriate staging of these rare cancers is discussed in light of current views of the biology of malignant melanoma arising at other skin sites, and the implications of Breslow thickness for management are considered. There is no good evidence in the literature that extirpation of the entire penis offers the only hope of cure for stage I penile melanoma.

Immunohistochemical staining of non-Hodgkin's lymphoma in paraffin sections using the MB1 and MT1 monoclonal antibodies.

We have performed a single blind trial to assess the value of the monoclonal antibodies MB1 and MT1 in lymphoma classification. Sixty cases of non-Hodgkin's lymphoma (NHL) were stained with MB1 and MT1 using an indirect immunoperoxidase technique in paraffin sections. The majority of B tumours (27/33) stained with MB1, and most of the T tumours (24/27) stained with MT1. The MB1 antibody often produced rather weak staining but it was apparently highly specific for B cells, with only three (3/27) of the T tumours (two cases of 'malignant histiocytosis' of the intestine (MHI) and one pleomorphic T-cell lymphoma) displaying 'false' positivity. The MT1 antibody generally produced very strong staining, but it was not very selective, with 14/33 of the B lymphomas displaying 'false' positivity. the cross-reactivity observed in 17 cases led to only three misdiagnoses, two B tumours being designated as T lymphomas and one T tumour being designated as a B lymphoma. In a few cases (7/17), dual staining with both antibodies precluded firm diagnosis. In other cases (6/17), classification was possible despite some of the tumour cells showing dual staining. The seventeenth case was a plasmacytoma displaying MT1 positivity only. While the monoclonal antibodies MB1 and MT1 are of use in classifying lymphomas in paraffin section, they are not entirely lineage-specific, and the uncritical use of these two reagents alone may give rise to misdiagnosis; the use of a panel of monoclonal antibodies may yield more accurate results. As with any immunohistochemical marker, their limitations should be recognized; interpretation must be judicious and always in the context of the histological appearances.

Sweet's syndrome: histological and immunohistochemical study of 15 cases.

Conventional histology and immunoperoxidase staining for fibrin, immunoglobulins, and complement components were used to look for evidence of cutaneous vasculitis and immune complex deposition in Sweet's syndrome. These features were not identified in any of the 15 cases studied. The lack of any vasculitis emphasises the distinctive character of Sweet's syndrome when compared with certain spontaneous and experimentally induced inflammatory skin lesions, and may imply a similarly distinctive pathogenesis.

The role of immunoperoxidase techniques on paraffin embedded tissue in determining the histogenesis of undifferentiated thyroid neoplasms.

Twenty cases of undifferentiated thyroid tumours were reviewed histologically. In seven cases the histogenesis was difficult to determine using morphological criteria. Immunohistochemical staining with a panel of antibodies to lymphoid and epithelial cells, including monoclonal antibodies directed against the leucocyte common antigen, cytokeratin, and epithelial membrane antigen confirmed that four of these cases were lymphomas and that one was a medullary carcinoma. In the remaining two cases immunohistochemistry was unhelpful. In the thirteen histologically typical tumours, the immunohistochemical profile was in keeping with their histogenesis as determined by morphological criteria. Immunohistochemical staining with a panel of selected antibodies allows the reliable diagnosis of undifferentiated thyroid neoplasms, when this cannot be reached using routine histological techniques.