Melanoma predilection for the lower limbs of women compared with men.

The lower limb is a common site for melanoma in women, but the reason for this is not fully understood. To investigate this phenomenon in more detail, we assessed the specific subsites of primary melanoma occurring on the lower limbs of females compared with males across age groups. In a records-based study at an oncology hospital in north-west of England, among an unselected sample of patients with primary invasive melanoma treated between 2002-2015, information was collected on patient age at diagnosis, sex, and co-morbidities, and the tumor thickness and anatomical subsite (thigh, lower leg, foot for lower limb). Of a total sample of 1,522 patients, 316 (227, 72% female) had lower limb melanoma. The most common subsite was lower leg (142 cases with F:M ratio =3.74), followed by thigh (55 cases with F:M = 1.83) and feet (30 cases with F:M = 1.15). At ages <40 years the odds of thigh to foot melanoma was 20 times higher in females than in males (OR 20.0, 95% CI 2.6-152.6) and 7.5 times higher on the lower limb (OR 7.5, 95% CI 1.1-49.2). For ages 40+ years, the odds of females developing thigh melanoma compared to foot melanoma was similar in males versus females (OR 0.8), while the corresponding odds of lower leg melanoma in females versus males remained significantly increased at ages 40-59 and 60+ (OR 4.2 and 2.8 respectively). Our study demonstrates the female predilection for lower limb melanoma persists over most but not all subsites.However, there is heterogeneity in the female to male occurence of lower limb melanoma across subsites and at different ages, which may be linked to relative influence of genetic and environmental risk factors.

Effect of dietary vitamin E on dimethylhydrazine-induced colonic tumors in mice.

This study investigates the effect of variations in dietary vitamin E on the incidence of dimethylhydrazine-induced colonic tumors in mice. Two groups of 65 LACA mice were given 28 weekly s.c. injections of dimethylhydrazine. The only difference in the management of the two groups was the dietary content of vitamin E; one group received 10 mg/kg, and the other group received 600 mg/kg. Of these two groups, 42 and 51 mice, respectively, survived, and there were significantly more adenomas, more adenomas with pleomorphic cytology, and more invasive carcinomas in the group receiving a low vitamin E supplement to their diet. It is suggested that vitamin E may have some part to play in the multifactorial effect of diet on colorectal carcinogenesis.

Protective effect of oral Salmonella enteritidis 11RX infection against colon tumor induction by 1,2-dimethylhydrazine in mice.

Infection of mice with Salmonella enteritidis 11RX has been shown previously to cause nonspecific immune stimulation and, consequently, resistance to subsequent challenge with a variety of transplantable tumors. The present study has examined the effect of infection with this organism in a chemical carcinogenesis system. Colonic tumors were induced in LACA and BALB/c x C57BL/6JF1 mice by weekly s.c. injection of 1,2-dimethylhydrazine (15 mg/kg) for 28 weeks. Infection of mice p.o. with live S. enteritidis 11RX at 8-week intervals during 1,2-dimethylhydrazine administration protected both strains against colon tumorigenesis. Significantly fewer infected than control BALB/c x C57BL/6JF1 mice had colonic tumors at or before termination of the experiment (34 or 40 weeks) (p less than 0.001 in all cases). Comparable results were obtained with both male and female mice. The difference in tumor incidence between control and infected LACA mice was not statistically significant, however; the number and size of the lesions was greater in control mice (p less than 0.02). Although it has not been proven that the protective effect is mediated by the immune system, the results are consistent with the operation of a macrophage-mediated surveillance system. It is suggested that enteric infections should be considered as a possible contributing factor in the epidemiology of human colonic cancer.

A case-control study of diet and benign proliferative epithelial disorders of the breast.

Benign proliferative epithelial disorders (BPED) of the breast are conditions which, although not proven precursors of breast cancer, are strongly associated with increased risk of this disease. In a case-control study conducted in Adelaide, South Australia, we investigated the association between dietary factors and risk of BPED. The study involved 383 cases of biopsy-confirmed BPED, 192 controls whose biopsy did not show epithelial proliferation, and 383 unbiopsied community controls matched to cases on age and area of residence. When cases were compared with community controls, there was little variation in the risk of BPED across levels of daily intake of energy, protein, and fat, but there was some suggestion of inverse associations with daily intake of retinol, beta-carotene, and fiber; in contrast, with biopsy controls as the comparison group, risk of BPED increased with increasing energy and fat intake but varied little with retinol, beta-carotene, and fiber intake. The results of this study provide additional evidence against roles for dietary energy and fat intake in the etiology of breast cancer. However, further studies of diet and BPED should be conducted in populations surveyed cross-sectionally for breast changes, in an attempt to limit or avoid the selection and misclassification biases to which studies of putative precursor lesions are susceptible.

The microanatomic location of metastatic melanoma in sentinel lymph nodes predicts nonsentinel lymph node involvement.

PURPOSE: Sentinel node biopsy is now widely accepted as the most accurate prognostic indicator in melanoma, and is important in guiding management of patients with clinical stage I or II disease. Patients with a positive sentinel node have conventionally undergone completion lymphadenectomy (CLND) of the involved basin, but only 20% have involvement beyond the sentinel node, suggesting that CLND may be unnecessary for the other 80% of patients. This study seeks to identify criteria that might be used to be more restrictive in selecting those who should undergo CLND. METHODS: A total of 146 patients were identified who had had a positive sentinel node biopsy for malignant melanoma. Their sentinel nodes and lymphadenectomy specimens were re-evaluated pathologically. The metastatic melanoma in each sentinel node was assessed according to its microanatomic location within the node (subcapsular, combined subcapsular and parenchymal, parenchymal, multifocal, or extensive), and this was correlated with the presence of involved nonsentinel nodes in the CLND. The depth of the metastases from the sentinel node capsule was also recorded. RESULTS: The metastatic deposits in the sentinel node were subcapsular in 26.0% of patients. None of these patients had any nonsentinel nodes involved on CLND. In the patients whose sentinel node metastases had a different microanatomic location, the rate of nonsentinel node involvement was 22.2% overall. CONCLUSION: The microanatomic location of metastases within sentinel nodes predicts nonsentinel lymph node involvement. In patients with only subcapsular deposits in the sentinel node, it is possible that CLND could safely be avoided.

Interobserver reproducibility of ulceration assessment in primary cutaneous melanomas.

In the recently revised melanoma staging system proposed by the American Joint Committee on Cancer (AJCC), ulceration assessment by the pathologist is a pivotal parameter. Patients upstaged because of ulceration might be included in adjuvant trials conducted in AJCC stage II melanoma patients. Therefore, accuracy based on interobserver reproducibility for melanoma ulceration assessment is crucial for proper clinical management. In some cases, it is extremely difficult, even for an experienced pathologist, to distinguish between trauma-induced ulceration, artifact and tumoral ulceration. Whether this difficulty may be resolved by the use of a more precise definition of ulceration has not been evaluated. Therefore, we have proposed a refined definition of melanoma ulceration and we tested whether this definition might improve the interobserver interpretative reproducibility of ulceration in primary cutaneous melanomas. The results of this study support the need for a more precise definition of melanoma ulceration that rules out biopsy trauma or processing artifact and could be incorporated into a standardised pathology worksheet for reporting primary melanomas.

Lymphatics in primary cutaneous melanoma.

Using Ulex europaeus I lectin (UEA1) to demonstrate endothelial cells, we have previously shown that frequency of capillary invasion correlates closely with maximum tumor thickness in primary cutaneous melanoma. UEA1 demonstrates both vascular and lymphatic capillaries; however, only vascular capillaries possess basement membranes. In order to ascertain whether these capillaries were lymphatic or vascular, we employed a double staining technique, using UEA1 in conjunction with a monoclonal anti-type IV collagen antibody. We studied 21 primary cutaneous melanomas. Seven of the 21 included lymphatic capillaries, while 14 did not. These lymphatic capillaries were very sparse and appeared to be residual dermal lymphatics rather than a result of lymphangiogenesis. Lymphatic permeation by melanoma was not seen in any of the tumors studied. There was no apparent association among tumor thickness, level of invasion, growth phase, necrosis, regression or mitotic index, and presence of lymphatics within the melanomas. Although scanty lymphatics are present in some primary cutaneous melanomas, this study does not suggest that lymphatic permeation plays a major role in the spread of melanoma to locoregional lymph nodes.

Vascular invasion in malignant melanomas. An independent prognostic variable?

The role of vascular invasion as a prognostic indicator in melanoma has not been fully evaluated, mainly due to difficulty in differentiating between capillaries and artefactual spaces caused by shrinkage in routine histological sections. However, immunohistochemical staining using Ulex europaeus I (UEA-I) permits accurate identification of tumor capillaries, thus facilitating recognition of vascular invasion. Sixty-six primary cutaneous melanomas were included in this study. Sections of each case were stained with UEA-I; then, vascular invasion at the level of the tumor capillary bed was sought. Hematoxylin-and-eosin-stained sections were reviewed; the thickness of each lesion was measured and the level of invasion and the growth phase of the tumors were also assessed. The frequency of vascular invasion was found to increase with increasing tumor thickness and with increasing level of invasion. Vascular invasion was seen in only one of 29 horizontal growth phase melanomas, whereas it was identified in 28 of 37 vertical growth phase tumors. Although these results would seem to indicate that vascular invasion within melanomas is unlikely to be an independent prognostic variable, they may partly explain the deteriorating prognosis associated with increasing tumor thickness. They also lend support to the concept of "horizontal" and "vertical" growth phase in melanoma.

Repeatability of interview-derived socio-demographic and medical information.

In this report, the repeatability of socio-demographic and medical information elicited by means of an interviewer-administered questionnaire is examined. One hundred and seven women who were controls in case-control studies of breast disease were re-interviewed approximately one year after initial interview. Both interviews addressed the same time period, namely that which preceded the first interview. For most of the quantitative variables studied, at least 70% of individuals provided two estimates (original and repeat) which were within one unit of each other. Also, comparison of the categorization of individuals on repeated measurements of qualitative variables (reports of events, operations and habits) revealed that most individuals were categorized consistently. This strong agreement between the original and repeat estimates was also reflected in the relatively high values of the summary measures of agreement (the intraclass correlation coefficient for quantitative variables and the Kappa statistic for qualitative variables) for most of the variables studied. The results of the present study on repeatability complement the results of previous research into the criterion validity of questionnaire-derived information and, taken together, suggest that information of relatively high quality may be obtained from such sources.

Methylxanthines and benign proliferative epithelial disorders of the breast in women.

The relationship between methylxanthine intake (caffeine, theobromine and theophylline) and risk of benign proliferative epithelial disorders (BPED) of the breast was examined in a case-control study conducted in Adelaide, South Australia. The study involved 383 cases with biopsy-confirmed BPED, 192 controls whose biopsy did not show epithelial proliferation, and 383 unbiopsied community controls individually matched to cases on age and area of residence. Overall, there was relatively little variation in risk of BPED with total methylxanthine intake, or with intake of caffeine or theophylline, while there was a positive association between theobromine intake and risk of BPED, but only when cases were compared with biopsy controls. Total methylxanthine intake was positively associated with risk of BPED showing severe atypia, but the trend in risk was statistically significant only when community controls formed the comparison group. These data do not provide strong support for an association between methylxanthine intake and risk of BPED.

An assessment of the operation of an external quality assessment (EQA) scheme in histopathology in the South Thames (West) region: 1995-1998.

AIMS: To describe the design and organisation of a voluntary regional external quality assessment (EQA) scheme in histopathology, and to record the results obtained over a three year period. METHODS: A protocol is presented in which circulation of EQA slides alternated with teaching sessions. Procedures for the choice of suitable cases, evaluation of submitted diagnoses, and feedback of results to participants are described. The use of teaching sessions, complementary to the slide circulations, and dealing with current diagnostic problems is also outlined. RESULTS: Participation rates in the nine slide circulations varied between 66% and 89%, mean 85%. Overall scores were predictably high but 4% of returns, from 10 pathologists, were unsatisfactory. These low scores were typically isolated or intermittent and none of the participants fulfilled agreed criteria for chronic poor performers. CONCLUSIONS: This scheme has been well supported and overall performances have been satisfactory. The design was sufficiently discriminatory to reveal a few low scores which are analysed in detail. Prompt feedback of results to participants with identification of all "incomplete" and "wrong" diagnoses is essential. Involvement of local histopathologists in designing, running, and monitoring such schemes is important.

Oat-cell carcinoma of the oesophagus: a recently recognized entity.

A primary oat-cell carcinoma of the oesophagus is described with an adjacent squamous carcinoma, both parts having characteristic ultrastructure. The origin of this mixed tumour is discussed together with the literature on oesophageal carcinomas having an oat-cell pattern.

A comparison of large block macrosectioning and conventional techniques in breast pathology.

Two techniques for the histological handling of breast specimens, namely conventional sampling using small blocks (SB) and a large block (LB) macrosectioning technique have been compared, with special emphasis on tumour size and in situ carcinoma, in an attempt to objectively demonstrate the advantages of the latter method. This is considered to be of particular importance in guiding the clinicians in their use of the many treatment modalities available for breast carcinoma. All cases were from the routine surgical caseload; 100 examined by the LB technique and 111 using conventional SB. The LB technique gave a reliable measurement of invasive carcinoma in 100% of cases compared to only 63% of SB cases. Ductal carcinoma in situ (DCIS), was found more frequently (80% versus 64%) and its extent was more easily and reliably measured in the large blocks. The extent of DCIS was significantly greater in all cases using large block techniques. Concurrent carcinomas were found more frequently in the LB series and these tumours were smaller than those in the SB series. Similar differences were noted with radial scars, and other proliferative lesions also had a higher incidence in the LB series. We conclude that the LB technique has sufficient advantages to recommend it as a standard technique in breast pathology.

Features of sentinel lymph nodes for melanoma may lead to re-diagnosis of the cutaneous primary: an unusual case and review of literature.

Although sentinel lymph-node biopsy is accepted as a reliable method of staging of melanoma, it is not without problems to the pathologist. It has been re-emphasised that aggregates of benign naevus cells are not uncommon. Usually these are easily identified by a combination of their benign cytology and location in the fibrous skeleton of lymph nodes. This case represents a combination of an unusual pseudo-malignant pattern in the primary lesion with unusual morphology of the sentinel lymph node. The latter prompted reassessment of the cutaneous lesion as a benign naevus. Confirmation of the diagnosis as cutaneous melanoma by a positive sentinel-node biopsy was averted only by a careful comparison of unusual features of the putative primary and the sentinel lymph node. This case illustrates the need for a rigorous protocol for pathological assessment of sentinel lymph nodes for melanomas to assure detection of all metastases but also to avoid misdiagnosis and over-treatment. It also supports "benign metastases" as the mechanism underlying at least some melanocytes in regional lymph nodes.

A method for deriving normal ranges from laboratory specimens applied to uric acid in males.

Plasma specimens from male blood donors gave a normal range for uric acid concentration of 3.3 to 7.5 mg/100 ml. Specimens from male outpatients, which were received in the laboratory for the analysis of urea but not of uric acid and proved to have normal concentrations of urea, showed a positively skewed distribution of values for uric acid from which a ;normal range' of 3.2 to 7.6 mg/100 ml was derived. We suggest that specimens from outpatients selected in the way described here may prove to be a convenient source of data for determining the normal range of other substances.

Relation between stage, grade, proliferation, and expression of p53 and CD44 in adenomas and carcinomas of the colorectum.

AIMS: To investigate the changes in and relations among p53, CD44 and MIB-1 expression in adenocarcinomas of the colorectum and to determine whether these changes are progressive across the adenoma-carcinoma sequence. METHODS: Expression of p53 protein, CD44 adhesion molecule and MIB-1 proliferation antigen was detected using immunohistochemistry in 68 colorectal carcinomas and 32 colorectal adenoma. The staining characteristics were compared with degree of dysplasia in adenomas, and differentiation and Dukes' stage in carcinomas. Results were analysed and assessed using Spearman's rank correlation and independent t tests. RESULTS: p53 staining was present in som adenomas and correlated with the degree of dysplasia. There was significantly more staining in carcinomas than adenomas and significant correlation between staining and Dukes' stage. CD44 staining was maximal in adenomas, diminished in carcinomas and was minimal in metastasising carcinomas. There was inverse correlation between p53 and CD44 expression across the adenoma-carcinoma-metastasising carcinoma sequence. MIB-1 expression was highest in carcinomas but did not correlate with either p53 or CD44 expression. CONCLUSIONS: There are progressive changes in p53, CD44 and MIB-1 expression in adenomas and carcinomas. A combination of these tests may prove useful in assessing which patients with adenomas are at greatest risk of progressing to carcinoma.

Cigarette smoking and benign proliferative epithelial disorders of the breast in women: a case-control study.

STUDY OBJECTIVE: The purpose of the study was to investigate the possible association between cigarette smoking and benign proliferative epithelial disorders of the breast. DESIGN: This was a case-control study with two different control groups. SETTING: The study was community based and took place in metropolitan Adelaide, South Australia. SUBJECTS: 506 biopsy proven cases between 18 and 75 years were identified, of whom 39 could not be approached because of surgeon refusal, 66 would not be interviewed and 18 were untraceable, leaving 383 for inclusion in the study. Controls were 192 women who had had a negative breast biopsy, out of a possible 259 (17 surgeon refusals, 39 interview refusals, 11 untraceable); and a randomly selected group of women matched to the index group for age and area of residence (582 subjects were approached to enrol 383 controls). MEASUREMENTS AND MAIN RESULTS: All breast biopsies were examined by one pathologist and classified using a standard system. Sociodemographic and medical information was collected by trained interviewers using structured questionnaires. Overall, and within menopausal strata, risk of benign proliferative epithelial disease for women who had ever smoked and for current and ex-smokers was similar to that for women who had never smoked. In premenopausal women, using community controls as the comparison group, risk decreased with cigarette-years of exposure, but the trend was not statistically significant. Risk appeared to increase when biopsy controls were used. There was no trend in the association when examined by degree of cytological atypia. CONCLUSIONS: The data suggest that cigarette smoking is not related to the risk of benign proliferative epithelial breast disease.

Benign breast disease: the relationship between its histological features and risk factors for breast cancer.

Associations between histologically defined proliferative, but benign, epithelial disorders of the breast and risk factors for breast carcinoma were examined in 568 patients whose breast biopsies were submitted consecutively to the laboratory. Some disorders were associated with multiparity. Blunt duct adenosis was associated with a family history of breast cancer. Apart from a positive association with fibroadenoma, use of oral contraceptives was not associated with any proliferative lesion. Proliferative epithelial lesion changes were not associated with other aspects of obstetric or gynecological history.

Malignant Schwannoma of cranial nerves.

The clinical presentation and histopathological features of 5 cases of malignant Schwannoma of cranial nerves are described. The ultrastructural appearances of one case and the pattern of nerve sheath cell differentiation of these tumours are also discussed. These uncommon tumours often are not diagnosed at initial presentation. Since the cases provide evidence that early diagnosis and surgical treatment are vital in the management of patients with this tumour criteria for its diagnosis are suggested.

Neoplastic cells containing lysozyme in gastric carcinomas.

A case of gastric carcinoma mostly composed of cells with histological, immunohistochemical and ultrastructural features of Paneth cells prompted a comparative investigation of the occurrence of similar cells in gastric, colorectal and mammary carcinomas. Cells containing lysozyme were demonstrated by the immunoperoxidase-PAP technique in 34.9% of 83 gastric carcinomas. They were found in 38% of intestinal-type and in 30% of diffuse-type tumours. Paneth-type granules were demonstrated ultrastructurally in 4 of 7 carcinomas in which lysozyme had been demonstrated immunohistochemically. No lysozyme was demonstrated in a series of 30 breast carcinomas and in only 1 of 27 cases of colorectal neoplasm. The possibility of using lysozyme as a marker for some carcinomas of gastric origin is considered.