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.

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.

Clostridial mycotic aneurysm of the suprarenal abdominal aorta.

Clostridial mycotic aneurysms are unusual. We therefore record a fatal case of a ruptured clostridial mycotic aneurysm of the suprarenal aorta which developed several weeks after the resection of a segment of gangrenous small bowel.

Accuracy in clinically evaluating pigmented lesions.

OBJECTIVE: To determine the ability of three doctors experienced in managing melanocytic lesions to diagnose correctly melanoma, dysplastic naevi, and various benign pigmented lesions. DESIGN: Independent clinical evaluation and histopathological assessment. SETTING: Pigmented lesion clinic, which patients attend without an appointment for early diagnosis of melanoma. PATIENTS: 86 Patients with lesions that were judged to be benign by at least one of the three doctors. INTERVENTIONS: The lesions were excised under local anaesthesia and sent for histopathological examination in coded bottles without clinical details. MAIN OUTCOME MEASURE: Comparison of clinical with histopathological diagnosis for each lesion. RESULTS: A total of 120 lesions were evaluated by at least two of the three doctors. The histopathological diagnoses were made by the same pathologist. The overall sensitivity (diagnostic accuracy) for the three doctors for all types of lesion was 50%. Of the 39 dysplastic naevi, only 19 were identified correctly by all observers, and a further 24 banal lesions were wrongly diagnosed as dysplastic by at least one doctor. Particular difficulty was experienced with small (less than 5 mm), flat lesions, which can be banal or potentially malignant. CONCLUSIONS: Critical diagnosis and management decisions concerning pigmented lesions should always be based on a combination of clinical and histopathological assessments and the history of the patient.

Vascular volume in B16 allografts and human melanoma xenografts estimated by means of Hoechst 33342.

The vasculature of B16, a murine melanoma and Mel-mo, a human melanoma, was studied using intravital staining of patent capillaries by the fluorescent bisbenzamine dye Hoechst 33342. Capillaries were numerous at the edge of tumours in both the lines studied, but were scarcer within the nodules. Vascular volume as a proportion of total tumour volume was estimated by means of point counting. In both B16 and Mel-mo, the percentage vascular volume was inversely related to log tumour weight. Tumour necrosis, which increased with tumour size, was inversely correlated with percentage vascular volume, emphasizing the central under-perfusion of these experimental tumour nodules. This pattern of perfusion, with greater density of functioning capillaries at the periphery of tumour nodules, was seen in both the tumour lines examined despite differences in the degree and pattern of necrosis.

Blood flow distribution within transplantable tumours in the mouse.

Tumour blood flow was estimated by fractional distribution of rubidium in two allografts (B16 melanoma and Lewis lung tumour) and two xenografts (Glioma 522, a human grade IV astrocytoma and Mel-mo, a human melanoma), in order to investigate the influence of certain tumour characteristics on tumour perfusion. In all four tumours perfusion decreased with increase in tumour weight. The rubidium extraction in Mel-mo was markedly lower than that of the other three tumours; this tumour was the most necrotic. Necrosis was patchy in Glioma 522 and Mel-mo, but predominantly central in B16 and Lewis lung tumour. However, all tumour nodules examined showed a similar pattern of rubidium extraction: high at the rim with a rapid fall towards the centre. It appeared that while overall blood flow may be related to the extent of necrosis, blood flow distribution within tumour nodules did not correlate closely its pattern.

The value of nucleolar organizer region staining in the differential diagnosis of borderline melanocytic lesions.

The technique of silver (Ag) staining of nucleolar organizer region-associated proteins (AgNORs) has been shown to be of value in differentiating between benign and malignant cells. We have studied 33 borderline melanocytic lesions, in which a diagnosis of melanoma had been seriously considered, in order to assess the value of this technique in a commonly encountered diagnostic situation. We found that benign naevus cells possessed single compact or granular AgNORs, whereas some malignant melanocytes possessed large, often loosely arranged groups of AgNORs. However, the pattern of AgNORs observed in melanocytes of some atypical but benign lesions was also seen in some melanomas. The differential diagnosis of borderline melanocytic lesions is not clarified by use of the AgNOR technique.

Pagetoid infiltration in primary cutaneous melanoma.

Pagetoid infiltration of the epidermis by melanocytes, also termed 'buckshot spread', is regarded by some as being essential for the confident histopathological diagnosis of primary cutaneous melanoma. We have reviewed 340 melanomas received over a 23 year period to assess the frequency of pagetoid infiltration and whether its presence bears any relationship with other histopathological features. Conspicuous pagetoid infiltration was present in 32.1% of the lesions and occasional melanocytes were observed within the stratum spinosum in a further 23.5% of cases. However, no melanocytes could be seen above the basal layer in 44.4% of the melanomas. The presence of pagetoid infiltration showed inverse correlation with tumour thickness, level of invasion, growth phase and mitotic count, and positive correlation with the presence and severity of regression. No association was found with the site of the primary lesion, melanocytic dysplasia or lentigo maligna in the adjacent epidermis, or with the presence of residual benign naevus cells in the epidermis. Thus, pagetoid infiltration of the epidermis was commonest in in situ or thin horizontal growth phase melanomas, and was conspicuous in only one-third of cases. While its presence is useful in the diagnosis of melanoma, its absence should not preclude it.

Re-excisions of scar in primary cutaneous melanoma: a histopathological study.

In many centres the wide excision and split-skin grafting remains the standard therapy for primary cutaneous melanoma. One-hundred and thirty-seven primary cutaneous melanomas were seen in our department during a 3-year period; 25 patients were subsequently subjected to re-excision of scar following the initial excision biopsy. Lymphatic permeation, field change in the epidermal melanocytes and micrometastases were sought in the re-excision specimens in order to examine the pathological basis for this therapy. Two of the 25 primary melanomas included in this study were known to have been incompletely excised at the time of initial biopsy and both re-excision specimens included a few nests of atypical melanocytes adjacent to one edge of the biopsy wound. Examination of the re-excision specimens failed to demonstrate evidence of direct lymphatic permeation by melanoma, or of a field change in the epidermal melanocytes adjacent to the melanomas, although five specimens from sun-exposed sites showed slight melanocyte atypia. One re-excision specimen did include a single small group of melanocytes, less than 120 microns in size, in the dermis within 2 mm of the initial excision biopsy site of a melanoma 8.4 mm in thickness. These results support the view that more extensive local therapy than complete excision of primary cutaneous melanoma with a narrow margin of adjacent normal skin, is unlikely to benefit the patient.

The vascularity of primary cutaneous melanoma.

In primary cutaneous malignant melanoma, the vascularity of the dermis immediately deep to the lesion may relate to tumour aggressiveness and to prognosis. These newly formed dermal vessels are incorporated into the melanoma to form the tumour microcirculation. We have assessed the percentage vascular volume in a series of primary melanomas in order to investigate the relationship between tumour vascularity and maximum tumour thickness. For the 64 melanomas included in this study, there appeared to be a significant relationship between the percentage vascular volume and the maximum tumour thickness. This relationship was not influenced by the presence of necrosis, vascular invasion, regression, or lymphocytic infiltrate, nor by the growth phase of the tumour. However, the percentage vascular volume was very low in the occasional thick melanoma, at least one of which was associated with prolonged survival. It seems possible that a low tumour vascularity could correlate with a relatively favourable outcome in cutaneous melanoma.

Dysplastic naevi--an alternative view.

The diagnosis of dysplastic naevus is in danger of falling into disuse in response to the continuing dispute as to its definition. This review tries to show that the lesion can be defined using histological and clinical criteria but that the individual features are not, by themselves, peculiar to dysplastic naevi. They are shared, in varying degrees, by other benign melanocytic naevi and by melanoma. The significance of these similarities is explained on the basis of the maturation of ordinary naevi and degrees of deviation from that common path. The recognition of severely aberrant differentiation in the form of classic dysplastic naevus is worthwhile, since in the appropriate clinical context and particularly in association with a family history of melanoma, it confers a very high risk of developing melanoma.

A non-parametric grading system for intestinal metaplasia: correlations with gastric tissue enzymes.

A novel method for grading intestinal metaplasia, with general applicability, is described. Highly significant agreement was found by kappa analysis both for intra-observer (k = 0.90) and for inter-observer (k = 0.85) variation, confirming the reproducibility of the method. The ranks derived by this method were correlated with gastric tissue levels of the enzymes beta-glucuronidase, lactic dehydrogenase (LDH), and %m-LDH. A significant (P less than 0.05) positive correlation was found between intestinal metaplasia and %m-LDH, but there was no correlation between intestinal metaplasia and beta-glucuronidase or LDH.

Epidermal melanocytes adjacent to melanoma and the field change effect.

The presence of a field change, affecting epidermal melanocytes in the skin surrounding melanomas, has been cited as a justification for performing radical excision of these lesions. Twenty-five consecutive re-excisions of melanoma specimens were examined and melanocytes per 100 keratinocytes counted continuously across the width of each, in order to ascertain whether melanocyte counts decreased from the centre to the periphery, as would be expected if there were a field change effect associated with the tumour. Melanocyte counts did not appear to diminish with increasing distance from the tumour site and were within the range seen in a previous study in which we demonstrated increased numbers of basal melanocytes and melanocyte atypia in sun-exposed skin from a control population. Melanocyte atypia of a mild degree was present in five of the 25 cases studied, but in no case was this greater than that observed in sun-exposed forearm skin. We therefore suggest that the 'field change effect' in epidermal melanocytes adjacent to melanoma could be a result of chronic sun exposure alone.

Nucleolar organizer regions in melanocytic dysplasia and melanoma.

Using silver (Ag) staining to demonstrate nucleolar organizer region-associated proteins (AgNORs), pigmented naevi exhibiting features of melanocytic dysplasia have been examined and compared with benign intradermal and compound naevi and with malignant melanomas. A highly significant difference was found between the numbers of AgNORs demonstrated in benign naevus cells and atypical melanocytes and in malignant melanocytes, suggesting that this technique may have a role in differentiating between difficult melanocytic lesions.

Melanocytic lesions of the palm and sole.

Pigmented lesions of palmar and plantar skin may cause diagnostic problems, partly because they are infrequently excised and also because some features of benign lesions in these sites may raise the suspicion of melanoma if considered alone. We have examined a series of benign melanocytic lesions and compared them with melanomas from these sites. The presence of severe melanocytic atypia was the most valuable feature in distinguishing between naevi and melanomas. Pagetoid infiltration of the epidermis by single atypical cells, or small groups of cells with abundant pale cytoplasm was seen only in melanomas, while transepidermal elimination of well-circumscribed nests was present only in benign lesions. A lymphocytic infiltrate was present in the dermis in 13 of 14 malignant lesions, but only two of the 26 naevi showed a sparse infiltrate: we suggest that the presence of a lymphocytic infiltrate should prompt a careful search for other features of malignancy. Other features examined, including elongation of rete ridges, pattern of melanocyte distribution at the dermo-epidermal junction, dermal sclerosis, and pigment in the stratum corneum or in the dermis, were seen in both naevi and melanomas and were not found to be useful in distinguishing benign from malignant lesions.

Autoimmune blistering diseases associated with HIV infection.

Two cases of autoimmune bullous skin diseases in HIV-positive men are described. One man had bullous pemphigoid limited to his legs and the second man developed pemphigus herpetiformis. The possible association between autoimmune bullous diseases and HIV infection is discussed.

Melanocytic lesions and melanocyte populations in human epidermis.

Basal melanocytes were counted and atypia assessed on an arbitrary scale in punch biopsies from the sun-exposed extensor aspect of the forearm of normal skin and from the covered skin of the buttock of patients with pigmented naevi and control subjects. The difference in melanocyte counts and in the presence of atypia between sun-exposed and covered skin was statistically highly significant. The only other difference was between melanocyte counts in covered skin from those with multiple atypical naevi and all other groups; the counts in the former were greater than those in the latter. No further difference was attributable to sun exposure, skin type or diagnostic group. Some degree of melanocyte atypia was seen in approximately half of the biopsies of sun-exposed skin, but atypia was seen in only six of 84 biopsies of covered skin. In each case atypia was present in the corresponding forearm biopsy and all six subjects had pigmented lesions (four with melanoma and two with multiple atypical naevi). It seems possible that while increased melanocyte counts in covered skin could correlate with the presence of atypical naevi, atypia of covered epidermal melanocytes could possibly relate to melanoma risk.

Aneuploidy in atypical fibroxanthoma: DNA content quantification of 10 cases by image analysis.

It has recently been reported that atypical fibroxanthoma (AFX) is a predominantly diploid lesion in contrast to malignant fibrous hystiocytoma (MFH) which is usually aneuploid. To test this hypothesis, DNA content quantification was undertaken on Feulgen-stained cytology and tissue section preparations from 10 cases of AFX by image analysis. The large atypical cells which characterize AFX were aneuploid in each case. Smaller spindle-shaped cells found in this lesion were diploid. The results suggest that AFX is indistinguishable from MFH by DNA content estimation and highlight an advantage of image analysis over flow cytometry.

Reconstruction after excision of soft tissue sarcomas of the limbs and trunk.

From a retrospective analysis of 180 surgical interventions for soft tissue sarcoma of the limbs and trunk, it was concluded that complete excision of the tumour can usually be achieved without sacrifice of major artery, vein, nerve or bone. In this series five major arteries were resected but only one required reconstruction. None of six resected major veins or seven resected nerves were reconstructed. Bone resection in the limb required plating in only two of eleven patients who had limb-sparing resection (there were nine amputations). Both in the limbs and the thorax, resection of bone often involved such a wide excision of the superficial soft tissues as to require a flap repair: four were used in the limbs and three in five chest wall resections. In the majority of operations (140/180) primary wound closure was possible. After 15 procedures for tumour predominantly involving the superficial tissues, split skin grafts were used. These were generally successful (13/15), even occasionally when high-dose radiotherapy had been given. In 16 cases earlier radiotherapy influenced the decision to use a flap repair. A total of 18 flap repairs were performed. In various situations Mersiline mesh (Ethicon, Ltd., UK), Silastic implants and omental swings were used. Wound breakdown in heavily irradiated tissues presented a major challenge for reconstruction. Although major reconstruction was required in only 27 operations (15 per cent), a thorough knowledge of the available methods of reconstruction and repair is essential to allow uninhibited resection with an optimal aesthetic and functional result.