John H. Little

International Pathologists Congruence Survey On Quantitation Of Malignant Melanoma

&NA; A congruence survey of pathologists in Brisbane, Adelaide, Oslo and Paris on classifying and grading histological features such as dermal invasion, cross‐sectional profile, mitotic activity and lymphocytic infiltrate was done on 147 cutaneous melanomas. The overall agreement was about 70%, about one pathologist in three or four disagreeing on each feature. Taking into account also the considerable number of slides in which agreement was less, the results are considered unsatisfactory. Agreement was highest in cross‐sectional profile and least in level of invasion. It is evident that the gradings are subjective and indicate the need for detailed histological description in making the criteria and the necessity of collaboration between pathologists to study slides and clarify problems. Experience is important and the slides must be of high technical excellence. Comparisons of results between different pathologists on the histological quantitations of malignant melanoma should take note of the degree of congruence achievable.

Malignant melanoma in Queensland: a study of 219 deaths.

A series of 219 patients who died within five years of histological diagnosis of their melanoma is reported. One hundred and fifty‐eight died of melanoma and in three melanoma contributed to death. Male to female ratio was about 2:1 There was a progressive increase of deaths in each cohort in males with aging, but in females only after 60 years of age. Fatal melanomas arose most commonly on the back. Face and thigh lesions were responsible for an approximately equal number of deaths and thigh lesions were shown to have a worse outlook than melanoma of the leg. This series contained a large proportion of patients with melanomas bigger than 2 cm. and of the 13 patients with lesions larger than 3 cm., 10 had metastases on registration with the Queensland Melanoma Project. The presence of only three flat melanomas would indicate a generally better outlook for this type of lesion. Ulceration and bleeding suggested a poor prognosis. The large number of patients (78) who had microscopic evidence of metastases on registration contributed to the poor survival in this series. Of the 78, 30 patients presented with metastatic disease and no primary melanoma was found. The findings from 29 autopsies indicated the ability of melanoma to disseminate widely. Fifty‐one patients died from causes other than melanoma, the more common being cardio‐vascular and cerebro‐vascular disease.

Malignant melanoma in Queensland: Pathology of 105 fatal cutaneous melanomas

&NA; The pathology of 105 primary cutaneous melanomas from 103 patients (70 males, 33 females) dead from melanoma is reported. Features of a melanoma adversely affecting prognosis were: presence of pedunculation and of a spherical shape (suggested by a low width/height ratio), increasing depth of dermal invasion, and ulceration. Pedunculated stage‐2 melanomas were placed in a separate category because they appeared to have a more malignant behaviour. We did not find that pleomorphism, mitotic rate, pigmentation or inflammation helped in assessing prognosis although further study may prove otherwise. It is desirable that comparison of results of different treatments are made on the same type of melanoma, from the same site and in the same sex. We should like to see a standard method of staging melanomas.

Adenovirus replication as an in vitro probe for drug sensitivity in human tumors

The feasibility of using adenovirus 5 as an in vitro probe for chemosensitivity in short-term cultures of human tumors was evaluated using human melanoma cell lines and primary cultures of melanoma biopsies. A convenient immunoperoxidase method was developed for quantitating viral replication 2 days after infection. Two different approaches were explored: the host cell reactivation assay (HCR) using drug-treated virus; and the viral capacity assay using drug-treated cells. The HCR assay detected sensitivity to 5-(3-methyl-1-triazeno)imidazole-4-carboxamide (MTIC) in Mer- (methyl excision repair deficient) cell lines as decreased ability of the cells to replicate MTIC-treated virus. This test should be applicable to DNA-damaging agents and repair-deficient tumors. Adenovirus replicated readily in nonproliferating primary cultures of melanoma biopsies; application of the HCR assays to this material identified one Mer- sample of 11 tested. Herpes viruses were not suitable for use in HCR because herpes simplex virus type 1 failed to distinguish Mer- from Mer+ melanoma cells; and nonproductive infection of MTIC-sensitive lymphoid cells with Epstein-Barr virus yielded an MTIC-resistant cell line. The second assay (viral capacity) involved determination of the inhibition of replication of untreated virus in treated cells. This approach correctly predicted sensitivity to hydroxyurea and deoxyadenosine in melanoma cell lines when compared with clonogenic survival assay. Viral capacity was also inhibited by cytosine arabinoside, fluorouracil, vincristine, adriamycin, 6-mercaptopurine and ionising radiation, and may therefore be useful for detecting sensitivity to a wide range of antitumor agents.

CUTANEOUS MELANOCYTES IN QUEENSLAND PATIENTS

A study of cutaneous melanocytes and dermal changes around non‐melanoma lesions and malignant melanomas in Queensland patients has been undertaken. The findings from the non‐melanoma group are reported in this paper. The aim of the study was to see if a melanoma affected the melanocytes in the surrounding epidermis. To do this, a base‐line for changes in the melanocytes in Queensland patients with non‐melanoma tumours was sought. The features studied were number, morphology and activity of melanocytes, epidermal pigmentation and solar‐induced dermal changes.

Frozen section diagnosis of suspected melanoma of the skin

Due to the frequency of malignant melanoma in Queensland urgent frozen section diagnosis of pigmented skin lesions suspected of melanoma has become a routine procedure, second only to breast lumps in frequency. Review of the Departments experience shows 329 pigmented skin lesions from 316 patients were diagnosed by urgent cryostat section. There were 3 main groups of lesions—about one half were malignant melanomas and about one quarter each were naevi and non-melanocytic lesions. Histological error occurred in 4 cases (1.2%) and in 2 cases of combined naevi resulted in unnecessary surgery. The recognition of the combined naevus is important in avoiding error as 11 tumours in the series were combined naevi. Seven were combined Spitz (juvenile melanoma) and common naevi at the junctional, compound or intradermal stage and 4 were combined blue or cellular blue and common naevi. The error rate of 1.2% is acceptable when compared with published rates of frozen section diagnoses on a wider range of tissues. The diagnosis was withheld in 19 lesions (5.8%) which on paraffin section were predominantly melanomas. The causes were superficial levels of tumour, heavy lymphocytic infiltration, partial tumour regression and unusual cell shape and arrangement in the melanomas. In all 3 groups most of the lesions were less than 15mm diam. and were flat. Nearly 40% of the melanomas were Level I or II. The majority of the naevi were compound naevi. The non-melanocytic tumours were mainly pigmented basal cell carcinomas and basal cell papillomas. As a result of the frozen section report, further treatment was performed in 83 (52%) of the malignant melanoma cases. It is concluded that cryostat section diagnosis of malignant melanoma in experienced hands is reliable and is of considerable value to the surgeon.

Tiptoeing through the melanocytic minefield

Fortunately the histological diagnosis of most benign and malignant pigment cell tumours and of non melano-cytic tumours of skin is not difficult. A problem is usually due to one major feature. An axiom is that no one feature is diagnostic of malignant melanoma. More detailed analysis is required searching for features supporting or opposing the major feature. Some of the major problems are tumours of large epithelioid, spindle and giant cells where differential diagnoses are melanoma, Spitz naevus and cellular blue naevus. When the cells are of naevul size the diagnosis could be banal naevus, dysplastic naevus or melanoma of naevul like cells. Abnormalities of site such as deep dermal extension raise possibilities of congenital naevus, cellular blue naevus and desmoplastic melanoma. Other worrying features are upward epidermal spread, disruptive lymphocytic infiltration, fibrosis, mitotic activity, foamy cytoplasm and spindle cells especially in non pigmented tumours. Deeper levels is probably the most helpful proceedure. Useful stains are melanin, iron, reticulin, PAS, trichome S100, keratin and vimentin. Melanoma MOABs and AgNORs still require evaluation. Further clinical history such as duration of pre-existing lesion, especially if congenital, past and family history and mole status of the patient can be useful. Be prepared to recheck the clinical history especially the patients age.