Nodular melanoma
Melanoma cells infiltrating the dermis
( C. Urso: Diagnosi istologica del melanoma cutaneo. In L. Borgognoni, L. Martini, V. Giannotti. Il melanoma cutaneo: attualitą e prospettive. Firenze, Giorgi & Gambi ed., 1999: 11-14)
Superficial spreading melanoma
The histological diagnosis of melanoma is a recent conquest; the histopathological profile of that tumor, in fact, has begun to be defined only since the second half of '60s. This was due to the efforts of some collegues, who unfortunately now are not still alive. Sophie Spitz, dead at the age of 46, taught us that cytological atypia and architectural disorder are not always connected to malignancy and separated the so called benign juvenile melanoma, now Spitz nevus, from malignant melanoma; Vincent McGovern, dead in a car crush in 1983, recognized, together with Clark, the most frequent type of melanoma, i.e. superficial spreading melanoma; Wallace Clark, dead in 1997, to whom we have to ackowledge an enourmous debt, from the histological classification of melanoma, now used in all over the world to the staging system in levels we use daily; Alexander Breslow, finally, who measuring the thickness of melanoma and found the most important prognostic parameter, that remains still now valid, although many sophisticated modern techniques are available. Why, however, is the histological diagnosis of melanoma difficult? It is possible to say that it is difficult mostly because melanocytic nevi do exist. Nevi are very common, but they are also very enigmatic. They can show highly variable cytological and architectural features and sometimes worrisome extraordinary analogies with melanoma: nevus cells begin to proliferate at the dermoepidermal junction, like melanoma cells; then, singular case in benign pathology, they cross the epidermal basal membrane going into the dermis, like melanoma cells, but, differently from these latter, without a malignant behavior. Such an extraordinary morphological resemblance associated with strongly divergent biological behaviors often makes the diagnosis of melanoma very difficult. Nevi and melanoma certainly have distinct histological features who enable the distinction; in both the fields, however, formidable simulators are hidden. First, nevi simulating melanoma: Spitz nevus which often shows marked cytological and architectural atypia, although it has a benign behavior; Reed nevus, frequent in female patients, often located on the inferior limbs, is considered a hyperpigmented variant of the former; desmoplastic nevus, a special variant of nevus in which desmoplastic stroma and some cytological features can create alarming images; deep penetrating nevus, somehow related to blue or combined nevi, can reach subcutaneous tissues, posing worrisome questions; recurrent nevus after imcomplete removal, in which the irregular proliferation of junctional melanocytes creates images difficult to be interpreted; nevi from some particular sites, as genital nevi, plantar and palmar nevi, which can show irregular architecture and phenomena of pseudoinfiltration, and, last, dysplastic nevus, on which there is not yet a definite concordance on the histological diagnostic parameters, showing however lentiginous proliferation, disordered nest proliferation, dyskaryosis, fibrosis and dermal lymphocytic infiltrate. Secondly, melanomas simulating nevi: nevoid melanoma, which shows bland architecture and cytology, and small cell melanoma which has small nevus-like cells, difficult to be distinguished from true nevus cells. Moreover, there are lesions which simulate melanoma simulators, as spitzoid melanoma, a spindle cell melanoma simulating the most classic amomg simulators: Spitz nevus. It is not enough: nevi and melanoma are not mutually exclusive, a melanoma, in fact, may arise in a preexisting nevus.
To orientate in such complex labyrinth of lesions which sometimes are sincere, but very often lie, many new techniques have been introduced along with traditional histology (hematoxylin-eosin, histochemistry): immunohistochemistry (S100 protein, HMB45, NK1/C3, Ki 67 [MiB1], PCNA, NSE, PALM 1, PALM2, etc.), cell kinetics (label index), cytofluorimetry, molecular biology (PCR); however, a magic molecule able to detect malignancy does not yet exist. It does not exist a histological marker which distinguishes malignant melanoma from melanocytic nevi. Of such special techniques, only some are really used in daily diagnostic practice. S100 protein, positive in nevus cells as well as in melanoma cells, can be used to evaluate some prognostic parameters (level, thickness), to recognize sparse melanoma cells in a almost totally regressed lesion. It may be also used to distinguish a melanoma metastasis from a metastasis from other undifferentiated tumors, but it is not able to distinguish nevi from melanoma. HMB-45 is expressed, albeit inconstantly, by melanoma cells; deep dermal nevus cells do not express it, whereas junctional and superficial dermal nevus cells do. Ki-67, a proliferativity marker, can be useful in some compound lesion (melanoma arising in a preexisting nevus). To-day, however, the diagnosis of nevi and melanoma is still based on classical morphology and new techniques have only an ancillary role. In the melanoma diagnosis, it is necessary to examine numerous elements; so, diagnosis is the final result of a long examination of different histological features. Among these, the most important features, speaking in favour of melanoma, are: dimension larger than 6 mm, asimmetry, poor circoscription of the lesion, single melanocytes prevailing over nests in some areas, especially in peripheral zones, irregular, pleomorphic and confluent nests,severe melanocytic atypia, pagetoid spreading with numerous suprabasilar melanocytes, at all epidermal levels, pagetoid cells (large melanocytes with large clear cytpoplasm), absence of melanocytic maturation (lack of dimensional reduction from upper melanocites to deeper ones), melanin in deep cells, mitoses in deep cells, cellular necrosis. Moreover, two further elements appear to be important. The first is the role of cytology in melanoma diagnosis, In fact, it seems to be inadequate to consider melanocytic atypia a feature in common between nevus and melanoma. The true atypia of melanoma is different from pseudoatipia of Spitz nevus and from dyskaryosis occurring in some nevi, in particuar in dysplastic nevi. Such features seem to be different in nature, rather than in degree. The second element is the recognition of pseudoinfiltration and its differentiation from infiltration. Such two histologic pictures, which are mutually exclusive, are due to the different nature of melanocytic proliferation involving the epidermis and are distinguishable from their histologic characteristics. The accurate study of these elements, together with a lucid examination of all histologic features of a lesion is the way we follow to the correct histologic diagnosis, that is, to understand what was occurring in a definite lesion, when surgical excision interrupted its life.
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The other pages
page 13: Merkel cell carcinoma
page 14: Basal cell carcinoma
page 15: Melanoma in paediatric age