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Dermatopathology: Practical & Conceptual April - June 2008
5. New Heights: “Animal-type” melanoma and entities related to it (Part I): Evolution of a concept
François Milette, M.D.
A. Bernard Ackerman, M.D.
Contents of Part I
I. Melanosis in horses and men? (Dick, 1832)
II. A précis of equine melanotic disease (Levene, 1971)
III. Melanoma arising in “blue nevi”? (Darier, 1925)
IV. Diffuse mesodermal pigmentation? (Carleton and Biggs, 1948)
V. Melanotic disorders in horses and men? (Levene, 1979)
VI. Pilar neurocristic hamartoma? (Tuthill, Clark, and Levene, 1982)
VII. Malignant melanoma arising in a blue nevus? (Pathy, Helm, Elston, Bergfeld and Tuthill, 1993)
VIII. Cutaneous malignant melanotic neurocristic tumor arising in neurocristic hamartoma? (Pearson, Weiss, Headington, 1996)
IX. Malignant melanoma with prominent pigment synthesis: “Animal-type melanoma”? (Crowson, Magro, Mihm, 1999)
X. Animal type melanoma? (Requena, de la Cruz, Moreno, Sangueza, Requena, 2001)
XI. Animal-type melanoma? (Kazakov, Rütten, Kempf, Michal, 2004)
XII. In the textbooks?
XIII. Melanomas in horses as described in veterinary medicine literature? (Valentine, 1995; Seltenhammer, 2004)
II. A précis of equine melanotic disease (Levene, 1971)
Melanosis equine is said to present itself in gray horses as their hairs whiten, that being a sign of aging. It manifests itself as a single nodule/tumor or multiple nodules/tumors that develop at rates variable, that often attain very large sizes (30 or 40 cm), and that are hard. Surgery does not affect the course of the process. A lesion traumatized heals well. No regression "spontaneous" seems to have been recorded. Spread to internal organs does occur, particularly to parotid glands, which also can be a site of the disease primary. Death has been attributable to massive involvement internal, but because animals tend to be sacrificed when ill severely, death usually is not attributed to the disease itself. Sites of predilection for equine melanotic disease at the outset of it are the anus, tail, and perigenital region. When the disease appears mostly in organs internal, it is the parotid glands that are the ones most likely to be affected.
The earliest changes histopathologic of equine melanotic disease are claimed to be in the connective tissue of the follicular bulb where spindle and cuboidal cells that house abundant melanin are manifest, they resembling the cells constituent of a so-called blue nevus. The proliferation, pigmented markedly, extends to the dermis, then the subcutaneous fat, and, not uncommonly, to fascia and skeletal muscle. Melanin is so abundant that characteristics nuclear, described as "bland." are difficult to visualize unless sections of tissue are bleached, such as by potassium permanganate.
At no stage of the process is the epidermis affected, according to the description classic. Some examples of the disease, however, exhibit melanin in quantity less copious, display nuclei more pleomorphic, and involve the epidermis, which means that, on occasion rare, the pattern architectural and the attributes cytopathologic are consonant with those of a malignant neoplasm.
Even if no such neoplasm overtly malignant is apparent, masses of pigmented cells identical to those of the early lesions appear subsequently in lymph nodes and in organs deep to them. The animal may become cachectic but the course of the disease, although variable, tends to be indolent.
In comparing equine melanotic disease to conditions melanocytic in human beings, Levene wrote as follows:
"The conflicting views of this [equine melanocytic] disease, reflected in the literature, are the result of the individual writer's experience (or rather "inexperience"?) of the range of clinical behaviour and pathological changes which the disease can show . . .
My own experience agrees with that of Peyronny,
"le pronostic de la mélanose du cheval est certainement très bénin. Ce n'est que dans des cas exceptionnels que l'on observe une marche maligne." (The prognosis of equine melanosis is certainly very benign. It is only in exceptional cases that we observe a malignant behavior.)"
For Levene, equine melanotic disease differed from melanocytic lesions in humans by virtue of four considerations thus:
Relationship to graying and whitening of the hair
Site of predilection, both primary (perianal, perigenital and tail regions) and secondary (salivary glands particularly).
Melanocytes productive of abundant melanin, which is transferred to other cells either by phagocytosis or, more likely, as in the case of sweat glands and normal squamous epithelium, by a process of "cytocrinia" (the same process by which melanin is transferred, in an epidermis normal, from melanocytes to keratocytes).
According to Levene, equine melanotic disease presents itself in two forms different decidedly from one another, he contrasting them in these words:
"In the slow or benign form of the disease the melanocytes, which must clearly proliferate in order to produce the large quantities of melanin encountered, are greatly outnumbered by phagocytic and non-phagocytic recipients of cytocrinia.
In the rapid or malignant form the melanocytes, which now show the conventional cytological changes of malignancy, are more easily identifiable, particularly when producing little melanin."
In brief, two expressions of presentation for equine melanotic disease have been set forth, one that is benign biologically and in which pigment marked results mostly from melanophages in numbers ever increasing, and a second, much rarer and malignant biologically, in which pigment is less prominent and melanocytes are typified by nuclei being pleomorphic, hyperchromatic, often in mitosis, and, not uncommonly, necrotic.
For Levene, parallels striking exist between the behavior of blue nevus in humans and equine melanotic disease. This is how he phrased those similarities:
"The blue nevus, usually defined as a benign melanocytic tumour located in the connective tissue of the dermis, is very rarely associated with remote spread. This unusual behavior follows two broad patterns. In one, the history of the lesion and the histological evidence point to either malignant change in a pre-existing blue nevus, or malignant blue nevus ab initio. In the other, there is discovered by chance the presence of regional lymph node deposits of blue nevus, either inert or very sluggish growth, in association with a banal blue nevus.
I have suggested the term benign metastasizing blue nevus might be an appropriate designation for the latter phenomenon."
In the judgment of Levene, there is a blue nevus benign, with and without metastases, and a blue nevus malignant, with and without metastases. In brief, in the model proposed by him, the presence or absence of metastasis is irrelevant to the determination of benignancy or malignancy. It is only the characteristics architectural and cytopathologic that assist coming to a decision for or against benignancy or malignancy.
Levene ended his treatise with these comments:
"The parallels in man to slow and rapid equine melanotic disease are "benign metastasizing blue nevus" and "malignant blue nevus" respectively . . . The resemblances are in behavior and histology of the deposits, the differences in the primary lesions and the limited capacity of the human benign type to spread beyond the regional nodes, or so we still believe, since there are no autopsy reports devoted to late studies on blue nevus . . .
To conclude, slowly and rapidly progressing equine melanotic disease, human blue nevus and its varied behavior, are manifestations of the growth potentialities of the dermal melanocytes. This may result in:
a localized tumour
a localized tumour with limited capacity for regional spread
tumor which metastasizes, the cells showing limited powers of proliferation, but considerable functional activity, resulting in melanin production which is deposited in local reticulo-endothelial cells
The "synthesis" of Levene is inducing of exophthalmus in a pathologist schooled in principles fundamental established by Virchow and propagated by successors of him. The formulation of Levene seems to indicate that he was either unknowledgeable about rudiments classic of pathology or thought them wrong.
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