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Pre-malignancy versus Pre-conditions for Malignancy


Mark A. Hurt MD

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It might surprise you to learn that there is no such thing as a pre-malignancy. There are, however, preconditions for malignancy.

When one refers to a squamous cell carcinoma, one refers to the malignancy. When one refers to a person who has skin (hopefully one does), who has repeated exposure to the skin by intense UVA & UVB and with frequent burns over an extended period of time, who has a family history of some types of cancer, etc., one refers to preconditions for the development of malignancy.

Yet, it doesn't follow in logic that all preconditions for malignancy result necessarily in the malignancy. Those preconditions must be positioned so that when an interaction occurs, the result is the malignancy.

Even more intriguing is the fact that some authors have used the term, premalignant (or pre-cancer), to refer to the actual malignancy.


Consider the case of Bowen's disease. Today, it is known and widely accepted as a form of superficial squamous cell carcinoma; most refer to it as "in situ" (Ackerman had a special way of considering it). Yet, what was Bowen's title? It was: "Pre-cancerous dermatosis." What did Bowen say about it? He said the following:

"The various cutaneous conditions that may precede the development of cancer have been sometimes grouped, more or less loosely, under the title "Precancerous Conditions," "Precancerous Keratoses," etc."

But, what did Bowen show us? He showed us superficial epithelial lesions with the cytopathological changes of cancer.


Consider the case of melanoma. in 1954, Allen & Spitz said this about it:

"The superficial melanocarcinoma, as indicated, refers not to the surface area, which is usually small, although it may be large, but specifically to the presence of minimal evidence of invasion. In other words, whereas the diagnosis of melanocarcinoma [Allen & Spitz argued that melanocytes were derived from keratocytes] cannot be properly made without evidence of invasion of the cutis or submucosa, that evidence may consist merely of several subepithelial clusters of cells or even several isolated cells. The analogous criterion would be that used for the differentiation of a superficially infiltrating squamous-cell carcinoma as opposed to leucoplakia or Bowen's disease (epidermoid carcinoma in situ of skin) on the one hand, and an obvious more deeply infiltrating carcinoma on the other."


Allen (1954) was crystal-clear about his position on the matter of pre-cancer versus cancer when he made the point that an "active junctional nevus" was the precursor of melanoma. He said it this way on pages 840 and 844 of his text:

"There has been some groundless confusion regarding the significance of the junctional nevus. It is rather gratuitously declared that the junctional nevus is not equivalent to a malignant melanoma and that therefore it is not so precarious as we have indicated. As is generally recognized, our thesis, of course, is not that every junctional or compound nevus becomes a melanocarcinoma, any more than that every radiation keratosis becomes a carcinoma. The point is that, with the exception of the few malignant blue nevi, every melanocarcinoma of the skin or mucous membrane arises from a junctional or compound nevus. By no single phrase has it been implied that the junctional nevus, or the junctional change as it exists in a compound nevus is essentially a malignant melanoma. Inasmuch as we have unequivocally stated in several publications that about 12 per cent of intradermal nevi of adults are compounded (that is, have a junctional component), and inasmuch as nevi of all sorts are so abundant in contrast to the relative infrequence of malignant melanomas, it is obvious that, fortunately, only a small percentage of junctional nevi undergoes cancerous transformation. However, in those restive junctional nevi, in which anaplastic and certain qualitative cellular changes have occurred, the odds are enormous that this altered junctional nevus, if allowed to remain, in time would evolve into a melanocarcinoma. The active or precancerous junctional nevus has one or more of the following elements: (1) the general features of nuclear anaplasia such as hyperchromatism, increase in nuclear and nucleolar size, irregular nuclear vacuolization, and mitotic figures; (2) subepithelial inflammatory reaction consisting preponderantly of lymphocytes and (3) cytoplasmic vacuolization and fine melanin pigmentation reaching to the uppermost layers, that is, to the stratum granulosum and stratum corneum. This latter feature is by far the most common and therefore the most revealing of in situ activity. However, with regard to the junctional nevus that we have described as quiescent it is injudicious to feel that they are all ultimately as insignificant to the patient as an ordinary intradermal mole. The fact is that, unlike the intradermal nevi, some of the quiescent junctional nevi -- luckily only a small proportion -- do become active and do eventuate in melanocarcinomas. To date, it is impossible to know which particular ones of the inactive junctional nevi will undergo malignant change."


In Allen's Plate 389-A, which I interpret as a melanoma in situ with a pagetoid pattern, he says of it the following:

"ACTIVE JUNCTIONAL NEVUS, designated "active" because of the atypia of the pleomorphic hyperchromatic cells. The odds are overwhelming that, if this lesion were untreated, it would evolve into a melanocarcinoma. In other words, this lesion is equivalent to melanocarcinoma in situ."


Of course, not all melanomas arise in fields of melanocytic nevi; most arise de novo; Allen was just wrong about this. Had readers of Plate 389-A taken Allen seriously, however, they would have realized that "active junctional nevus" should have been abandoned as a contradiction, and melanoma in situ should have won the day because melanoma in situ is, in fact, a form of melanoma; but, that is not what happened.


In 1971, taking his cue from Allen & Spitz (above), Wayte made the following statement:

"B. Intradermal invasion. Intradermal invasion is an absolute criterion for the diagnosis of malignant melanoma. Unless penetration through the epidermal basement membrane can be demonstrated, then -- no matter how pleomorphic the melanocytes -- the lesion cannot be designated a malignant melanoma."


These examples are key in illustrating the problem with the concept of pre-cancer or pre-malignancy. In both cases, the lesions are themselves malignant, albeit in rudimentary forms. The superficial squamous carcinoma is carcinoma. The melanoma that has not reached the dermis is still melanoma (in situ). Yet, historically, the superficial forms of the malignancies had to achieve some "depth" in order for them to be considered malignancies.

Perhaps another way to illustrate the problem is this way: one can identify the preconditions of a pregnancy, but the preconditions are not the same as the pregnancy. One can also identify the preconditions of some patients who develop malignancies; the preconditions are not the same as the malignancies.


The fallacy of pre-cancer is that it is illogical; The "lesion" before it was a cancer was not, in fact, a lesion at all (in most cases) -- much less a cancer.



References:

Ackerman AB, Mones J. Squamous-cell carcinoma in situ is a fiction! J Cutan Pathol. 2009 Jan;36(1):74-5; author reply 76. PubMed PMID: 19125737.

Bowen JT. Precancerous dermatoses: a study of two cases of chronic atypical epithelial proliferation. J Cutan Dis Syph 1912;30:241-255.

Allen AC, Spitz S. Histogenesis and clinicopathologic correlation of nevi and malignant melanomas. Current status. AMA Arch Dermatol Syphilol 1954; 69:150-171.

Allen AC. Nevi and malignant melanomas (Chapter 24). In: The Skin. A clinicopathologic treatise. St. Louis: CV Mosby Company, 1954, pp 840-844.

Wayte DM. Pathology of Nevi and Melanomas (Chapter 26) in: Helwig EB, Mostofi FK. The Skin by 30 authors. Baltimore: The Williams & Wilkins Company. 1971; p522
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Dr. Phillip McKee

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A very nice and succinct review of a difficult topic. The situation is further compounded by the issue of dysplastic nevus with severe cytological atypia. I am often asked how I make the disinction between the latter and in situ melanoma and to be honest it can sometimes be very difficult. The fact that the treatment is the same for both doesn't satisfy my curiosity or the dilemma. Perhaps one day we will have molecular data to solve the problem that I really believe in.
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