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Prolonging the debate about precursors of invasive squamous cell carcinoma.


Robledo F. Rocha

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A busy Friday prevented me from participating in Case 875 of spot diagnosis, but I make a point of getting into the relevant discussion brought up by Dr. Sasi Attili. Foresseing my comment could be the last one, I thought it was a good idea prolong the debate in my own blog.

A number of key principles are enshrined in the medical science, and the fact that tumors are monoclonal proliferations is one of them. That implies any tumor arise from the clonal expansion of a single cell which has undergone nonlethal genetic damage.

An inescapable conclusion can be drawn from this principle of the oncogenesis: lesions, even the so-called preneoplastic ones, do not transform into tumors. Only individual cells do.

It turns out that some lesions may result from the action of factors capable of creating a favorable intrinsic environment for the emergence of neoplastic-related mutations in individual cells, or from the action of factors capable themselves to induce directly these mutations.

Several factors are known to be associated with neoplastic-related mutations in individual cells of the epidermis, including, first and foremost, sunlight, arsenic, psoralens and ultraviolet-A radiation (PUVA), and human papillomavirus (HPV). Thus, lesions may crop up in the epidermis due to long-term exposure to these factors or to other lesser-known agents. Even though designated according to the causative factor as actinic keratosis, arsenical keratosis, PUVA keratosis, Bowen disease, and so forth, such lesions are composed of cells with neoplastic-related mutations, i.e., they all are already neoplastic lesions. They are not keratinocytic dysplasia or intraepidermal squamous precursor lesions. Each of them is early squamous cell carcinoma since the clone that compose these lesions is the very same clone that will compose the advanced squamous cell carcinoma after the progression of the disease.

Probably the theory that the so-called keratinocytic dysplasias are precursors of invasive squamous cell carcinoma emerged from the ascertainment that, in the majority of cases, actinic keratosis, arsenical keratosis, PUVA keratosis, Bowen disease, and so forth, do not evolve, inexorably, into a frankly aggressive squamous cell carcinoma characterized by rapid growth, infiltration of underlying tissues like subcutaneous fat or bone, and distant metastasis. This happens just because early squamous cell carcinoma may remit spontaneously, remain unchanged for many years even without treatment, or have its progress halted by an effective therapeutic intervention.

Moreover, it's impossible to unequivocally establish, both clinically and microscopically, from when the so-called keratinocytic dysplasias must be referred as invasive squamous cell carcinoma. There's no reliable criteria to distinguish one from the other just because they are a single process that begins superficially and may progress.

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Thanks for your thoughts Dr. Robledo. Though I agree that a cell/ tumour is malignant whether it is in-situ or ex-situ, for practical purposes malignancy is a term that is used and should be restricted to ex-situ/ invasive tumours as unnecessarily (for semantic reasons) changing the terminology, would lead to over treatment of in-situ lesions with a good/ excellent prognosis.

Differentiation of invasive from in-situ disease is difficult in early cases and the point I was trying to make is that existing (albeit poor) literature suggests that this differentiation makes a huge difference as far as prognosis/ management is concerned. So this is not an issue we can simply drown in argument, but something that needs further study/ evaluation as to whether early invasion in BD has definite prognostic implications or not.
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Mark A. Hurt MD

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Sasi,

If I were to say to you that a solar (actinic) keratosis is a superficial form of squamous carcinoma, and usually a very treatable form of it, I suspect that you would not consider that statement too controversial today, but you might not agree with it because it is not a fungating mass with deep tissue involvement.

100 years ago no one would have believed it either, because cancer to them was the fungating mass.

George Adami, who practiced in Montreal, and who wrote a large text on tumors at the turn of the 20th Century, regarded as "typical," neoplasms that were benign. For him, "atypical" tumors were malignant neoplasms.

Bowen, in 1912, regarded the lesion that, today, we regard as "carcinoma in situ," something different: "precancerous dermatosis." A carcinoma was the fungating mass, not the subtle lesion we know today as carcinoma in situ or Bowen's disease.

Sutton and Sutton, father and son, dermatologists in the Kansas City area of the USA, I believe in the 1930’s, argued that the in situ component of a SCC is, in fact, part of the carcinoma -- one of the earliest identifications of the phenomenon.

For melanoma in situ, the situation has been similar. Lever, in 1949, proposed the concept, yet it was abandoned, more or less, until 1981, when Kamino and Ackerman resurrected it. Yet, 10 odd years before their article, Wayte, writing in a book edited by Helwig, titled “The Skin,” stated that "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 as malignant melanoma.” (p522)

It is not too difficult to surmise from this that superficial malignancy was simply discounted -- malignancy was a phenomenon that "began" only after the dermis was involved.

On this principle, there is no basis to treat a patient until there is dermal involvement! Actinic keratosis, Bowen's Disease, and melanoma in situ, are not cancer; only dermal expressions of those lesions are cancer.

I charge that this is simply untrue. All are cancers, and the superficial forms are the most treatable -- in fact curable in most cases.

From what you have indicated, I don't think you believe that carcinomas in situ or melanomas in situ are “precancerous,” but I think that many out there still believe it.

Mark
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I can completely understand your viewpoint, but I don't think we will ever agree on this issue, as I am speaking from a clinician/ patient point of view and you are speaking from a non-clinical/ pathologist's viewpoint. Irrespective of the potential of the single cells to metastasize or not, I find it a bit silly to tell a patient who has field change actinic keratosis all over his face/ hands etc, that their entire exposed skin is 'cancer'!! This is probably even on the verge of being unethical! Just imagine, the patient leaving the consulting room with a feeling that he is a walking time bomb riddled with cancer all over his skin!

We do have to understand and empathise with the patient's understanding of the term 'cancer'. For reasons you have already mentioned, the term 'cancer' has a much serious import, as far as the patient is concerned. So yes, I do use terms like 'pre-cancer' or 'sun-damage' to explain these 'in-situ' entities to the patient. Colleagues across the ocean might not agree with this, but this is my view as a 'clinician first' and dermatopathologist second. Most of the dermatologists and pathologist in the UK certainly share this view point.

That aside, I would also like to share my thoughts on the definition of 'cancer' (I consider the term 'malignancy' synonymous). Wolfgang Weyers had written an excellent article on this topic. [1], where he says 'Malignancy must be defined by the potential of a lesion, not by realization of that potential, namely, death of the patient. A neoplasm is malignant long before the patient is dead, it is malignant from the outset if it has ‘‘the potential to kill by destruction
locally or by metastases widely. [2]’’. I suspect that you share this view too? Though I like this definition, I do think that this definition as well is riddled with irony/ flawed.

If 'potential' is the only necessity for a cell to be called malignant, then every living cell, by nature of its ability to multiply, has that inherent 'potential'. So going by that definition, every living cell is malignant. What is the need for a histological examination? We can declare the cell/ lesion 'malignant' even without examining it!

In my opinion, the main difference between a 'benign' and 'malignant' cell is not the potential itself but the probability of that potential manifesting (probability of the realisation of the cells potential, rather than the actual realisation).

The probability of the inherent potential manifesting in the case of 'physiological'/ 'benign' cells is negligibly low and by that criterion I would say that for practical purposes they are not 'malignant'.

The same applies to in-situ tumours like AK and BD, which also have a negligibly low probability of manifesting their inherent potential (though the probability is slightly higher than a physiological cell). I am yet to see an actinic keratosis kill a patient. It kills a patient when it 'invades' or 'metastasizes'. It cannot kill the patient when it is in-situ!.

However, when do we then actually call something malignant? What should be the probability (of the tumour killing the individual, if left alone) level , at which we can call something 'malignant'? 2%? 5%? 10% 100%? Maybe if researchers and clinicians agree with my hypothesis, a consensus can be arrived at, in future. For now, I will use my own judgement and common sense in determining whether a lesion has a 'low' or 'high enough' probability of 'killing' the patient.

Though I do understand Wolfgang Weyer's analogy of the enemy being an enemy whether he is in his own home country or in your land (he compares that to a malignant cell being 'malignant' whether it is in the epidermis or not); I disagree that you have the right to name & kill the enemy, when they are in their own ground and haven't done any harm to you either directly or indirectly. An enemy cannot kill you if you are in your own ground, unless he fires a missile at you. I don't think cells have acquired missile launching capabilities yet! Maybe one day, when humans mutate enough, this might happen and I would have to eat my words. Until then............




1. Weyers W. The fallacy of the concept of invasion-critique in historical perspective with implications for diagnosis of early malignant neoplasms. Am J Dermatopathol. 2011;34:91-102.

2. Ackerman AB, Briggs PL, Bravo F. Differential Diagnosis in
Dermatopathology III. Philadelphia, PA: Lea & Febiger; 1993:193.
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Dr. Richard Carr

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Clearly in situ lesions [b]do not[/b] have capability to metastasise. They could theoretically kill if they replaced the entire integument though! I think pre-(cursor to) cancer is fine as a pragmatic explanation to the patient of the likely (or not) potential of the lesion doing serious harm. Certainly the management of such lesions can on occasions be more injurious to the patient with some of the modalities of gun-ho therapy than the actual lesion itself when they might (perhaps occasionally) undergo spontaneous resolution in some cases.
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