By Cyrus Milani, M.D.
Melanoma may be manifested in any body site that is a derivative of the Ectodermal Anlage. As such, it may be seen in any body location, primarily on the skin but also including central nervous system, inner eye and genitalia.
Melanoma is most prevalently seen on the skin, particularly on sun exposed skin. In this clinical manifestation its biological behavior is different and less virulent and is mostly seen during higher decades in life. It may have a protracted clinical course, as the dermal sun damaged fibers significantly delay penetration of malignant cells into the dermis. What we call today a melanoma in situ and used to be called Hutchinson's freckle, usually with a lengthy clinical course, is a type that has been known since previous centuries.
Manifestation of melanoma on the skin not exposed to sun is generally in a significantly younger individual revealing a more virulent biological behavior and apparently has a different trigger mechanism still unknown to scientists.
Melanoma on nervous system membranes and inner eye may be even seen in infancy and is usually lethal in a short period of time.
Melanoma may be histologically diagnosed in the dermis in its initial manifestation without presence of epidermal involvement. Dermis is a derivative of Mesodermal Anlage and not of ectoderm. Science has no answer as to why such is the case. We may only speculate that such a melanoma might have initially appeared in the epidermis, with penetration into the dermis, later regressing on the epidermis, leaving no sign of such regression.
HISTOLOGIC CRITERIA FOR DIAGNOSING MELANOMA
Microscopically, melanoma is diagnosed by the presence of a combination of signs on the microscopic slide that have been set as criteria:
- Asymmetry of nest or solitary melanocyte arrangement within the epidermal junction or above it
- Preponderance of melanocytes as solitary units over nests of melanocytes at the junction of dermis and epidermis
- Presence of melanocytes as solitary units or groups above different levels of the junction
- Lack of circumscription
- Presence of sun damage on the exposed skin
- Asymmetry of distribution of nests of melanocytes, inflammatory cells and melanin pigment within the dermis
- Pleomorphism of nuclei of melanocytes
- Presence of mitotic figures particularly towards the bottom of the lesion
- Authors other than A. Bernard Ackerman, M.D., might have other criteria not included here.
Size of melanocytic cells and or nuclei is a factor that needs to be evaluated with caution. Histologic findings in Spitz's type of nevus are a good example. In the Spitz's nevus, now considered a benign lesion and initially diagnosed by Sophie Spitz as a childhood melanoma, melanocytes appear very "atypical," truly large and somewhat pleomorphic as compared to some melanomas that reveal quite small monomorphous cells (1)(2)(3).
Not every melanoma manifests all the criteria. At times, only one or two criterion may be present. It is the weight of the criterion or the criteria that leads us to diagnosing the lesion as benign or malignant. This is the reason that at times there is a complete disagreement between multiple "experts" in diagnosing a case as either nevus or melanoma. This inability needs to be the source of humility for all. However, "experts" usually develop a skill which is the "art" in diagnosing pigmented lesions.
In spite of our better understanding of the pigmented lesions and melanoma, particularly our enhanced ability in the early diagnosis of the latter, diagnosing some manifestations of melanoma for us the mortals and ordinaries is still a quandary. It is on any given day that we the common, even as a highly experienced pathologist/dermatopathologist (?? supposed expert??), face a dilemma at the objective lens of the microscope: I have not seen one like this before. What can I call this one? This is true whether the lesion is pigmented or non-pigmented, although more so for the former. (3)(4)(5). Frequently, even as a highly experienced dermatopathologist in regards to the pigmented lesions, there is not a day that by looking through the lens of the microscope, I do not truly feel humbled (3).
INTER-RELATIONSHIP OF MELANOMA AND NEVUS
Nature, in its unlimited wisdom, does not follow the rules that man sets, even if based on scientific experimentation! Our senses are not perfect and our rules are accordingly faulty. This is best shown by the most influential American Philosopher of Science of the second half of the twentieth century, Thomas Kuhn, a physicist, with his Paradigm and Paradigm shifts opinion. He indicates that even our experimental proofs of scientific theories may be inaccurate as the outcome of experiments are usually based on the initial pre-assumed theorization, the end result changing with the change of the pre-assumption set up. As scientists we all know about many theories and dogmas that during centuries have become outdated as new information has been gathered.
Overall, malignancy is a multi-factorial disease with unknown trigger mechanism(s). In approximately ninety percent of cases melanoma manifests itself de novo. In about ten percent of cases melanoma may be associated with any type of nevus including the so called "dysplastic nevus." Prevalence of melanoma is not associated more strongly with a nevus that reveals the so called "atypia" or "dysplasia" (1, 2).
In the later decades of the twentieth century, two non-specific and unclear terms, "Atypia" and "Dysplasia" were added to the term "Nevus" indicating that these lesions may eventuate in becoming Melanoma. (6-in regards to specificity). The terms "Dysplastic Nevus," which still is being used by a majority of microscopists, albeit in a significantly lesser numbers, and now the almost defunct terminology, "Dysplastic Nevus Syndrome," were then coined.
Webster's New Collegiate Dictionary (1973 Edition) defines the word "atypical" as "not typical, irregular, unusual." The same dictionary defines "dysplasia" as "abnormal growth or development."
Contrary to how pathologists use these words in their daily diagnostic vocabulary, there is not a credible definition for such words- they are truly ambiguous and are used in a wide range of diagnostic terminologies with different meaning, ranging from slightly different from the "typical" to a pre-malignant stage or even malignancy.
Propagation of the idea of "Dysplastic Nevus" and "Dysplastic Nevus Syndrome" in the late twentieth century, largely in newspapers available to the public, resulted in hysteria of epidemic proportions in the United States. Lines of parents formed in clinics asking for evaluation and treatment, and, we must say now, unnecessary excision of their multitude of pigmented lesions (1, 2).
A. Bernard Ackerman M.D. solely questioned the validity of this terminology. The use of "Dysplastic Nevus" and "Dysplastic Nevus Syndrome" was being supported by a majority of other authors. Now the relatively small percentage of his students and followers continue to abstain from using these very non-specific words and terminologies. In general, a majority of microscopists know that the association of melanoma with nevi is not restricted to dysplastic nevi only. Melanoma is seen equally in association with nevi other than dysplastic nevi (1, 2, 3).
Missed diagnosis of melanoma in pigmented lesions is the highest incidence in which physicians, whether a pathologist or a clinician, are professionally / legally sued and a source of significant morbidity to the patient at the hand of physicians. The current trend of increasing numbers of clinicians preparing and or reading and reporting their own patients' biopsies from within their own practice, will, undoubtedly, significantly add to the harm and misery of patients at the hands of healers.
Obviously, Nature in its own mystical-never the same, infinitely wise ways does not conform to the rules and criteria which are the product of our easily deceivable powers of senses. We may strongly hypothesize that it is highly unlikely that in the realm of matter and life, as we know it, perfection exists. Thus, admitting that the list is not meant to be exhaustive, we may claim that either our criteria and rules, or the ability of our senses to perceive accurately, or our neuronal interpretations of the messages transmitted from the surface of the slide to our neurons or all the above, individually and or collectively, are imperfect, which leads us back to the title of this article and the Tribute to A. Bernard Ackerman, M.D, Melanoma or Not.
A Bernard Ackerman, M.D., Bernie as he liked to be called by all, taught that in Pigmented Lesions, there are three diagnoses: Melanoma, Nevus or I do not know. (1)(2) In the latter case, he preached that the case needs to be referred to an expert who can diagnose it as either of the two entities mentioned before the latter. However, it is conceivable and even probable that recognized experts may also miss diagnosing lesions accurately. (Personal Experience in case(s) referred to University Level Experts-4).
Development of newer immuno-histologial Markers has somewhat helped us to diagnose benign and malignant pigmented lesions and shall continue to assist us as even newer testing becomes available.
In regards to our trials in making the diagnostic process simple, we need to follow the ways of nature, which in its utmost wisdom reveals a high degree and principle of simplicity. Likewise, in pathologic diagnoses, a group of us who are "Lumpers" try to simplify diagnostic terminologies by including any variation as an acceptable part of the whole, and another groups of us are "Splitters," for whom the slightest difference and variation points to a new diagnostic terminology. Bernie was a "Lumper" and I, his student, was a "Lumper" too, even before I met Bernie.
By our definitions of the proven, required pathophysiologic quality of malignant cells that proliferate uncontrollably to their own eventual demise, versus benign cells having a STOP process in the act of proliferation in the repair or renewal processes, we are defining that there must not be a natural gradation of cells from benign to malignant. If that is acceptable, then, we can not assume that there are gradations of "Atypia" and "Dysplasia" in benign nevi towards melanoma. If this proposal is acceptable, then, certain defining qualities such as "Atypia" and "Dysplasia" need not be used with benign nevi to justify "excision" with "Adequate Margin." The issue of "Association of Melanoma with any type of Benign Nevi" is unrelated to the fallacy of assuming that there might be a tendency for previously formed benign cells in transforming to a malignant state. Even in such association, it is the trigger that stimulates a melanocyte to become malignant de novo, thus a melanoma becomes manifested within a nevus as a separate Neoplasm and not that the particular type of nevus is a precursor of melanoma (6-in regards to specificity).
As to why an obvious majority may yet be oblivious to the declining value of these non-specific terms, there might be a number of reasons, a range of possibilities that may or may not be a contributory factor to the continuous usage of such terminologies:
- True belief - Bernie truly, but diabolically believed in their lack of merit. But authors who have used such non-specific words as "atypia," "dysplasia," etc., truly believed in their merit.
- Habit - The majority of people in charge of training programs still use such terminologies. We humans like our comfort zones and abhor change in general, which allows for the continuation of usage of such terminologies by a significant number of prominent figures in the industry.
- Younger generation - This makes it difficult for the younger generation of the rank and file to consider otherwise. Lack of attention to the specifics, as the science of medicine is replete with a significant number of similar words with non-specific meanings that continue to be used, just because everyone is still using them.
- Fear of legal repercussions - Pathologists continue using these terms as a defense against getting sued when they are not certain about the exact diagnosis.
- The list is not meant to be exhaustive. It was also already noted that perfection may not/does not exist in the realm of matter.
And this is where the Genius of Bernie lies: seeing facts clearly and in focus within a zone of chaos, a person who innately lived outside the "conformity box" of society. Was he as fallible as any of us but perhaps less so? Of course he was. Was he occasionally in the left field in diagnostic viewpoints? Of course he was. Was he cavalier and uncaring about the effect of his spoken, harsh, critical words against others? Of course he was. He, in my interpretation, chose to utter the truth as he understood it as opposed to be politically correct.
Yet, he touched the lives of us all, friends and foes, although, in any case, he was a highly respected professional in our approach to the Science and Art of Diagnostic Microscopy.
And more so, he served so capably the patient-our master for whom we serve our trade as well as training the next generation of dermatopathologists and practicing the science and his elevated art of Dermatopathology with distinction. He so highly contributed to our understanding of Dermatopathology. He knew how to print books that are pleasantly readable and highly informative. He, even in one short year of Fellowship, instilled in me more understanding of pathology than in my previously lengthy and probably lethargic professional experience platform (3, 5)!
His contributions are many faceted, will be long lasting and are dearly missed.
Single-handedly, in his younger years, whether he receives credit for it or not in some texts, he clearly classified the inflammatory diseases of the skin in an easily understandable algorithmic method, out of a previously chaotic realm and contributed so profoundly to the diagnosis of pigmented lesions and many other areas of dermatopathology and dermatology. The above mentioned contributions are but a few of many. His eloquent speeches, his towering presence-always leaving a profound impression on the audience although negative for a few, his so beautifully written tens of articles and books, his booming voice and penetrating eyes, all contributed to his being the greatest teacher that I have ever had and makes me profoundly indebted to him. I am certain that there are many more who would agree with me.
It is in this light that I salute my mentor Bernie, support many of his diagnostic terminologies/criteria, and I believe that he was the
"GREATEST DERMATOPATHOLOGIST OF OUR TIME IF NOT OF ALL TIMES."
How blessed and fortunate I am/we are to have lived in his era.
REFERRENCES:
1) A. Bernard Ackerman, M.D.: Many Printed Articles and Books in Dermatopathology
2) Personal Communication with A. Bernard Ackerman, M.D., 1995 Fellowship Training
3) Professional Experience in Diagnosing Over 20,000 Melanomas since 1996-Present
4) Kittane M. Ranganath, M.D., Medical Director, OmniPath Diagnostics Headquarters in CA, and Jerome Wollman, M.D., Director of Quality Assurance ( in CA & TX ) and Residency Training Program OmniPath Diagnostics in CA--Academic, Sub-Specialized Pathologists: Personal Communication
5) Experience in Signing-Out over 1.5 and close to 2 Million Surgical Specimens in Multiple areas of Sub-Specialized Pathology in a Carrier Spanning from 1969 to the Present
6) What Would Webster do? Editorial Journal of Cutaneous Pathology, 2011:38:5-7, Timothy H. McCalmont, MD, Editor in Chief
