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Dermatopathology: Practical & Conceptual

July – September 2010 | Volume 16, No. 3

To count or not to count—that is the question!

Böer, Almut

On counting

Soon after language developed, humans began counting. [1] It is assumed that the decimal system developed because humans started counting their fingers and thumbs. In the earliest traces of a counting system, numbers are built up with a repeated sign for each group of 10 followed by another repeated sign for 1. [1] A big accomplishment for calculation with numbers was the introduction of the number 0, which seems to have been achieved first in India. A dot or a circle was used when the place in a number had no value. The decimal system evolved fully in the 9th century, when it was adopted in the Arabic culture. About two centuries later, the Indian digits reached Europe through Arabic manuscripts and became known as Arabic numbers. The completed decimal system is very effective for calculation and it became an international method of communication.

Usually we learn counting at least up to 10 before entering primary school. Counting is a simple mathematical procedure and it is considered to be an objective measurement which results in data that can easily reproduced by anybody applying the same method, i.e., counting the number of apples in a basket should give the same result no matter who performs the act of counting. In general medicine, blood cell counts provide important and easily retrieved information about the function of the bone marrow. In dermatology, counting is used to determine the number of blisters as an objective measurement of severity in pemphigus vulgaris just as the number of pustules is used in acne vulgaris, counting melanocytic nevi has been used to identify patients at risk for melanoma. In dermatopathology, the number of terminal follicles in anagen, catagen, and telogen, and of vellus follicles is used in the assessment of alopecias.

In striking contrast to the objectivity implied by the procedure of counting, numbers themselves have something magic: Consider “all good things come in threes,” “a cat has seven lives,” the pentagram as a satanic symbol, but also the numbers of Fibonacci. In medicine, too, there is a magic of numbers. We are impressed easily with high numbers of publications of a colleague, with high impact factors of a journal, with huge numbers of patients included in a study, and with any kind of p value indicating significance. It is interesting that we tend to believe such numbers rather than to call them into question. What if the number of publications of a colleague is the result of political constellations and not of own merit? What if the high impact factor of a journal developed by deliberate self-citations? What if the statistics used in a study on huge numbers of patients is faulty? Even though we know that such things happen, we tend to consider them highly unlikely. And, after all, our possibilities to reveal unequivocally scientific misconduct are very limited.

A survey

Recently a new melanoma classification has been suggested. [2] The authors state that “primary tumor mitotic rate is now a required element for the seventh edition melanoma staging system.” Mitotic rate is used in this classification to determine T1b melanomas and patients classified as having a T1b melanoma usually undergo sentinel lymph node biopsy.

In a survey we asked colleagues whether they now count mitotic figures in melanomas measuring 1 mm or less in thickness or not. [3] Moreover, we wanted to learn the opinions of colleagues about mitotic rate being a prognostic factor in melanomas measuring 1 mm or less in thickness.

I want to express my sincere thanks to all colleagues who participated in this survey. The answers and opinions given have lively stimulated my thoughts and considerations about this matter and I am sure they will do the same for readers of this journal. I was impressed by the comprehensive and profound replies of several colleagues who provided thoughts and evidence that I had not been aware of before. And I was amused by the brevity of the answers of other colleagues, short and crisp but long enough to say everything!

The number of colleagues who are now counting mitotic figures in melanomas turned out to be almost equal to that of colleagues who decided not to do so despite the recent publication of Balch et al (15 versus 13). Interestingly, several dermatopathologists emphasized that they only counted mitotic figures because they were forced to do so by the referring dermatologic surgeons.

In the opinions provided by our colleagues several critical aspects of the matter are addressed repeatedly:

1. There is not universally accepted method of counting mitoses in melanomas < 1 mm in thickness. Colleagues pointed out that because of a lack of standardization interobserver variablility would be high.

2. The presence of mitoses in the deep portion of thick melanomas is an agreed upon criterion for differentiation of melanomas from melanocytic nevi, but mitoses are also present in some benign melanocytic nevi.

3. No single histomorphological criterion can predict the prognosis of an individual patient with melanoma.

4. Studies on the predictive value of mitoses are controversial. The validity of the statistics applied in such studies has been disputed.

5. Upstaging of some melanomas < 1mm in thickness because of the presence of mitotic figures leads to more sentinel lymph node operations, a procedure which as itself is controversial.

6. Classifications are changed so often that their validity is called into question.

All these aspects are worth consideration. At this point, the most critical is, in my opinion, the first one. If the number of mitoses in a melanoma really has a meaning, it is crucial that everybody who diagnoses melanomas histopathologically, counts them in exactly the same way. Unfortunately, the article by Balch et al. does not provide precise instructions in that regard nor does it demonstrate that in all cases included in the study mitoses were counted in exactly the same way.

How many sections should be examined? Should these be serial sections or step sections? Should they be counted on sections stained with hematoxylin and eosin or should an immunohistochemical staining for mitoses be performed? Should mitoses be counted also in intraepidermal parts of the melanoma? How does one ensure that no mitotic figures of epithelial, endothelial, inflammatory cells are counted as mitoses of the melanoma? How does one deal with melanomas arising in congenital nevi knowing that those nevi may harbor mitotic figures and knowing how difficult it is often to decide whether intradermal nests of melanocytes are part of the melanoma or of the nevus associated with it?

I would volunteer to reassess sections of the 38,918 melanomas included in the study of Balch et al. in order to identify a reproducible and practical method of counting mitoses in thin melanomas. Only after that having been accomplished I would believe statistical analysis of that data if it also shows prognostic implications of a count of mitotic figures in melanomas < 1 mm in thickness.

The topic is still open for discussion. Colleagues are invited to comment on the matter. All correspondence will be published in the next issue of this journal.

Almut Böer-Auer, M.D.

Editor-in Chief

References

1. http://www.historyworld.net

2. Balch CM, Gershenwald JE, Soong SJ, Thompson JF et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. 2009 Dec 20;27(36):6199-206. Epub 2009 Nov 16.

3. No authors listed. Question to Colleagues: Do you count mitotic figures in melanomas measuring 1 mm or less in thickness? Dermatopathology: Practical & Conceptual. 2010;16(3):5.