Clues for When to Suspect High-Mitotic-Rate Melanoma

Veronica Hackethal, MD

August 21, 2014

For the first time, clinical characteristics of high mitotic rate melanomas have been linked to histopathologic changes. The findings could aid in clinical decision-making and the earlier identification of these types of aggressive cancers, researchers say.

"We found that patients at risk for high-mitotic-rate melanoma tend to be male, elderly, and have a history of cumulative solar field damage," said researcher Sarah Shen, BMedSci, MBBS, a dermatology trainee at Alfred Hospital in Victoria, Australia. "Clinically, these tumors can appear atypical and are more likely to be nonpigmented, rapidly growing, nodular, and/or ulcerated. Practicing physicians should be made aware of such characteristics of aggressive primary melanomas."

Mitotic rate is a measure of how fast a tumor cell is dividing. The higher the mitotic rate, the worse the prognosis, Dr. Shen explained.

The study was published online on August 20 in JAMA Dermatology.

Not all melanomas appear overtly suspicious.

"The take-home message from our study for patients is that if there is any lesion that is rapidly changing or growing, please see your doctor because not all melanomas appear overtly suspicious," Dr. Shen said. "Clinicians should heed patients' concerns when they present with a lesion that has recently changed, and not dismiss it as benign or inflammatory, regardless of how innocuous it may look clinically."

For their cross-sectional study, Dr. Shen and colleagues conducted a retrospective review of 2397 cases of primary invasive melanoma treated at Alfred Hospital from January 2006 to December 2011. Histologic confirmation was available for 1500 primary invasive melanomas from 1441 patients.

Two dermatopathologists reviewed the original slide specimens, and all patients underwent clinical skin examination.

Of patients with the highest mitotic rates (≥10/mm²), 45% were 70 years or older, and men outnumbered women by more than 2 to 1.

Table. Characteristics Associated With High-Mitotic-Rate Melanoma

Characteristic Odds Ratio 95% Confidence Interval
History of solar keratosis 1.3 1.1–1.6
Head and neck location 1.4 1.0–1.9
Male 1.5 1.3–1.8
Nonpigmentation 1.9 1.4–2.5
Ulceration 2.0 1.5–2.7
Age ≥70 years 2.1 1.7–2.8
Nodular subtype 2.5 1.8–3.4
Tumor thickness 1–4 mm 4.5 3.2–6.1
Rapid growth 12.5 8.4–18.5
Tumor thickness >4 mm 12.6 7.5–21.1


The nodular melanoma subtype was strongly associated with a higher mitotic rate, with superficial spreading and lentigo maligna melanoma linked to inactive mitotic rates, Dr. Shen reported. Desmoplastic melanoma, a rare type of malignant melanoma, tended to be like nodular melanoma, but had low mitotic activity.

Patients who had previously experienced blistering sunburns had lower mitotic activity (P = .02), as did patients with a family history of melanoma (P < .001).

Of note, 62% of melanomas with higher mitotic rates (≥5/mm²) were detected by patients, not their healthcare providers.

There is a dearth of clinical guidelines on ways to clinically differentiate skin lesions with high mitotic rates from less aggressive ones, write Samuel Balin, MD, PhD, a dermatology resident at the David Geffen School of Medicine at University of California, Los Angeles (UCLA), and Raymond Barnhill, MD, MSc, professor of pathology and codirector of dermatopathology at UCLA and melanoma researcher at Institut Curie in Paris, in an accompanying editorial.

Drs. Balin and Barnhill acknowledge that the study is "scientifically sound," but point out that it is not clear which method best assesses and links mitotic activity to clinical outcome.

"Evaluating pigmented lesions in the clinical setting is a difficult task," they explain. However, Dr. Shen and colleagues "provide clinicians with more data and ultimately another tool to factor into their clinical decision-making process."

"By understanding the clinical characteristics of more rapidly growing tumors, clinicians can better guide their own screening and treatment decisions and better counsel patients, from diagnosis through treatment, and ultimately to prognosis." Drs. Balin and Barnhill note.

The results of this study might encourage clinicians to "pay more attention to a subpopulation of patients that may be at increased risk for high-mitotic-rate melanoma and increased mortality," Dr. Barnhill told Medscape Medical News. That subpopulation includes elderly men and people with melanomas that are found in the head and neck, are growing rapidly, are without pigmentation, and are without standard clinical characteristics found in common melanomas.

Several issues could be at play in the results. One is that this study calls attention to a particular type of melanoma that arises de novo, rather than the more traditional type linked to significant sun exposure, family history, and nevi. Another possibility is that elderly men might not pay as much attention to their skin, Barnhill pointed out.

"One simple factor may be that we're simply seeing melanomas at a more advanced stage because they're not being detected earlier," he said.

Studies are needed to assess the best way to detect mitoses and how well these methods correlate with prognosis, Dr. Barnhill noted. Reproducibility might also be an issue.

"In general, Australia has the highest incidence of cutaneous melanoma in Caucasian patients," Dr. Barnhill added. "Then the question becomes: can these results be generalized to populations in other western countries? I believe the study is good and it may be generalizable, but I would say one cannot be certain of that."

"Cancer screening in general is a difficult problem because there has been evidence that it can do harm as well as good," Dr. Barnhill emphasized. He noted that potential harms include increased skin biopsies, patient morbidity, and psychological harm. "In the context of not wanting to do more harm than good, certainly everyone would agree that we want to detect melanomas in high-risk populations at a less-developed stage in order to decrease mortality."

The authors, Dr. Balin, and Dr. Barnhill have disclosed no relevant financial relationships.

JAMA Dermatol. Published online August 20, 2104. Abstract, Editorial


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