Diagnosing nail unit melanomas at a faster clip
By Warren R. Heymann, MD, FAAD
Aug. 16, 2023
Vol. 5, No. 32
Every dermatologist has examined a pigmented nail, wondering if the pathologic process reflects a nail unit melanoma (NUM) or subungual melanoma (SUM) versus a benign melanocytic lesion (melanocytic activation, lentigo, or nevus), pigmented onychomycosis, or hemorrhage. A definitive diagnosis requires a nail unit biopsy, but patients may be reluctant to have the procedure performed due to the risk of nail dystrophy. Dermatologists may also be leery about the procedure, not only because of the cosmetic concerns but also because of a lack of training on properly performing a soft-tissue specimen from the nail unit, and/or the perceived technical difficulty of a nail unit biopsy. (1)
It is essential to diagnose a NUM as soon as possible. Although it is understandable why the diagnosis of a NUM may be delayed (patients — or their clinicians — may not examine the nails often enough or may shy away from a biopsy), that is not an excuse. NUM accounts for an estimated 0.7% to 3.5% of cutaneous melanomas in whites and up to 20% of melanomas in dark-skinned and Asian populations. By the time NUM is diagnosed, the median Breslow thickness has been reported to be between 3.2 and 4.0 mm with 5-year survival ranging from 18% to 58%. Compared with similarly staged non-acral melanomas, acral melanomas have higher rates of locoregional recurrence and worse survival. According to Zhang et al, “NUM most commonly presents as a pigmented longitudinal band in a single nail plate. Longitudinal melanonychia that occupies more than 40% of the width of the nail plate is concerning for NUM. Radial growth phase NUM may not affect integrity of the nail plate, but vertical growth phase can cause nail dystrophy and ulceration. Extension of pigment to the nail folds (Hutchinson sign) is a helpful clue but is not pathognomonic for malignancy. One-quarter of NUM lack pigment.” (2)
Is there a simple, rapid, painless way to identify patients at risk for NUM? Nail clippings may be the answer.
Diagnostic applications of nail clippings have been thoroughly reviewed by Stephen et al, finding utility in diagnosing onychomycosis, hemorrhage, localizing the origin of pigmentation within the nail matrix in cases of melanonychia, onychomaticoma, and forensics (used for perpetrator DNA and heavy metal poisoning). (1,3) This commentary focuses on using nail clippings to expedite the diagnosis of NUM.
Before we discuss the nail plate itself, Ruben and McCalmont emphasize that “close scrutiny of epithelium attached to or dangling from the nail plate represents an overlooked means to facilitate the diagnosis of nail unit melanoma.” The authors have evaluated medicolegal consultations in which the diagnosis of NUM was missed because the plate was examined but the dangling epithelium was ignored. They conclude that the attached ungual epithelium should be examined to keep microscopists in the laboratory rather than the courtroom. (4)
In 2015, Lee et al reported the case of a 65-year-old woman with a color change of the first fingernail demonstrating longitudinal melanonychia and brown pigmentation around the proximal nail fold. Because of a clinical impression of SUM, the nail was extracted. Histopathology from the nail plate showed numerous variably sized cellular remnants. The attached nail plate epithelium had a considerable number of atypical melanocytes. Immunohistochemical analysis demonstrated that the cellular remnants within the nail plate were positive for HMB45. The author noted that in unpublished data, in benign pigmented lesions, melanin is mainly observed in the nail plate rather than in cellular remnants, suggesting that the extracted nail plate alone could be helpful in diagnosing SUM. (5)
Subsequently, there have been several reports confirming Lee’s findings. A particularly instructive case was reported by Boni et al, in which a 36-year-old man with presumed traumatic onychodystrophy demonstrated S-100+ melanocytes within the nail plate (which was sampled to rule out secondary onychomycosis). A standard nail unit biopsy was then performed, revealing melanoma in situ. (6)
Rodriguez et al reported an additional case of NUM in situ in a 58-year-old woman with longitudinal melanonychia of the right thumbnail who initially declined a nail matrix biopsy but relented after melanocyte remnants were found in the nail plate. Even if melanocyte remnants are not observed, patients with melanonychia can benefit from a nail clipping by determining the location of the pigmentation within the nail plate for surgical planning (ventral nail plate pigment correlates with pigmentation of the distal matrix, while dorsal plate pigment suggests that the pigment originates in the proximal matrix). The authors discuss two significant pitfalls in utilizing nail plates to serve as triage for NUM: 1) the nail plate sample should be at least 4 mm in length (best obtained by a dual action nail nipper); 2) the lack of reliability of immunoperoxidase staining in nail plate specimens (which may be secondary to nail softening techniques in processing). Despite these vagaries, the authors implore dermatologists and dermatopathologists to routinely evaluate melanonychia by submitting nail clippings for histopathology. (7)
It is exciting to realize that a simple nail clipping may help diagnose NUM. More studies are necessary to have a grasp on the sensitivity and specificity of the procedure. Patients with melanocyte remnants in nail clippings must have a standard nail unit biopsy. If the clinical suspicion for NUM is high, and a nail clipping is unrevealing, I would still encourage that patient to have a standard nail unit biopsy. This simple procedure may diagnose life-threatening NUMs at a faster clip.
Point to Remember: Nail clippings demonstrating melanocyte remnants serve as a triage for those patients who should have a nail matrix biopsy performed to evaluate for a nail unit melanoma.
Our expert’s viewpoint
Adam Rubin, MD, FAAD
Associate Professor of Dermatology at the Hospital of the University of Pennsylvania
As a dermatologist and dermatopathologist focused on nail unit disorders, I have always had an interest in nail clippings, and this interest continues to grow. Nail clippings can be helpful for the diagnosis of many different conditions affecting the nail unit. Most commonly nail clippings are performed by dermatologists in the investigation of onychomycosis. For the dermatologist, nail clippings have many advantages. Patients are familiar with the procedure because it is part of routine grooming. When clipped correctly, the procedure itself should be painless. There are no special procedures to submit the specimen, as the nail clipping can be placed in a formalin-filled container in the same way a skin biopsy would be.
With increasing experience and accumulated data in the literature, it has become clear that the presence of melanocytes or melanocyte remnants in the nail plate is an important diagnostic feature associated with an underlying diagnosis of nail unit melanoma. In two prior reports, I had seen melanocytes and melanocyte remnants in nail clippings from patients who had the nail clippings performed to evaluate for onychomycosis. In this most recent report, the patient had an obvious pigmented lesion in the nail unit yet she specifically had declined a nail matrix biopsy. Nail clipping was done purposefully for the evaluation of melanoncychia. All of these cases were ultimately diagnosed as nail unit melanoma in-situ.
The benefits of a nail clipping in the evaluation of melanonychia are many and include providing information regarding the location of pigmentation in the nail matrix for surgical planning, as well as potentially demonstrating histopathologic features of other dermatoses and tumors affecting the nail unit. Additionally, the dermatopathology laboratory receiving the specimen does not need any special materials to process or evaluate the nail clipping, and the turnaround time is similar to other specimens from other parts of the skin.
Caution must be invoked in the interpretation of the results of nail clippings sent for the evaluation of melanonychia. While the presence of melanocytes or melanocyte remnants in the nail clipping is a red flag to move forward urgently with a nail matrix biopsy, the absence of this finding does not exclude that a melanoma is present in the nail unit that was clipped. As Dr. Heymann mentioned, there are some technical challenges related to the use of softening solutions applied to soften the nail for sectioning in the laboratory that often affect the ability of melanocytes or melanocyte remnants staining with immunoperoxidase melanocyte markers reliably. The lack of immunoperoxidase staining does not exclude that melanocytes or their remnants are present, the recognition of them is mostly done with examination of the hematoxylin and eosin-stained sections of the nail clipping. The age of the patient is very important. Melanocytes or their remnants may be seen in the nail plate in children with benign lesions, so the presence of this feature in a pediatric nail clipping should be interpreted with caution.
On a practical level, when performing the nail clipping, it is important to clip the nail all the way across, in an even fashion, preferably in a single piece that definitely includes the area of pigmentation in it. By clipping the nail in this manner, it can be most easily handled by the dermatopathology laboratory staff, and the best quality sections can be obtained for the dermatopathologist to interpret.
As Dr. Heymann notes, more work is needed to evaluate the sensitivity and specificity of nail clippings for the evaluation of melanonychia and the diagnosis of nail unit melanoma. At this juncture, we know that it is certain that this diagnostic maneuver will offer helpful information for each patient and their dermatologist to determine the best next steps to determine the etiology of their melanonychia.
Stephen S, Tosti A, Rubin AI. Diagnostic applications of nail clippings. Dermatol Clin. 2015 Apr;33(2):289-301. doi: 10.1016/j.det.2014.12.011. Epub 2015 Feb 24. PMID: 25828720.
Zhang J, Yun SJ, McMurray SL, Miller CJ. Management of Nail Unit Melanoma. Dermatol Clin. 2021 Apr;39(2):269-280. doi: 10.1016/j.det.2020.12.006. Epub 2021 Feb 11. PMID: 33745639.
Grover C, Bansal S. The nail as an investigative tool in medicine: What a dermatologist ought to know. Indian J Dermatol Venereol Leprol. 2017 Nov-Dec;83(6):635-643. doi: 10.4103/ijdvl.IJDVL_1050_16. PMID: 28980535.
Ruben BS, McCalmont TH. The importance of attached nail plate epithelium in the diagnosis of nail apparatus melanoma. J Cutan Pathol. 2010 Oct;37(10):1028-9, 1027. doi: 10.1111/j.1600-0560.2010.01593_2.x. PMID: 20718897.
Lee DY. Variable Sized Cellular Remnants in the Nail Plate of Longitudinal Melanonychia: Evidence of Subungual Melanoma. Ann Dermatol. 2015 Jun;27(3):328-9. doi: 10.5021/ad.2015.27.3.328. Epub 2015 May 29. PMID: 26082594; PMCID: PMC4466290.
Boni A, Chu EY, Rubin AI. Routine nail clipping leads to the diagnosis of amelanotic nail unit melanoma in a young construction worker. J Cutan Pathol. 2015 Aug;42(8):505-9. doi: 10.1111/cup.12558. PMID: 26272255.
Rodriguez O, Elenitsas R, Jiang AJ, Abbott J, Rubin AI. A call for nail clipping histopathology to become an essential component of the routine evaluation of melanonychia: Benefitting patients as a triage and surgical planning maneuver. J Cutan Pathol. 2022 Dec 14. doi: 10.1111/cup.14377. Epub ahead of print. PMID: 36515435.
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