By Jan Bowers, contributing writer

“You can’t trust the nail,” remarked Richard K. Scher, MD, a dermatologist with nearly 50 years of experience in treating nail disorders. When it comes to detection and diagnosis of nail unit cancer, “you do the best you can, but it’s easy for errors to occur.” Dr. Scher, who is clinical professor of dermatology at Weill Cornell Medicine/Dermatology, noted that half the cases of nail unit, or subungual, melanoma are missed on the first examination. Even when telltale longitudinal melanonychia is spotted, he said, many physicians are hesitant to perform a biopsy for fear of permanently damaging the nail. Squamous cell carcinoma (SCC) of the nail unit can be equally elusive and can mimic several benign conditions, such as infections — sometimes causing patients to undergo months of ineffective treatment before cancer is suspected.

Because nail cancer is rare, many dermatologists have little or no first-hand experience in diagnosing and treating it. Dermatology World talks with four nail experts for insights into what to look for in a clinical exam, key dermoscopic features, when and how to biopsy, and current treatments.

Subungual melanoma

A subset of acral lentiginous melanoma, subungual melanoma is fortunately rare — comprising only 0.7 to 3.5% of all melanoma cases. Because diagnosis is often delayed, it has a poorer prognosis than cutaneous melanoma: the five-year survival rate ranges from 16 to 87%. It occurs most often on the thumb and big toe, and is more common in darker-skinned individuals than in Caucasians, Dr. Scher said. In children it’s extremely rare. “In teenagers and young adults it’s also rare but it happens, and as you get into adulthood, especially the elderly, it gets more common,” said Adam I. Rubin, MD, associate professor of dermatology at the Hospital of the University of Pennsylvania and a specialist at the Penn Medicine nail clinic.

Causes elusive

The causes of subungual melanoma are a topic of lively discussion, with no agreement on a single underlying cause. “Family history is definitely a factor and trauma is a factor. It’s sometimes associated with an infection,” said Dr. Scher. “The nail plate filters out UVB radiation completely and only a small portion of UVA penetrates so UVA light is thought to be a very small potential factor,” said Dana Stern, MD, assistant clinical professor of dermatology at the Mount Sinai Medical Center and a nail specialist. “We believe that nail melanoma occurs due to the complex interplay between genetics and trauma to the nail. There is some new data showing a possible causal relationship with UV, but more research needs to be done.”

Trauma to the nail has long been suspected as a potential cause of melanoma, but the relationship is something of a chicken-and-egg question. “At this point, the association is not clear,” said Dr. Rubin. “It’s a relatively common situation where someone will traumatize a nail, then they see something there that they show a dermatologist, and there may be a melanoma there. So we don’t know if the trauma just brings that nail to the attention of the patient, and they see that there’s been a change, or if there is some relationship between the nail being traumatized and the development of a cancer at that site. More information is needed about that.”

Clinical examination, sans polish

In a clinical examination, “a thorough examination of all 20 nails, oral mucosa, and relevant history is key,” said Dr. Stern. Dr. Scher insists that every physical exam should include the fingernails and toenails. In addition, “patients should be told in advance that they must remove their nail polish. I won’t accept patients who refuse to take their polish off.” Dr. Stern agrees that nail abnormalities can be easily camouflaged with nail cosmetics, contributing to a delay in potential diagnosis. “I saw a woman in her early 20s who had been covering a nail melanoma with an acrylic nail because she thought it was ugly.”

What are the key clues to detection of subungual melanoma? Dr. Stern cites the “ABC rule” from an article published by Levit, Kagen, and Scher, et al in the Journal of the American Academy of Dermatology (2000; 42:269-274):

• Age, race: Range 20-90 years old, peak at 5th to 7th decades. Asian, African, Native American.

• Band (nail band): Brown or black pigment; breadth ≥ 3mm; border irregular or blurred.

• Change: Rapid increase in size or growth rate of nail band; lack of change: failure of nail dystrophy to improve despite adequate treatment.

• Digit involved: Thumb — hallux — index finger; single digit — multiple digits; dominant hand.

• Extension: Extension of pigment to involve proximal or lateral nail fold (Hutchinson’s sign) or free edge of nail plate.

• Family or personal history of previous melanoma or dysplastic nevus syndrome.

Physicians should also look for signs of cuticle manipulation, or picking, which can lead to melanocytic activation, Dr. Stern added, and they should ask about drugs the patient may be taking (particularly tetracycline, HIV medications, anti-malarials and chemotherapy drugs) and whether the patient is pregnant.

The majority of patients with subungual melanoma present with longitudinal melanonychia (a dark streak in the nail), which dermatologists readily recognize as suspicious, Dr. Rubin said. “However, there is a relatively high percentage of amelanotic melanomas that can be very difficult to diagnose, and can mimic benign conditions — an ingrown nail, for example, or a pyogenic granuloma. It’s very tricky, so I think you have to have a high suspicion and a low threshold to biopsy the nail if it’s not responding to therapy, because these amelanotic melanomas will get worse if they’re ignored. When I think about the cases of amelanotic melanoma that I’ve seen, often it’s a surprise. They can have a very benign or nonspecific appearance.”

Dermoscopy clues

Although not a substitute for biopsy, dermoscopy can be extremely valuable in helping to distinguish melanoma from benign conditions, Dr. Scher noted. He described some dermoscopic features that serve as clues for identifying specific conditions: Melanocytic activation “produces regular gray/brown lines. Lentigo lines are regular, thinner, and usually brown. The nevus has brown lines with dots or globules, and — very importantly — nests of melanocytes. When it goes beyond that and becomes melanoma, you see irregular spacing, irregular thickness, and loss of parallelism. With dermoscopy, regularity is usually good and irregularity is definitely not good.”

For Dr. Stern, the key is to be able to recognize a micro-Hutchinson sign on dermoscopy at the periungual skin. “Any periungual pigment on dermoscopy will automatically equate to a need for biopsy,” she said. “When the bands are brown or grayish background with thin, regular gray lines — almost homogenous by the naked eye — they should be watched with serial dermoscopy every six months, and if stable, this follow-up schedule can be elongated. This pattern fits the majority of longitudinal melanonychias, which rarely if ever progress to melanoma. The melanonychias with darker regular lines within and pseudo-Hutchinson signs can be more challenging and require more frequent follow-up, and if there’s a change, biopsy.”

As a reference for dermoscopic features, Dr. Stern recommended an International Journal of Dermatology article titled “Proposed classification of longitudinal melanonychia based on clinical and dermoscopic criteria” (2014;53(5):581-585). The South Korean authors of a recent JAMA Dermatology article (2018;154(8):890-896) investigated the dermoscopic findings of 19 patients with biopsy-proven subungual melanoma in situ (SMIS) and 26 patients with benign longitudinal melanonychia and established a predictive scoring model for the diagnosis of SMIS in patients with adult-onset longitudinal melanonychia affecting a single digit.

Biopsy challenges

Because malignancies of the nail unit can mimic benign conditions, and vice versa, obtaining a biopsy is critical to making a definitive diagnosis of a clinically suspicious lesion, said Christopher J. Miller, MD, director of the Penn Dermatology Oncology Center. However, practitioners face a couple of barriers. “First, most people don’t have the benefit of doing a lot of nail procedures. They’re uncomfortable with the anatomy,” he explained. “Second, it’s hard to do a definitive diagnosis by doing a biopsy through the nail plate, because that’s not where the diagnosis lies in most cases. You need to biopsy the matrix for melanoma, and often, the nail bed for squamous cell carcinoma. The matrix extends about half the distance from the edge of the lumula to the joint, so if you have a dark, pigmented streak, usually to get to the right place you have to reflect the proximal nail fold back toward the joint so you can see. Your biopsy should sample where the pigment starts within the matrix.” The larger the portion of the matrix that’s removed, the higher the likelihood that the nail plate will grow back abnormally, Dr. Miller said. “And if you remove all of the matrix, it won’t grow back at all. However, your first priority has to be the biopsy.”

Another challenge to diagnosis, said Dr. Rubin, “is having a pathologist who is familiar with interpreting specimens from the nail. They are different and need different processing by the lab staff than pathology specimens from other parts of the skin. If you’re not sure if your pathologist has a good handle on how to interpret nail pathology, then you may be more reluctant to do the procedure.”

For typical longitudinal melanonychias that are located within the central nail plate, “a matrix shave biopsy has become the preferred technique among many nail specialists,” said Dr. Stern. “A 3mm punch biopsy of the matrix is also appropriate, but more ideal when the pigment is less than 3mm. A 3mm punch biopsy is the simplest and most efficient of the nail biopsy techniques for longitudinal melanonychia, and is a great technique for entry-level nail surgery.”

Most dermatologists don’t have access to nail specialists, but “you don’t need a nail specialist to do a great nail biopsy,” Dr. Rubin said. Dr. Miller, who offers instruction in biopsy techniques at AAD meetings (see sidebar) concurred, insisting that any dermatologist who understands nail anatomy can perform a high-quality nail unit biopsy.

Treating in situ and invasive melanoma

Years ago, “many patients underwent amputation, even for in situ melanoma. If you had asked the surgeon, he would have said you never know if you’ve gotten the whole thing out unless you amputate the digit,” said Dr. Scher. “Now we know that’s not necessary, and conservative surgery is more common.” Dr. Miller sees that shift as part of a broader trend, noting that “all of surgery has undergone a shift from the idea that more is better to the idea that precision is better.” However, the shift from amputation to precision surgery for nail unit tumors has been slower, he believes, because “the nail unit anatomy is so specialized, and so few people are experts at it.” Dr. Rubin concurred that the standard of care is now functional surgery, where wide excision of the nail unit is performed but the remainder of the digit is left intact. “That allows the patient to continue to use the digit in the normal way, but they don’t have a nail.” The wound can be covered with a skin graft, he added, or left to heal by secondary intention.

The treatment decision is based on how far the melanoma has advanced, Dr. Rubin said. For melanoma in situ (the majority of subungual melanomas), removal of the nail unit is generally sufficient to prevent recurrence. Melanoma that has spread to the bone requires amputation. But for those in between? “The controversy lies with invasive melanomas that maybe are invasive but not extensive. That might be the most difficult area we’re dealing with at this time, because there are no specific guidelines about the depth at which a melanoma either requires amputation or can safely be treated with functional surgery.”

The extent of invasion is determined through the microscopic appearance of either a biopsy sample or an entire excised specimen, Dr. Miller said. He added another compelling reason that detection in the in situ phase is critical because there is very little soft tissue between the nail matrix and the bone of the distal phalanx. “If you have an invasive melanoma originating in the nail matrix, it may be difficult to get a clean margin of soft tissue superficial to the bone, and you may be forced to amputate just as a matter of safety because you can’t be sure that your deep margin is clear. If you have melanoma in situ, you should not need to amputate.” Mohs surgery is appropriate for some melanomas, he added.

Identifying nonmelanoma cancer of the nail

As with cutaneous cancers, both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) can occur in the nail unit. However, BCC in the nail is so rare that Dr. Miller said he has never treated one, and medical literature on the topic consists mostly of small case studies. SCC is also relatively rare (though more common than nail unit melanoma), with an estimated incidence ranging from three cases in 250,000 hospital admissions to 14 cases in 50,000 dermatological consultations, according to a recent review of the literature (J Hand Surg Am. 2018;43:374-379). This analysis of 74 international publications found that SCC of the nail unit affected more men than women (70% vs. 30%), and the mean age at presentation was 61 years (patient age ranged from 22 to 92). The study also demonstrated a strong correlation with human papillomavirus (HPV), a condition that Dr. Miller said he sees in the majority of his patients with SCC of the nail. Other predisposing factors identified in the study include skin contact with certain chemicals (including arsenic), exposure to UV light and ionizing radiation, trauma, immunosuppression, tobacco use, and congenital conditions such as xeroderma pigmentosa and epidermodysplasia verruciformis.

SCC of the nail can present in a number of different ways, “which can also make it confusing,” said Dr. Rubin. “One way would be an oozing area of space under the nail. Another could be a growth that looks like a wart but is not responding to therapy, or is extensive.” Most nail unit SCCs start on the skin folds around the nail and then grow under it, said Dr. Miller, “but you can get nail unit SCCs that start subungually. If you have a nail unit SCC that’s limited just to the subungual epithelium, under the nail plate, it usually presents as a red streak or spot. Or, the nail plate will separate from the nail bed (onycholysis).”

Benign conditions such as trauma and fungal infection can result in onycholysis, so a biopsy may be necessary to determine the presence of SCC. Particularly in high-risk patients with HPV, any time a nail disorder looks suspicious and does not respond to therapy, a biopsy is needed, Dr. Rubin said. A punch or shave biopsy can easily be performed on the nail folds, he noted, but “in order to access the matrix you have to recline the proximal nail fold, and in order to get to the nail bed, you have to do some kind of avulsion. Those are tactically more difficult and time-consuming.” As with nail unit melanoma, interpretation of the biopsy specimen can be challenging to a pathologist who is unfamiliar with nail malignancies, Dr. Rubin noted, but “I would say that specimens for squamous cell do tend to be a little bit easier to interpret than the specimens sent for melanoma. However, still they can be very difficult.”

Treatment options

Once the diagnosis is made, the treatment for SCC of the nail unit is relatively straightforward, Dr. Rubin said, adding that “in general” the treatment is Mohs surgery, although amputation may be necessary if the malignancy has spread to the bone. The analysis published in the Journal of Hand Surgery revealed “bone involvement” in half the cases. The authors concluded that “a wide local surgical excision should be performed when there is no involvement of the distal phalangeal bone…when SCCNU does invade bone, amputation of the distal phalanx or disarticulation of the involved digit is indicated.” However, in Dr. Rubin’s view, “most of the time Mohs surgery can take care of the problem. Of course, these cases that are intermediate are probably more difficult,” he remarked. “The more extensive a tumor is, there’s not much give in that area of the body. There are not that many alternative maneuvers that can be done. It’s a small space.” 

Infection inspection

Read more about diagnosing and treating onychomycosis at staging.aad.org/dw/monthly/2017/august/infection-inspection.