Preventing Misdiagnosis of Rare Skin Diseases

When it comes to diagnosing unusual dermatologic diseases, a careful history from the patient and a close eye for diagnostic work-up detail can help shorten the road from A to B and get patients on the appropriate treatment and management path.

This article offers strategies to help prevent misdiagnosis of 2 rare skin diseases: Merkel cell carcinoma and actinic prurigo.

Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is a rare, aggressive form of skin cancer. Approximately 3000 new cases of MCC are diagnosed annually in the United States. Tumors from MCC usually occur in sun-exposed areas, are common on the head and neck of older White men, and carry a high risk of recurrence and metastasis. The main risk factors for MCC include UV exposure, advanced age, and immunosuppression, and the development of MCC is associated with the Merkel cell polyomavirus.

Although the lesion itself can appear suspicious to the astute clinician, many dermatologists may miss the diagnosis upon first examination, according to Paul Nghiem, MD, PhD, professor and head of the Division of Dermatology and the George F. Odland Endowed Chair in Dermatology at the University of Washington in Seattle.

“Statistics show that even dermatologists get the clinical diagnosis of MCC wrong the majority of the time,” Nghiem said. “The main challenge is to decide that a biopsy needs to happen. Most dermatologists who biopsy an MCC will be surprised by the pathology report because MCC does not have a specific appearance and it is uncommon.”

In a systematic cohort study of 195 patients diagnosed with MCC between 1980 and 2007,¹ Nghiem and colleagues aimed to define the clinical characteristics of MCC to identify features that may help clinicians better recognize the aggressive skin cancer. Their findings showed that 88% of MCCs were asymptomatic (nontender)—despite rapid growth in the prior 3 months (63% of lesions) and being red or pink (56%). In addition, 56% of lesions were presumed to be benign, with a cyst or acneiform lesion being the most common diagnosis given (32%), followed by lipoma (6%) and dermatofibroma (5%).

The investigators summarized the most significant clinical characteristics of MCC in an AEIOU acronym:

• A—asymptomatic
• E—expanding rapidly
• I—immunosuppressed
• O—older than 50 years
• U—UV-exposed sites

According to Nghiem, almost all patients with MCCs will have 3 or 4 clinical features in AEIOU. He noted, however, to be cautious because these characteristics are not MCC specific and may apply to other lesions. A biopsy will be telling.

“If you’ve got an older patient who is immunosuppressed and has a history of nonmelanoma skin cancer...and sun-damaged skin and presents with a suspicious quickly growing nodule on the skin, a biopsy should be performed and will likely be definitive,” Nghiem said.

Performing a biopsy early on is advantageous because, according to Nghiem, the cancer will have already spread beyond the primary site in more than one-third of cases. Therefore, it is paramount to treat MCC appropriately soon after the diagnosis is made.

The management of MCC is more complicated than any other skin cancer, but fortunately, there is increasing agreement in many aspects of how MCC should be managed. Nghiem noted that MCC management should follow a multidisciplinary approach. Surgery is often, but not always, the first step in treatment. Unlike melanoma, a full work-up for staging (full body scan and usually a sentinel lymph node biopsy) is indicated in almost all cases before deciding on therapy because the tumor will have spread beyond the primary site in almost half of cases.

“Clinicians should be wary and have a lower threshold to perform a biopsy in patients with prior skin cancers and a nontender lesion arising on sun-exposed skin, especially if the immune system is compromised,” Nghiem said. “Even if you’re not thinking about MCC upon first examination, such features should be of concern and make the clinician lean toward biopsy.”

Actinic Prurigo

Also having UV exposure in its pathogenesis, actinic prurigo is another rare dermatologic disease that is challenging to treat and manage. A rare form of idiopathic photodermatosis, actinic prurigo primarily affects sun-exposed areas, including the face, neck, dorsal surface of the upper extremities, lips, and conjunctival mucosa. The disease follows a chronic course, with patients typically presenting with indurated, intensely pruritic erythematous papules, nodules, and excoriated plaques on sun-exposed areas of the skin.

“When a patient presents with an intensely pruritic skin eruption that’s restricted to sun-exposed areas, dermatologists need to think of all the differential diagnoses related to photosensitive sun-induced reactions,” said Bernard A. Cohen, MD, a professor of dermatology and pediatrics at Johns Hopkins University School of Medicine in Baltimore, Maryland. “Given the fact that actinic prurigo is persistent, sometimes lasting for months, can recur, or [that] the patient [may continue] to get sun exposure, it can be a horribly itchy, life-compromising reaction.”

Current histological and research findings suggest that actinic prurigo is an ongoing type 4 hypersensitivity reaction with still unknown other immunopathogenic processes, including the involvement of the HLA-DR4 gene; the infiltration of CD4 lymphocytes, eosinophils, and mast cells; and a serum increase in IgE. Lesions appear hours or days after sun exposure (long- and short-wave UV-A and UV-B), which is contrary to the course of solar urticaria, in which skin lesions appear only minutes after UV exposure.

“Actinic prurigo may look a little urticarial at first, but it is persistent and will not disappear easily within 24 hours like urticaria would,” Cohen said. “Solar urticaria is something that lasts just minutes to hours, certainly less than 24 hours by definition, whereas actinic prurigo will be persistent and continue to spread and may eventually even involve areas that are not sun-exposed, such as the buttocks.”

The main differential diagnosis of actinic prurigo is polymorphous light eruption, followed by atopic dermatitis with photosensitivity and solar urticaria. Although actinic prurigo can affect people of all ages, approximately one-third of patients are children, with boys and girls being equally affected. In adult-onset actinic prurigo, however, women are affected 2 times more often than men.

Because many patients first develop symptoms during childhood, Cohen said the main clinical consideration to rule out in this younger population is atopic dermatitis with photosensitivity. In adults, photoallergic contact dermatitis and chronic actinic dermatitis are other dermatologic conditions that need ruled out in patients presenting with photosensitivity of a chronic nature.

Meticulous history taking is requisite during the consultation and can help clinicians rule out other potential differential diagnoses. Contrary to polymorphous light eruption and other dermatoses in which UV and photosensitivity play a central role in disease pathogenesis, actinic prurigo will be different particularly in its long-term persistence and can progress even though patients protect themselves from sunlight. Nevertheless, disease management for actinic prurigo begins with sun protection and sunlight avoidance.

Early diagnosis and proper management are key to help limit patient morbidity. Current treatments include topical antihistamines, corticosteroids, emollients, and photochemotherapy, as well as systemic therapies for severe cases.

“Topical corticosteroids are the first-line therapy, and to optimize treatment outcomes, it is crucial to apply them in the beginning when lesions first appear,” Cohen said. “The earlier you recognize the symptoms, the earlier you can start an aggressive topical therapy, [and] the better the chances of effectively treating actinic prurigo.”

Reference:

1. Heath M, Jaimes N, Lemos B, et al. Clinical characteristics of Merkel cell carcinoma at diagnosis in 195 patients: the AEIOU features.J Am Acad Dermatol. 2008;58(3):375-381. doi:10.1016/j.jaad.2007.11.020