Skin may provide first clues to systemic illness

Courtney Reynolds Schadt, M.D., F.A.A.D.Dermatologists have an opportunity to play a pivotal role in the fast, accurate identification and diagnosis of systemic diseases, according to Courtney Reynolds Schadt, M.D., F.A.A.D., assistant professor of dermatology at the University of Louisville in Louisville, Ky.

"The skin can be the presenting symptom of an internal disease,” Dr. Schadt says.  “There is a very broad differential for rashes and nodules. Having the appropriate differential diagnosis and doing a biopsy guides the diagnosis and management of patients." She spoke to colleagues at the 73^rd annual meeting of the American Academy of Dermatology (San Francisco, 2015)

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Conditions that are primarily systemic can have dermatological manifestations, with symptoms such as erythema and pruritus, points out Dr. Schadt. Chronic cutaneous graft-vs.-host disease (GVHD), for example, is a condition that can be treated with systemic therapies like extracorporeal photophoresis or psoralen ultraviolet A (PUVA) therapy. One study demonstrated that topical tacrolimus ointment can be effective for the itching and erythema in patients with steroid-refractory disease1.

Cardiac sarcoidosis

The noncaseating granulomas of sarcoidosis can mask a variety of underlying problems. Nearly any organ in the body can be involved when sarcoidosis is present, including the eyes and the heart. Approximately 25% of patients with sarcoidosis have dermatologic symptoms and, in some cases, the cutaneous symptoms are the only expressions of the condition. About 20% of patients with sarcoidosis have cardiac involvement, and the condition can be fatal, Dr. Schadt notes. Cardiac sarcoidosis is, in fact, one of the most common causes of sudden death in African-American men.

"It is important for us as dermatologists to be aware of the potential cardiac complications in patients with cutaneous sarcoidosis," says Dr. Schadt, noting that cardiac sarcoidosis can present as complete heart block. She advises that patients with cardiac sarcoidosis undergo cardiac evaluations that include an electrocardiogram and echocardiogram.2

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In a recent study, 32% of patients without known sarcoidosis presenting with unexplained Mobitz type II or third degree AV block were diagnosed with cardiac sarcoidosis.3

Treatments for sarcoidosis include steroids, doxycycline, isotretinoin, thalidamide, and the biologic agent adalimumab, Dr. Schadt notes.

NEXT: Cutaneous lymphoma

Cutaneous lymphoma           

Soon Bahrami M.D.Being current with the classification of cutaneous lymphomas is key to arriving at correct diagnoses, says Soon Bahrami M.D., assistant professor of medicine at the University of Louisville in Louisville, KY. The World Health Organization/European Organization for Research and Treatment of Cancer has put forth a classification of cutaneous lymphomas based on clinical, histological, immunohistochemical, and molecular aspects.4

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Anatomic location of a lesion can be a clue when narrowing down cutaneous lymphomas like follicular lymphoma, the most common cutaneous B-cell lymphoma, explains Dr. Bahrami.

While marginal zone lymphomas appear below the head and neck, and diffuse large B-cell lymphoma is usually present on the leg, lesions of follicular lymphoma almost always appear on the head and neck, Dr. Bahrami says.

Immunohistochemistry results are variable depending on the type of lymphoproliferative disorder, but certain key results are instrumental to diagnosing certain entities as is the case of blastic plasmacytoid dendritic cell neoplasm and CD123 positive cells, says Dr. Bahrami.

"What a dermatopathologist is excited about [are] CD123 [cells] that are diffusely positive," Dr. Bahrami explaines. "That is the clincher."

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As this disease often presents as aleukemic leukemia cutis initially only involving the skin, dermatologists are well-positioned to assist in the early detection of the condition, Dr. Bahrami adds.

"There are very few conditions where we use can use the term always, but blastic plasmacytoid dendritic cell neoplasm always presents in the skin," Dr. Bahrami says. "[Dermatologists] are the ones on the front line of this diagnosis. About 50% of patients will only have skin involvement and nothing leukemic. It is the so-called aleukemic leukemia cutis is what this refers to. In time, they will go on to develop it. Men are more commonly affected, about two-thirds of patients, and they are more commonly older patients, usually 60 and above."

Nodular, disseminated, and bruise-like lesions can present in blastic plasmacytoid dendritic cell neoplasm, but there are a host of clinical presentations. Central nervous system involvement occurs in about 10% of patients, with pulmonary involvement also being described, Dr. Bahrami says.

Biopsy is crucial to the correct diagnosis of blastic plasmacytoid dendritic cell neoplasm, according to Dr. Bahrami. "It can be a tricky one, so you want to work with a dermatopathologist who keeps abreast of lymphoid neoplasms,” she says. “They need to be able to use their immunohistochemistry to get to the right diagnosis."

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Once the right diagnosis is made, flow cytometry is necessary to see if the blood is involved. Bone marrow aspirate and CT scans should also be conducted, according to Dr. Bahrami. "Once you have determined how advanced the disease is, there is a whole host of chemotherapies and therapeutic regimens that you can try," she says. "There is nothing really great to treat this lesion."

Dr. Bahrami recommends that patients should be monitored every three months to assess if their blood has become leukemic, adding that the neoplasm is extremely aggressive, with "median survival [at] about 12 to 14 months" and a 0% survival rate at five years.

Patients who present with one single cutaneous lesion and no initial blood involvement have been reported to have better survival rates than those who present with more disseminated lesions, suggesting that there may be a cutaneous sanctuary. Dr. Bahrami says, "with a small number of cases, it is hard to say."

NEXT: Genetic syndromes

Genetic syndromes    

The skin serves as a window for some genetic syndromes, and dermatology can have a significant impact on the outcomes via early recognition, according to Dr. Bahrami.

Birt-Hogg-Dubé syndrome is an autosomal dominant condition that affects the skin with benign skin tumors that develop on the face and other sites. Pulmonary disease and other comorbidities can develop. Patients who have Birt-Hogg-Dubé syndrome need to be recognized early because they can develop spontaneous pneumothorax, Dr. Bahrami stresses.

To make the diagnosis, one major or two minor diagnostic criteria should be met, Dr. Bahrami says. 

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If colon cancer develops in Birt-Hogg-Dubé syndrome patients, it is more likely sporadic and not genetically linked to the syndrome.

In Muir-Torre syndrome, another hereditary cutaneous cancer syndrome, colon cancer is the most common visceral malignancy.

Like Birt-Hogg-Dubé syndrome, Muir-Torre syndrome is autosomal dominant. Muir-Torre syndrome occurs as a result of a defect in mismatch repair proteins. The most common protein defect in the skin lesions is related to a loss of MSH2, explains Dr. Bahrami, noting that the patients develop cutaneous sebaceous tumors that can serve as a clue to early recognition. Immunohistochemical testing can assess for loss of protein expression and allows dermatopathologists to triage these patients.

NEXT: Septic vasulopathy

Septic vasulopathy

Cindy England Owen M.D., M.S.Bacterial septic vasculopathy can occur in patients who are not immunosuppressed and studies indicate that cutaneous manifestations can be an early sign, explains Cindy England Owen M.D., M.S., assistant professor of dermatology and director of the ACB Dermatology Clinic at the University of Louisville, KY.

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She highlights as an example a pediatric case of septic vasculopathy where rapid diagnosis of community-acquired MRSA bacteremia was made using punch biopsies for frozen section, tissue culture, and hematoxylin and eosin stain. Investigations showed no immune dysfunction in the child. She adds that the focus of the original infection was not identified.

She notes one study that looked at cutaneous lesions in 32 patients diagnosed with bacterial septic vasculopathy found that cutaneous manifestations were an early event in more than 90% of patients. The mortality rate in this study was 28%, which points to the importance of early recognition of cutaneous signs for prompt diagnosis and treatment. A minority of the patients were immunosuppressed.

"The majority of patients were healthy, so a high index of suspicion should be maintained even in previously healthy patients presenting with signs of septic vasculopathy," Dr. Owen says. 5

Whereas before community-acquired MRSA (CA-MRSA) and hospital-acquired MRSA (HA-MRSA) were considered to be two distinct entities, there is now overlap in the two conditions, Dr. Owen says. 

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"We are starting to see CA-MRSA in the hospital and HA-MRSA in the community," she notes, adding that the most common CA-MRSA strain is USA 300.

In terms of choosing appropriate therapies for CA-MRSA, clinicians should obtain culture with antibiotic sensitivity testing. Because clindamycin resistance is a concern, the double-disk diffusion method or D-zone test should be performed to assess for inducible clindamycin resistance prior to using clindamycin as monotherapy.

"Make sure you know the results of the test before you use clindamycin alone," Dr. Owen says, noting that chloroquines can also develop rapid resistance to CA-MRSA and should not be used.

NEXT: Chemical toxicities

Chemical toxicities

Dr. Owen notes the case of a young patient with neuropathy and rapid onset of significant hair loss and explains how obtaining a detailed history of the patient's occupation and a simple bedside hair pull test was instrumental in establishing the differential diagnosis.

The bedside trichogram (using a dermatoscope) revealed anagen hairs on hair pull test, which, together with his pattern and timing of hair loss, suggested anagen effluvium, a rare form of hair loss in patients not undergoing chemotherapy.

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"Thallium was the culprit," Dr. Owen says, describing how further questioning revealed that the patient worked with thallium in a laboratory as part of his graduate chemistry program. Extremely elevated serum and urine thallium levels confirmed the diagnosis.

Thallium toxicity is extremely rare and often the result of intentional poisoning. In this patient, following confirmation of the diagnosis, treatment with Prussian blue and hemodialysis resulted in a complete recovery, Dr. Owen says.

NEXT: HIV and AIDS

HIV and AIDS

Nicholas Compton M.D., assistant professor in the division of dermatology at the University of Washington in Seattle, Wash., says that inflammatory conditions often represent a cutaneous manifestation of the immune dysregulation seen in patients with HIV, especially in those with advanced disease, and that both common and uncommon inflammatory skin conditions develop in patients with HIV.

Seborrheic dermatitis is the most common inflammatory skin condition seen in patients with HIV and can be seen at all stages of HIV, Dr. Compton says. It can be treated with topical steroids and ketoconazole or tar shampoo.

"The reason for the high prevalence is not entirely understood. It is thought to be because of the high burden of Malessezia on the skin,” he says.

In patients with HIV on antiretroviral therapy and uncontrolled psoriasis, it is preferable to choose a treatment that is not immunosuppressive, such as acitretin, Dr. Compton says.

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Dr. Compton notes that the progression of psoriasis appears to be correlated with advanced HIV disease. "It is a little bit odd that you get a worsening of your psoriasis, a Th1 mediated disease, in more advanced (HIV) disease because of the Th2 predominant cytokine profile in advanced HIV," he says, adding that patients with HIV may present with several morphologies of psoriasis overtime or concomitantly.

Adam D. Lipworth, M.D.Psoralens plus ultraviolet A (PUVA) may not be a suitable therapy for patients with HIV who develop psoriasis because these patients can be photosensitive as a result of HIV disease itself or because of the HIV therapies that they are taking, Dr. Compton explains. Narrow band UVB (NB-UVB) appears to be safe, however.

Dermatologic conditions like onychomychosis and seborrheic dermatitis are also very common in HIV patients. Non-specific rash can result with HIV infection and, if a patient's HIV status is unknown, that patient should be tested, says Adam D. Lipworth M.D., an instructor at Harvard Medical School and Director, Program for Infectious Diseases of the Skin, and Director, Process Improvement, Department of Dermatology, Boston, Mass.

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Umbilicated papules with a white core suggest molluscum, a condition that signifies low CD4 count. "Giant facial molluscum in HIV signals advanced immunosuppression or can be a manifestation of the immune reconstitution inflammatory syndrome (IRIS)," Dr. Lipworth says.

Herpes simplex with acyclovir resistance, most commonly seen among HIV patients, can often be effectively treated with high dose valcyclovir or acyclovir, though refractory cases require thymidine-kinase independent medications, Dr. Lipworth notes.

Carrie Kovarik M.DCarrie Kovarik M.D., associate professor of dermatology, dermatopathology, and infectious disease at the University of Pennsylvania in Philadelphia, Penn., discussed skin malignancies related to HIV.

Kaposi's sarcoma, which can have cutaneous manifestations, is the malignancy that has the highest relative risk of development in patients with AIDS. Leiomyosarcoma is one malignancy related to Epstein-Barr virus that is linked to AIDS, particularly in children.

The beneficial effect of antiretroviral therapy may be less pronounced when human papilloma virus (HPV)-related disease has progressed with HIV immunosuppression, because HPV-specific immunity has been irreversibly damaged and/or HPV-related changes have persisted for long periods of time, says Dr. Kovarik.

"The damage has been done, and patients may be forever predisposed to squamous cell carcinomas, for example," Dr. Kovarik says.

What may appear as routine warts in locations such as the areas around the fingernails may actually be digital squamous cell carcinoma, linked to high-risk HPV types, Dr. Kovarik notes. "If you have transplant patients or patients with HIV/AIDs, monitor them and treat them aggressively," she says.

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Oral lesions can present in patients with HIV and HPV, in particular, so clinicians should look for this condition, mainly in the men having sex with men population, Dr. Kovarik says. "Look in [their] mouths, and I encourage you to treat the condylomas that you see,” she says.

Extensive flat warts can be present, particularly in adults who have HIV and HPV, and they can be adequately treated with glycolic acid, Dr. Kovarik.

Recent research and a recent classification puts forth that children with HIV who present with Kaposi's sarcoma have better outcomes if they have limited skin or lymph node involvement.6

"The staging system is different from adults," Dr. Kovarik says. "Those who had fewer skin lesions without visceral involvement did better."

Disclosures: Dr. Schadt, Dr. Bahrami, Dr. Owen, Dr. Lipworth, Dr. Kovarik, and Dr. Compton all report no relevant disclosures.

References:

1. Choi CJ, Nghiem P. Tacrolimus ointment in the treatment of chronic cutaneous graft-vs.-host disease: a case series of 18 patients. Arch Dermatol. 2001;137(9):1202-6.

2. Kron J, Ellenbogen KA. Cardiac sarcoidosis: contemporary review. J Cardiovasc Electrophysiol. 2015;26(1):104-9.

3. Nery PB, Beanlands RS, Nair GM, et al. Atroventricular block as the initial manifestation of cardiac sarcoidosis in middle-aged adults. J Cardiovasc Electrophysiol. 2014;25(8):875-81.

4. Burg G, Kempf W, Cozzio A, et al. WHO/EORTC classification of cutaneous lymphomas 2005: histological and molecular aspects. J Cutan Pathol. 2005;32(10):647-74.

5. Delgado-Jiménez Y, Fraga J, Requena C, et al. Acute bacterial septic vasculopathy. Int J Dermatol. 2013;52(9):1071-80.

6. Cox CM, El-Mallawany NK, Kabue M, Kovarik C, Schutze GE, Kazembe            PN, Mehta PS. Clinical characteristics and outcomes of HIV-infected children diagnosed with Kaposi sarcoma in Malawi and Botswana. Pediatr Blood Cancer. 2013;60(8):1274-80.