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Histologic overreliance on mucin for diagnosis may prove…sticky

DII small banner By Warren R. Heymann, MD
July 27, 2017

Cutaneous lupus mucinosis
Cutaneous lupus mucinosis. A, Before treatment, large nodules covered with erythematous skin are seen on the lower back. B, After treatment with systemic prednisolone and tacrolimus, the sizes of the nodules are decreased and pigmentation is observed on the surface of the nodules. (The camera angle is slightly different between A and B.)
Credit: JAAD
I am certain that I would have diagnosed tumid lupus in the patient presented by Gottesman et al (1) – a 31 year-old man with edematous papules and nodules with histologic features demonstrating subtle vacuolar alteration at the epidermal-dermal junction, a superficial and deep perivascular and periadnexal lymphocytic infiltrate, and abundant mucin between collagen bundles (1). I would have performed a lupus-relevant review of systems, checked lupus serologies, routine labs, advised sunscreen, and prescribed hydroxychloroquine. All excellent choices except for one problem — the patient had mucinous syphilis, not tumid lupus (TL).

I tip my hat in admiration of Gottesman et al. The patient’s only symptoms were ocular (blurry vision, eye pain, and light sensitivity). The skin lesions appeared in crops over the course of a year, mostly over the trunk and legs. The authors acknowledged that he had a same-sex partner with a history of syphilis, so they checked an RPR and FTA-ABS, both of which were positive. Immunohistochemistry for Treponema pallidum demonstrated a single spirochete. Treatment with benzathine penicillin G resulted in rapid resolution of his ocular symptoms and skin lesions on his flank and back, leaving atrophic scars; the chest and extremity lesions remained unchanged. The authors reasonably concluded that syphilis should be considered in the differential diagnosis in connective tissue diseases presenting with papulonodules.
The following is the abstract of a strikingly similar case presented by Patricio et al (2):

 A previously healthy 24-year-old man presented with an erythematous, non-pruritic and painless papulonodular skin rash affecting the trunk, upper arms (excluding palms), neck, face, forehead and scalp. He had a penile ulcer for the past 2 weeks, almost healed at the time of observation. The patient tested positive for syphilis and HIV-1; he claimed being negative for HIV 6 months earlier. As the palms were not affected, we performed a skin biopsy for the differential diagnosis between secondary lues and acute HIV seroconversion reaction. Benzathine penicillin (2 400 000 units) was administrated and antiretroviral therapy started. Although the skin biopsy was compatible with secondary syphilis, there was no change in the skin rash 3 weeks after the first penicillin administration. Another 2 doses of penicillin were given but 4 weeks later the rash persisted. A second biopsy revealed a mucinous skin infiltration, compatible with nodular mucinosis.
Immunohistochemistry for T. pallidum was not performed in this case. The authors suggested that their patient had a secondary papulonodular mucinosis in the evolution of healing disseminated cutaneous syphilis, questioning if the HIV itself or the immunosuppression had any role in the development of cutaneous mucinosis.

Despite the different conclusions of the two groups, given the parallels between these two cases, I think it is safe to state that syphilis can be associated with papulonodular mucinosis — determining if it is a manifestation of active infection, or an inciting stimulus of the disorder despite adequate treatment, will require further study.

The overarching teaching point, however, is that overreliance on mucin as a diagnostic criterion for connective tissue diseases may be a problematic pitfall for dermatopathologists. Histopathologically, TL resembles classic lupus erythematosus because of its superficial and deep lymphohistiocytic inflammatory infiltrates and dermal mucin. However, unlike classic lupus erythematosus, there is little or no epidermal or dermal-epidermal involvement. Antinuclear antibodies are usually negative. (3)

Further along the dermal mucinosis spectrum from TL, Nodular cutaneous mucinosis (NCM) usually presents as multiple asymptomatic, smooth, dermal nodules favoring the trunk and extremities. It may be the initial clue to the diagnosis of systemic lupus erythematosus (SLE) as patients may present with these lesions many years prior to the development of other manifestations of SLE. Nodular cutaneous mucinosis may wax and wane with SLE activity and according to circulating antibody titers. Lesions may worsen with increased ultraviolet light exposure. Approximately 79% of patients with NCM have been found to have SLE, primarily as renal and articular disease. (4)

Vincent and Chan assessed mucin in 135 skin specimens showing LE, graft vs. host disease, erythema multiforme/fixed drug eruption, lichen planus, polymorphous light eruption (PMLE), urticaria, eczematous dermatitis, psoriasis and normal skin with and without photodamage.

They demonstrated that mucin in the papillary dermis failed to distinguish among entities, concluding that while LE is associated with increased mucin deposition, scant to moderate amounts of mucin alone has limited specificity and is common in other dermatitides or photodamaged skin. (5)

Excellent case reports compel readers look back at what transpired previously and alter practice in the future. Disseminated papulonodular lesions with histologic mucin should also encourage dermatologists to consider lichen myxedematosus, generalized or pretibial myxedema, reticular erythematosus mucinosis, cutaneous focal mucinosis, or papular granuloma annulare in their differential diagnosis. (6) I will no longer look at TL or NCM without thinking about lues. Syphilis remains the ultimate mimicker.

1. Gottesman SP, et al. Late latent mucinous syphilis mimicking connective tissue disease. J Cutan Pathol 2017; 44: 578-81.
2. Patricio C, et al. Nodular mucinosis misdiagnosed as non-responsive secondary syphilis. BMJ Case Rep 2015; 2015; Aug 26; 2015
3. Hsu S, et al. Tumid lupus erythematosus. Cutis 2002; 69: 227-30.
4. Elkeeb L, et al. Nodular cutaneous mucinosis associated with systemic lupus erythematosus. Int J Dermatol 2014; 53: 1389-91.
5. Vincent JG, Chan MP. Specificity of dermal mucin in the diagnosis of lupus erythematosus: Comparison with other dermatitides and normal skin. J Cutan Pathol 2015; 42: 722-9.
6. Werth V, Newman S. Cutaneous lupus mucinosis (Papulonodular mucinosis, papular and nodular mucinosis of lupus, papular and nodular mucinosis of Gold). Clinical Advisor – CDS: Decision Support in Medicine, 2017.

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