Dermatologic Look-Alikes

Nodularis

Prurigo nodularis (PN) is a condition characterized by firm pruritic lesions caused by repeated scratching of intensely itchy skin. It often occurs secondary to other causes of itch including primary dermatologic conditions and systemic conditions.

Data on the prevalence of PN is variable. One study in individuals aged 18 to 64 years found the prevalence of PN to be 72 per 100,000 people.1 Another study reported the prevalence to range from 36.7 to 148.3 per 100,000 people based on the specific diagnostic code used.2 Mean age of presentation is in the sixth and seventh decades of life.1 The condition is slightly more predominant in females and in patients with skin of color, especially Black patients (3.4-fold increased odds compared with White people).1 The disease is significantly associated with anxiety, depression, and other mental health disorders as well as HIV and hematologic malignancies (lymphomas), diabetes, liver and thyroid disorders, and end-stage renal disease.1 Prurigo nodularis is also associated with other dermatologic disorders including atopic dermatitis, psoriasis, and neurotic excoriation.1

The pathophysiology of PN is largely attributed to immune and neural dysregulation.3 The lesions contain dense dermal infiltrates of mast cells, eosinophils, and T-cells, which release mediators and cause a powerful inflammatory response, include any conditions that might result in intense itching including primary skin conditions such as atopic dermatitis and systemic conditions such as HIV, lymphoma, diabetes, liver disease, thyroid disorders, and end-stage renal disease.

The diagnosis of PN is made clinically when patients describe severe pruritus that is constant, paroxysmal, or intermittent for 6 or more weeks.3 Patients can have associated burning or stinging sensation.3 Physical examination often reveals clustered hyperkeratotic symmetric nodules, usually on extensor surfaces. Patients should be screened for comorbidities including mental health disorders, thyroid disorders, diabetes, HIV, and malignancy.3 Patients should be encouraged to stay up to date with their age-appropriate cancer screenings.The basic laboratory tests recommended for evaluation are a complete blood cell count (CBC) and complete metabolic panel (CMP).3 Additional screens including hemoglobin A1c, thyroid function tests, HIV testing, and hepatitis serologies should also be considered in the presence of additional risk factors as discussed previously.3

A skin biopsy is not usually necessary but may be useful for diagnosis in cases with atypical presentations. Biopsy is characterized by orthohyperkeratosis, irregular epidermal hyperplasia, hypergranulosis, increased dermal fibroblasts and capillaries, and sometimes increased nerve fiber density.3 The differential diagnosis for PN includes hypertrophic lichen planus, pemphigoid nodularis, nodular scabies, multiple keratoacanthomas, cutaneous T-cell lymphoma, dermatofibromas, mastocytosis, and pilomatrixomas.4,5 resulting in intense pruritus.3 Eosinophils are key players and release specific granules such as eosinophil cationic protein, eosinophil protein X, and major basic protein, which are known to be neurotoxic.3 T-cells play a role in the severe itching and inflammation by the action of cytokines interleukin (IL)-31 and IL-4, both of which have increased activity in PN lesions.3 The dermis of PN lesions exhibits neural hyperplasia with an increase in multiple neuropeptides including calcitonin generelated peptide (CGRP) and substance P.3 The former causes neurogenic inflammation by enhancing mast cell and eosinophil activity, which in turn can perpetuate pruritus.3 Risk factors

Hypertrophic lichen planus (LP) is often misdiagnosed as PN. Hypertrophic LP may clinically appear identical to PN, though the former condition commonly presents on the lower legs and may present as thick plaques rather than nodules. On biopsy, the 2 conditions may appear similar with both showing acanthosis of the epidermis, hypergranulosis, hyperkeratosis, and increased fibroblasts and capillaries. However, in hypertrophic lichen planus, basal cell degeneration is found in the tips of the rete ridges.4 Another differential to consider is pemphigoid nodularis, an uncommon form of bullous pemphigoid, which is distinguished by its blistering lesions and biopsy with positive immunofluorescence for basement membrane immunoglobulin G (IgG) and C3 autoantibodies in the basement membrane.4

Treatment for PN is targeted at reducing itch that in turn allows the nodules to heal.3 High-potency topical corticosteroids, which target the immunologic aspect of the disease, are first-line agents.3,5 Flurandrenolide or betamethasone valerate medicated tape or intralesional triamcinolone are other potential options.3 The neurologic pathophysiology can be targeted with anesthetic agents (1% pramoxine solution, lidocaine spray), which have shown some efficacy in chronic PN.3,5 In the nonsteroidal category, 1% pimecrolimus cream is effective in reducing itch.3 Another alternative is phototherapy, especially in patients with limited treatment options; narrowband UV-B therapy is a first-line option but PUVA has also shown efficacy.3

Although topical agents and phototherapy work for some patients with PN, most are refractory to these treatments and need adjunctive systemic therapies.3 Systemic immunosuppressants such as cyclosporine and methotrexate target the immunologic aspect of PN and reduce inflammation and itch.3 Similarly gabapentin and pregabalin are systemic therapies for modulating neurologic dysregulation in PN.3 In addition, antidepressants, neurokinin-1 receptor (NK-1) antagonists, and opioid receptor modulators have shown promise.3 In 2022, the FDA approved dupilumab, which inhibits IL-4 and IL-13, for the treatment of PN. Currently, it is the only drug that is FDA approved for PN.

The patient in this case was diagnosed clinically with prurigo nodularis in the setting of atopic dermatitis and was started on therapy with dupilumab injections.

CASE #2 Hypertrophic Lichen Planus

Hypertrophic lichen planus (LP) is a variant of lichen planus. It presents as intensely pruritic, hyperkeratotic nodules and plaques most commonly located on the shins, ankles, and interphalangeal joints in a symmetric distribution, sometimes with fine scaling.6,7 Because of the pruritic nature of the lesions, chronic scratching leads to the formation of firmer, red and/or violet plaques and nodules with follicular accentuation. 6 One author describes the appearance of hypertrophic LP as similar to “rapidly cooled variants of igneous rocks”3 marked by “fine-grained or aphanitic texture” with “occasional vascular vesicular [pocked] surface and variable colors from dark pink to gray-black.”8

Data on the epidemiology of hypertrophic LP is scarce. Most estimates are based on variable data on LP as a whole, with the worldwide incidence estimated to be 1%.9 The condition occurs slightly more frequently in females with age of onset in the fifth and sixth decades of life.9 While many studies suggest that LP does not have a predilection for any particular race or ethnicity,4 some studies have identified a higher prevalence of hypertrophic LP in patients with skin of color.6

The pathophysiology of hypertrophic LP is unknown. Researchers have proposed that CD8+ T cells are activated against basal keratinocytes. Additionally, intracellular adhesion molecule-1 (ICAM-1) and Th1 cytokines such as interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, IL-1, IL-6, and IL-8 are involved in perpetuating the inflammatory response.10 Chronic inflammation, chronic venous insufficiency, Koebner phenomenon, and eosinophils are also significant drivers in the disease pathogenesis.7,11 Variable data also suggest an association between LP and hepatitis C; however, this link remains unproven.10,11 Finally, chronic hypertrophic LP and the chronic inflammation associated with intense itch-scratch cycles may also lead to the development of squamous cell carcinoma.10,11

Hypertrophic LP may be diagnosed clinically. Biopsy can confirm the diagnosis if necessary.10 Providers should question patients on medication history (to assess for the possibility of drug-induced LP), oral or genital lesions (to assess for mucosal involvement), and dysphagia (to assess for esophageal involvement).10 The patient should have a full body skin examination, including the anogenital region and mucosal surfaces in order to identify all the possible sites of disease.10 While hypertrophic LP most commonly occurs on the shins and ankles, it can also be found on the trunk, upper extremities, mucosal sites, nails, or in a generalized distribution. 11 As mentioned earlier, patients should be assessed for risk factors for hepatitis C as it has been associated with LP, and hepatitis C viral serologies can be checked in those patients.10

Histopathology reveals epidermal hyperplasia, hypergranulosis, and lamellated hyperkeratosis centered on follicular infundibula and acrosyringia.7 Basal cell damage is usually restricted to the tips of the rete ridges and band-like infiltration may be absent in the dermis of hypertrophic LP lesions.7 Finally collagen bundles are oriented vertically in the papillary dermis along with an increased amount of eosinophils.7

The differential diagnosis of hypertrophic LP includes prurigo nodularis (PN), lichen simplex chronicus, squamous cell carcinoma, psoriasis, and nodular scabies.7,11 Because of the clinical similarities between PN and hypertrophic LP, studies have focused on the role of dermoscopy in identifying the