Neutrophilic Eccrine Hidradenitis

Neutrophilic eccrine hidradenitis (NEH) was initially described in acute myelogenous leukemia (AML) patients undergoing chemotherapy.[1, 2] Neutrophilic eccrine hidradenitis has since been reported in persons with various neoplastic and nonneoplastic conditions and in otherwise healthy individuals; however, most documented cases have continued to be observed in the setting of AML, usually in association with chemotherapy; the name toxic erythema of chemotherapy has been proposed.[3] It has also been associated with other drugs, including pegfilgrastim, the antiplatelet agent ticagrelor, and infliximab, as well as various infections.[4, 5, 6, 7, 8]

Patients with this uncommon, self-limited condition usually present with fever and nonspecific cutaneous lesions. Children may develop a palmoplantar variant of neutrophilic eccrine hidradenitis unassociated with underlying disease.[9]  Plantar neutrophilic hidradenitis is associated with Pseudomonas overgrowth in sweaty or wet sneakers and has also been dubbed Pseudomonas hotfoot. A skin biopsy specimen demonstrating characteristic pathologic changes of the eccrine glands is required to confirm a diagnosis of neutrophilic eccrine hidradenitis.

Also see the Medscape articles Acute Myelogenous Leukemia and Chronic Myelogenous Leukemia.

The mechanism(s) of neutrophilic eccrine hidradenitis (NEH) is unknown, although neutrophilic eccrine hidradenitis pathologic changes observed with intradermal bleomycin injections support a direct toxic effect of chemotherapy. More than 70% of oncology patients who develop neutrophilic eccrine hidradenitis do so after their first course of chemotherapy.[10] Cases linked to chemotherapeutic agents have developed at a wide range of 2 days to 2 years after initiation. Some patients experience recurrences of the cutaneous eruption upon reintroduction of the chemotherapeutic regimens. A diagnosis of toxic erythema of chemotherapy has been proposed for this group of disorders, to emphasize the overlapping clinical and histological features with similar eruptions.[3]

Reports of neutrophilic eccrine hidradenitis heralding the onset of both AML[11] and chronic myelogenous leukemia,[12] the relapse of AML,[13] and being induced by granulocyte colony-stimulating factor[14] suggest that the condition is in the spectrum of other neutrophilic dermatoses that have been observed in patients with cancer: erythema elevatum diutinum, intraepidermal immunoglobulin A (IgA) pustulosis, pyoderma gangrenosum, subcorneal pustular dermatosis, Sweet syndrome (and it localized variant, neutrophilic dermatosis/pustular vasculitis of the dorsal hand), and vasculitis. The inflammatory infiltrate of mature polymorphonuclear leukocytes is the unifying characteristic of this group of conditions.[10]

Cases of neutrophilic eccrine hidradenitis in otherwise healthy individuals,[15] occurring with a variety of nonchemotherapeutic agents, in Behçet disease,[16] in chronic granulomatous disease,[17] and in the setting of various infections suggest it could simply be an altered inflammatory response to nonspecific stimuli. Neutrophilic eccrine hidradenitis in young children may be triggered by thermal damage of eccrine glands.[9]

The cause of neutrophilic eccrine hidradenitis (NEH) is unknown. A direct toxic effect of chemotherapy and a paraneoplastic mechanism have both been proposed to explain neutrophilic eccrine hidradenitis in the context of malignancy. Cases of neutrophilic eccrine hidradenitis resolving after withdrawal of chemotherapy and recurring upon reinstitution of the same regimen favor the former. Also supporting a direct toxic drug response is a study showing that the intradermal injection of bleomycin can yield local neutrophilic eccrine hidradenitis changes.[18] However, skin lesions arising after chemotherapy have developed anywhere from 2 days to 2 years later. A diagnosis of toxic erythema of chemotherapy has been proposed for this group of disorders, to emphasize the overlapping clinical and histologic features with similar eruptions.[3]

Favoring a paraneoplastic process are case reports of neutrophilic eccrine hidradenitis heralding the onset of both AML[11] and chronic myelogenous leukemia[12] and the relapse of AML.[13] Neutrophilic eccrine hidradenitis has also been observed in otherwise healthy individuals[15] ; in chronic granulomatous disease[17] ; in Behçet disease[16] ; with acetaminophen[19] ; with granulocyte colony-stimulating factor[14] and pegfilgrastim[5] ; with cyclophosphamide therapy for lupus[20] ; with methotrexate therapy for actinic reticuloid[21] ; with carbamazepine usage[22] ; with cetuximab treatment[23] ; with BRAF inhibitors[24] ; with antiretroviral medications[25] ; in azathioprine hypersensitivity syndrome[26] ; ticagrelor[4] ; FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy[27] ; infliximab use[8] ; and with HIV, Serratia, Enterobacter,Nocardia, Staphylococcus, Streptococcus, Mycobacterium chelonae, and COVID-19[6, 7] infections.

Frequency

The frequency of neutrophilic eccrine hidradenitis (NEH) is unknown.

Sex

A slight male predominance is found in cases of neutrophilic eccrine hidradenitis.[28]

Age

Neutrophilic eccrine hidradenitis has been reported in individuals as young as 6 months and as old as 79 years.

Many patients experience recurrent symptoms with subsequent courses of chemotherapy. One patient avoided painful recurrences with prophylactic dapsone. Possible hematologic toxicity with dapsone in the setting of chemotherapy regimens is a concern.[29] Neutrophilic eccrine hidradenitis (NEH) is typically a self-limited process. It does not appear to portend a worse prognosis for the underlying malignancy when occurring in that setting.

Most reported cases of neutrophilic eccrine hidradenitis (NEH) have been in patients with acute myelogenous leukemia (AML) who are undergoing chemotherapy, frequently with cytarabine. Granulocytopenia may be found in such cases. Other malignancy and chemotherapy associations exist. As noted previously, cases have been documented in AML and chronic myelogenous leukemia patients who were not on chemotherapy. Some otherwise healthy individuals have inexplicably developed biopsy-proven lesions of neutrophilic eccrine hidradenitis. Some healthy patients (both children[30] and adults[31] ) have developed papules and plaques of idiopathic neutrophilic eccrine hidradenitis, especially in the summertime.

Regardless of the clinical setting, patients with neutrophilic eccrine hidradenitis develop skin lesions and frequently report fever. Half the patients are asymptomatic, but pain and tenderness are not uncommon. The palmoplantar variant of neutrophilic eccrine hidradenitis typically occurs in healthy children; however, one child in remission after acute lymphoblastic leukemia developed generalized extension.[32]

The cutaneous lesions of neutrophilic eccrine hidradenitis (NEH) are protean. Neutrophilic eccrine hidradenitis lesions may be solitary or multiple. Erythematous or purpuric macules, papules, nodules, or plaques are described most frequently. Hyperpigmented plaques, annular lesions,[33] and sclerodermoid changes[34] have also been noted. Tenderness may be elicited. The trunk or limbs are most often involved. Neutrophilic eccrine hidradenitis simulating orbital cellulitis,[35] facial cellulitis,[36] symmetrical ear swelling,[37] miliaria rubra,[38] and acanthosis nigricans[39] have been documented.

See the image below.

Courtesy of Jeffrey P. Callen, MD.

A CBC count should be performed for all patients found to have neutrophilic eccrine hidradenitis (NEH) by skin biopsy who have not been previously diagnosed with a malignancy.

A punch biopsy of a representative lesion should be performed.

Routine biopsy specimens reveal a dense neutrophilic infiltrate within and around eccrine glands, with necrosis of eccrine epithelial cells. Some severely neutropenic patients may have a paucity or absence of neutrophils histologically, but the necrosis of eccrine glands is evident. Apocrine gland involvement, squamous syringometaplasia, dermal hemorrhage, dermal edema, epidermal spongiosis, basilar vacuolization, focal keratinocyte necrosis, mucin deposits, and mild, superficial panniculitis may be observed. Associated leukocytoclastic vasculitis has been reported.[40] Immunohistochemical staining from a healthy adult patient with recurrent summertime generalized neutrophilic eccrine hidradenitis (NEH) showed decreased expression of dermcidin on the secretory portion of the eccrine glands.[31]

Cases revealing histologic features of both acute febrile neutrophilic dermatosis (Sweet syndrome) and neutrophilic eccrine hidradenitis have been reported.[41]

See the histological image below.

Neutrophilic infiltrate on hematoxylin and eosin stain (100X). Courtesy of Jeffrey P. Callen, MD, and Vilma Fabre, MD.

Many neutrophilic eccrine hidradenitis (NEH) patients are asymptomatic and do not require therapy for the self-limited eruption. Some patients may seek relief of pain and/or fever, and various conservative measures, including contact cooling, have been used to reduce discomfort.[42]

The patient's primary care provider should be informed of the possible implications of this rare disorder. If the patient has been previously diagnosed with a malignancy, the treating hematologist or oncologist should be notified.

Dapsone has been used in the prevention of recurrent neutrophilic eccrine hidradenitis (NEH).[29]

Neutrophilic eccrine hidradenitis (NEH) is typically a self-limited eruption. Continue symptomatic care as needed.

Pain relief is sometimes necessary in neutrophilic eccrine hidradenitis (NEH). Nonsteroidal anti-inflammatory drugs (NSAIDs) appear to be the simplest intervention and decrease associated fever. Systemic corticosteroids have not been universally effective in neutrophilic eccrine hidradenitis and confer more immunologic risks to the patient undergoing chemotherapy for treatment of malignancy. An individual with idiopathic neutrophilic eccrine hidradenitis was successfully treated with colchicine.[43] Generalized lesions in a child with idiopathic neutrophilic eccrine hidradenitis resolved in 2 weeks with topical steroid treatment.[44]

Class Summary

Nonsteroidal anti-inflammatory drugs (NSAIDs) have analgesic and antipyretic activities. They inhibit cyclo-oxygenase activity and prostaglandin synthesis. Other mechanisms may exist as well, including inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell-membrane functions.

Ibuprofen (Ibuprin, Advil, Motrin, Addaprin, Provil)

Ibuprofen is the drug of choice for mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Ketoprofen

Ketoprofen is used for relief of mild to moderate pain and inflammation. Initially, small dosages are indicated in patients who are small and/or elderly and in those with renal or liver disease. Doses greater than 75 mg do not increase therapeutic effects. Administer high doses with caution, and closely observe the patient for response.

Naproxen (Anaprox, Naprelan, Naprosyn)

Naproxen is for relief of mild to moderate pain; it inhibits inflammatory reactions and pain by decreasing the activity of cyclo-oxygenase, which results in a decrease of prostaglandin synthesis.

Flurbiprofen

Flurbiprofen may inhibit the cyclo-oxygenase enzyme, which, in turn, inhibits prostaglandin biosynthesis. These effects may result in analgesic, antipyretic, and anti-inflammatory activities.