Are You Confident of the Diagnosis?
What you should be alert for in the history
Neutrophilic eccrine hidradenitis (NEH) is a rare cutaneous disorder that was first recognized and described in 1982. Seventy percent of NEH cases have been observed in patients with acute myeloid leukemia (AML), after receiving chemotherapeutic agents, in particular anthracycline and cytarabine, although it has been reported to occur with anticancer drugs such as bleomycin, chlorambucil, cyclophosphamide, doxorubicin, lomustine, mitoxantrone, and vincristine.
NEH has also been found to occur in other hematologic malignancies (chronic lymphocytic leukemia, Hodgkin’s and non-Hodgkin’s lymphoma). Therefore, any patient presenting with a cutaneous rash on the palms and soles that has a history of an oncological disease and chemotherapy exposure may have NEH and this condition should be high on the differential diagnosis list.
In most cases, NEH occurs 8-15 days after initiating chemotherapy. The vast majority of cases last anywhere between 6-33 days and then spontaneously resolve after chemotherapeutic agent is stopped. NEH may reoccur with reintroduction of the chemotherapy. Infrequently, NEH can be seen in association with other underlying diseases, such as lupus erythematosus and Behçets syndrome, which are treated with systemic agents such as cyclophosphamide.
Rare individual case reports have been reported to occur in patients with solid tumors including: testicular cancer, Wilm’s tumor, bronchogenic carcinoma, breast cancer, and osteosarcoma. NEH has been reported to occur in patients inflicted with the human immunodeficiency virus (HIV) that have undergone therapy with zidovudine and acetaminophen. The use of granulocyte colony stimulating factor (G-CSF) has been described to also cause NEH.
Although most cases are not associated with an infection, several reports of NEH caused by various bacterial species has been reported. Positive cultures in these cases leads to more than a casual relationship. This has led some to term the condition infectious eccrine hidradenitits. Many bacteria have been described including Serratia marcescens, Staphyloccus aureus, Streptococcus species, Enterobacteriaceae, Nocardia asteroides, Pseudomonas aeruginosa, Mycobacterium fortuitum, and Enterobacter cloacae.
Characteristic findings on physical examination
On physical examination, NEH may present in a multitude of manners. The classical cases are usually described as erythematous macules, papules, plaques, or nodules of varying sizes (Figure 1). Purpura may or may not be present. They are most commonly found on the distal extremities. It can also be commonly found on the proximal upper trunk, upper limbs, and face (particularly the periorbital areas in an asymmetrical fashion). The latter lesions may mimic cellulitis of the facial structures. Rare presentations have been shown to affect the breasts symmetrically in a circumferential distribution. Most cases are associated with either tenderness, pain, pruritus, and even edema. Rarely the lesions are asymptomatic. Patients often have a fever and constitutional symptoms.
Some cases may have pustules, either isolated or coalesced into larger plaques. This is a more frequent finding in the infectious form of NEH. Lastly, the clinical characteristic can be polymorphous and the lesions can be isolated, multiple, grouped or disseminated. NEH has also been shown to exhibit pathergy.
Expected results of laboratory studies
Laboratory findings will often show an isolated neutropenia.
Skin biopsy is used to make the definitive diagnosis of NEH. The histological charactaristics of NEH involves a neutrophilic infiltrate around eccrine glands and coils and deep dermal blood vessels, with or without vacuolar degeneration and necrosis of the epithelial cells of the eccrine coils (Figure 2). Other histology features include diffuse dermal edema, either hemorrhagic, diffuse or involving a perivascular infiltrate of lymphocytes, neutrophils, macrophages and eosinophils. There can also be an abcess-like accumulation of neutrophilis at the junction between reticular dermis and upper subcutaneous tissue. The epidermis is never affected.
There is a broad differential diagnosis when NEH is considered in a patient. Although NEH has rarely been associated with bacterial infections like Serratia, Enterobacter, Staphylococcus aureus, other infectious process should be considered. To rule out infectious NEH, a culture of the lesion should be done. Surface cultures are usually worthless, and a tissue culture is preferred.
Pseudomonas aeruginosa has been implicated in causing a variety of forms of infectious folliculitis. These occur most frequently after exposure to a contaminated water source. Hot Tub folliculitis is the most frequently seen and recognized form of Pseudomonas folliculitis. The “Hot-Foot” syndrome is also caused by Pseudmonas aeruginosa infection of the adnexal structures of the plantar aspect of the foot. Clinically patients present with an acute onset of extremely tender red papules and nodules. Some will have constitutional symptoms such as fever and chills. Skin biopsies of the lesions reveal a dense neutrophilic infiltrate in the dermis, periadnexally and extending into the subcutis. Tissue cultures will grow the bacteria.
Almost all cases have been caused by exposure to a water source (swimming pool) contaminated with Pseudomonas. It is theorized to occur on the foot due to the abrasive concrete surface at the bottom of the pools, which can cause microabrasions and allow bacteria to enter the skin. It should be noted that a report of Pseudomonas eccrine hidradenitis has been reported in the setting of a child with acute AML.
Erythema multiforme should also be on the differential, but this condition has more of a symmetrical distribution, in contrast to NEH, which is asymmetrical, and there are no target lesions or mucous involvement. The histology will help differentiate the two.
Vasculitis can be distinguished with histology, where there is a predominance of neutrophils in the vascular walls versus the eccrine glands as seen in NEH.
Sweet syndrome, which is also associated with hematological malignancies, occurs with hyperleukocytosis, where NEH is associated with granulocytopenias occuring after chemotherapy administration. In addition, neutrophils are not limited to the dernis around eccrine coils and glands in Sweet syndrome, but found in the whole dermis. Lastly, Sweet syndrome is not typically associated with chemotherapy.
Erythema elevatum diutinum are lesions resticted to dorsum of hands, elbows and knees, but also have vasculitis, leukocytoclasis and fibrinoid necrosis on histology, differentiating it from NEH.
Idiopathic eccrine palmo-plantar hidradentis was once thought of as NEH, but is now its own entity, as mainly seen in healthy children, limited to palms and soles and triggered by physical factors, not chemotherapy. These patients do not have any underlying disease or drug intake.
Drug-induced coma as seen in barbiturate use, narcotics, benzodiazepines and tricyclic antidepressants (TCAs), will commonly show eccrine gland necrosis. However, the distinction is made on histology where necrosis of eccrine coils are seen but additionally, spongiosis and or intradermal or subdermal vesicles can be noted.
Syringosquamous metaplasia, a disease in which the normal ductal epithelium transforms into squamous epithelium. It can be differentiated from NEH by histology; the former does not affect the eccrine coils and the latter does. Syringosquamous metaplasia is resticted to the extremities and intertriginous areas, where NEH can be found in a broader distribution of the body.
Pyoderma gangrenosum (PG), which is usually associated with systemic diseases such as ulcerative colitis and Crohn’s disease or leukemias. Therefore, a history of inflammatory disease will favor PG. Also, the histology will help differentiate because PG involves a subepidermal neutrophilic infiltrate whereas NEH is around the eccrine coils.
It is very important to recognize NEH because some studies have shown that it may herald the onset of malignancy such as AML or CML, raising the hypothesis that NEH may be part of a paraneoplastic syndrome. Similarly, it may herald the relapse of AML. Additionally, understanding and clinically diagnosing NEH in a timely manner is imperative in order to prevent the use of prolonged antibiotics, which is not indicated in this condition.
Who is at Risk for Developing this Disease?
Ninety percent of NEH occurs in patients with malignancy. It has a slight male predominance with a mean age of 40.3 years. It is mainly seen in Caucasians, although there have been some rare reports of NEH seen in patients from Japan, Korea, China, and Central America. To date, no African-American patients have been reported with NEH.
It occurs most commonly in acute myeloid leukemia (AML), although it has also been reported in other hematologic malignancies like CLL, Hodgkins and non-Hodgkin lymphoma. Infrequently, it can occur in patients with solid tumors like testicular carcinoma, Wilm’s tumor, lung cancer, breast cancer, and osteosarcoma. It is usually seen in those patients receiving chemotherapy drugs, particularly anthracycline and cytarabine, although it can occur with all anticancer drugs. Rarely, it has been seen in patients with HIV that are not on chemotherapy, but on zidovudine of acetaminophen. There have been a few cases of NEH seen in patients receiving G-CSF.
There have been a few cases that have shown NEH associated with an infection, particularly Nocardia, S marescens, Enterobacter cloacae and S aureus.
What is the Cause of the Disease?
The pathogenesis is unknown, although two major theories exist. One theory suggests that the drug (chemotherapeutic agent as well as others) is concentrated in eccrine sweat glands and has a direct cytotoxic effect on the eccrine secretory coils and ductal cells. The second theory suggests that NEH is part of a spectrum of neutrophilic dermatoses, such as Sweet syndrome and is a reaction pattern to various underlying causes.
Once chemotherapy is initiated, the lesions can erupt which most frequently occurs 8-15 days after initiating the chemotherapy. Rare case reports have placed the eruption at 3 months after the chemotherapy agent was used and in another 24 months later. Additionally, the lesions can occur after the first course of chemotherapy or any subsequent course thereafter. It is estimated to have a 33% relapse rate. Interestingly, these relapses can occur in the presence of the same chemotherapeutic agent or with a different one.
Systemic Implications and Complications
It is important to diagnose NEH, since it may herald the onset of hematological malignancy including AML, CML, or its relapse. Most cases are diagnosed after the initiation of chemotherapy. Infectious causes need to be confirmed with tissue culture and treated with the appropriate antimicrobial agent based on culture and sensitivities. This also supports the position that follow-up is very important in patients with NEH since it can precede the development of a neoplasm. There are no associated systemic complications of NEH, except for fever and pain. Nonsteroidal antiinflammatory drugs (NSAIDs) can be given to help these symptoms.
NEH completely resolves on its own, usually after the offending drug is discontinued, within a few days or weeks. Some have found systemic medications to be helpful, specifically prednisolone, NSAIDs and dapsone to help with fever, pain, or edema that can be associated with NEH. It has been shown that dapsone can be used prophylactically to help prevent recurrence in subsequent cycles of chemotherapy administration (Table I). In the cases where there was an associated infection with NEH, antibiotics were given to clear the infection and resolution of the lesions was noted.
|No therapy necessary in most cases as it will self resolveTriamcinalone 0.1% cream may hasten the resolution||Skin biopsy for cuture if infection is suspected||Cool oatmeal baths may help with the pruritus|
|Recurrent cases due to chemotherapy regimens can be pre-treated with dapsone 50mg daily starting 2 days before chemotherapy and ending 7 days after the course of chemotherapy regimen|
|Prednisone at 1mg/kg and tapering over 3 weeks is helpful symptomatically. NEH may recur upon completion of the taper.|
|NSAIDS can be used to treat any discomfort, although the benefit is likely minimal|
NSAIDS, nonsteroidal antiinflammatory drugs.
Optimal Therapeutic Approach for this Disease
Once the diagnosis is established with a skin biopsy, the most prudent course is watchful waiting. Topical corticosteroids such as triamcinalone 0.1% cream or clobetasol 0.05% cream used once or twice daily can hasten the resolution. Recurrent cases have been treated with dapsone orally, prednisone, and NSAIDs. No prospective randomized therapeutic trials have been performed and all recommendations are based on case reports. Therapy for infectious causes of NEH is based on the organism cultured and the sensitivities to various antimicrobials.
It is important to warn patients that relapses can occur. It can occur with the initiation of the same chemotherapy drug, a different drug, or spontaneously. During relapse, the course of NEH is usually the same. In some cases relapse did not occur, even in the setting of another cycle of the same chemotherapeutic agent. In the cases of recurrent NEH with chemotherapies, the prophylactic use of dapsone has been shown to be very helpful.
Unusual Clinical Scenarios to Consider in Patient Management
Most cases of NEH are idiopathic or chemotherapy-induced. Infectious casues of NEH are rare and should be considered in neutropenic patients, and those that are worsening with supportive care. Tissue culture is the best apporach to determine the causative microbe responsible. Swabs of the skin are inadequate. Hematoxylin and eosin (H&E) staining will sometimes reveal organisms in the eccrine gland coils and that may be the first clue to an infectious agent. Coverage for staphylococcal and streptococcal infections should be used empirically until the culture and sensitivities are reported.
“Hot-Foot” syndrome typically has an acute onset after exposure to contaminated water. Most cases spontaneously resolve. The pathology will show a more diffuse and deeper neutrophilic infiltrate. There is however a case of “Hot-foot” syndrome that was the initial presentation of a child that was subsequently found to have AML.
What is the Evidence?
Bachmeyer, C, Aractingi, S. “Neutrophilic eccrine hidradenitis”. Clin Dermatol. vol. 18. 2000. pp. 319-30. (An excellent and thorough review article that reviews 51 cases of NEH and focuses on the clinical and histological features of the cases. A nice review of possible pathomechanisms is presented.)
Harrist, TJ, Fine, JD, Berman, RS, Murphy, G, Mihm, JC. (The original case reports that describes and distinguishes NEH as an independent entity.)
Lee, WJ, Kim, CH, Chang, SE, Lee, MW, Choi, JH, Moon, KC, Koh, JK. “Generalized idiopathic eccrine hidradenitis in childhood”. Int J Dermatol. vol. 49. 2010. pp. 75-8. (Nice case report that describes the clinical presentation of NEH in childhood. The discussion section is an excelent review.)
Cohen, P. “Neutrophilic dermatosis occuring in oncology patients”. Int J Dermatol. vol. 46. 2007. pp. 106-11. (A commentary that describes NEH in oncological patients and differentiates it from Sweet syndrome.)
Srivastava, M, Scharf, S, Meehan, SA, Polsky, D. “Neutrophilic eccrine hidradenitis masquerading as facial cellulitis”. J Am Acad Dermatol. vol. 56. 2007. pp. 693-6. (This paper presents a case of an adult female with leukemia that was diagnosed with facial cellulitis. After a skin biopsy the diagnosis was rendered and the patient was taken off all the medications used to treat the cellulitis. The paper also reviews some of the known etiologic causes of NEH.)
Belot, V, Perrinaud, A, Corven, C, de Muret, A, Lorette, G, Machet, L. “Adult idiopathic neutrophilic eccrine hidradenitis treated with colchicine”. Presse Medicale. vol. 35. 2006. pp. 1475-8. (This paper discusses NEH in terms of its clinical and histological finidnigs. The authors report successful therapy using colchicine in an adult female with no underlying cause of her NEH.)
Shih, I, Huang, Y, Yang, C, Yang, L, Hong, H. “Childhood neutrophilic eccrine hidradenitis: a clinicopathologic and immunohistochemical study of 10 patients”. J Am Acad Dermatol. vol. 52. 2005. pp. 963-6. (This paper describes the characteristics of NEH in 10 children, from ages 6 months to 14 months, as well as investigating whether IL-8 was expressed in the skin tissue. Immunostaining for IL-8 was negative in all cases.)
Nijsten, TEC, Meuleman, L, Lambert, J. “Chronic pruritic neutrophilic eccrine hidradenitis in a patient with Behçet’s disease”. Br J Dermatol. vol. 147. 2002. pp. 797-800. (This paper reports a case of NEH found in a patient with Behçet’s syndrome and hypothesizes that NEH is a reactive inflammatory dermatosis that can be seen as a secondary process to a multitude of disorders, including Behçet’s syndrome.)
Bachmeyer, C, Reygagne, P, Aractingi, S. “Recurrent neutrophilic eccrine hidradenitis in an HIV-1 infected patient”. Dermatology. vol. 4. 2000. pp. 328-30. (This is one of a few case reports describing NEH in a patient with a coexistng HIV infection. The recurring and relapsing nature of the NEH make this an unusually interesting case report. One confounding factor was that the patient was also diagnosed with a B-cell non-Hodgkin’s lymphoma.)
Shear, NH, Knowles, SR, Shapiro, L, Poldre, P. “Dapsone in prevention of recurrent neutrophilic eccrine hidradenitis”. J Am Acad Dermatol. vol. 35. 1996. pp. 819-22. (This is the first report of successful prophylactic use of dapsone in a patient that had developed NEH with each course of chemotherapy. The authors initiated dapsone 2 days before the chemotherapy was begun and continued it for 2 weeks after the chemotherapy dose. The patient did not have any recurrence of NEH while on dapsone.)
Oono, T, Matsuura, H, Morizane, S, Yamasaki, O, Iwatsuki, K. “A case of infectious eccrine hidradenitis”. J Dermatol. vol. 2. 2006. pp. 142-5. (This solitary case report described a patient with NEH that they felt was secondary to a gram-positive organism. All cultures were negative, but they felt this was infectious in nature due to the finindings of multiple gram-positive organisms within the lumen of eccrine glands. The involved tissue also was shown to express high levels of human beta defensin 2(hBD-2). The patient’s NEH resolved spontaneously without therapy. The role of the innate immune sysytem is discussed in eccrine gland microbial surveillance.)
Fiorillo, L, Zucker, M, Sawyer, D. “The pseudomonas hot-foot syndrome”. N Engl J Med. vol. 345. 2001. pp. 335-8. (A complete resource on psudomonas hot-foot syndrome. Reviews 40 cases of the syndrome and the various presentations and manifestations of this syndrome.)
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