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Table of Contents
CASE REPORT
Year : 2019  |  Volume : 37  |  Issue : 4  |  Page : 222-225

Pazopanib as a new culprit in neutrophilic eccrine hidradenitis


1 Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linkou and Keelung; College of Medicine, Chang Gung University, Taoyuan, Taiwan
2 Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linkou and Keelung; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Dermatology, Xiamen Chang Gung Hospitals, Xiamen, China; Cancer Vaccine and Immune Cell Therapy Core Laboratory; Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou, Taiwan
3 Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linkou and Keelung; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Dermatology, Xiamen Chang Gung Hospitals, Xiamen, China; Cancer Vaccine and Immune Cell Therapy Core Laboratory; Immune-Oncology Center of Excellence, Chang Gung Memorial Hospital, Linkou; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan

Date of Submission16-Jul-2018
Date of Decision08-Jan-2019
Date of Acceptance12-Mar-2019
Date of Web Publication22-Nov-2019

Correspondence Address:
Dr. Chun-Bing Chen
Department of Dermatology, Chang Gung Memorial Hospitals, Taipei, Linkou and Keelung; College of Medicine, Chang Gung University, Taoyuan; Department of Dermatology, Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Taipei, Linkou and Keelung; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ds.ds_6_19

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  Abstract 


Neutrophilic eccrine hidradenitis (NEH) usually manifests as asymptomatic or painful infiltrated erythematous papules or plaques of variable sizes. It is characterized by dense neutrophilic infiltration and necrosis of the eccrine secretory coils in histopathology. The condition is most commonly reported in patients with hematologic malignancy, who have been undergoing chemotherapy. Direct drug toxicity to the eccrine glands has been proposed to be the cause of NEH. Although several drugs have been reported to induce NEH, the tyrosine kinase inhibitors have only rarely been identified as culprits in the literature. Here, we present a case of pazopanib-related NEH in a patient with uterine adenocarcinoma, in which NEH recurred after the reintroduction of pazopanib. To the best of our knowledge, this is the first report of a case of pazopanib-related NEH.

Keywords: Neutrophilic eccrine hidradenitis, pazopanib, tyrosine kinase inhibitor, uterine adenocarcinoma


How to cite this article:
Wang FY, Chen WT, Shen MH, Chung WH, Chen CB. Pazopanib as a new culprit in neutrophilic eccrine hidradenitis. Dermatol Sin 2019;37:222-5

How to cite this URL:
Wang FY, Chen WT, Shen MH, Chung WH, Chen CB. Pazopanib as a new culprit in neutrophilic eccrine hidradenitis. Dermatol Sin [serial online] 2019 [cited 2020 Jul 10];37:222-5. Available from: http://www.dermsinica.org/text.asp?2019/37/4/222/271504




  Introduction Top


Neutrophilic eccrine hidradenitis (NEH) was originally described in 1982 as a distinctive neutrophilic dermatosis in a patient with acute myelogenous leukemia (AML) receiving chemotherapy.[1] It usually presents as asymptomatic or painful infiltrated erythematous papules or plaques of variable sizes and is characterized by the histological findings of numerous neutrophils infiltrating around and within the eccrine secretory coils, as well as the vacuolar degeneration and necrosis of coil cells.[1],[2] NEH has previously been reported to be associated with various medications, malignancies, infections (including human immunodeficiency virus infection), occlusions, and Behcçet's disease.[1],[2],[3],[4],[5] Despite this broad range of associated conditions, most of the previously reported cases of NEH occurred in AML patients following chemotherapy, especially with cytarabine.[2],[3] Two major hypotheses for the pathogenesis of NEH have been proposed. One is that the condition results from direct drug cytotoxicity to the eccrine coils via secretions in the sweat.[3],[6],[7],[8] The other hypothesis classifies NEH as one of the neutrophilic dermatoses.[3],[4],[9],[10] NEH should be differentiated from cellulitis, Sweet syndrome, and leukemia cutis due to its clinical manifestation and patients' characteristics. The correct diagnosis of NEH can prevent the application of unnecessary treatment to NEH patients.


  Case Report Top


The present case involved a 34-year-old female patient who had suffered from uterine adenocarcinoma for 2 years. A staging laparotomy was performed followed by six cycles of chemotherapy with cisplatin and ifosfamide at that time.

However, about 3 months before hospitalization this time, the patient began to experience fever, abdominal pain, and hematuria. Tumor recurrence with invasion to her bladder was found. She then underwent excision of the recurrent pelvic adenosarcoma and started to receive pazopanib 800 mg per day. There was no other concomitant medication.

After 9 weeks of pazopanib therapy, the patient suffered from tender erythematous rashes on the bilateral thighs associated with fever. The initial impression of a gynecologist was cellulitis, so the pazopanib treatment was halted, and the patient was hospitalized for antibiotic therapy. She received oxacillin followed by augmentin, and her treatment was then escalated to teicoplanin and amikacin. Nevertheless, the skin lesions still progressed and her fever persisted after 1 week of antibiotic therapy. Therefore, we visited her at her dermatology consultation. The physical examination revealed multiple well-demarcated, erythematous, edematous, tender plaques with variable diameters of 5–11 cm on the bilateral thighs. The plaques exhibited no epidermal changes [Figure 1]. A skin biopsy was taken from one of the left thigh lesions. The histopathological findings demonstrated mild hyperkeratosis, mild acanthosis, papillary edema, perivascular lymphocytic infiltrate with neutrophils, and focal extravasation of erythrocytes in the dermis. The sweat glands were also infiltrated by lymphocytes and neutrophils, and neutrophils were also seen in the lumens of the sweat glands [Figure 2]. The final diagnosis was NEH. The patient's antibiotic treatment was thus stopped, and she began to receive 8 mg of oral methylprednisolone twice per day. The skin lesions and fever subsided gradually, with only some postinflammatory hyperpigmentation remaining. However, she was then started again on pazopanib therapy after her recovery, and recurrent skin lesions were noted 3 weeks later. Methylprednisolone at 4 mg per day was then given for further treatment. After a subsequent 3-month-long course of pazopanib treatment, she had no recurrent rashes.
Figure 1: Cutaneous eruptions seen in a patient with recurrent uterine adenocarcinoma following pazopanib treatment. (a) There were multiple well-demarcated erythematous edematous tender plaques on the bilateral thighs. (b) The plaques had variable diameters of 5–11 cm with no epidermal changes

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Figure 2: Histopathological pictures of the skin biopsy. (a) Overview of the specimen in lower magnification showed mild hyperkeratosis, mild acanthosis, papillary edema, perivascular lymphocytic infiltrates with neutrophils, and focal extravasation of erythrocytes in the dermis. The sweat glands were also infiltrated by inflammatory cells (H and E, ×20). (b) The inflammatory cells infiltrating the sweat glands were mainly lymphocytes and neutrophils (H and E, ×100). (c) Lymphocytes and neutrophils infiltrated around and within the sweat gland coils and lumens (H and E, ×200). (d) Closer view of neutrophilic infiltration and mild eccrine necrosis

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  Discussion Top


NEH can be categorized into three main types according to its different etiologies and susceptible groups. The majority of reported cases of NEH have occurred in patients with malignancies, especially patients with AML, who were receiving chemotherapy.[2],[3] A second form of NEH, affecting the palms and soles of healthy children, is also called idiopathic plantar hidradenitis or NEH in children. This type of NEH may be associated with exercise causing heavy sweating or occlusive footwear. Most of the children with this type of NEH experienced spontaneous resolution.[2] Finally, NEH can also result from bacterial infections, such as infections caused by Serratia, Staphylococcus, Enterococcus, Mycobacterium, and Pseudomonas,[11],[12],[13],[14] and these infections may cause community outbreak contamination.[2]

Bachmeyer and Aractingi[3] reviewed 51 reported cases of NEH, excluding cases involving the palmoplantar and microorganism-related types. Their analysis of these 51 patients revealed that a slight majority of the patients were male and that their mean age was about 40 years. The clinical manifestation of NEH in these patients was variable, although they most commonly presented with infiltrated erythematous papules or plaques without epidermal changes. These lesions could be painful or asymptomatic. Purpuric changes or the formation of pustules were found in some cases. The diversity in the size, number, and affected body sites of the skin lesions in these cases of NEH made the diagnosis more challenging; however, the pathergy phenomenon and axillary or inguinal area sparing were noted as possible clues. Fever and neutropenia might also occur in NEH patients.[2] As a result, NEH should be carefully differentiated from cellulitis, Sweet syndrome, and leukemia cutis in clinical practice.

Ninety percent of the 51 NEH patients reviewed by Bachmeyer and Aractingi suffered from some form malignancy, most commonly AML.[3] They have reported other hematologic malignancies or solid tumors. With respect to solid tumors, testicular carcinoma was most often reported. However, there were no previous NEH cases involving uterine adenocarcinoma. In the past NEH cases, nearly all the patients had a history of drug administration before the NEH lesions appeared. Most of those medications consisted of antineoplastic therapy, and it is notable that cytarabine and the anthracycline were most commonly implicated. Nonetheless, other medications, such as granulocyte colony-stimulating factor, may also induce NEH. One hypothesis for the pathomechanism of NEH is that it may be due to the direct cytotoxic effects of the drugs on the eccrine glands. Therefore, recurrences may occur when a patient is exposed again to the same therapy. Meanwhile, NEH has been reported as a paraneoplastic syndrome, although that is only true for a few cases. NEH could occur before the onset or relapse of a hematologic malignancy.[15],[16],[17] In the present case, the NEH recurred after the reintroduction of pazopanib treatment for uterine adenocarcinoma. According to the chronological order of the patient's clinical history and the further identification of a probable cause based on the Naranjo scoring criteria, the data for this patient strongly suggested that her NEH was pazopanib induced.[18]

Pazopanib, with commercial name of votrient, is a multi-targeted receptor tyrosine kinase inhibitor. It mainly works by inhibiting vascular endothelial growth factor receptor, platelet endothelial growth factor receptor, and stem-cell factor receptor and by blocking tumor growth by inhibiting angiogenesis.[19] The most common side effects of pazopanib are liver dysfunction and hypertension. There have only been a few reports about dermatologic adverse events induced by pazopanib, including hair color changes, hypopigmentation, hand–foot skin reactions, and stomatitis.[19],[20] Previous studies had, however, demonstrated a case of NEH induced by a tyrosine kinase inhibitor. In that case, the only reported case, the patient received 400 mg of oral imatinib mesylate daily. Three months later, progressive erythematous papules were noted on the patient's medial thighs and hands, and the histopathological findings for these papules indicated NEH. The lesions disappeared within 3 weeks after the discontinuation of imatinib. However, the gradual reintroduction of imatinib did not lead to a recurrence of NEH in this case.[21] Although treatment of NEH with colchicine, dapsone, and corticosteroids has shown benefits clinically, most cases of NEH spontaneously resolve within several weeks after discontinuing the culprit medication.[2],[3] Dapsone treatment has, meanwhile, shown the prevention of recurrent NEH in subsequent cycles of the culprit drug.[22]


  Conclusion Top


We present here a case of NEH following pazopanib use in a patient with uterine adenocarcinoma, wherein the reintroduction of pazopanib induced a recurrence of NEH. To the best of our knowledge, this is the first case of pazopanib-related NEH. Although NEH is rare in patients with uterine adenocarcinoma or undergoing pazopanib treatment, it should be included in the differential diagnosis. The correct diagnosis of NEH can prevent the application of unnecessary treatments to NEH patients.

Ethical approval

The study was approved by the Institutional Review Board of Chang Gung Medical Foundation, in compliance with Taiwanese law (IRB no. 201901180B0).

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest



 
  References Top

1.
Harrist TJ, Fine JD, Berman RS, Murphy GF, Mihm MC Jr. Neutrophilic eccrine hidradenitis. A distinctive type of neutrophilic dermatosis associated with myelogenous leukemia and chemotherapy. Arch Dermatol 1982;118:263-6.  Back to cited text no. 1
    
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Moreno A, Barnadas MA, Ravella A, de Moragas JM. Infectious eccrine hidradenitis in a patient undergoing hemodialysis. Arch Dermatol 1985;121:1106-7.  Back to cited text no. 11
    
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Bassas-Vila J, Fernández-Figueras MT, Romaní J, Ferrándiz C. Infectious eccrine hidradenitis: A report of 3 cases and a review of the literature. Actas Dermosifiliogr 2014;105:e7-12.  Back to cited text no. 14
    
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Pierson JC, Helm TN, Taylor JS, Elston DM, Tuthill RJ. Neutrophilic eccrine hidradenitis heralding the onset of acute myelogenous leukemia. Arch Dermatol 1993;129:791-2.  Back to cited text no. 15
    
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Gómez Vázquez M, Peteiro C, Toribio J. Neutrophilic eccrine hidradenitis heralding the onset of chronic myelogenous leukaemia. J Eur Acad Dermatol Venereol 2003;17:328-30.  Back to cited text no. 16
    
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Yasukawa K, Kato N, Aikawa K, Kodama K, Hamasaka A, Hata H. Neutrophilic eccrine hidradenitis with sclerodermoid change heralding the relapse of acute myelogenous leukemia: Is this a paraneoplastic phenomenon? Dermatology 2007;215:261-4.  Back to cited text no. 17
    
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Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239-45.  Back to cited text no. 18
    
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Sternberg CN, Donskov F, Haas NB, Doehn C, Russo P, Elmeliegy M, et al. Pazopanib exposure relationship with clinical efficacy and safety in the adjuvant treatment of advanced renal cell carcinoma. Clin Cancer Res 2018;24:3005-13.  Back to cited text no. 20
    
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Dib EG, Ifthikharuddin JJ, Scott GA, Partilo SR. Neutrophilic eccrine hidradenitis induced by imatinib mesylate (Gleevec) therapy. Leuk Res 2005;29:233-4.  Back to cited text no. 21
    
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Shear NH, Knowles SR, Shapiro L, Poldre P. Dapsone in prevention of recurrent neutrophilic eccrine hidradenitis. J Am Acad Dermatol 1996;35:819-22.  Back to cited text no. 22
    


    Figures

  [Figure 1], [Figure 2]


This article has been cited by
1 Pazopanib
Reactions Weekly. 2020; 1788(1): 184
[Pubmed] | [DOI]



 

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