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E-IJD® - CURRENT PERSPECTIVE
Year : 2022  |  Volume : 67  |  Issue : 2  |  Page : 206
Haematologic-related malignancy-induced eosinophilic dermatoses (He Remained): A narrative review


From the Department of Dermatology, IMS and SUM Hospital, Bhubaneswar, Odisha, India

Date of Web Publication13-Jul-2022

Correspondence Address:
Akash Agarwal
Junior Resident, Department of Dermatology, IMS and SUM Hospital, Bhubaneswar, Odisha
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.ijd_847_21

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   Abstract 


He remained(Hematologic Related Malignancy- induced Eosinophilic dermatoses) is a new eponym introduced to describe a dermatoses previously described under several terminologies such as eosinophilic dermatoses of haematological malignancy, exaggerated arthropod bite reactions, insect bite-like reactions and T-cell papulosis associated with B-cell malignancies. This chronic relapsing remitting disease has a pleomorphic presentation mimicking a variety of dermatological conditions. The underlying pathophysiology is however poorly understood. It is a paraneoplastic phenomenon hence an underlying haematological malignancy must always be looked for. Response to conventional modalities of treatment such as oral corticosteroids is rapid and satisfactory. Other newer modalities are also in the pipeline. In this manuscript, we present a narrative review of this recently described entity with data identified via a search on 27 September, 2021 in PubMed, EMBASE and MEDLINE using the term 'Eosinophilic dermatoses of haematological malignancy' AND 'Hematologic related malignancy-induced eosinophilic dermatoses'. A total of 67 cases reported in the literature from the year 2012 onward have been included. The literatures pertaining to insect bite-like reactions and exaggerated insect bite hypersensitivity have been excluded in this review.


Keywords: Eosinophilic dermatosis of haematological maligancy, He remained, insect bite like reaction


How to cite this article:
Kar BR, Agarwal A. Haematologic-related malignancy-induced eosinophilic dermatoses (He Remained): A narrative review. Indian J Dermatol 2022;67:206

How to cite this URL:
Kar BR, Agarwal A. Haematologic-related malignancy-induced eosinophilic dermatoses (He Remained): A narrative review. Indian J Dermatol [serial online] 2022 [cited 2022 Aug 17];67:206. Available from: https://www.e-ijd.org/text.asp?2022/67/2/206/350852





   Introduction Top


Cutaneous manifestations in patients of haematological malignancies are common and have a wide range of presentations. It can occur as a result of direct infiltration of neoplastic cells into the skin, as a paraneoplastic phenomenon, as a secondary to disease-induced immunosuppression or as a result of chemotherapy and radiotherapy.

'He Remained' is an acronym coined by Cohen et al. that stands for haematologic-related malignancy-induced eosinophilic dermatoses. It is a new nomenclature introduced to describe what was earlier known as 'eosinophilic dermatoses of hematological malignancies (EDHM)'.[1]

This history of this dermatoses dates way back to 1965, wherein Weed and his colleagues first described an exaggerated insect bite hypersensitivity to mosquito bites in eight patients of chronic lymphocytic leukaemia (CLL). Subsequently, in 1999, Barzilai et al.[2] reported a case series of eight patients with haematological malignancies who developed a similar rash wherein patients denied a history of insect bites. Thus the terminology 'insect bite like reaction in patients with hematologic malignant neoplasm' was put forward. In 2001, Byrd and his colleagues then proposed the expression 'eosinophilic dermatoses of myeloproliferative disease' and laid down the diagnostic criteria. Farber et al.[3] in 2012, given the association of this eruption with haematological malignancies predominantly, suggested using the phraseology eosinophilic dermatosis of haematologic malignancy (EDHM) which is accepted worldwide. In 2018, Visseaux and his group of researchers studied 38 patients with a B-cell haematological malignancy and found that T-cell lymphocytic infiltrate and not eosinophils was common to a majority of the patients. They, therefore, suggested using the phrase 'T cell papulosis with B cell malignancy'.[4]

In this article, we present a narrative review of clinical features, pathogenesis histopathology, differential diagnosis and management of this recently described entity. Data regarding this entity were identified via a search on 27 September, 2021 in PubMed, EMBASE and MEDLINE using the term 'Eosinophilic dermatoses of hematological malignancy' AND 'Hematologic related malignancy-induced eosinophilic dermatoses'. A total of 67 cases reported in the literature from the year 2012 onward have been included [Table 1]. The literatures pertaining to insect bite-like reactions and exaggerated insect bite hypersensitivity have been excluded in this review.
Table 1: Literature review of 'Eosinophilic dermatoses of haematological malignancy'

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   Pathogenesis Top


The underlying pathogenesis is not completely understood. Initially, it was believed that this entity was an exaggerated insect bite hypersensitivity in patients with haematological malignancy. It was postulated that the underlying B cell malignancy induces over activity of eosinophils along with immune dysregulation, leading to hypersensitivity to various stimuli including insect bites, pyogenic infections or chemotherapy.[26] However, subsequently this theory has not been supported with many biological data. In many studies, patients have categorically denied a history of insect bite, exposure to insects or seasonal variation in lesional severity. Apart from lesions on the extremities which are expected in insect bite pathology, involvement of head and neck and other non-exposed areas of the body have also been described. In a study by Visseaux et al.[4] including 38 patients, only 12% clinicians and 7% of pathologists suspected insect bite hypersensitivity in patients of CLL with similar eruption based on clinical history and examination and biopsy findings, respectively.

In 2012, Mitteldorf et al.[27] first suggested the possible role of leukaemic cells in the pathophysiology of He remained by carrying out fluorescence in situ hybridization on the skin specimens. They found that B lymphocytes are present in the infiltrate ranging between 0 and 70%. The B lymphocytes were CD20 positive and coexpressing CD5 and CD23 which are markers of CLL. Meiss et al.[18] demonstrated that neoplastic B cells are frequently found (up to 20% of infiltrate) in patients when evaluated systematically. Visseaux et al.[4] found small aggregates of tumour B cells in nearly 50% of the patients while a monoclonal immunoglobulin heavy locus (IgH) gene rearrangement similar to peripheral blood was found in 71.4% of cases. Interestingly, these patients did not have significant monoclonal T-cell receptor (TCR) gene rearrangement in the skin lesions. This suggests that tumour B-cells with skin-homing properties can induce a T-cell immune reaction capable of causing spontaneous regression and preventing the development of true leukaemia or lymphoma cutis.

There have been conflicting reports regarding the onset of He remained in relation to underlying malignancy. The causal relationship of haematological malignancy with the cutaneous eruption is supported by the fact that in many instances, the skin lesions tend to resolve with the remission of underlying malignancy and show a tendency to recur during relapse.[28] On the other hand, a lack of correlation of skin changes with the haematological disorder course has also been documented in the existing literature.[26]

Two possible explanations have been put forward to explain the above-observed discrepancy. One school of thought suggests that leukaemic cells enter the skin and drive a helper T cell type 2 (Th2) driven response or cause an eosinophil and basophilic activation via antibodies against the high-affinity IgE receptor (FceRI). This is supported by the fact that there is worsening of He remained during the progression of underlying haematological malignancy. The other concept is that the leukaemic cells act as bystander cells in the dermis. They cause immune dysregulation via a process of tropism by disruption of adhesion molecules. In the majority of the cases where the haematological malignancy is in partial or complete remission, He remained has still been observed probably due to minimal residual activity of neoplastic cells and its ability to sustain the Th2 cell response.[29]

In a study by Maglie et al. to study the expression of T and B cell and pruritogenic markers in He remained patients and bullous pemphigoid (BP) patients, an overexpression of Th2 associated molecules was observed in both He remained and BP patients compared to healthy controls. The authors noted enhanced expression of GATA binding protein 3 (Th2 marker), IL-4 and IL-31 common to both He remained and BP explaining why dupilumab has shown efficacy in both diseases. A strong expression of eotaxin-1 was also observed in He remained patients. Interestingly however, low expression of B cells was seen in He remained patients unlike previous reports. This again highlights the fact that possibly leukaemic cells interfere with the local immune mediators, promoting a Th2-type inflammatory response.[30]


   Clinical Features Top


Clinically, patients present with a polymorphic pruritic rash comprised of erythematous indurated papules, nodules and urticarial plaques or in some cases as vesicles or bullae. The lesions can be distributed all over the body, on both the exposed and non-exposed areas. Extremities are the commonest site of involvement. There is usually no history of insect bite before eruption or complaints of seasonal variation of lesions. The diagnosis is made when other causes of tissue eosinophilia such as scabies, drug reactions and BP have been excluded [Figure 1].[12]
Figure 1: A 61-year male patient of He remained who presented with intensely pruritic polymorphic urticarial and prurigo-like eruptions all over the body for the past 15 days. He was previously diagnosed with chronic lymphocytic leukaemia and was on his second cycle of chemotherapy with bendamustin and rituximab

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Three main clinical patterns have been described in relation to He remained[29]:

  1. Bullous pattern: predominant vesiculobullous lesions mimicking BP
  2. Insect-bite like pattern: urticarial papules and vesicles presenting as papular urticaria
  3. Cellulitis-like pattern: urticarial plaques and/or nodules mimicking Wells syndrome.


Two patients with herpes zoster-like dermatomal rash have also been described in the literature.[10],[17]

A distinct presentation of EDHM has also been described with clinical features of erythematous pruritic, sterile follicular papules and pustules termed as 'eosinophilic pustular folliculitis'.[23]

The diagnosis of He remained is mostly made in patients of CLL. Other malignancies associated are lymphomas (especially non-Hodgkin lymphoma, diffuse large B cell lymphoma and mantle cell lymphoma), leukaemias (acute leukaemias) and other haematological disorders such as multiple myeloma.[3]

CLL patients with He remained tend to present in the fifth to seventh decade of life. The cutaneous eruptions occur usually months to years after the diagnosis of underlying CLL but cases preceding the diagnosis of underlying malignancy have also been described.[12]


   Histopathology Top


The epidermis shows eosinophilic spongiosis with intraepidermal or subepidermal vesiculation in some cases. Full-scale necrosis of the epidermis has also been described. The dermis classically reveals moderate to severe superficial and deep perivascular and interstitial infiltrate comprising lymphocytes and eosinophils. The lymphoid infiltrate is mainly comprised of T lymphocytes with no antigenic mutation [Figure 2].[3] In long-standing cases, flame figures which represent degranulated eosinophilic major basic protein deposited on collagen bundles, may be observed.[5] Other uncommon findings include lymphoid nodules, lymphocytic vasculitis and eosinophilic panniculitis (eosinophils within subcutaneous fat). In patients with follicular papules and pustules, an inflammatory infiltrate consisting of lymphocytes and eosinophils is observed around the hair follicles and sebaceous glands, similar to Ofuji disease.[23]
Figure 2: Histopathology reveals significant superficial dermal and perivascular collections of eosinophils without evidence of vasculitis. H&E × 100

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In patients with vesicles and subepidermal split on histopathology, direct immunofluorescence of peri-lesional skin is negative thereby helping to rule out BP.


   Diagnostic Criteria Top


The diagnostic criteria were put forward by Byrd et al.[28]

  1. Pruritic papular, nodular and/or vesiculobullous eruption not responsive to standard treatments;
  2. Histopathology revealing eosinophil-rich superficial and deep dermal lymphohistiocytic infiltrate with a significant presence of eosinophils;
  3. Exclusion of other causes of tissue eosinophilia; and
  4. Diagnosis of haematologic malignancy.



   Differential Diagnosis Top


The differential diagnosis to be considered for He remained are exaggerated insect bite reaction, leukaemia cutis, neutrophilic eccrine hidradenitis, Wells syndrome and BP. The clinical and histopathological features differentiating each entity have been discussed in [Table 2].
Table 2: Differential diagnosis of He remained

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Various cutaneous manifestations of haematological malignancies have also been tabulated [Table 3].[31]
Table 3: Cutaneous manifestations of haematological malignancies

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   Investigations Top


  • A complete haemogram may reveal raised eosinophils.
  • The diagnosis is purely histopathological after ruling out other causes of tissue eosinophilia.
  • Direct immunofluorescence done to rule out BP is negative.



   Treatment Top


The treatment of He remained is challenging given the chronic relapsing nature of the disease. There is also a lack of evidence-based recommendations for this particular entity. The treatment is based on case series and case reports.

  • Systemic and topical corticosteroids are considered the first line of therapies. Most of the patients respond to corticosteroid therapy but the efficacy is short-lived with relapse on tapering.
  • Immunosuppressants such as methotrexate and azathioprine can be used as steroid-sparing agents.
  • Other therapies tried with little success are doxycycline, dapsone, colchicine, intravenous immunoglobulin, interferon-alpha, nicatinamide and ultraviolet A1 (UVA1) phototherapy.[12]
  • Targeted therapies:


  • Omalizumab: a single report of successful use has been described.[20]
  • Dupilumab: Many case reports have been recently reported with excellent response to dupilumab in this entity. The efficacy of dupilumab further strengthens the postulated theory that Th2-cell activation plays a role in the pathogenesis of He remained.[17],[21]


  • Future prospects:


  • Bertilimumab: It is a monoclonal antibody against eotaxin-1 which has been observed to be strongly positive in He remained and BP patients.


Clinical trials in BP have shown encouraging results and further studies are needed to prove efficacy in He remained.[32]

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.
Cohen PR. Hematologic-Related Malignancy-Induced Eosinophilic Dermatosis (He Remained): An eosinophilic dermatosis predominantly associated with chronic lymphocytic leukemia. J Am Acad Dermatol 2020;82:e13-4.  Back to cited text no. 1
    
2.
Barzilai A, Shpiro D, Goldberg I, Yacob-Hirsch Y, Diaz-Cascajo C, Meytes D, et al. Insect bite-like reaction in patients with hematologic malignant neoplasms. Arch Dermatol 1999;135:1503.  Back to cited text no. 2
    
3.
Farber MJ, La Forgia S, Sahu J, Lee JB. Eosinophilic dermatosis of hematologic malignancy. J Cutan Pathol 2012;39:690-5.  Back to cited text no. 3
    
4.
Visseaux L, Durlach A, Barete S, Beylot-Barry M, Bonnet N, Chassine A, et al. T-cell papulosis associated with B-cell malignancy: A distinctive clinicopathologic entity. J Eur Acad Dermatol Venereol 2018;32:1469-75.  Back to cited text no. 4
    
5.
Qiao J, Sun CE, Zhu W, Zhu D, Fang H. Flame figures associated with eosinophilic dermatosis of hematologic malignancy: Is it possible to distinguish the condition from eosinophilic cellulitis in patients with hematoproliferative disease?. Int J Clin Exp Pathol 2013;6:1683-7.  Back to cited text no. 5
    
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Two AM, Li C, Hata T. A case of eosinophilic dermatosis of hematologic malignancy in a patient with multiple myeloma. Dermatol Online J 2014;20:21256.  Back to cited text no. 6
    
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Martires K, Callahan S, Terushkin V, Brinster N, Leger M, Soter NA. Eosinophilic dermatosis of hematologic malignancy. Dermatol Online J 2016;22:13030/qt8467m0j9.  Back to cited text no. 8
    
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Jayasekera PS, Bakshi A, Al-Sharqi A. Eosinophilic dermatosis of haematological malignancy. Clin Exp Dermatol 2016;41:692-5.  Back to cited text no. 9
    
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Bari O, Cohen PR. Eosinophilic dermatosis of hematologic malignancy mimicking varicella zoster infection: Report in a woman with chronic lymphocytic leukemia and review of the literature. Dermatol Pract Concept 2017;7:6-15.  Back to cited text no. 10
    
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Lucas-Truyols S, Rodrigo-Nicolás B, Lloret-Ruiz C, Quecedo-Estébanez E. Eosinophilic dermatosis of hematologic malignancy. Dermatosis eosinofílicas asociadas a procesos hematológicos. Actas Dermosifiliogr 2017;108:e39-44.  Back to cited text no. 11
    
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Grandi V, Maglie R, Antiga E, Vannucchi M, Delfino C, Lastrucci I, Gunnella S, et al. Eosinophilic dermatosis of hematologic malignancy: A retrospective cohort of 37 patients from an Italian center. J Am Acad Dermatol 2019;81:246-9.  Back to cited text no. 12
    
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Mariano M, Cavallotti C, Muscardin L, Cameli N. Eosinophilic dermatoses (exaggerated insect bite-like reaction) associated with hematological malignancy: Report of three cases. Indian J Dermatol Venereol Leprol 2018;84:93-5.  Back to cited text no. 13
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14.
Sato-Sano M, Teixeira SP, Vargas JC, Baiocchi O, Enokihara M, Gomes EE, et al. Lenalidomide in the management of eosinophilic dermatosis of hematological malignancy. J Dermatol 2019;46:618-21.  Back to cited text no. 14
    
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Rajput CD, Nikam BP, Malani SS. Paraneoplastic eosinophilic dermatosis in a case of chronic lymphocytic leukemia. Indian Dermatol Online J 2019;10:61-3.  Back to cited text no. 15
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16.
Jencks A, Kiavash K, Daveluy S, Thompson AD. Eosinophilic dermatosis of myeloproliferative disease in a young adult with diffuse large B-cell lymphoma. Am J Dermatopathol 2019;41:303-8.  Back to cited text no. 16
    
17.
Jin A, Pousti BT, Savage KT, Mollanazar NK, Lee JB, Hsu S. Eosinophilic dermatosis of hematologic malignancy responding to dupilumab in a patient with chronic lymphocytic leukemia. JAAD Case Rep 2019;5:815-7.  Back to cited text no. 17
    
18.
Meiss F, Technau-Hafsi K, Kern JS, May AM. Eosinophilic dermatosis of hematologic malignancy: Correlation of molecular characteristics of skin lesions and extracutaneous manifestations of hematologic malignancy. J Cutan Pathol 2019;46:175-81.  Back to cited text no. 18
    
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Almeida FT, Caldas R, Rodrigues AP, Ferreira O, Brito C. Eosinophilic dermatosis of hematologic malignancy: A case report. Dermatol Online J 2020;26:13030/qt4k8908jb  Back to cited text no. 19
    
20.
Lor M, Gates G, Yu Y. Eosinophilic dermatosis of hematologic malignancy effectively controlled with omalizumab maintenance therapy. Dermatol Ther 2020;33:e14206.  Back to cited text no. 20
    
21.
Goyal A, Lofgreen S, Mariash E, Bershow A, Gaddis KJ. Targeted inhibition of IL-4/13 with dupilumab is an effective treatment for eosinophilic dermatosis of hematologic malignancy. Dermatol Ther 2020;33:e13725.  Back to cited text no. 21
    
22.
Núñez-Hipólito L, Moya-Martínez C, Requena L. Generalized pruriginous eruption on a patient with leukemia. JAMA Dermatol 2020;156:1369-70.  Back to cited text no. 22
    
23.
Bailey CAR, Laurain DA, Sheinbein DM, Jones HA, Compton LA, Rosman IS. Eosinophilic folliculitis, eosinophilic dermatosis of hematologic malignancy and acneiform follicular mucinosis: Two case reports and a review of the literature highlighting the spectrum of histopathology. J Cutan Pathol 2021;48:439-50.  Back to cited text no. 23
    
24.
Ho TC, Compton L, Sheinbein D, Custer PL. Eosinophilic dermatosis of malignancy involving the eyelid. Ophthalmic Plast Reconstr Surg 2021;37:e196-8.  Back to cited text no. 24
    
25.
Maglie R, Ugolini F, De Logu F, Simi S, Senatore S, Montefusco F, et al. Dupilumab for the treatment of recalcitrant eosinophilic dermatosis of haematologic malignancy. J Eur Acad Dermatol Venereol 2021;35:e501-3.  Back to cited text no. 25
    
26.
Bairey O, Goldschmidt N, Ruchlemer R, Tadmor T, Rahimi-Levene N, Yuklea M, et al. Insect-bite-like reaction in patients with chronic lymphocytic leukemia: A study from the Israeli Chronic Lymphocytic Leukemia Study Group. Eur J Haematol 2012;89:491–6.  Back to cited text no. 26
    
27.
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28.
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29.
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30.
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31.
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