Haematologic-Related Malignancy-Induced Eosinophilic Dermatoses (He Remained): A Narrative Review.

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. Copyright:

Introduction

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’

Authors	Year of publication	Number of patients	Underlying malignancy	Latency between haematological diagnosis and He remained	Morphology of lesions	Distribution of lesions	Treatment given
Farber et al.[3]	2012	1	CLL	Prior to oncology diagnosis	Erythematous pruritic papules and nodules	Face, scalp, neck, trunk and bilateral extremities	Multiple treatment with prednisolone, doxycyclline
Qiao et al.[5]	2013	1	CLL	3 years	Recurrent pruritic eruptions of oedematous plaques	On the extremities, face and trunk	Oral corticosteroids
Two et al.[6]	2014	1	Multiple myeloma	1 year after MM diagnosis	Multiple pruritic, grouped vesicles	Right forearm, left lower extremity and left trunk	Topical corticosteroids
Penn et al.[7]	2015	1	Diffuse large B cell lymphoma	Onset with relapse of lymphoma	Pruritic papules and vesicles	On the extremities	-
Martires et al.[8]	2016	1	CLL	Following diagnosis of CLL	Pruritic, oedematous and vesicobullous skin	Lesions of the face and extremities	-
Jayasekera et al.[9]	2016	1	CLL	12 months	Papules and indurated plaques	Lower limbs	Oral prednisolone
Bari et al.[10]	2017	1	CLL	72 months	Dermatomal and non-dermatomal vesciles	Back	Obinutuzumab
Lucas-Truyols et al.[11]	2017	4	3 CLL 1 MF	2-120 months	Papules and plaques	Upper and lower limbs	Topical and oral corticosteroids
Grandi et al.[12]	2018	37	B cell CLL: 19 B cell NHL: 11 Multiple myeloma: 2 Acute leukaemia: 4 Aggressive T-cell lymphoma: 1	5-191 months	Most common morphology: Papules f/b plaques and nodules	Most common area of distribution: Lower limbs f/b upper limbs	Oral corticosteroids
Mariano et al.[13]	2018	3	2 CLL 1 NHL	Following chemotherapy	Predominantly bullous lesions	Lower limbs	-
Sata-Sano et al.[14]	2019	1	Mantle cell lymphoma	Presented with malignancy	Erythematous and infiltrative papules with a central crust	Distributed over his entire body surface, but mainly on the back	Topical steroids and antihistaminics
Rajput et al.[15]	2019	1	CLL	Lesions started before diagnosis of CLL	Multiple erythematous papules, oedematous urticarial plaques and purpuric lesions of varying sizes were present	Over the face, neck, trunk, upper and lower extremities	Oral corticosteroids
Jencks et al.[16]	2019	1	Diffuse large B cell lymphoma	5 months after completion of CHOP chemotherapy	Erythematous, oedematous nodules with central vesiculations	Face and extremities	Topical corticosteroids
Jin et al.[17]	2019	1	CLL	Following CLL diagnosis	Zosteriform erythematous erosions with scaling and crusting	Left face and chest	Dupilumab
Meiss et al.[18]	2019	5	CLL	35-282 months (4 cases) 1 case: Prior to oncologic diagnosis (1 month)	Itchy papular, urticarial and/or vesiculobullous eruptions	-	-
Almeida et al.[19]	2020	1	Myelodysplastic syndrome	Prior to oncologic diagnosis	Purpuric rash	Neck	Patient died due to primary oncology
Lor et al.[20]	2020	1	CLL	12 months	Oedematous plaques and urticated rash with bullae	Trunk and extremities	Omalizumab and NVUVB phototherapy
Goyal et al.[21]	2020	1	CLL	Following CLL diagnosis	Dusky urticarial targetoid plaques	Trunk and extremities	Dupilumab
Núñez-Hipólito et al.[22]	2020	1	Acute myeloid leukaemia	Following diagnosis of malignancy	Erythematous eruption composed of small indurated and oedematous papules	Flanks, lower legs, breasts and scalp	Oral and topical corticosteroids
Bailey et al.[23]	2021	1	CLL	Few months after diagnosis of CLL	Erythematous papular rash	On the neck and face	-
Ho et al.[24]	2021	1	CLL	Following diagnosis of CLL	Tender, ulcerated lesion	On eyelid	-
Maglie et al.[25]	2021	1	CLL	2 months after completion of chemotherapy	Polymorphic pruritic rash	Upper and lower limbs	Dupilumab

Pathogenesis

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

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

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

Bullous pattern: predominant vesiculobullous lesions mimicking BP

Insect-bite like pattern: urticarial papules and vesicles presenting as papular urticaria

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.[1017]

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

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

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

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

Pruritic papular, nodular and/or vesiculobullous eruption not responsive to standard treatments;

Histopathology revealing eosinophil-rich superficial and deep dermal lymphohistiocytic infiltrate with a significant presence of eosinophils;

Exclusion of other causes of tissue eosinophilia; and

Diagnosis of haematologic malignancy.

Differential Diagnosis

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

	Clinical features	Histopathology
Exaggerated insect bite reaction of haematological malignancy	History of insect bite will be present with an underlying diagnosis of haematological malignancy. Clinical manifestations can vary from pruritic papules and nodules to frank vesicles and bullae in exposed areas predominantly.	Can range from epidermal eosinophilic spongiosis to full thickness epidermal necrosis. Dermal lymphoid cell and eosinophilic collection is seen in all cases. Flame figures are a common finding
Neutrophilic eccrine hidradenitis	Patients present as tender erythematous papules and plaques over trunk and extremities. Usually seen after chemotherapy (cytarabine) in patients with haematological malignancy (AML)	A dense neutrophilic infiltrate around eccrine glands and infiltrating it. Necrotic eccrine coil is hallmark.
Leukaemia cutis	Morphology can range from erythematous papules and nodules to pustular lesions and ulcers. Underlying haematological malignancy	Subtle to diffuse perivascular and periadnexal infiltration of leukaemic cells with necrotic and mitotic figures and nuclear pleomorphism. Grenz zone may be noted.
Wells syndrome	Prodrome of itch or stinging sensation with subsequent development of annular or circinate erythematous-oedematous plaques. Groove sign is classical. Polymorphous eruption resembling He remained is also reported. Association with underlying haematological malignancy is described but not always	Tissue eosinophilia is present. Flame figures are not pathognomonic and are noted in later stages of illness only.
Bullous pemphigoid	Classically an elderly patient with multiple tense bullae over an urticarial base Underlying haematological malignancy may be present	Subepidermal split with neutrophilic and eosinophilic fluid collection DIF is diagnostic in cases of confusion
He remained	Polymorphic eruption in the form of pruritic erythematous papules, plaques and nodules over both exposed and non-exposed areas Tense blisters resembling bullous pemphigoid has been described	Perivascular predominant eosinophilic infiltrate in the papillary and mid-dermis, with occasional flame figures

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

Table 3

Cutaneous manifestations of haematological malignancies

Mechanism of cutaneous manifestation	Associated dermatoses
Primary neoplastic infiltration of skin	Leukaemia cutis (Acute myeloid leukaemia [AML] associated)
	Lymphoma cutis
	Pinch purpura, cryoglobulinaemia, diffuse plane xanthomata and Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome (Associated with plasma cell disorders)
	Cutaneous histiocytosis
Immune mediated and paraneoplastic manifestations	Neutrophilic dermatoses.
	Sweet syndrome (associated with AML and myelodysplastic syndrome [MDS])
	Pyoderma gangrenosum (AML, chronic myeloid leukaemia and multiple myeloma)
	Eosinophilic dermatoses:
	He remained (CLL)
	Bullous pemphigoid
	Autoimmune skin disorders such as alopecia areata, vitiligo, cutaneous vasculitis (associated with MDS)
	Paraneoplastic pemphigus (Non-Hodgkin lymphoma (NHL), CLL and Castleman’s disease)
	Miscellaneous
	Intractable pruritus (Hodgkin lymphoma [HL], NHL)
	Aquagenic urticaria (Polycythaemia rubra vera)
	Acquired icthyoses (HL)
	Erythema nodosum (HL)
Skin lesions due to immunodeficiency	Various cutaneous bacterial, viral and fungal infections (due to immunocompromised, and often neutropenic, states due to underlying malignancy)
	Skin manifestations of anaemia, polycythaemia
Chemotherapy and radiotherapy induced	Various specific and non-specific adverse effects are observed
Cutaneous graft versus host disease [GVHD]	Recipients of allogeneic haematopoietic stem cell transplants induced by immune-competent donor cells attacking host tissues.
	Two types:
	Acute cutaneous GVHD: widespread, symmetrical, maculopapular or morbiliform exanthema with a predilection for the palms and soles.
	Chronic GVHD: spectrum of eruptions simulating lichen planus and connective tissue disorders including scleroderma and lichen sclerosis

Investigations

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

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.[1721]

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.