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Unusual direct immunofluorescence (DIF) pattern in pemphigus herpetiformis- A case report


1 Department of Pathology, Shri Guru Ram Rai Institute of Medical and Health Sciences, Dehradun, Uttarakhand, India
2 Department of Dermatology, Venereology and Leprosy, Shri Guru Ram Rai Institute of Medical and Health Sciences, Dehradun, Uttarakhand, India

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Date of Submission19-Jul-2020
Date of Decision14-Feb-2021
Date of Acceptance21-Mar-2022
Date of Web Publication13-Sep-2022
 

   Abstract 


Pemphigus herpetiformis (PH) is an autoimmune intraepithelial bullous skin disorder. A 61-year-old female presented with history of multiple pruritic erosions, ulcers all over body, and diffuse loss of hair over scalp. Oral and genital mucosas were uninvolved. Subcorneal separation with suprapapillary thinning of epidermis, neutrophilic spongiosis, and elongation of rete ridges were seen on histopathology. Direct immunofluorescence (DIF) revealed IgG deposits in intercellular zone in fish net like pattern and focal linear IgA deposits along basement zone. Indirect immunofluorescence (IIF) revealed antibodies to desmoglein1 (Dsg-1) positive. A final diagnosis of PH was given. The patient responded well to treatment with dapsone and steroids.

Keywords: Desmoglein1, direct immunofluorescence, indirect immunofluorescence, pemphigus herpetiformis


How to cite this URL:
Kavita R, Sheenam A, Neelima B, Jitender BS. Unusual direct immunofluorescence (DIF) pattern in pemphigus herpetiformis- A case report. Indian J Pathol Microbiol [Epub ahead of print] [cited 2022 Sep 25]. Available from: https://www.ijpmonline.org/preprintarticle.asp?id=356002





   Introduction Top


Pemphigus comprises a group of life-threatening, autoimmune, intraepidermal bullous skin diseases caused by immunoglobulins directed against keratinocytes. Histologically, it is characterized by acantholysis.[1],[2] Two major types are pemphigus vulgaris (PV) and pemphigus foliaceous (PF). Pemphigus herpetiformis (PH) is one of the atypical variant of pemphigus that differs in clinical, histological, and immunopathological characteristics from the two classical types.[3] It represents about 7% of pemphigus disease and is seen predominantly in middle-aged and elderly individuals presenting with intense pruritic and vesiculobullous lesions. Clinically, it present as dermatitis herpetiformis (DH) and immunopathologically as PF.[4],[5] We hereby, present a case of PH with unusual DIF.


   Case Report Top


A 61-year-old female presented with a 4 weeks history of multiple intensely pruritic erosions over trunk and limbs. Initially, the disease started as vesiculobullous lesions all over body after consumption of some unknown drug. On clinical examination, diffuse loss of hair over scalp along with multiple erosions and ulcers all over body (40% body surface area) was observed [Figure 1]. Oral and genital mucosas were uninvolved. Clinically, the differential diagnosis of DH, drug-induced pemphigus, bullous systemic lupus erythematosus (SLE), and toxic epidermal necrolysis (TEN) were considered. Peripheral eosinophil count was within normal limits and antinuclear antibody (ANA) profile was negative.
Figure 1: Pretreatment photograph of multiple lesions over scalp and right thigh along with diffuse loss of hair over scalp

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Skin biopsy from the lesions over the left forearm was sent in formalin for histopathological examination and from perilesional area in saline for DIF. The tissue was processed and embedded as per the standard protocol followed in the department. Sections were cut and stained with haematoxylin and eosin (H&E). On histopathological examination epidermis exhibited focal spongiosis and hydropic degeneration of the basal layer. There was an area of subcorneal separation with suprapapillary thinning, neutrophilic spongiosis, and elongation of rete ridges [Figure 2]. The superficial dermis showed edema, moderate mixed inflammatory infiltrate, and mild pigment incontinence. No vesicle with acantholytic keratinocytes or row of tombstone appearance or prominence of eosinophils was observed.
Figure 2: Microphotograph shows neutrophilic spongiosis and elongation of rete ridges (H&E, 100x)

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DIF revealed IgG deposits in squamous intercellular zone in fish net like pattern and focal linear IgA deposits along basement membrane zone. There were no IgM/C3c deposits [Figure 3]a and [Figure 3]b.
Figure 3: (a) DIF Photomicrograph shows IgG deposits in Fish net pattern in the squamous intercellular zone of epidermis. (400X) (b) DIF Photomicrograph shows linear IgA deposits along basement membrane at dermoepidermal junction (400X)

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Indirect immunofluorescence (IIF) for desmoglein1 (Dsg-1) and desmoglein3 (Dsg-3) antibodies revealed presence of antibodies to Dsg-1. Antibodies to Dsg-3 were negative. Hence, a final diagnosis of PH was given. The patient responded well to treatment with dapsone and steroids. Intense pruritis and occurrence of new lesions substantially reduced within 1 month [Figure 4].
Figure 4: Posttreatment photograph of same areas showing improvement

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   Discussion Top


Earlier, PH was known by different terms including DH with acantholysis, mixed bullous disease, and sulfonamide responsive pemphigus. In 1975, Jablonska first coined the term herpetiform pemphigus.[3] The original diagnostic criteria of Jablonska provided useful but limited help in distinguishing PH from PV and PF. These criterias were further modified by Laws et al.[4] and included:

  1. Pruritus
  2. Urticated erythema (±blister or erosion)
  3. Eosinophilic spongiosis
  4. Epidermal intercellular deposits of IgG
  5. Variable acantholysis


Clinically, PH presents with erythematous vescicular and/or bullous lesions arranged in a herpetiform pattern, usually seen on the trunk and the upper portion of the limbs. Peripheral eosinophilia is seen in 40% of the cases.[4],[6] Pruritus is typically present and mucosal involvement is uncommon. The disease can be localized or generalized. A few studies have also reported association of PH with malignancies like lung cancer, prostate cancer, esophageal carcinoma, and cutaneous angiosarcoma.[2],[5]

Histopathologically, it differs from PV and PF because of the predominance of spongiosis with or without acantholysis. There can be eosinophilic spongiosis (20%), neutrophilic spongiosis (20%), or mixed eosinophilic – neutrophilic spongiosis (60%). Subcorneal pustules and intraepidermal vesicles filled with neutrophils and eosinophils are also seen. The dermal papillae may show neutrophilic microabscesses.[7],[8]

The pathogenesis of PH is due to the autoantibodies against desmosomal proteins, predominantly Dsg-1 and Dsg-3.[9] Their presence in the serum is responsible for variable acantholysis in PH. Dsg-1 autoantibodies favor subcorneal acantholysis and Dsg-3 autoantibodies cause suprabasal acantholysis. The difference in acantholysis, as seen in PH compared to the classical types PV and PF, is because of the fact that the autoantibodies in PH are less virulent. Moreover, the autoantibodies target different epitopes on the autoantigens which only cause inflammation by cytokines and complement activation leading to edema and spongiosis without acantholysis.[10] The changes in the epitopes that are targeted by antibodies may also be responsible for late evolution of some cases of PH into PV or PF. Recently, reactivity against antigens like desmocollin1 (Dsc-1), desmocollin3 (Dsc-3), and 178-kDa antigen have also been reported.[7]

DIF on perilesional skin shows IgG deposits on the surface of keratinocytes.[1] In the present case, intercellular IgG deposits and focal linear IgA deposits were seen. Laws et al.[4] mentioned in their case series that the variable prevalence of C3 may relate to the IgG subclass as IgG1 and IgG3 have a higher affinity for complement. They also found linear IgA in basement membrane zone in one of their case and weak IgA in an intercellular pattern in another case. Although the reason behind IgA deposits was unclear, they suggested that focal linear IgA may be indicative of the relation of PH with DH or overlap/concomitant presence of linear IgA dermatosis/Bullous pemphigoid.

IIF demonstrates the presence of IgG autoantibodies in the patient's serum that bind to the epidermal components usually Dsg-1, less commonly Dsg-3, Dsc-1 and 3, and an unknown 178-kDa protein.[2] In both the techniques, IgG subclass 4 predominates. The disease has an indolent course, patients respond well to dapsone given as monotherapy or in combination with steroids. Immunosuppressive agents such as azathioprine and cyclophosphamide can also be used.


   Conclusion Top


The diagnosis of PH is difficult for the clinician as well as the pathologist. Intense pruritic, vesiculobullous lesions without involvment of oral mucosa should prompt the diagnosis of PH and correlation with histological and IF findings confirms the diagnosis of PH. The disease has a good prognosis and responds well to treatment with corticosteroids and dapsone.

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.
Wu H, Brandling-Bennett HA, Harrist TJ. Noninfectious vesiculobullous and vesicopustular diseases. In: Elder DE, Johnson BL, Murphy GF, Xu X, editors. Lever's Histopathylogy of the Skin. Philadelphia: Lippincott Williams & Wilkins; 2009. p. 235-77.  Back to cited text no. 1
    
2.
Porro AM, Caetano Lde V, Maehara Lde S, Enokihara MM. Non-classical forms of pemphigus: Pemphigus herpetiformis, IgA pemphigus, paraneoplastic pemphigus and IgG/IgA pemphigus. An Bras Dermatol 2014;89:96-106.  Back to cited text no. 2
    
3.
Jablonka S, Chorzelski TP, Beutner EH, Chorzelska J. Herpetiformis pemphigus, a variable pattern of pemphigus. Int J Dermatol 1975;14:353-9.  Back to cited text no. 3
    
4.
Laws PM, Heelan K, Al-Mohammedi F, Walsh S, Shear NH. Pemphigus herpetiformis: A case series and review of the literature. Int J Dermatol 2015;54:1014-22.  Back to cited text no. 4
    
5.
Shrestha P, Tajhya RB, Pokharel A. Pemphigus herpetiformis: A rare clinical variant of pemphigus. Nepal J Dermatol Venereol & Leprol [Internet]. 2016;13:61-5.  Back to cited text no. 5
    
6.
Varghese S, George S, Jacob M, Chandi SM. Pemphigus herpetiformis. Indian J Dermatol Venereol Leprol 1995;61:301-2.  Back to cited text no. 6
[PUBMED]  [Full text]  
7.
Karray M, Badri T. Pemphigus Herpetiformis. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482415/. [Update 2020 Jan 21].  Back to cited text no. 7
    
8.
Huhn KM, Tron VA, Nguyen N, Trotter MJ. Neutrophilic spongiosis in pemphigus herpetiformis. J Cutan Pathol 1996;23:264-9.  Back to cited text no. 8
    
9.
Kasperkiewicz M, Kowalewski C, Jablonka S. Pemphigus herpetiformis: From first description until now. J Am Acad Dermatol 2014;70:780-7.  Back to cited text no. 9
    
10.
Ishii K, Amagai M, Komai A, Ebihara T, Chorzeiski TP, Jablonka S, et al. Desmoglein 1 and desmoglein 3 are the target autoantigens in herpetiform pemphigus. Arch Dermatol 1999;135:943-7.  Back to cited text no. 10
    

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Correspondence Address:
Azad Sheenam,
Department of Pathology, Shri Guru Ram Rai Institute of Medical and Health Sciences, Dehradun, Uttarakhand
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_879_20



    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

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