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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 24  |  Issue : 2  |  Page : 91-95

Pemphigus – A clinical study with clinico-immuno-histopathologic correlation


1 Department of Dermatology, Sree Gokulam Medical College, Thiruvananthapuram, Kerala, India
2 Department of Dermatology, Medical College, Kottayam, Kerala, India

Date of Web Publication17-Sep-2019

Correspondence Address:
Dr. P N Mini
Department of Dermatology, Sree Gokulam Medical College, Thiruvananthapuram, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jmgims.jmgims_18_16

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  Abstract 


Background: Pemphigus is a group of autoimmune blistering disease of the skin and mucous membranes with an incidence of <2 cases per 100,000 population. The aim is to evaluate the clinical pattern and to study the correlation between clinical, histopathological, and immunofluorescence findings in pemphigus. Materials and Methods: All newly registered patients with flaccid blisters and erosions on the skin with/without oral erosions during 2 years from May 2009 to April 2011 were evaluated by detailed history, clinical examination, cytological, pathological, and direct immunofluorescence studies, and results correlated. Results: Of the 43 patients studied, 36 (83.72%) had pemphigus vulgaris and 7 (16.28%) had pemphigus foliaceus with maximum patients in the age group of 40–59 years and M:F ratio of 1:1.3. Cytologically, acantholytic cells were demonstrated in 88.37%, histopathological correlation was seen in 100% cases, and direct immunofluorescence was positive in 97.37% of the 38 cases in which it was performed. Conclusion: Clinico-immuno-histopathologic correlation is seen in most cases of pemphigus, and although a combination of clinical, cytological, histopathological, and immunofluorescence findings virtually eliminates the chances of error in the diagnosis of pemphigus, histopathology may suffice in most cases.

Keywords: Acantholytic cells, Nikolsky sign, pemphigus, Tzanck smear


How to cite this article:
Mini P N, Sadeep M S. Pemphigus – A clinical study with clinico-immuno-histopathologic correlation. J Mahatma Gandhi Inst Med Sci 2019;24:91-5

How to cite this URL:
Mini P N, Sadeep M S. Pemphigus – A clinical study with clinico-immuno-histopathologic correlation. J Mahatma Gandhi Inst Med Sci [serial online] 2019 [cited 2019 Nov 14];24:91-5. Available from: http://www.jmgims.co.in/text.asp?2019/24/2/91/267003




  Introduction Top


Pemphigus is a group of autoimmune blistering diseases of the skin and mucous membranes characterized histologically by intraepidermal blisters due to the loss of cell-to-cell adhesion of keratinocytes and immunopathologically by immunoglobulin G (IgG) autoantibodies directed against the cell surface of keratinocytes.[1] Pemphigus has a worldwide distribution but is more common among people of Ashkenazi Jewish and Mediterranean descent. It affects both sexes equally and most commonly develops during the fifth to seventh decade of life.[2],[3] Incidence is <2/100,000 population and pemphigus vulgaris (PV) is the most common form.[4]

In PV and its subtype pemphigus vegetans, the blister occurs just above the basal layer.[5] In pemphigus foliaceus (PF) and its two subtypes, endemic PF and pemphigus erythematosus, blistering occurs in the granular layer.[5] The demonstration of IgG deposits in the intercellular space by direct immunofluorescence (DIF) is ideally required for the diagnosis of pemphigus.[6] According to the studies, epidemiology of pemphigus has shown a different trend in India compared with Western literature.[7]

We undertook this study to evaluate the clinical pattern of pemphigus patients attending the outpatient clinic of the department of dermatology in a tertiary care center in South India and to study the correlation between the clinical, histological, and immunofluorescence findings in pemphigus.


  Materials and Methods Top


All the newly registered patients with flaccid blisters and erosions on the skin and scalp with/without oral erosions attending the outpatient clinic of the department of dermatology and venereology for 2 years from May 2009 to April 2011 were included in the study after obtaining institutional ethical clearance and informed consent from patients.

Exclusion criteria included patients with other blistering disorders with tense blisters such as bullous pemphigoid, dermatitis herpetiformis, linear IgA bullous dermatosis, epidermolysis bullosa, and fixed drug eruptions.

A detailed history was taken, and meticulous clinical examination was done. Tzanck smear was taken from lesions in all cases and examined microscopically for acantholytic cells and inflammatory cells. Skin biopsy was done and the specimen was sent for histopathologic examination in all and DIF in most. Other routine investigations, renal and liver function tests, Chest X-ray, and ultrasound abdomen were done and any abnormalities were noted. All the patients were advised treatment either with tapering doses of systemic steroids or dexamethasone-cyclophosphamide pulse or dexamethasone-azathioprine pulse.


  Results Top


[Table 1] shows the baseline demographic profile and clinical, histopathological, and immunofluorescence findings of study patients. Of the 43 patients studied, 36 (83.72%) suffered from PV and 7 (16.28%) had PF. [Figure 1]a and [Figure 1]b shows clinical photograph of PV patient with oral and nasal erosions and cutaneous erosions.
Table 1: Clinico-immuno-histopathological data of pemphigus

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Figure 1: Clinical photograph of Pemphigus vulgaris patients showing (a) oral and nasal erosions, (b) cutaneous erosions

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[Figure 2]a and [Figure 2]b shows PF patient with erythematosus pattern of facial lesions and superficial cutaneous erosions, vesicles, scaling, and crusting.
Figure 2: Clinical photograph of Pemphigus foliaceus patients showing (a) erythematosus pattern of facial lesions, (b) superficial cutaneous erosions, vesicles, scaling, and crusting

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Their ages ranged from 18 to 85 years. Eleven patients (25.58%) in the age groups of 40–49 and Eleven patients (25.58%) in the age group 50–59 years, 6 patients (13.95%) in the age group of 60–69 and 6 patients (13.95%) 30–39 years. Of the 43 patients, there were 19 (44.19%) males and 24 (55.81%) females with M: F ratio of 1:1.3.

The majority of patients (65.12%) presented themselves within 1–6 months of disease onset with the median time of 3 months in PF and 6 months in PV. Initial site of presentation was oral mucosa in 24 (66.66%) patients and skin in the rest. The time period between the onset of oral and skin lesions varied from 2 to 22 weeks (average: 12 weeks). In PV patients, the predominant skin lesions were vesicles, bullae, and fresh or crusted erosions. In PF, superficial erosions, vesicles, and scaly plaques constituted the predominant lesions. One male PF patient presented with generalized erythroderma. Generalized distribution of lesions was seen in 34 (79.07%) patients. In only 1 (23.26%) PV patient, lesions were confined to mucosae with oral and nasal involvement. The sites of involvement in decreasing order of frequency were trunk in 41 cases (95.35%), mucosae and scalp in 38 each (88.37%), face in 2 (60.47%), limbs in 25 (58.14%), and flexures in 22 (51.16%).

Nikolsky sign could be elicited in 24 (57.14%) of the 42 patients in whom it was attempted. It could not be elicited in one patient with lesions confined to oral and nasal mucosae. Of the 38 patients in whom bulla spread sign was elicited, it was positive in 34 (89.47%). It could not be elicited in 5 (11.63%) cases, 4 with no intact vesicles/bullae at presentation and 1 with only mucosal erosions. In none of the patients, healing of lesions was followed by scarring. Postinflammatory hyperpigmentation was seen in 36 patients (85.71%).

In our series, nail changes noted included paronychia in 15 (34.88%), longitudinal ridging in 12 (27.91%), and nail plate discoloration in 11 (25.58%). All with paronychia were in the active stage of PV. It was of acute onset in 13 (30.23%) and acute exacerbation of chronic paronychia in 2 (4.65%).

Common comorbidities included hypertension in 13, diabetes mellitus in 22, thyroid swelling and hemorrhoids in 5, and bronchial asthma in 4. One of the patients had autoimmune thyroiditis and 4 had nontoxic goiter. None of the above diseases was found to influence the course of pemphigus except in a pregnant lady in whom the disease exacerbated during the second trimester (5th month) of pregnancy.

Sixteen (37.21%) patients showed leukocytosis ranging from 11,000 to 13,000 and 13 (30.23%) patients showed hyperglycemia at pretreatment evaluation. Erythrocyte sedimentation rate was elevated in 10 patients (23.26%) in the range of 15–40 mm/h.

Using Tzanck smear, acantholytic cells were demonstrated in 38 (88.37%) patients, 34 (94.44%) with PV and 4 (57.14%) with PF. Of the rest, three showed neutrophils, one showed eosinophils, and in one, no inflammatory cells were demonstrated. Two patients with PV did not show acantholytic cells, one with only a few tense blisters and another with only mucosal erosions. Of the four pemphigus cases with no blisters on the skin at presentation, acantholytic cells were demonstrated from oral erosions in three patients. [Figure 3] shows the histopathology of PF with subcorneal blister (E) and PV showing suprabasal blister with acantholytic cells (F) (hematoxylin and eosin-stained section at × 10).
Figure 3: H and E 10 shows Histopathology of Pemphigus foliaceus with subcorneal blister (a) and Pemphigus vulgaris showing supra basal blister with acantholytic cells (b) (H and E, ×10)

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Using histopathological study, all the patients with PV showed suprabasal split and all with PF showed subcorneal split. The blisters histopathologically demonstrated acantholytic cells in 33 (76.74%) specimens, 26 with PV and 7 with PF. The other cells were neutrophils in 10 (23.26%), eosinophils in 6 (13.95%), and lymphocytes in 2 (4.65%). Row of tombstone appearance was seen in 9 (25%) specimens, and suprabasal cleft with villi formation was seen in 7 (19.44%) specimens with PV.

Direct immunofluorescence was done in 38 cases of which it was positive in 37 (97.37%) and negative in 1 patient with mucosal erosions alone in whom the tissue was taken from the oral mucosa. The immunoreactants deposited in the intercellular space were IgG alone in 6 (15.79%) and IgG and C3 in 29 (76.32%). In 5 PV patients, C3 deposits were seen only in the lower epidermis, and in 2 (28.57%) of the 7 PF patients, IgG and C3 deposits were seen more toward the upper epidermis. DIF showing intercellular IgG deposition in pemphigus (G) is shown in [Figure 4].
Figure 4: Direct immunofluorescence showing intercellular immunoglobulin deposition in Pemphigus

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Clinical, histopathological, and immunofluorescence correlation was seen in 36 (94.74%) of the 38 patients in whom direct immunofluorescence was performed. One patient with tense blisters clinically suggestive of bullous pemphigoid showed cytologic, histopathologic, and direct immunofluorescence findings of pemphigus. Another patient who presented with only oral and nasal erosions clinically and histopathologically correlated for PV, but DIF was negative. In all the five patients with absent acantholytic cells on Tzanck smear, histopathology, and direct immunofluorescence were confirmatory of pemphigus.

Conventional steroid in tapering doses was given in 19 patients (44.19%), dexamethasone-cyclophosphamide pulse in 20 (46.51%), and dexamethasone-azathioprine pulse in 4 (9.30%). The other adjuvants given were dapsone in 4 and intravenous Ig in 2 patients with severe generalized uncontrolled disease. Among the 43 patients, 2 (4.65%) patients died during the study period, one an 85-year-old diabetic and hypertensive female PV patient who died of septicemia and metabolic disturbances and the other a 42-year-old diabetic male PV patient who died after clinical remission due to cerebrovascular accident.


  Discussion Top


In this series of the 43 pemphigus patients, 83.72% had PV subtype and 16.28% had PF. The studies by Soner et al.[8] in Turkey (PV – 83% and PF – 17%), Wohl et al.[9] in Israel (PV – 81.8%, PE – 7.3%, PF – 5.5%, and pemphigusvegetans– 3.6%), Sehgal et al.[10] in India (PV – 75% and PF – 13%), and Handa et al.[11] (PV – 97.6% and PF – 1.2%) showed similar results with a preponderance of PV, but the study by Aboobaker et al.[12] in South Africa showed PF to be more common (PF – 55.4% and PV – 44.64%). In a study assessing IgG subclass in UK and Indian patients, the proportion of PV and PF was almost equal in UK patients, while PV was predominant in Indian patients.[13]

The mean age was 47 years in our study which is in concordance with the studies by Soner et al.[8] in Turkey, Mahe et al.[14] in Mali, and Chayde et al.[15] in Iran which showed mean age to be 43, 46.7, and 42 years, respectively. However, in Indian studies by Sehgal et al.[10] and Kar et al.,[16] maximum number of patients were in the age group of 21–40 and 31–40 years, respectively.

According to the literature, pemphigus occurs equally in male and female patients, although there are variations among different studies.[17] In our series, there was a slight female predominance with M: F ratio of 1:1.3 which is in concordance with studies by Soner et al.[8] in Turkey and Alsaleh et al.[18] in Kuwait which showed ratios of 1:1.4 and 1:2, respectively. However, the studies in India by Sehgal et al.,[10] Handa et al.,[11] and Kar et al.[16] showed male predominance with M: F ratio being 1.7:1, 1.36:1, and 2.5:1, respectively.

In our study, majority of patients (65.12%) presented themselves within 1–6 months of disease onset. In the study by Handa et al., majority presented within 1–12 months of onset.[11] In 50%–70% of PV, oral lesion is the initial clinical presentation which may precede skin lesions by average of 5 months, and 90% have oral involvement.[19],[20],[21]

In our series also, initial site of presentation was oral mucosa in 55.81% of patients, the time period between onset of oral and skin lesions varied from 2 weeks to 22 weeks (average 12 weeks), and eventually, oral involvement was seen in 79.07%. As in a study by Alsaleh et al.,[18] only one PF patient in our series had oral erosions. According to Stanley,[22] painful erosions are the most common skin lesions in pemphigus, as seen in our series in 97.67%. As in our study, cutaneous lesions are typically present on the upper trunk, head, neck, and intertriginous areas such as axilla and groin.[23] Hale et al. reported 49% with nasal or laryngeal involvement or both in their study.[24] In our study, patients had genital mucosal (32.56%), nasal (911.63%), and conjunctival (9.3%) involvement.

According to Kickle,[23] lesions can be pruritic but are usually painful and accompanied by a burning sensation. In our study also, only 12 (27.91%) had pruritus, but 37 (86.05%) had pain and/or burning sensation.

According to our study, paronychia is a sign of activity of the disease. Paronychia has been described as a sign heralding an exacerbation of pemphigus.[25] Associations with autoimmune thyroid disease and Grave's disease have been reported.[26],[27] In our study, five had thyroid swelling, one with autoimmune thyroiditis, and the rest had nontoxic goiter.

Pemphigus is rarely encountered in pregnancy as the disease usually affects people in the fifth and sixth decades of life. Only 27 cases with immunopathological confirmation of pemphigus have been reported in pregnancy,[28] and we had a pregnant PV patient in our series.

Nikolsky sign is indicative of active acantholysis and it is only moderately sensitive but highly specific for pemphigus.[29],[30] As per this study, it is seen in active stages of disease but with only moderate sensitivity. According to Grando et al., bulla spread is positive in active disease;[31] as per our study, positivity is definitely suggestive of pemphigus. As per our study, Tzanck smear with positive acantholytic cells helps in early diagnosis in most cases before confirmatory histopathologic and immunofluorescence reports are available.

According to our study, histopathological examination is probably the best choice in our setup as it yielded 100% positive results and also helps in differentiating between the subtypes. Moreover, it is less expensive and results can be made available earlier compared to DIF. In our study, DIF was positive in 97.37%, similar to the study by Mysorekar et al.,[32] which showed DIF positivity in 98.1% in pemphigus group. DIF is positive in 90%–100% of patients with active disease,[33] but a disadvantage is the difficulty in distinguishing PV and PF on the staining pattern. According to our study, DIF even helps in differentiating between the subtypes in some cases, as in 13.88% PV cases, immune deposits were seen only in the lower epidermis, and in 28.57% PF cases, deposits were seen more toward the upper epidermis. DIF is confirmatory but may be negative for oral specimens, especially in older lesions. Since the usage of systemic corticosteroid therapy, mortality rates have dropped from 60% to 10% or less and in our case series, mortality rate was 4.65%.


  Conclusion Top


Although a combination of clinical, cytological, histopathological, and immunofluorescence findings virtually eliminates the chances of error in the diagnosis of pemphigus group of immunobullous disorders, histopathology may suffice in most cases, especially in our setup.

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.



 
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