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DERMATOPATHOLOGY ROUND
Year : 2022  |  Volume : 67  |  Issue : 4  |  Page : 409-414
Pure bullous pyoderma gangrenosum, a challenging clinico-pathological diagnosis: Critical literature review with emphasis on diagnostic criteria


1 From the Department of Pathology, Hospital Ramón y Cajal, Madrid, Spain
2 Department of Dermatology, Hospital Ramón y Cajal, Madrid, Spain
3 Department of Medical Oncology, Hospital Ramón y Cajal, Madrid, Spain

Date of Web Publication2-Nov-2022

Correspondence Address:
Patricia Garcia-Abellas
Department of Pathology, Hospital Ramón y Cajal, M-607, km. 9, 100, 28034 Madrid Madrid
Spain
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijd.ijd_1133_20

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   Abstract 


Pyoderma gangrenosum (PG) is an uncommon, idiopathic, neutrophilic dermatosis characterised by large necrotic ulcers. Occasionally, patients develop atypical presentations, including pustular, bullous, and vegetative lesions. Bullous pyoderma gangrenosum (BPG) is considered an extremely rare form. We describe a case of BPG in a 76-year-old man, with active oncological history, including a recent diagnosis of hairy cell leukemia. Diagnosis of PG was delayed because of atypical clinical presentation that mimicked necrotising fasciitis. The patient was treated with diverse intravenous antibiotics and several surgical procedures. The suspicion of neutrophilic dermatosis arose from the histopathological studies. In the setting of mandatory clinico-pathological correlation, the aim of this report is to point out the morphological characteristics that allow recognition of this uncommon variant of pyoderma gangrenosum.


Keywords: Bullous, haematologic malignancies, neutrophilic dermatosis, pathergy, pyoderma gangrenosum


How to cite this article:
Garcia-Abellas P, Fernández-Guarino M, Díaz-Guimaraens B, Soto-Castillo JJ, Torres-Jiménez J, Carrillo-Gijón R. Pure bullous pyoderma gangrenosum, a challenging clinico-pathological diagnosis: Critical literature review with emphasis on diagnostic criteria. Indian J Dermatol 2022;67:409-14

How to cite this URL:
Garcia-Abellas P, Fernández-Guarino M, Díaz-Guimaraens B, Soto-Castillo JJ, Torres-Jiménez J, Carrillo-Gijón R. Pure bullous pyoderma gangrenosum, a challenging clinico-pathological diagnosis: Critical literature review with emphasis on diagnostic criteria. Indian J Dermatol [serial online] 2022 [cited 2022 Dec 4];67:409-14. Available from: https://www.e-ijd.org/text.asp?2022/67/4/409/360303





   Introduction Top


Pyoderma gangrenosum (PG) and sweet syndrome are the most representative examples of neutrophilic dermatosis, cutaneous disorders characterised by the presence of sterile neutrophilic infiltrates on the skin. Pathogenically, neutrophilic dermatosis is included within the heterogeneous spectrum of auto-inflammatory syndromes.[1]

The classical ulcerative PG presents as deep ulcers with central necrosis and undermined, violaceous borders. The histology, although non-specific, helps to rule out other causes of skin ulceration.[2],[3]

Several atypical variants of PG have been described, including pustular, vegetative, and bullous sub-types.[3],[4] Unfortunately, most of the cases of bullous PG (BPG) are reported in old review articles[5],[6] and provide scant or no details about the morphologic characteristics of the lesions. Moreover, many of the published cases of BPG are mixed variants, with concurrent ulcerative or miscellaneous types of lesions. The clinico-pathological characteristics of BPG remain obscure. Classical textbooks of dermatopathology include vaguely BPG into the group of atypical neutrophilic dermatosis.

To the best of our knowledge, only 18 cases of pure BPG have been previously described in the literature since 1993. The aim of this article is to show in detail a pure case of bullous PG, highlighting its distinctive clinical and pathological features.


   Clinical Case Top


A 76-year-old man presented in the emergency department of Ramón y Cajal hospital in December 2019 with fever and a painful plaque on the dorsum of the left hand.

He had a medical history of hairy cell leukemia (HCL) and advanced colorectal cancer. He received five cycles of chemotherapy: oxaliplatin, 5-fluorouracyl and leucovorin, combined with cetuximab, and the anti-epidermal growth factor receptor (EGFR), finishing in November 2019. He was also under treatment with the granulocyte-colony stimulating factor (G-CSF).

Physical examination revealed a painful, edematous, and haemorrhagic plaque with poorly defined borders on the dorsum of the left hand with haemorrhagic, serosanguineous bulla [Figure 1]a. Analytical tests were normal. He was admitted with a suspected diagnosis of infectious cellulitis versus necrotising fasciitis. After taking blood cultures and performing surgical drainage, intravenous antibiotics were administered.
Figure 1: (a) Clinical picture of the initial lesion showing a poorly defined, large, edematous, and equimotic plaque, with haemorrhagic bulla, on the dorsum of the left hand. (b) Haemorrhagic bulla that subsequently presented on the right forearm. (c) Details of haemorrhagic bulla, with bright erythematous halo, that appeared on the trunk

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Three days later, five new haemorrhagic plaques and bullae appeared on the legs, trunk, and contralateral arm, surrounded by an intense red halo [Figure 1]b and [Figure 1]c. The left-hand plaque continued to advance, spreading to his forearm and fingers. Bullous lesions developed superficial necrosis without ulceration. These new lesions showed some resemblance to entities such as septic vasculitis, mucormycosis, and adverse erythema multiforme-like drug reaction. New systemic antibiotic and anti-fungal agents were initiated.

Seven days later, the fever and cutaneous lesions were unresponsive to systemic antibiotics, and all the cultures were negative. Finally, a surgical debridement of the large plaque was performed. The specimen submitted for pathological examination consisted of a grayish cutaneous fragment 12 × 10 × 0,7 cm in size, with friable consistency. Its surface was studded with superficial erosions, without ulceration. Histological sections showed dense neutrophilic infiltrates throughout the dermis and subcutaneous fat, with massive abscess formation [Figure 2] and [Figure 3]. The epidermis was damaged with erosions covered by purulent exudate [Figure 4], intra-epidermal vesicles, and exocytosis of neutrophils and erythrocytes, producing a bullous reaction [Figure 5]. There was no evidence of vasculitis, thrombosis, or granulomas. Stains for fungi were negative. Tissue cultures for bacteria, fungi, and mycobacteria were repeatedly negative. The lesion showed a notorious worsening after the surgical procedure. The combination of data raised a suspicion for neutrophilic dermatois.
Figure 2: Panoramic histological view of large confluent abscesses filling the dermis and hypodermis under the preserved epidermis (H and E × 20)

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Figure 3: Medium power showing details of the large collections of neutrophils and haemorrhagic foci in the dermis (H and E × 100)

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Figure 4: Panoramic, histological view of superficial erosion, covered by purulent exudate (H and E × 20)

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Figure 5: Histological details of haemorrhagic intra-epidermal vesicles (H and E × 100)

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Under the clinicopathological consideration of BPG, the patient was treated with pulsed intravenous methylprednisolone for 3 days, and substantial clinical improvement was evident after 24 hours. Treatment with oral cyclosporine and prednisolone was subsequently initiated. After 3 weeks of therapy, the lesions gradually stabilised. They finally healed after gradual weaning from immunosuppressive therapy.


   Discussion Top


The classical ulcerative PG usually presents as deep, extremely painful ulcers with central necrosis. A violaceous color and undermined, purplish borders are characteristic.[2],[3],[7] Lesions have predilection for lower extremities and characteristically heal leaving cribriform scarring. Occasionally, PG appears in atypical forms, with pustular, vegetative, or bullous lesions [Table 1].[2],[3],[5] Some patients have mixed variants with more than one type of lesion occurring concurrently.[8],[9],[10]
Table 1: Variants of pyoderma gangrenosum with their histological and clinical differences

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It is well known that PG is associated with a variety of systemic disorders in approximately 50% of patients. Among the most common associated diseases are inflammatory bowel disease (IBD), inflammatory arthritis, and haematologic disorders.[2],[3],[5],[7],[10]

Bullous PG was first described by Perry and Winkelmann in 1972[11] as a variant of pyoderma gangrenosum in patients with haematologic malignancies. This sub-type is extremely rare with an estimated incidence of less than one case per million people per year.[12] In about 70% of cases, BPG precedes, accompanies, or follows haematologic diseases,[2] particularly acute myeloid leukemia.[10],[13] Our patient was diagnosed with hairy cell leukemia 3 months before BPG onset. Only a few cases of PG associated with hairy cell leukemia have been reported,[14],[15],[16],[17],[18] and interestingly, one of them is a bullous variant, with good response to anti-leukemic treatment.[14]

Drugs should be considered as a possible triggering event for PG, particularly cocaine, isotretinoin, propylthiouracil, and sunitinib.[19] PG has also been reported in oncological patients receiving treatment with G-CSF.[20],[21] In our case, skin lesions appeared 20 days after the G-CSF therapy onset and followed a rapidly progressive and aggressive course. The acute presentation of the lesions does not seem to parallel the indolent clinical course of hairy cell leukemia. Thus, in this case, both circumstances could be considered as possible causal agents: hairy cell leukemia as the haematologic disorder and G-CSF as the triggering agent. Remarkably, the patient's recovery coincided in time with discontinuation of G-CSF therapy and the start of immunosuppressive treatment.

As described by Perry and Winkelman,[11] the principal feature of BPG is superficiality, with scant ulceration and little tissue destruction. Ulceration, when present, is always superficial. Moreover, an intense neutrophilic infiltrate is very characteristic. Textually, “So many polymorphonuclear leucocytes were present that the dermis could best be described as a large abscess”. Besides, BPG is mostly found in upper extremities.[3],[4],[5],[6],[13],[22] All these data distinguish BPG from classic PG.

Clinically, some BPG lesions start as large, dark-red, indurated plaques. They are very painful, with a surrounding erythematous and warm area. Plaques quickly develop into haemorrhagic, serosanguineous bullae. Other lesions show bullous features at their onset, appearing as haemorrhagic bullae with a bright erythematous halo that spreads centrifugally without undermining. Bullae can break down into superficial, shallow ulcers. Several types of lesions can be present in the same patient, concurrently or along time [Table 1]. In this way, our patient showed indurated, ecchymotic plaques and haemorrhagic bullae that fulfilled the above-mentioned characteristics. The differential diagnosis included medium-sized vessel vasculitis, purpura, neutrophilic dermatosis, septic vasculitis, infectious cellulitis, and ecthyma.

Similarly, histologic characteristics in our case gathered all the features described in BPG. Lesions usually appear as erosions or superficial ulcerations.[2],[5],[7],[11],[22] There is partial preservation of the epidermis, showing intra-epidermal or sub-epidermal vesiculation and neutrophilic and erythrocytic exocytosis.[6],[13],[23] A massive neutrophilic infiltrate fills the dermis and hypodermis, forming large abscesses, without vasculitis or any sign of specific infection. In agreement with the clinical findings, lesions tend to lack significant necrotic or ulcerative phenomena affecting deeper tissues.[2],[11]

Around 70 cases of BPG have been reported in the literature since it was first described.[11] Unfortunately, most of them are old cases collected in review articles of BPG.[5],[6] In these publications, clinical and pathological details of the lesions are absent or very scant. Furthermore, many reported cases entitled as BPG are atypical or mixed variants. Some of them show different kinds of lesions, including deep ulcerated and bullous or blister type ones. Some other cases start as bullae but progressively undergo deep ulcerations.[5],[14],[22],[23],[24],[25],[26] Finally, some reviewers consider atypical and bullous PG as synonymous.[4],[13]

When reviewing the literature, only 18 previous reports describing pure bullous cases have been found since 1993. All of them included the referred characteristics [Table 2]. In our opinion, atypical and mixed forms are more common than pure bullous ones. The presence of common PG features such as deep ulceration, undermined borders, and cribriform scarring makes the diagnosis in mixed cases easier.
Table 2: Summary of pure bullous pyoderma gangrenosum described in the literature since 1993

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Clinically, our case posed a difficult, challenging, differential diagnosis with infections and vasculitis. The purple, blistering appearance of some of the lesions in the setting of a patient with multiple treatments raised the possibility of an adverse drug reaction. Nevertheless, the exacerbation of the large plaque after surgical procedures was a clear sign of pathergy. These data, with the additional histopathological findings, were vital clues for the final diagnosis of BPG.

In conclusion, the variety of clinical manifestations and the non-specific histology make PG a challenging diagnosis with a frequent misdiagnosis of 10%.[41] Therefore, good clinico-pathological correlation (always in the setting of indispensable laboratory and complementary tests) is very important for a swift diagnosis of PG that can avoid potentially catastrophic outcomes.[2],[13],[24] This is especially crucial in atypical forms as the herein described. This case highlights the importance of maintaining a strong clinical suspicion in patients with a history of rapidly progressive, non-infectious blister or superficial ulceration that worsens after surgical procedures. This phenomenon, well known as pathergy, contraindicates aggressive surgical debridement.

To sum up, ecchymotic plaques and superficial haemorrhagic bullae without tendency to deep ulceration are the clinical hallmarks of BPG. When ulceration appears, it takes the form of a shallow, superficial ulcer, which cures without leaving a cribriform scar. Histologically, the main feature is a massive neutrophilic infiltrate in the dermis/hypodermis, with the absence of necrosis or deep ulceration. Intra-epidermal/sub-epidermal vesicles and exocytosis of neutrophils can be observed.

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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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2]



 

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