Mycosis fungoides bullosa: An unusual presentation of a rare entity

Ig: immunoglobulin MF: mycosis fungoides INTRODUCTION Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphomawith an incidence of 6 cases per million per year. Classic MF in adults can present in different stages, including the patch, plaque, and tumor stages. While patients with early patch or plaque stage MF usually have an indolent course, patients developing skin tumors require systemic or radiation therapy due to their aggressive course. In addition, several clinico-pathologic variants of MF have been described; eg, poikilodermatous, granulomatous, hypopigmented, folliculotropic, and vesiculobullous variants. Blistering is not usually associated with MF, but when present, it is typically associated with aggressive course and poor prognosis. Vesiculobullous MF has only been reported in 35 cases in the literature. Being a less recognized variant, it can easily be missed or confused with other bullous disorders, leading to delayed diagnosis and management. We present a male patient with generalized vesiculobullous MF. The blisters were arranged in an annular pattern mimicking adult linear IgA bullous dermatosis. The lesions rapidly progressed to tumors necessitating aggressive treatment. The diagnosis of bullous MF was made based on the clinical and histologic findings.


INTRODUCTION
Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma with an incidence of 6 cases per million per year. 1 Classic MF in adults can present in different stages, including the patch, plaque, and tumor stages. 2 While patients with early patch or plaque stage MF usually have an indolent course, patients developing skin tumors require systemic or radiation therapy due to their aggressive course. 3 In addition, several clinico-pathologic variants of MF have been described; eg, poikilodermatous, granulomatous, hypopigmented, folliculotropic, and vesiculobullous variants. 4 Blistering is not usually associated with MF, but when present, it is typically associated with aggressive course and poor prognosis. 5 Vesiculobullous MF has only been reported in 35 cases in the literature. Being a less recognized variant, it can easily be missed or confused with other bullous disorders, leading to delayed diagnosis and management.
We present a male patient with generalized vesiculobullous MF. The blisters were arranged in an annular pattern mimicking adult linear IgA bullous dermatosis. The lesions rapidly progressed to tumors necessitating aggressive treatment. The diagnosis of bullous MF was made based on the clinical and histologic findings.

CASE REPORT
A 43-year-old man presented with a 1-year history of progressive, generalized pruritic skin eruption. There was no history of viral infections, contact allergy, systemic illness, or oral drug intake.
Physical examination revealed generalized infiltrated plaques on the trunk and extremities covering most of his body surface area. The plaques were studded with multiple vesicles and bullae (flaccid and tense), arranged in a characteristic annular pattern mimicking adult linear IgA bullous dermatosis. Some of the blisters were ruptured and associated with exudative superficial erosions (Fig 1). There was no mucosal involvement. The patient was well-appearing and denied systemic symptoms.
Skin biopsies were taken from the plaques and bullae. Histologic examination revealed both intraepidermal and subepidermal blisters, along with infiltration of the upper dermis and dermo-epidermal junction by atypical lymphocytes with migration into the epidermis (epidermotropism) (Fig 2, A). With higher magnification, lymphoid cells were observed to be large with convoluted nuclei (Fig 2, B). Immunohistochemical analysis revealed the infiltrate to consist of predominantly T cells, the phenotype of which was CD3 1 , CD4 1 , and CD8 À (Fig 2, C and D). Direct immunofluorescence for IgG, IgA, immunoglobulin M, and C3 was negative.
Based on these findings, the diagnosis of vesiculobullous MF was made. The patient was lost to follow-up but returned 4 months later with new skin lesions on the back. Examination revealed a painless, erythematous, eroded 4 3 6-cm tumor on the back (Fig 3, A). The patient had a mobile, non-tender axillary lymph node (1 3 2 cm).
Histologic examination of the nodule showed diffuse atypical lymphoid infiltrate involving the full thickness of the dermis and extending to the subcutaneous tissue (Fig 3, B). By immunohistochemical analysis, the infiltrate was CD3 1 , CD4 1 , and CD8 À (Fig 3, C and D). Core biopsies of the axillary lymph node revealed reactive lymphadenopathy. A bone marrow biopsy revealed no involvement. Computed tomography of the neck, chest, abdomen, and pelvis was normal. Clinical and histologic findings were consistent with stage IIB MF (tumor stage). Despite aggressive therapy including cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisolone, the condition rapidly progressed with continuous appearance of new lesions and tumors, resulting in death of the patient less than 1 year after the onset of the bullous lesions.

DISCUSSION
The vesiculobullous variant is a very rare clinical subtype of MF. According to Bowman et al, 6 the diagnosis is made by the presence of the following: (1) Vesiculobullous lesions 6 typical lesions of MF (patches, plaques, tumors); (2) typical histologic features of MF (atypical lymphoid cells, epidermotropism, Pautrier microabscess) with The pathologic mechanism underlying blister formation in MF has not been elucidated. One explanation is the confluence of Pautrier microabscesses in MF lesions, which may lead to intraepidermal bulla formation. 7 Alternatively, the proliferation of neoplastic lymphocytes and/or the release of lymphokines by malignant T cells may result in a loss of cohesion between keratinocytes and the basal lamina. 8,9 The main differential diagnosis is autoimmune bullous disease, that has been reported to occur concurrently with classic MF. 10,11 In our patient, the blisters were arranged in an annular pattern similar to adult linear IgA bullous dermatosis; however, immunofluorescence testing was negative. 12 Annular MF has been previously described both in the absence of bullae 13 and associated with vesicles and bullae, similarly to our case. 12,14 Bullae in MF may also be seen in the setting of eczema herpeticum. 15 Bullous drug eruption and bullous impetigo should also be considered as a differential diagnosis. In our case, this was excluded by the absence of history of drug intake and the absence of characteristic histologic findings; eg, necrotic keratinocytes and eosinophils.
The diagnosis of this rare entity is challenging, and the suspicion can only be raised by the presence of typical lesions of MF along with vesiculobullous lesions. Our patient had generalized MF plaques of prolonged duration with severe itching that developed into tumors in a short period of time.
This presentation highlights the aggressive nature of this variant. The treatment of bullous MF follows the usual treatment of MF according to the clinical stage. Phototherapy, methotrexate, interferon, bexarotene, radiotherapy, and histone deacetylase inhibitors are established treatments used in other variants of MF and have also been shown to improve bullous MF lesions. 16,17 Epidemiologic, clinical, and histologic aspects of previously reported cases of bullous MF are presented in Table I. Review of previously reported cases revealed that bullous MF has a predilection for male patients with a mean age of 61.5 6 15 years. The bullous lesions may arise de novo or on top of typical MF lesions. Bullous MF may present with flaccid or tense bullae, may have negative or positive Nikolsky sign, and may be generalized or localized, without specific predilection site. Regarding the histopathology of bullous MF, the line of cleavage may be intraepidermal, at different levels, or subepidermal; however, the majority of the patients displayed the CD4 1 MF phenotype.
The case is usually treated as plaque or tumor stage MF, taking into consideration that the appearance of bullous lesions in a patient with MF appears to carry a poor prognosis; almost half the reported patients died within 1 year of the appearance of bullae, despite aggressive therapy. 6 To conclude, we present a case of vesiculobullous MF with a distinguished presentation and a rapidly progressive course. Dermatologists should keep in mind the diverse presentations of MF to avoid misdiagnosis and delayed management.

Conflicts of interest
None disclosed.   24 Bullae on normal and involved skin Van Velde, 1974 25 Bullae within MF plaques Subepidermal bullae Konrad, 1982 8 Bullae on both normal and affected legs Maeda et al, 1987 26 Several bullous eruptions Subcorneal bulla, numerous leukocytes, and large atypical lymphocytes Kartsonis et al, 1990 9 Pruritic rash and blisters 1 MF plaques and tumor Intraepidermal and subepidermal bullae Follicular mucinosis Leonine facies Turner et al, 1994 27 Bullae on both normal and affected legs Atypical lymphoid cells Subepidermal bullae Franken and Haneke, 1995 28 Bullae on hands, legs, feet, and sole Aranha et al, 1997 29 MF patches and plaques 1 vesicles and bullae  40 Bullous erosions of the trunk and limbs Nikolsky sign negative Epidermal cleavage 1 atypical lymphocytes Inguinal lymphadenopathy CD4 1 , CD8 À , CD30 À Juzot et al, 2020 16 Blisters on the trunk and lower limbs Subepidermal bullae Wu et al, 2020 41 Flaccid bullae and erosions on the scalp, neck, trunk, and extremities