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IMPORTANCE: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a recently described severe adult-onset autoinflammatory disease that is associated with myeloid lineage-restricted ubiquitin-activating enzyme 1 (UBA1) somatic variations that primarily affect the skin (Sweet syndrome), cartilage, and bone marrow. Skin symptoms have been poorly described. OBJECTIVE: To better describe clinical and pathological skin manifestations and their pathophysiology in VEXAS syndrome. DESIGN, SETTING, AND PARTICIPANTS: This multicenter retrospective case series study of clinical and histological features of 8 patients with VEXAS syndrome and skin involvement was conducted in France from December 2007 to March 2021, with molecular data obtained from March to April 2022. Any UBA1 variations were detected by Sanger or next-generation sequencing that was performed on bone marrow and formalin-fixed paraffin-embedded tissue sections of skin lesion biopsies. RESULTS: All 8 patients were men, and the median age at symptom onset was 65.5 years (interquartile range, 54-76 years). All patients had neutrophilic dermatosis skin lesions, including tender red or violaceous papules, sometimes edematous, without fever, arthralgia, recurrence or pathergy, inflammatory edematous papules on the neck and trunk (sometimes umbilicated), and firm erythematous purpuric or pigmented infiltrated plaques and nodules. Three patients had livedo racemosa. The infiltrates were perivascular and consisted of mature neutrophils with leukocytoclasia, which were admixed with myeloperoxidase-positive CD163-positive myeloid cells with indented nuclei and lymphoid cells in all cases. A sequencing analysis of paired bone marrow samples and skin lesion biopsies identified the same loss-of-function UBA1 variation in both samples for all patients. CONCLUSIONS AND RELEVANCE: This case series study describes the different clinical presentations of skin lesions found in VEXAS syndrome, which is characterized histologically by neutrophilic dermatosis. The findings suggested that the dermal infiltrates seen in VEXAS skin lesions are derived from the pathological myeloid clone. This suggests that using therapies that target the pathological clone may be effective in the long-term management of the disease.

Background and design Cutaneous pleomorphic small T-cell lymphoma is a rare, recently recognized lymphoma, different from mycosis fungoides and Sezary syndrome. Only a few cases have been reported and no treatment modalities have been defined. We reviewed the clinical, histologic, immunohistochemical, molecular biologic, and follow-up data of 11 primary cutaneous pleomorphic small T-cell lymphomas. Results The lesions presented as red purplish nodules, tumors, or plaques. The infiltrate consisted of small pleomorphic lymphoid cells without epidermotropism in nine patients and with a propensity to infiltrate the dermis and subcutaneous fat. Most cases were CD4+/CD8-. A T-cell clone was detected in the skin lesions of nine patients tested. The mean follow-up was 70.1 months and the median follow-up was 20 months. Ten patients are alive with three having persistent lesions. Interferon alfa-2a induced partial or complete remissions in five patients. Interferon alfa-2a combined with a regimen containing doxorubicin chlorhydrate induced a complete remission in a patient suffering a relapse after cyclophosphamide and interferon alone. Conclusions Cutaneous pleomorphic small T-cell lymphoma is a well-defined type of low-grade cutaneous lymphoma with favorable prognosis. Interferon and/or chemotherapy are the treatment of choice in patients with large tumor burden.

Background Peripheral nodal follicular T-cell lymphomas expressing follicular helper T-cell (T FH ) markers have recently been identified. Such lymphomas are characterized by a nodal neoplastic T-cell proliferation accompanied by numerous reactive B cells and demonstrate some overlap with nodal angioimmunoblastic T-cell lymphoma (AITL). We identified 5 cases of cutaneous T-cell lymphoma with a peculiar pathologic aspect and expression of T FH markers. Observations The mean age of the patients was 61 years (range, 33-78 years). Four patients had multiple papules, plaques, and nodules predominating on the trunk and the head. One had a nodular plaque on the face. Lesional T-cell clonality was found in all 5 patients, and blood T-cell clonality in 4 of the 5. Nodal involvement was never found. Patients had no systemic symptoms and no biological signs of AITL. In 3 cases, findings from skin biopsy specimens were initially misdiagnosed as primary cutaneous follicle B-cell lymphoma due to major B-cell infiltrate and CD10 positivity. Rituximab-containing therapies were ineffective in these cases, and biopsy specimens after treatment with rituximab showed medium- to large-sized atypical T-cell skin infiltrate expressing T FH markers (CD10, Bcl-6, PD-1, CXCL13, and ICOS). The final diagnosis proposed for all patients was cutaneous T FH lymphoma. The patient with localized disease was successfully treated with radiotherapy. Patients with diffuse disease showed marked resistance to treatments, with only 1 case of complete remission after allogeneic hematopoietic stem cell transplantation followed by bortezomib and donor-lymphocyte infusion. Bexarotene, methotrexate, thalidomide, interferon alfa, gemcitabine, liposomal doxorubicin, or multiagent chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) were either ineffective or induced transitory partial remission. Conclusions We describe an original clinicopathologic series of primary cutaneous lymphomas with T FH phenotype, suggesting the existence of a new entity among cutaneous T-cell lymphomas. Relations of these lymphomas with the provisional entity of primary cutaneous small to medium CD4 + pleomorphic T-cell lymphoma need to be further addressed.

Background Specific cutaneous lesions of Waldenstrom macroglobulinemia are rare and include neoplastic cell infiltrates, IgM bullous disease, and so-called IgM-storage papules, which characterize cutaneous macroglobulinosis (CM). Observations We report 2 patients with CM. In patient 1, CM started as small papules, as reported in most of the previously published case studies of CM. In patient 2, lesion evolution was remarkable by its severity, with large ulcerated nodules, and the disease progressed rapidly. As mentioned for half the previously described patients, peripheral neuropathy was suspected in patient 2 and demonstrated in patient 1, with production of antibodies to myelin-associated glycoprotein. Conclusions To the best of our knowledge, rituximab treatment of Waldenstrom macroglobulinemia associated with CM has not been described previously. Rituximab caused complete remission of the lesions in patient 1, whereas disease rapidly progressed in patient 2, and the patient died. These observations suggest that evolution of the cutaneous IgM-storage lesions reflects that of the underlying Waldenstrom macroglobulinemia, and CM is not a prognostic marker.

Objective To study the exact frequency and the histological features of cutaneous intolerance to mechlorethamine (CIM) hydrochloride therapy in patients with cutaneous T-cell lymphomas, including Langerhans cell histiocytosis. Design A multicenter prospective study was conducted from January 1, 1994, to May 31, 1996, in 12 different hospitals in France. Patients Of the 52 patients with cutaneous T-cell lymphomas or Langerhans cell histiocytosis, 35 were men and 17 were women, aged 18 to 87 years. Of the 52 patients, 35 had mycosis fungoides, 8 had nonepidermotropic cutaneous lymphoma, 7 had lymphomatoid papulosis, 1 had Sezary syndrome, and 1 had Langerhans cell histiocytosis. Methods Patients were treated with topical applications of a 0.02% aqueous solution of mechlorethamine. The diagnosis of CIM was determined by the presence of erythema and pruritus. Patients who developed CIM underwent closed patch testing with three 10-fold dilutions of 0.02% mechlorethamine solution. A positive patch test result was the presence of erythema and pruritus, a weak result was the presence of simple erythema without pruritus, and a negative result was the absence of erythema and pruritus. Skin biopsy specimens from patients with positive patch test results were obtained in patients who developed CIM. The biopsy specimens were reviewed, and the results determined by 2 pathologists (E.T. and J.W.). The histopathological findings were classified in 3 categories: (1) spongiotic dermatitis, (2) irritant dermatitis, and (3) insignificant or normal. In September 1998, the referring physicians were contacted if mechlorethamine therapy had been continued in patients with CIM. Results Of the 52 patients, 43 were evaluated for tolerance to mechlorethamine therapy. Of the 43 patients, CIM developed in 23, from 4 days to 9 months after the initiation of mechlorethamine therapy. Of those 23 patients, CIM developed within 3 months in 21 and within 1 month in 13. Closed patch tests were performed in 21 of the 23 patients who developed CIM. The results of the patch test were positive in 12, weak in 4, and negative in 5. Of these 21 patients, 14 skin biopsy specimens were obtained in 14 different patients who had positive or weak patch test results. The specimens showed histological features that were consistent with spongiotic dermatitis in 9 patients, irritant dermatitis in 2, and insignificant or normal in 3. All 9 patients with histological features of spongiotic dermatitis discontinued mechlorethamine therapy. All 5 patients without histological features of spongiotic dermatitis were able to resume mechlorethamine therapy. These results do not correlate with those of previous study results. Conclusions Mechlorethamine therapy is a cost-effective and easily administered treatment for cutaneous T-cell lymphomas. Our study shows that allergic dermatitis caused by mechlorethamine therapy is an early and frequent adverse reaction in patients with cutaneous T-cell lymphomas. The most common histological feature of patients with CIM is spongiotic dermatitis.

Background The differential diagnosis of cutaneous lymphoid hyperplasia and B-cell lymphoma may be difficult. Whether the detection of clonal immunoglobulin gene rearrangement in the cutaneous lesion is predictive of a malignant outcome remains controversial. We therefore studied cases of cutaneous lymphoid hyperplasia by polymerase chain reaction analysis. Design Retrospective study of patients seen between 1988 and 1996. Setting Two dermatology university departments. Patients Twenty-four patients with cutaneous lymphoid hyperplasias were included according to clinical, histopathological, and immunophenotypic criteria. Main Outcome Measures Clinical, histopathological, and laboratory findings. Results There were 13 men and 11 women (mean age, 49 years) who presented with erythematous or violaceous papules or nodules. The lesions were unique in 13 cases and multiple in 11 cases. All patients had immunochemical evidence of a mixed T- and B-cell infiltrate with polytypic B cells. Polyclonality was demonstrated in 23 patients, whereas a dominant B-cell clone was detected in 1 patient. No lymphoma developed during the follow-up (median, 4 years). In the same period, we studied 53 cases of B-cell lymphomas. Thirty-five (66%) of the 53 cases had a detectable clonal immunoglobulin gene rearrangement. Conclusions In the majority of our cases, polyclonality demonstrated by polymerase chain reaction analysis was in accordance with the diagnosis of cutaneous lymphoid hyperplasia. In 1 of the 24 patients, the presence of a B-cell clone could be evidenced. This fact did not modify the treatment as there were no histological or immunophenotypic signs suggestive of a lymphoma.

Objective To determine if a therapeutic regimen of twice-weekly applications of mechlorethamine hydrochloride and betamethasone dipropionate cream is effective in the treatment of early-stage mycosis fungoides while increasing cutaneous tolerance. Design Prospective nonrandomized study conducted from November 1999 to November 2002. Setting Eleven university or hospital dermatology departments in France. Patients Sixty-four consecutive patients with newly diagnosed early-stage mycosis fungoides (stage IA, n = 33; stage IB, n = 26; stage IIA, n = 5). Interventions Patients were treated with twice-weekly applications of a 0.02% aqueous solution of mechlorethamine followed by an application of betamethasone cream during a 6-month period. Main Outcome Measures The primary end point was the rate of complete response during the treatment. Secondary end points were mean delay to achieve complete response, rate of severe cutaneous reactions of intolerance, and rate of relapse after achieving complete response. Results Thirty-seven patients (58%) had a complete response after a mean ± SD treatment duration of 3.6 ± 2.5 months: 20 (61%) of 33 patients with stage IA disease, 15 (58%) of 26 patients with stage IB disease, and 2 (40%) of 5 patients with stage IIA disease. Eighteen patients (28%) developed severe cutaneous reactions of intolerance that necessitated treatment discontinuation. Relapse was observed in 17 patients (46%) after a mean ± SD time of 7.7 ± 6.5 months. Conclusions A regimen of twice-weekly applications of mechlorethamine and betamethasone cream is an effective treatment for early-stage mycosis fungoides. The decreased frequency of applications provides an advantage to the patient by being easy to use with limited adverse effects.

Objective To determine whether cutaneous involvement in patients with angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is related to a clonal T-cell proliferation. Design Retrospective study. Setting University hospitals. Patients Ten patients with AILD and cutaneous involvement. Main Outcome Measure The T-cell receptor-γ (TCRG) gene rearrangement was studied with the use of polymerase chain reaction and denaturing gradient gel electrophoresis in blood, nodal, and skin samples. Skin and nodal samples were investigated also for the presence of Epstein-Barr virus (EBV) RNA by in situ hybridization. Results A transient morbilliform eruption of the trunk was seen most often. Other cutaneous features were infiltrated plaques and purpuric or urticarial lesions. A clonalTCRGgene rearrangement was detected in 7 skin samples, corresponding to a maculopapular eruption with a histological pattern of nonspecific mild lymphoid dermal infiltrate in 6 patients, and to erythematous plaques with histological findings of typical cutaneous lymphoma in 1 patient. In the 5 patients in whom aTCRGgene rearrangement was evidenced in skin and lymph node samples, identical clones were detected in both. Five patients died by the end of the study, with a mean survival of 33.2 months. Four of these 5 patients had a clonal infiltrate in skin and lymph nodes. The EBV RNA was detected in only 1 of 10 skin biopsy specimens and in 5 of 8 lymph nodes tested. Conclusions Cutaneous involvement is often related to a clonal T-cell proliferation in AILD, even when clinical and histological features are nonspecific. Cutaneous infiltrate seems to be clonally related to the nodal T-cell proliferation. The role of EBV infection in skin lesions was not evidenced.

Background Epstein-Barr virus (EBV) has been demonstrated in angiocentric immunoproliferative lesions, suggesting that it could be a causative factor. We investigated for the presence of EBV in 12 primary and 2 secondary cutaneous angiocentric lymphomas (CALs). Observations In the 2 secondary CALs, strong reactivity for EBV RNAs and latent membrane protein 1 were detected on paraffin-embedded sections. In contrast, 10 of 12 primary CALs were completely negative for EBV RNAs and latent membrane protein 1. In 2 primary CALs, EBV RNAs and latent membrane protein 1 were detected in few tumor cells. In the group of primary CALs, 8 of 12 were still alive at last follow-up, 3 died of systemic lymphoma, and 1 died of another cause, whereas both patients with secondary CALs died of disease within 1 year. Conclusion Differences in the presence of EBV and clinical behavior between primary and secondary CALs suggest that different mechanisms are operative in the pathogenesis of these conditions, and indicate that the 2 groups should be considered separately.

Objective: To test the hypothesis that drug-induced pseudolymphoma and hypersensitivity syndrome are 2 distinct clinical entities. Design: Retrospective study from 1980 to 1993. Setting: Departments of dermatology and medicine of 5 referral universitary hospitals. Patients: Twenty-four patients who met arbitrary criteria selected as being suggestive of lymphoma, with probable drug cause. Patients with other definite cutaneous drug-induced eruptions were excluded. Intervention: None. Main Outcome Measures: Suspect drugs; clinical, biological, and pathological findings; and evolution of each case and of 110 published case reports. Results: Two groups were separated according to their mode of onset and clinical aspect. Three patients (and 15 cases in the literature) had subacute papulonodular or infiltrated plaques, without visceral involvment. Skin biopsy specimens showed a dense lymphocytic infiltrate mimicking lymphoma. Healing was constant when the drug was stopped. The 21 remaining patients (and 95 published cases) had an acute widespread eruption, with fever, enlarged lymph nodes, and multivisceral involvement. Lymphocytosis, atypical lymphocytes, eosinophilia, hepatitis, and high levels of lactate dehydrogenase were frequent. Skin biopsy findings were usually not specific (lymphocytic infiltrate and keratinocyte necrosis) but sometimes mimicked lymphoma. Severe forms and relapses occurred, even after the drug was stopped. The inducing drugs were the same in the 2 groups. Conclusions: These 2 groups correspond to drug-induced pseudolymphoma and hypersensitivity syndrome. We think that they are 2 distinct entities with different clinical and biological features and outcome, even if the pathological findings are sometimes similar. Prospective studies are needed to confirm these facts, to evaluate the therapy, and to follow up patients. Arch Dermatol. 1996;132:1315-1321

Background: In the course of mycosis fungoides, pilofollicular manifestations without mucinosis (papules, keratoses, comedones, or epidermal cysts) are rare (15 cases reported). Therefore, histological and clinical diagnoses may be difficult. The clinical course and histopathological and immunohistochemical findings in 9 patients are described. Observations: Pilofollicular lesions were present at the onset (n=3), before (n=3), or during a relapse of mycosis fungoides (n=3). Comedones and epidermal cysts were most frequent (n=5). They disappeared with lymphoma therapy (n=4), therapy with isotretinoin (n=3), or spontaneously (n=1), or they persisted (n= 1). Clues to the histopathological diagnosis consisted of pilotropism of the infiltrate with minor alteration of the hair follicle walls. The infiltrate was monomorphous and composed of sezariform CD4 + lymphocytes. Pilotropic or peripilofollicular infiltrates, or the absence of infiltrate, were detected in consecutive biopsy specimens obtained from the same patient. The keratinocyte expression of intercellular adhesion molecule type 1 was observed in the hair follicle bulb in front of the pilotropic infiltrate but not in the epidermis. No staining was observed in biopsy specimens of 6 of 7 patients with follicular mucinosis, of folliculitis lesions, or of normal hair follicles. Conclusions: Our findings indicate the role of adhesion molecules in pilotropism leading to mechanical obstruction of the follicle by tumoral cells followed by hyperkeratosis and cyst formation. It remains to be determined if the expression of intercellular adhesion molecule type 1 is the cause or the consequence of pilotropism. By becoming more aware of it, this variant of mycosis fungoides is probably not so rare. (Arch Dermatol. 1996;132:683-687)

Background and Design: Cutaneous pleomorphic small T-cell lymphoma is a rare, recently recognized lymphoma, different from mycosis fungoides and Sezary syndrome. Only a few cases have been reported and no treatment modalities have been defined. We reviewed the clinical, histologic, immunohistochemical, molecular biologic, and follow-up data of 11 primary cutaneous pleomorphic small T-cell lymphomas. Results: The lesions presented as red purplish nodules, tumors, or plaques. The infiltrate consisted of small pleomorphic lymphoid cells without epidermotropism in nine patients and with a propensity to infiltrate the dermis and subcutaneous fat. Most cases were CD4 + /CD8 - . A T-cell clone was detected in the skin lesions of nine patients tested. The mean follow-up was 70.1 months and the median follow-up was 20 months. Ten patients are alive with three having persistent lesions. Interferon alfa-2a induced partial or complete remissions in five patients. Interferon alfa-2a combined with a regimen containing doxorubicin chlorhydrate induced a complete remission in a patient suffering a relapse after cyclophosphamide and interferon alone. Conclusions: Cutaneous pleomorphic small T-cell lymphoma is a well-defined type of low-grade cutaneous lymphoma with favorable prognosis. Interferon and/or chemotherapy are the treatment of choice in patients with large tumor burden. (Arch Dermatol. 1995;131:1009-1015)

Chronic graft-vs-host disease (GVHD) is a significant problem in patients who undergo bone marrow transplantation (BMT). It shares common clinical and histologic characteristics with lichen planus. The association of hepatitis C virus (HCV)-induced chronic hepatitis and lichen planus has been reported recently. 1 To evaluate the possible role of HCV in the pathogenesis of chronic GVHD, two studies were performed in the BMT unit of our institution. Patients and Methods.Cohort Study. One hundred twenty-six consecutive patients who underwent allogeneic BMT between January 1987 and December 1991, with more than 6 months of follow-up post-BMT, were analyzed retrospectively. The mean age was 31 years. Chronic GVHD was defined as previously. 2 Serum samples were obtained before and after BMT (mean delay, 11 months; [range, 6 to 54 months]). Anti-HCV antibodies were sought by a second-generation enzyme-linked immunosorbent assay (ELISA 2.0, Ortho Diagnostic Systems, Raritan, NJ) and a second-generation recombinant immunoblot

• Background and Design.— The pathophysiology of toxic epidermal necrolysis (TEN) remains largely unknown. Toxic epidermal necrolysis is considered a hypersensitivity reaction to drugs, but direct evidence of an immunologic mechanism is still lacking. Lymphopenia and a decrease in the numbers of circulating CD3- and CD4-positive lymphocytes have been reported in acute phase, but, to our knowledge, no study of cellular immune functions of patients with TEN has been reported so far. Herein, we investigated several T-cell functions in a series of 11 patients with TEN. Peripheral blood mononuclear cells (PBMC) obtained in the acute phase were tested together with PBMC obtained after the patient's recovery and compared with those of age- and sex-matched healthy control subjects. Results.— Phytohemagglutinin-induced proliferations and lymphocyte responses in allogeneic mixed lymphocyte reactions were not impaired in the acute phase compared with those after recovery in the same patients and with those in control subjects. In contrast, natural killer cytotoxicity and allogeneic cytotoxic responses were significantly decreased in early TEN. The most striking feature was the significantly impaired ability of acute-phase lymphoid cells to activate allogeneic T cells. Patient PBMC in acute-phase TEN did not inhibit the proliferation induced by patient PBMC after recovery, suggesting that their defect was not related to the presence of radioresistant suppressor cells. The phenotypic expression of HLA-DR, -DQ, and -DP antigens on circulating peripheral blood lymphocytes was then assessed by immunoalkaline phosphatase staining and flow cytometry. Results showed decreased percentages of HLA-DR-positive mononuclear cells and a decreased density of HLA-DR antigens, mainly on monocytes, in acute-phase TEN. Conclusions.— These results demonstrate that peripheral blood lymphocytes of patients with TEN have an impaired ability to activate allogeneic T cells. This defective antigen presentation is not secondary to the presence of suppressor lymphocytes, but it is probably related to a decreased expression of HLA-DR antigens on circulating mononuclear cells in acute-phase TEN. (Arch Dermatol.1993;129:721-727)

To the Editor.— Hydrocarbon ingestion is commonly observed in domestic accidents or attempted suicides. Only a few cases, however, of hydrocarbon injection have been reported. Petroleum distillates injected intravenously may induce severe accidents. Subcutaneous or intramuscular injections essentially cause necrosis of subcutaneous tissues. We report two cases, one of febrile panniculitis and one of sterile abscesses. Report of Cases.—Case 1.— A 24-year-old man attempted suicide by subcutaneous injection of 10 mL of lighter fluid in both hands, the elbow folds, and the neck. On admission, he was febrile and presented with large erythematous painful swellings at the sites of injections (Fig 1). Significant laboratory test results were as follows: leukocytes, 18× 10 9 /L, with 0.8 neutrophils; and blood cultures and cultures of subcutaneous aspirate, negative. He was treated by parenteral oxacillin. Diabetes insipidus without hydroelectrolytic disorders appeared a few days later. The cutaneous and subcutaneous necrosis spread to adjacent tissues with abscess formation. Direct examination of the pus revealed numerous altered neutrophils

To the Editor.— In the November 1983ArchivesTagami et al1 suggested that delayed hypersensitivity plays a crucial role in the development of drug-induced toxic epidermal necrolysis (TEN). They reported positive intradermal and epicutaneous skin test reactions as well as an abnormal result of the lymphocyte transformation test (LTT) in a woman 2½ months after TEN was induced by ampicillin