Arturo P. Saavedra

Three Patients with Full Facial Transplantation

Unlike conventional reconstruction, facial transplantation seeks to correct severe deformities in a single operation. We report on three patients who received full-face transplants at our institution in 2011 in operations that aimed for functional restoration by coaptation of all main available motor and sensory nerves. We enumerate the technical challenges and postoperative complications and their management, including single episodes of acute rejection in two patients. At 6 months of follow-up, all facial allografts were surviving, facial appearance and function were improved, and glucocorticoids were successfully withdrawn in all patients.

Biomarker evaluation of face transplant rejection: association of donor T cells with target cell injury.

This series of 113 sequential biopsies of full facial transplants provides findings of potential translational significance as well as biological insights that could prompt reexamination of conventional paradigms of effector pathways in skin allograft rejection. Serial biopsies before, during, and after rejection episodes were evaluated for clinicopathological assessment that in selected cases included specific biomarkers for donor-versus-recipient T cells. Histologic evidence of rejection included lymphocyte-associated injury to epidermal rete ridges, follicular infundibula, and dermal microvessels. Surprisingly, during active rejection, immune cells spatially associated with target cell injury consisted abundantly or predominantly of lymphocytes of donor origin with an immunophenotype typical of the resident memory T-cell subset. Current dogma assumes that skin allograft rejection is mediated by recipient T cells that attack epidermal targets, and the association of donor T cells with sites of target cell injury raises questions regarding the potential complexity of immune cell interactions in the rejection process. A more histopathologically refined and immune-based biomarker approach to assessment of rejection of facial transplants is now indicated.

Erdheim-Chester disease presenting with cutaneous involvement: a case report and literature review.

Erdheim–Chester disease (ECD) is a rare, systemic, non‐familial histiocytic disorder, first described by Jakob Erdheim and William Chester in 1930. Most patients have multiple sites of involvement at presentation. The most common site of involvement is the long bones of the axial skeleton, which is seen almost universally, followed by the nervous system, heart, lungs, orbit and retroperitoneum, which are seen in up to 50% of cases. 1 Cutaneous involvement is rarely a presenting symptom of ECD, with two reported cases in the English literature. 2 The diagnosis of ECD is rarely made by skin biopsy because of the relative rarity of cutaneous involvement as a presenting feature, and also perhaps because of the difficulty in distinguishing the histopathological appearance from potential mimics. The importance of distinguishing ECD from other cutaneous disorders with similar pathology lies in the implications for both treatment and prognosis. ECD is an aggressive, often fatal disorder, with death from disease occurring in greater than 50% of patients.

5-Hydroxymethylcytosine expression in metastatic melanoma versus nodal nevus in sentinel lymph node biopsies

Sentinel lymph node biopsies are conducted to stage patients with newly diagnosed melanomas that have histopathological attributes conferring defined levels of metastatic potential. Because benign nevic cells may also form ‘deposits’ in lymph nodes (nodal nevus), the pathological evaluation for metastatic melanoma within sentinel lymph nodes can be challenging. Twenty-eight sentinel lymph node biopsy cases containing either metastatic melanoma (N=18) or nodal nevi (N=10) were retrieved from the archives of the Brigham and Women’s Hospital, Department of Pathology (2011–2014). In addition, two sentinel lymph node cases that were favored to represent metastatic disease but whose histopathological features were viewed as equivocal, with melanoma favored, were also included. Dual labeling for the melanocyte lineage marker, MART-1, and the epigenetic marker, 5-hydroxymethylcytosine, a functionally significant indicator that has been shown to distinguish benign nevi from melanoma, was performed on all cases using immunohistochemistry and/or direct immunofluorescence. All (18 of 18) metastatic melanoma cases showed complete loss of 5-hydroxymethylcytosine nuclear staining in MART-1-positive cells, and all (10 of 10) nodal nevus cases demonstrated 5-hydroxymethylcytosine nuclear staining in MART-1-positive cells. In addition, 5-hydroxymethylcytosine staining confirmed the favored diagnoses of metastatic melanoma in the two ‘equivocal’ cases. Thus, 5-hydroxymethylcytosine may be a useful adjunctive marker to distinguish between benign nodal nevi and metastatic melanoma during the evaluation of sentinel lymph node biopsies for metastatic melanoma.

HIV infection predisposes skin to toxic epidermal necrolysis via depletion of skin-directed CD4+ T cells

BACKGROUND A greater incidence of adverse cutaneous drug eruptions, including toxic epidermal necrolysis (TEN), occurs among HIV-infected patients. OBJECTIVE We sought to determine if immunophenotypical differences exist in the inflammatory infiltrates of TEN lesions from HIV-infected individuals versus noninfected individuals. METHODS The inflammatory infiltrates in 12 cases of TEN from HIV-positive patients were characterized and compared with the infiltrates present in 12 cases of TEN from HIV-negative patients. RESULTS TEN infiltrates consisted of CD3, CD4, and CD8 immunoreactive T lymphocytes in both the dermis and epidermis. HIV infection was associated with an 8-fold increase in the ratio of CD8(+) to CD4(+) T cells infiltrating the dermis (P = .006) and a decrease in the number of dermal CD4(+) cells (P = .044). There was also a significant decrease in the ratio of CD25(+) to CD4(+) cells in the epidermis of HIV-infected skin (P = .011). LIMITATIONS This study is limited by small sample sizes. CONCLUSION A decrease in the number of skin-directed CD4(+) cells and an increase in the ratio of CD8(+) to CD4(+) cells exists in TEN lesions among HIV-infected individuals and likely contribute to an increased risk of developing drug reactions because of the loss of skin-protective CD4(+)CD25(+) regulatory T cells.

SJS/TEN 2017: Building Multidisciplinary Networks to Drive Science and Translation

Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) is a life-threatening, immunologically mediated, and usually drug-induced disease with a high burden to individuals, their families, and society with an annual incidence of 1 to 5 per 1,000,000. To effect significant reduction in short- and long-term morbidity and mortality, and advance clinical care and research, coordination of multiple medical, surgical, behavioral, and basic scientific disciplines is required. On March 2, 2017, an investigator-driven meeting was held immediately before the American Academy of Dermatology Annual meeting for the central purpose of assembling, for the first time in the United States, clinicians and scientists from multiple disciplines involved in SJS/TEN clinical care and basic science research. As a product of this meeting, this article summarizes the current state of knowledge and expert opinion related to SJS/TEN covering a broad spectrum of topics including epidemiology and pharmacogenomic networks; clinical management and complications; special populations such as pediatrics, the elderly, and pregnant women; regulatory issues and the electronic health record; new agents that cause SJS/TEN; pharmacogenomics and immunopathogenesis; and the patient perspective. Goals include the maintenance of a durable and productive multidisciplinary network that will significantly further scientific progress and translation into prevention, early diagnosis, and management of SJS/TEN.

Transmission of Donor-Specific Skin Condition From Donor to Recipient of Facial Allograft

Facial allotransplantation allows for unprecedented restoration in the most disfigured patients. We recently reported excellent functional and aesthetic results 1 year after central face transplantation (1). Starting approximately 2 weeks after transplant, the facial allograft developed persistent redness. Biopsies obtained from the facial allograft were always consistent with acute rejection grade I and II, resistant to increases in systemic immunosuppression and topical administration of clobetasol cream (days 27–35 and 37–45) or tacrolimus cream (days 26–33, 38–43 and 76–113). On day 115, a diagnosis of rosacea was made on the basis of pathology reports consistent with incidental chronic folliculitis/rosacea. The patient started treatment with metronidazole gel to the face twice per day, which proved effective in eliminating facial redness. Biopsies at 6 and 12 months demonstrated no signs of rejection. After 6 months of therapy, biopsy showed perivascular and periadnexal lymphocytic infiltrate amongst ectatic vessels, suggestive of rosacea. Similarly at 12-month biopsy revealed superficial perivascular lymphocytic infiltrate with a follicular infundibular component.

Nail dystrophy, edema, and eosinophilia: harbingers of severe chronic GVHD of the skin in children

The prognostic value of adnexal findings in chronic GVHD (cGVHD) has not been investigated in children. Dermatologic examinations were performed in a severe cohort of 11 children with skin cGVHD seen over a 2-year period. Findings were compared with 25 additional patients with skin cGVHD and 97 control patients. In 36 patients with skin cGVHD, nail dystrophy was present in 45% of patients, and was significantly associated with sclerotic disease and lung cGVHD. Pterygium inversum unguis (PIU) was associated with severe lung disease, with significantly lower % predicted FVC and FEV1 in those with PIU than those without. Forty-four percent of GVHD patients had preceding peripheral edema and 56% had preceding peripheral eosinophilia. Peripheral edema and eosinophilia were significantly associated with sclerotic cGVHD and persisted until the diagnosis of cGVHD in all patients. Comparison of data with control patients showed that incidence of nail dystrophy, incidence of peripheral edema and mean peak peripheral eosinophil count of patients with skin cGVHD was significantly higher than those without cGVHD. This study suggests that nail dystrophy, persistent peripheral edema and persistent peripheral eosinophilia are harbingers of severe cGVHD of the skin in children. The presence of PIU may be a harbinger of severe lung involvement.

Recurrent ALK-negative anaplastic large T-cell lymphoma presenting as necrotizing vasculitis.

Abstract:Anaplastic large cell lymphoma (ALCL) is a T-cell lymphoma histologically characterized by expression of CD30, a cell surface receptor present on activated T cells and B cells. ALCL may occur in a primary cutaneous form or as systemic ALCL with lymph node involvement. Anaplastic lymphoma kinase (ALK) is a tyrosine kinase that induces neoplastic transformation as a result of translocational fusion with an activating promoter. The presence of ALK can be used to distinguish between primary cutaneous ALCL and systemic nodal ALCL in certain cases. Primary cutaneous and systemic ALCL metastatic to the skin are histologically indistinguishable. “Leukemic vasculitis”—an uncommon finding in cases of cutaneous leukemia and even more exceptional in cutaneous lymphoma—refers to a pattern of vasculitis occurring as a direct result of infiltrating neoplastic cells. We report a fatal case of recurrent ALK-negative ALCL presenting as ulcerating skin lesions in a patient previously treated with the new anti-CD30 agent brentuximab vedotin. Biopsy revealed a necrotizing vasculitis resulting from the infiltration of neoplastic cells reminiscent of the patient’s primary malignancy. We review the clinical and pathological findings of ALCL and present this case to highlight a subtle diagnostic clue in assessing recurrence of cutaneous lymphoma.

A pilot study comparing histological and immunophenotypic patterns in stage 4 skin graft versus host disease from toxic epidermal necrolysis

Stage 4 skin graft‐versus‐host disease (GVHD) is associated with poor prognosis and high mortality rates. Clinical and histologic similarities with toxic epidermal necrolysis (TEN) make it difficult to distinguish between these 2 life‐threatening conditions.