IgG4 Expression in Primary Cutaneous Marginal Zone Lymphoma: A Multicenter Study.

BACKGROUND: Primary cutaneous marginal zone lymphoma (PCMZL) is the second most common B-cell lymphoma of the skin. A recent study has demonstrated a strikingly high prevalence of immunoglobulin (Ig)G4 expression in PCMZL with plasmacytic differentiation. OBJECTIVE: The objective was to investigate the incidence of IgG4 expression in PCMZL, and its correlation with clinical and immunophenotypic features. MATERIALS AND METHODS: Multicenter study that utilized immunohistochemistry and in-situ hybridization to evaluate the expression of IgG4, Ig light (κ and λ), and heavy chains (IgM, IgG), and the ratio of T (CD3+) and B (CD20+) cells in biopsy specimens from 30 patients with PCMZL and to correlate these findings with the clinical features. RESULTS: IgG4 expression was observed in 4 out of 30 patients (13%) with PCMZL. Patients with IgG4-positive lymphomas were 57 to 77 years of age (mean, 69) at biopsy. The lesions were solitary in 2 patients with IgG4-positive lymphomas, and were most commonly located on the trunk. Patients with IgG4-negative lymphomas experienced earlier disease onset at an average age of 53 years. The majority of the IgG4-negative cases presented with localized disease, on the trunk and upper extremities. There was no significant difference in the IgG4-positive versus negative cases for the following parameters: Ig κ or λ restriction, B-cell or T-cell predominance, and site of the lesions. CONCLUSIONS: IgG4 expression was observed in a minority of PCMZL patients. We did not identify significant clinical or immunophenotypic differences between IgG4 positive and negative cases.

Characterization of the tumor microenvironment in primary cutaneous CD30-positive lymphoproliferative disorders: a predominance of CD163-positive M2 macrophages.

BACKGROUND: The tumor microenvironment is essential for tumor survival, growth and progression. There are only a few studies on the tumor microenvironment in cutaneous CD30-positive lymphoproliferative disorders. METHODS: We assessed the composition of the tumor microenvironment using immunohistochemistry studies in skin biopsies from cases diagnosed with lymphomatoid papulosis (LyP: 18 specimens), primary cutaneous anaplastic large-cell lymphoma (PC-ALCL: 8 specimens), and reactive diseases harboring CD30-positive cells (18 specimens). RESULTS: The predominant cells present in LyP and PC-ALCL were CD163+ M2 macrophages (44.7%, 35%), followed by CD8+ tumor infiltrating lymphocytes (11%, 15%), FOXP3+ T-regulatory cells (9%, 4.5%) and programmed cell death 1(PD-1) + lymphocytes (2.2%, 6.8%). In contrast, CD30-positive reactive inflammatory and infectious disorders were characterized by higher numbers of CD123+ plasmacytoid dendritic cells (6.3%) when compared to LyP (1%), and PC-ALCL (1.1%). CONCLUSIONS: Key differences exist between the microenvironment of CD30-positive lymphoproliferative disorders and reactive conditions harboring CD30-positive lymphocytes. The high number of tumor associated macrophages, and the close vicinity of these immune cells to the CD30-positive tumor cells might suggest that tumor associated macrophages have direct influence on tumorigenesis in LyP and ALCL. Therefore, modulation of M2 macrophages may represent a new therapeutic strategy in cutaneous CD30-positive lymphoproliferative disorders.

Extensive and Progressing Congenital Dermal Melanocytosis Leading to Diagnosis of GM1 Gangliosidosis.

Congenital dermal melanocytosis (CDM) is a birthmark composed of macular blue-grey hyperpigmentation commonly observed in the lumbosacral region of infants. Generally resolving by childhood, it is traditionally considered a benign condition, but it may be a sign of underlying lysosomal storage disease. We report a case of biopsy-confirmed CDM in a 2-month-old girl of Brazilian descent later diagnosed with infantile GM1 gangliosidosis.

Contribution of longitudinal follow up and clinical pathological correlation in the diagnosis CD30-positive skin infiltrates.

The diagnosis of a CD30+ cutaneous infiltrate is often difficult and requires clinicopathologic correlation. To further evaluate this challenge, initial clinical and histopathologic diagnoses were correlated with final clinicopathologic diagnosis in 44 cases with CD30 immunopositivity. Dermatopathologic evaluation confirmed the initial clinical diagnosis in 65% of the suspected benign cases, all cases of suspected lymphomatoid papulosis (LyP), and 72% of clinically malignant cases. In the 25 patients with clinical suspicion for lymphoma, the histopathologic diagnoses included lymphoma in 18, LyP in 2, CD30+ lymphoproliferative disorder (CD30 LPD) in 3 and hypersensitivity reaction in 2 patients. Clinicopathologic correlation led to a change in three cases diagnosed histopathologically as anaplastic large cell lymphoma (ALCL) reclassified as LyP type C, and one patient diagnosed as CD30 LPD clinically evolved as herpes virus infection. Furthermore, five cases reported as CD30 LPD received more specific diagnoses after clinicopathologic correlation (LyP type C in three, and ALCL in two patients). Clinicopathologic correlation is essential in establishing the correct diagnosis of CD30 LPD, in particular the distinction of ALCL from LyP type C. In this setting, the histopathologic diagnosis of CD30 LPD is advisable in the absence of clinical data.

Loss of expression of 5-hydroxymethylcytosine in CD30-positive cutaneous lymphoproliferative disorders.

BACKGROUND: The methylation of DNA at position 5 of cytosine, and the subsequent reduction in intracellular 5-hydroxymethylcytosine (5-hmC) levels, is a key epigenetic event in several cancers, including systemic lymphomas. However, no studies have analyzed this epigenetic marker in cutaneous lymphomas. Therefore, we aimed to analyze the expression of 5-hmC in cutaneous CD30-positive lymphoproliferative disorders and compare it with a control group composed of reactive infectious and inflammatory disorders with CD30-positive cells. METHODS: Retrospective case series study with immunohistochemical analysis using anti-CD30 and anti-5-hmC antibodies in control (n = 19), lymphomatoid papulosis (LyP) (n = 27) and primary cutaneous anaplastic large cell lymphoma (ALCL) (n = 14) specimens. RESULTS: Complete loss of 5-hmC nuclear staining by CD30+ cells was observed in 63% of LyP cases, 57% of ALCL cases and 0% of control cases. CONCLUSIONS: The presence of 5-hmC+ and CD30+ lymphocytes was highly suggestive of a benign process. In contrast, loss of 5-hmC nuclear staining was highly suggestive of a lymphoproliferative disorder (ALCL or LyP). Under these circumstances, the use of 5-hmC staining can be a useful adjunctive tool for discriminating between neoplastic CD30+ lymphoproliferations and inflammatory/infectious simulators harboring reactive CD30+ cells.

Community differentiation of the cutaneous microbiota in psoriasis.

BACKGROUND: Psoriasis is a common chronic inflammatory disease of the skin. We sought to characterize and compare the cutaneous microbiota of psoriatic lesions (lesion group), unaffected contralateral skin from psoriatic patients (unaffected group), and similar skin loci in matched healthy controls (control group) in order to discern patterns that govern skin colonization and their relationship to clinical diagnosis. RESULTS: Using high-throughput 16S rRNA gene sequencing, we assayed the cutaneous bacterial communities of 51 matched triplets and characterized these samples using community data analysis techniques. Intragroup Unifrac ß diversity revealed increasing diversity from control to unaffected to lesion specimens. Likewise, principal coordinates analysis (PCoA) revealed separation of the lesion samples from unaffected and control along the first axis, suggesting that psoriasis is a major contributor to the observed diversity. The taxonomic richness and evenness decreased in both lesion and unaffected communities compared to control. These differences are explained by the combined increased abundance of the four major skin-associated genera (Corynebacterium, Propionibacterium, Staphylococcus, and Streptococcus), which present a potentially useful predictor for clinical skin type. Psoriasis samples also showed significant univariate decreases in relative abundances and strong classification performance of Cupriavidus, Flavisolibacter, Methylobacterium, and Schlegelella genera versus controls. The cutaneous microbiota separated into two distinct clusters, which we call cutaneotypes: (1) Proteobacteria-associated microbiota, and (2) Firmicutes-associated and Actinobacteria-associated microbiota. Cutaneotype 2 is enriched in lesion specimens compared to control (odds ratio 3.52 (95% CI 1.44 to 8.98), P <0.01). CONCLUSIONS: Our results indicate that psoriasis induces physiological changes both at the lesion site and at the systemic level, which select for specific differential microbiota among the assayed clinical skin types. These differences in microbial community structure in psoriasis patients are potentially of pathophysiologic and diagnostic significance.

Apremilast for discoid lupus erythematosus: results of a phase 2, open-label, single-arm, pilot study.

BACKGROUND: Discoid lupus erythematosus (DLE) is a chronic inflammatory disorder mediated by Th1 cells. Apremilast is a novel oral PDE4 enzyme inhibitor capable of blocking leukocyte production of IL-12, IL-23, TNF-a, INF- with subsequent suppression of Th1 and Th17-mediated immune responses, and proven clinical efficacy for psoriasis as well as rheumatoid and psoriatic arthritis. OBSERVATIONS: Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) showed a significant (P<0.05) decrease after 85 days of treatment with apremilast 20 mg twice daily in 8 patients with active discoid lupus. The adverse events related to the drug were mild and transient. CONCLUSIONS: This is the first open label study to use apremilast as a treatment modality for discoid lupus. Our observations indicate that apremilast may constitute a safe and effective therapeutic option for DLE.

Psoriasis and Down syndrome: a report of three cases and a potential pathophysiologic link.

Psoriasis is thought to result from an influx of Th1 and Th17 cells driven by the production of cytokines such as interferon (IFN)-gamma, IL-2, and tumor necrosis factor (TNF)-alpha elicited by skin immunocytes. We report three cases of patients with chronic plaque psoriasis and concomitant Down syndrome. Although there is no direct link between Down syndrome and the Th17 pathway, there are data supporting a dysregulation of the IFN system in this patient population. The percentage of Th1 lineage cells (IFN-gamma producing CD4+ and CD8+ T cells) is substantially higher in patients with Down syndrome and serum levels of IFN-gamma in patients with Down syndrome are significantly elevated when compared to healthy controls. We propose that people with Down syndrome have a greater prevalence of psoriasis secondary to both high serum levels of and an enhanced sensitivity to IFN-gamma.

The management of EGFR inhibitor adverse events: a case series and treatment paradigm.

BACKGROUND: Epidermal growth factor receptor (EGFR) inhibitors are widely used medications in the treatment of cancers. OBJECTIVE: To review the cutaneous adverse events related to EGFR inhibitors. METHODS: A retrospective chart review of all cases referred for the management of cutaneous adverse events after the initiation of EGFR inhibitor therapy between the years of 2006 and 2009 was performed. The study was approved by the institutional review board. RESULTS: Four men and 11 women had cutaneous adverse events while receiving erlotinib (mean dose: 112.5 mg) for lung and pancreatic cancer. The most common cutaneous adverse reaction observed was a papulopustular rash in 12 cases (80%). Eczema and xerosis were the only findings in three patients, alopecia in one case, and nail changes in three cases. The treatment modalities prescribed were doxycycline and topical antibiotics for the papulopustular rash; topical high potency steroids, tacrolimus, pimecrolimus, and moisturizers for xerosis and eczema; and cetirizine for the pruritus. The paronychia was treated with warm soaks, topical steroids, and podiatry referral. The majority of patients improved with symptomatic therapy, with the exception of one patient who experienced herpes zoster super infection and Stevens-Johnson syndrome. The patient was hospitalized and required discontinuation of the erlotinib therapy. CONCLUSION: The most common cutaneous adverse event in our cohort was papulopustular rash, followed by eczema and xerosis. Patients were managed with symptom target therapy, and suspension of the EGFR inhibitor was rarely required. As the use of EGFR inhibitors increases, it is important to promptly identify and treat adverse events. Further studies are necessary to develop targeted therapeutic and preventative measures.

In search of prognostic indicators for lymphomatoid papulosis: a retrospective study of 123 patients.

BACKGROUND: Lymphomatoid papulosis (LyP) is a benign recurrent papulonodular skin eruption with histologically malignant features that sometimes (10%-20%) progresses to lymphoma. OBJECTIVE: We retrospectively evaluated the clinical course of patients with LyP and identify prognostic factors possibly indicating a malignant course. METHODS: Clinical, histopathologic, and immunologic features and molecular genetics were examined and correlated with clinical course and outcomes. Immunophenotyping and chemokine profiling were performed in select skin biopsy samples. A follow-up questionnaire was sent to patients. Clinical course and association with neoplastic disorders were correlated with LyP subtypes, molecular genetics, and immunophenotyping studies. RESULTS: Of 123 patients with LyP (1991-2008) followed up a mean of 4 years (range, 2 months to 14 years), 17 (14%) had an associated hematologic malignancy, 8 of which were mycosis fungoides. Histopathologic analyses demonstrated classic LyP type A (n = 69), B (n = 13), or C (n = 6), and a slight predominance of T-cell CD8 marker expression for type A. More than one type of lesion was present in 9 patients with a higher incidence of hematologic malignancies. T-cell receptor gene rearrangement positivity was about two times higher, with LyP associated with hematologic malignancy (82% vs 44%; odds ratio 5.7; P = .02). Chemokine studies in a subset of 25 patients showed chemokine receptor (CCR) CCR4(+) and thymus and activation-related chemokine (TARC(+)) in all LyP types and CCR3(+) and chemokine-related receptor (CXCR) CXCR3(+) in types B and C. LIMITATIONS: Retrospective study design is a limitation. CONCLUSIONS: Positive T-cell receptor gene rearrangement or diagnosis of mixed-type LyP may be a prognostic indicator of disease more prone to progress to lymphoma.

SAPHO syndrome associated with hidradenitis suppurativa successfully treated with infliximab and methotrexate.

SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) is a rare chronic inflammatory musculoskeletal disorder of unknown etiology observed in children and young adults, which involves both osteo-articular inflammation and skin abnormalities. We review the case of a 22-year-old male, who presented with a 5-year history of hidradenitis suppurativa (HS), acne vulgaris, joint stiffness, and pain. Previous ineffective treatments included isotretinoin and oral antibiotics. Marked improvement of all cutaneous features was noticed after the first dose of infliximab and methotrexate; continued treatment resulted in the complete remission of the arthritis and enthesopathy. This case report demonstrates the efficacy and safety of infliximab and methotrexate in refractory SAPHO syndrome.

Clinical, histopathologic, and immunophenotypic features of lymphomatoid papulosis with CD8 predominance in 14 pediatric patients.

BACKGROUND: Lymphomatoid papulosis (LyP) is a cyclic papulonodular eruption that is clinically benign and histologically malignant. Association with hematologic neoplasias has been reported in 5% to 20% of all cases. OBJECTIVE: We sought to review the clinical and histopathologic features of LyP in pediatric patients. METHODS: We searched for the records of all patients with a clinical and histopathologic diagnosis of LyP seen at our clinic from January 1991 through April 2008. The cases of pediatric patients (aged < 20 years) were reviewed in detail. RESULTS: Of 123 patients with LyP identified, 14 (11%) were in the pediatric age group. Most were male (64%); mean age of onset was 12 years. Type A LyP was identified in 12 patients, one patient had type B, and none had type C (type not determined in one case). Ten cases showed CD8 predominance by immunohistochemistry. T-cell intracytoplasmic antigen staining was positive in 3 cases of CD8(+) LyP type A and the one case of LyP type B. Lesional T-cell receptor gene rearrangement studies were negative in 9 of 10 patients with LyP type A. The average follow-up time was 5.5 years. Lesions improved with treatment in most cases, and none of the cases were associated with hematologic malignancies. LIMITATIONS: This was a retrospective review. CONCLUSIONS: Among our pediatric patients, we noted a predominance of CD8(+) LyP, which does not seem to have an aggressive course. Further longitudinal studies are necessary to evaluate prognostic differences between CD4(+) and CD8(+) LyP and their biological significance.

Resolution of CD8+ lymphomatoid papulosis after surgical excision of the type AB-thymoma.

Lymphomatoid papulosis (LyP) is a disease characterized by cyclic eruptions of papulonodular lesions, which undergo spontaneous healing. Lymphoid malignancies are present in 10%-15% of cases. The type AB thymoma is an epithelial neoplasm composed of both type A (lymphocyte-poor) and type B (lymphocyte-rich) areas. Chemokines are chemotactic cytokines, responsible for leukocyte motility and direct movement. Interactions between chemokines and their receptors have been correlated with homing of lymphoma cells to various tissues. We describe a patient whose type B LyP CD8 lesions completely resolved after surgical removal of type AB thymoma. The chemokine profile was similar in both tissues: thymus- and activation-regulated chemokine and CCR4 were focally positive in the thymoma. Thymus- and activation-regulated chemokine was positive in the epidermotropic cells and in the majority of the dermal lymphocytes in the LyP specimen, whereas CCR4 was focally positive in the dermal lymphocytes. Monokine induced by interferon-g (Mig) staining showed strong positivity in the dermal lymphocytes and in localized areas of the thymoma, but an immunostain for the Mig receptor (CXCR3) highlighted only a few scattered cells in both tissues (less than 3%). Both tissues were negative for regulated upon activation, normal T-cell expressed and secreted (RANTES) and CCR3. In summary, we report the association of a CD30-negative CD8-predominant LyP and a type AB thymoma, with similar chemokine profiles. The rarity of both conditions and the precise regression of LyP after removal of the thymoma argue against a coincidental observation. We recommend that a search for thymoma be included in the workup of LyP. Further chemokine profiling in other cases of LyP may assist in understanding their role in this disease.