IntroductionPyoderma gangrenosum (PG) is a rare inflammatory ulcerative disease with unknown pathophysiology and etiology. It is associated with many systemic inflammatory, autoimmune, and neoplastic diseases.1DaCunha M. Siscos S. Downing M. Tarantino I. Hall J. Pyoderma gangrenosum controlled with rituximab.JAAD Case Rep. 2019; 5: 593-595Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar,2Bhat R.M. Pyoderma gangrenosum: An update.Indian Dermatol Online J. 2012; 3: 7-13Crossref PubMed Google Scholar The clinical presentation varies widely but commonly manifests as painful, progressive, and well-demarcated ulcers with blue/gray serpiginous borders.2Bhat R.M. Pyoderma gangrenosum: An update.Indian Dermatol Online J. 2012; 3: 7-13Crossref PubMed Google Scholar The histopathology of PG is non-specific but typically includes dense neutrophilic infiltration with necrosis and hemorrhage.3Powell F.C. Hackett B.C. Pyoderma gangrenosum.in: Wolff K. Goldsmith L. Katz S. Gilchrest B. Paller A.S. Leffell D. Fitzpatrick's Dermatology in General Medicine. 8th Edition. McGraw-Hill, 2011: 371-372Google ScholarThese variations and inherent uncertainties of PG can make definitive diagnosis challenging, and more common processes such as infections, vasculidities, and malignancies must first be excluded. Suggested criteria for PG are: progression of the ulcer(s), ruling out more common ulcerative diseases and atypical infections, confirmation of associated systemic diseases, and response to treatments.4Kridin K. Cohen A.D. Amber K.T. Underlying systemic diseases in pyoderma gangrenosum: a systematic review and meta-analysis.Am J Clin Dermatol. 2018; 19: 479-487Crossref PubMed Scopus (36) Google Scholar Therapy typically includes immunosuppression and wound care, but treatment of underlying systemic diseases, seen in this case report, has been shown to be successful.5Bostan E. Günaydın S.D. Karaduman A. et al.Excellent response to bortezomib in a patient with widespread ulcerative pyoderma gangrenosum accompanied by pulmonary involvement and IgA monoclonal gammopathy.Int Wound J. 2019; 16: 1052-1054PubMed Google ScholarCase reportA 51-year-old female presented with a history of three episodes of suspected PG over two years. She was initially evaluated at an emergency department in 2017 and was found to have rust-colored sputum and a presumed pneumonia. After she did not respond to antibiotics and her chest computed tomography images worsened, a transthoracic lung biopsy was performed revealing bronchocentric granulomatous inflammation and fibrosis. Bacterial, fungal, and acid-fast bacilli cultures were negative. She was noted to have a nasal septum perforation, which raised concern for granulomatosis with polyangiitis, but no vasculitis was seen on biopsy, and the antineutrophil cytoplasmic antibodies were negative. The cutaneous site of her lung biopsy developed an ulcer that quickly expanded and was clinically diagnosed as PG (Fig 1). This required skin-grafting and pulse-dosed methylprednisolone before resolving. The pneumonitis also resolved with methylprednisolone. Months later, she again developed a progressive ulceration of her trunk (Fig 2). This ulcer again responded to pulse steroids and skin-grafting.Fig 2PG ulcer of the abdomen requiring skin-grafting. PG, Pyoderma gangrenosum.View Large Image Figure ViewerDownload Hi-res image Download (PPT)At presentation in our clinic, on her left anterior hip, she had a 1-cm erosion with yellowish exudate and granulation tissue with surrounding redness but no drainage or fluctuance (Fig 3). Intralesional triamcinolone 10 mg/cc was injected in the office along with a superficial bacterial culture which was negative for Staphylococcus aureus. Over several weeks, her ulcer grew, despite increasing doses of oral prednisone of up to 60 mg/day and cyclosporine 100 mg twice a day (Fig 4). Pulse IV methylprednisolone therapy was again required for control.Fig 3Early PG on the left anterior hip appearing after prednisone taper. PG, Pyoderma gangrenosum.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 4Recalcitrant PG. PG, Pyoderma gangrenosum.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Laboratory work-up was notable for antinuclear antibody positivity (titer, 1:360), slightly elevated rheumatoid factor (16.7 IU/ml), erythrocyte sedimentation rate (63 mm/hr), and CRP (4.0 mg/L). Rheumatology performed serum protein electrophoresis, showing a faint IgA lambda monoclonal spike of 0.1 g/dL. Bone marrow aspiration revealed a clonal population of neoplastic plasma cells on flow cytometry, fluorescence in-situ hybridization analysis, and histopathology. After the healing of the ulcer, immunosuppression was discontinued and the oncology team initiated six cycles of cyclophosphamide, bortezomib, and dexamethasone. The patient's IgA monoclonal gammopathy became undetectable, and the patient has been in remission of PG for over one year.DiscussionPG represents one of the neutrophilic dermatoses. These are clinically dissimilar diseases united by morphological overlap, polymorphonuclear infiltrates on histopathology, extracutaneous neutrophilic infiltrates, and frequent associations with systemic disease.6Wallach D. Vignon-Pennamen M.D. From acute febrile neutrophilic dermatosis to neutrophilic disease: forty years of clinical research.J Am Acad Dermatol. 2006; 55: 1066-1071Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar Manifesting this clinical heterogeneity, this patient's pulmonary involvement by PG was difficult to diagnose due to this uncommon location and mimicry of pneumonia. Additionally, it is exceedingly rare for the lungs to be the initial and sole site of PG involvement.7Sakata K.K. Penupolu S. Colby T.V. Gotway M.B. Wesselius L.J. Pulmonary pyoderma gangrenosum without cutaneous manifestations.Clin Respir J. 2016; 10: 508-511Crossref PubMed Scopus (6) Google Scholar However, pulmonary involvement is the most common extracutaneous site of PG, and such cases are more often associated with hematologic disease than classic PG.8Borda L.J. Wong L.L. Marzano A.V. Ortega-Loayza A.G. Extracutaneous involvement of pyoderma gangrenosum.Arch Dermatol Res. 2019; 311: 425-434Crossref PubMed Scopus (26) Google Scholar,9Gupta A.S. Greiling T.M. Ortega-Loayza A.G. A systematic review of pyoderma gangrenosum with pulmonary involvement: clinical presentation, diagnosis and management.J Eur Acad Dermatol Venereol. 2018; 32: e295-e297Crossref PubMed Scopus (9) Google Scholar As we observed, PG with pulmonary involvement is often presumed to be a pneumonia until it becomes clear that antibiotics are ineffective. A lung biopsy was performed, resulting in an ulcer at the surgical incision. In light of this pathergy, cutaneous PG with pulmonary involvement was more strongly considered. This demonstrates the difficulty of diagnosing PG, particularly when it does not manifest in a typical location. In fact, her diagnosis was still in question, when we considered granulomatosis with polyangiitis, given her lung lesions and perforated nasal septum, though the absence of primary vasculitis on biopsies and a negative test for antineutrophil cytoplasmic antibodies made PG more likely.Once a working diagnosis of PG is established, immunosuppression with systemic corticosteroids, steroid-sparing agents, and tumor necrosis factor inhibitors are often required. This patient had recurrent PG despite aggressive parental steroid use in combination with a steroid-sparing agent. In recalcitrant clinical cases, an underlying systemic disease may be present.5Bostan E. Günaydın S.D. Karaduman A. et al.Excellent response to bortezomib in a patient with widespread ulcerative pyoderma gangrenosum accompanied by pulmonary involvement and IgA monoclonal gammopathy.Int Wound J. 2019; 16: 1052-1054PubMed Google Scholar Our evaluation for typical associated conditions such as inflammatory bowel disease, inflammatory arthritis, solid organ malignancies, myelodysplastic syndrome, and hematologic malignancy was negative.4Kridin K. Cohen A.D. Amber K.T. Underlying systemic diseases in pyoderma gangrenosum: a systematic review and meta-analysis.Am J Clin Dermatol. 2018; 19: 479-487Crossref PubMed Scopus (36) Google Scholar Urine and serum electrophoresis demonstrated a subtle IgA lambda gammopathy, which was confirmed on subsequent bone marrow biopsy to represent a plasma cell dyscrasia. Although unusual, PG of the lungs with histology showing pulmonary granulomatous inflammation was reported in one of two cases by Gade et al,10Gade M. Studstrup F. Andersen A.K. Hilberg O. Fogh C. Bendstrup E. Pulmonary manifestations of pyoderma gangrenosum: 2 cases and a review of the literature.Respir Med. 2015; 109: 443-450Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar and their literature review indicated that granulomatous histology was seen in 2% of cases of PG with pulmonary involvement. The letter by Bostan et al reporting PG with pulmonary involvement, large truncal cutaneous ulcers, and an IgA gammopathy responsive to bortezomib was strikingly similar to our case.5Bostan E. Günaydın S.D. Karaduman A. et al.Excellent response to bortezomib in a patient with widespread ulcerative pyoderma gangrenosum accompanied by pulmonary involvement and IgA monoclonal gammopathy.Int Wound J. 2019; 16: 1052-1054PubMed Google Scholar While the specific underlying mechanism of this association has not been fully elucidated, dysregulation of the immune system through defective cell-mediated responses or deposition of immunoglobulins in vessels has been postulated.2Bhat R.M. Pyoderma gangrenosum: An update.Indian Dermatol Online J. 2012; 3: 7-13Crossref PubMed Google Scholar Treatment of the present patient's underlying hematologic disorder will hopefully prevent future episodes of PG. The purpose of this case report is to highlight an unusual case of recalcitrant cutaneous PG with pulmonary involvement associated with an underlying plasma cell dyscrasia and IgA gammopathy. In future cases of atypical PG, consideration of a similar underlying process may result in a timely diagnosis and successful treatment plan, preventing additional morbidity and even mortality. IntroductionPyoderma gangrenosum (PG) is a rare inflammatory ulcerative disease with unknown pathophysiology and etiology. It is associated with many systemic inflammatory, autoimmune, and neoplastic diseases.1DaCunha M. Siscos S. Downing M. Tarantino I. Hall J. Pyoderma gangrenosum controlled with rituximab.JAAD Case Rep. 2019; 5: 593-595Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar,2Bhat R.M. Pyoderma gangrenosum: An update.Indian Dermatol Online J. 2012; 3: 7-13Crossref PubMed Google Scholar The clinical presentation varies widely but commonly manifests as painful, progressive, and well-demarcated ulcers with blue/gray serpiginous borders.2Bhat R.M. Pyoderma gangrenosum: An update.Indian Dermatol Online J. 2012; 3: 7-13Crossref PubMed Google Scholar The histopathology of PG is non-specific but typically includes dense neutrophilic infiltration with necrosis and hemorrhage.3Powell F.C. Hackett B.C. Pyoderma gangrenosum.in: Wolff K. Goldsmith L. Katz S. Gilchrest B. Paller A.S. Leffell D. Fitzpatrick's Dermatology in General Medicine. 8th Edition. McGraw-Hill, 2011: 371-372Google ScholarThese variations and inherent uncertainties of PG can make definitive diagnosis challenging, and more common processes such as infections, vasculidities, and malignancies must first be excluded. Suggested criteria for PG are: progression of the ulcer(s), ruling out more common ulcerative diseases and atypical infections, confirmation of associated systemic diseases, and response to treatments.4Kridin K. Cohen A.D. Amber K.T. Underlying systemic diseases in pyoderma gangrenosum: a systematic review and meta-analysis.Am J Clin Dermatol. 2018; 19: 479-487Crossref PubMed Scopus (36) Google Scholar Therapy typically includes immunosuppression and wound care, but treatment of underlying systemic diseases, seen in this case report, has been shown to be successful.5Bostan E. Günaydın S.D. Karaduman A. et al.Excellent response to bortezomib in a patient with widespread ulcerative pyoderma gangrenosum accompanied by pulmonary involvement and IgA monoclonal gammopathy.Int Wound J. 2019; 16: 1052-1054PubMed Google Scholar

While much is known about acute infection pathogenesis, the understanding of chronic infections has lagged. Here we sought to identify the genes and functions that mediate fitness of the pathogen Pseudomonas aeruginosa in chronic wound infections, and to better understand the selective environment in wounds. We found that clinical isolates from chronic human wounds were frequently defective in virulence functions and biofilm formation, and that many virulence and biofilm formation genes were not required for bacterial fitness in experimental mouse wounds. In contrast, genes involved in anaerobic growth, some metabolic and energy pathways, and membrane integrity were critical. Consistent with these findings, the fitness characteristics of some wound impaired-mutants could be represented by anaerobic, oxidative, and membrane-stress conditions ex vivo, and more comprehensively by high-density bacterial growth conditions, in the absence of a host. These data shed light on the bacterial functions needed in chronic wound infections, the nature of stresses applied to bacteria at chronic infection sites, and suggest therapeutic targets that might compromise wound infection pathogenesis.

Biofilms have been implicated in delayed wound healing, although the mechanisms by which biofilms impair wound healing are poorly understood. Many species of bacteria produce exotoxins and exoenzymes that may inhibit healing. In addition, oxygen consumption by biofilms and by the responding leukocytes, may impede wound healing by depleting the oxygen that is required for healing. In this study, oxygen microsensors to measure oxygen transects through in vitro cultured biofilms, biofilms formed in vivo within scabs from a diabetic (db/db) mouse wound model, and ex vivo human chronic wound specimens was used. The results showed that oxygen levels within mouse scabs had steep gradients that reached minima ranging from 17 to 72 mmHg on live mice and from 6.4 to 1.1 mmHg on euthanized mice. The oxygen gradients in the mouse scabs were similar to those observed for clinical isolates cultured in vitro and for human ex vivo specimens. To characterize the metabolic activities of the bacteria in the mouse scabs, transcriptomics analyses of Pseudomonas aeruginosa biofilms associated with the db/db mice wounds was performed. The results demonstrated that the bacteria expressed genes for metabolic activities associated with cell growth. Interestingly, the transcriptome results also indicated that the bacteria within the wounds experienced oxygen‐limitation stress. Among the bacterial genes that were expressed in vivo were genes associated with the Anr‐mediated hypoxia‐stress response. Other bacterial stress response genes highly expressed in vivo were genes associated with stationary‐phase growth, osmotic stress, and RpoH‐mediated heat shock stress. Overall, the results supported the hypothesis that bacterial biofilms in chronic wounds promote chronicity by contributing to the maintenance of localized low oxygen tensions, through their metabolic activities and through their recruitment of cells that consume oxygen for host defensive processes.

ABSTRACT Evidence‐based ulcer care guidelines detail optimal components of care for treatment of ulcers of different etiologies. We investigated the impact of providing specific evidence‐based ulcer treatment components on healing outcomes for lower limb ulcers (LLU) among veterans in the Pacific Northwest. Components of evidence‐based ulcer care for venous, arterial, diabetic foot ulcers/neuropathic ulcers were abstracted from medical records. The outcome was ulcer healing. Our analysis assessed the relationship between evidence‐based ulcer care by etiology, components of care provided, and healing, while accounting for veteran characteristics. A minority of veterans in all three ulcer‐etiology groups received the recommended components of evidence‐based care in at least 80% of visits. The likelihood of healing improved when assessment for edema and infection were performed on at least 80% of visits (hazard ratio [HR] = 3.20, p = 0.009 and HR = 3.54, p = 0.006, respectively) in patients with venous ulcers. There was no significant association between frequency of care components provided and healing among patients with arterial ulcers. Among patients with diabetic/neuropathic ulcers, the chance of healing increased 2.5‐fold when debridement was performed at 80% of visits ( p = 0.03), and doubled when ischemia was assessed at the first visit ( p = 0.045). Veterans in the Pacific Northwest did not uniformly receive evidence‐based ulcer care. Not all evidence‐based ulcer care components were significantly associated with healing. At a minimum, clinicians need to address components of ulcer care associated with improved ulcer healing.

Clinical Practice Points•Cutaneous T-cell lymphoma (CTCL) is a subtype of lymphoma. Involvement of the central nervous system (CNS) is a rare complication and is reportedly associated with poor prognosis.•CNS involvement in CTCL manifests as parenchymal or leptomeningeal metastases.•Awareness of potential CNS involvement in CTCL is critical in recognizing or identifying the disease and initiating CNS-directed treatment. •Cutaneous T-cell lymphoma (CTCL) is a subtype of lymphoma. Involvement of the central nervous system (CNS) is a rare complication and is reportedly associated with poor prognosis.•CNS involvement in CTCL manifests as parenchymal or leptomeningeal metastases.•Awareness of potential CNS involvement in CTCL is critical in recognizing or identifying the disease and initiating CNS-directed treatment. A 64-year-old woman with longstanding facial and body eczematous dermatitis presented with large ulcerating masses on the neck and right upper eyelid as well as multiple erythematous scaly plaques on the trunk and extremities (Fig. 1A). Skin biopsy and T-cell receptor (TCR) gene rearrangement studies were consistent with cutaneous T-cell lymphoma (CTCL), mycosis fungoides (MF) type (CTCL/MF). Dermatopathology showed psoriasiform dermatitis with an epidermotropic T-cell infiltrate with enlarged and hyperchromatic nuclei. Flow cytometry revealed that the atypical T cells were CD3 positive (CD3+) and CD4+, with loss of CD8, CD5, and CD7 positivity and only rare CD30 positivity. A clonal TCR gamma chain gene rearrangement was found by PCR. Peripheral blood flow cytometry was negative for circulating atypical lymphocytes. During the patient's evaluation, the tumor over the right orbit rapidly enlarged and ulcerated (see Fig. 1B). She developed neurologic symptoms including a subtle left hemiparesis, left-sided limb ataxia, mild intention tremor, and difficulty with cognition and word finding. Magnetic resonance imaging (MRI) of the brain showed minimal contrast enhancement; however, the fluid attenuated inversion recovery (FLAIR) sequence revealed a large right hemispheric signal abnormality in the right centrum semiovale (Fig. 2A, B). Cerebrospinal fluid (CSF) cytology and flow cytometry were negative for infection or tumor. Brain biopsy was recommended to the patient, but she declined. Based on the clinical scenario, the cancer was staged as IVB CTCL/MF with parenchymal central nervous system (CNS) involvement. The patient underwent electron beam radiation therapy with a cumulative dose of 36 Gy to her cutaneous tumors, with significant shrinkage of these masses (see Fig. 1C, D). After the development of neurologic signs and symptoms, she was treated with oral dexamethasone and high-dose intravenous methotrexate (HD-MTX) (8 g/m2). She completed 8 cycles of HD-MTX (4 cycles administered once every 2 weeks and subsequently 4 cycles once every 4 weeks) with complete resolution of neurologic symptoms and normalization of brain MRI changes (see Fig. 2C, D). The patient's patch-stage skin lesions initially improved with HD-MTX but slowly recurred off therapy. Maintenance chemotherapy with oral bexarotene was started, which was changed to intravenous romidepsin therapy after she developed additional cutaneous tumors. One year after her initial presentation, the patient is fully functional in her daily activities, with a normal neurologic examination, and has stable cutaneous disease. Follow-up brain MRI found no evidence of recurrent or residual metastasis.Figure 2(A) MRI of the Brain, Axial FLAIR Sequence Pretreatment Study, Demonstrating High Signal Intensity in the Right Deep Periventricular White Matter With Associated Mass Effect. (B) MRI of the Brain, T1 Postcontrast Axial Sequence Pretreatment Study, Showing Speckled Enhancement in the Right Periventricular White Matter, Striatum, and Internal Capsule. (C, D) MRI of the Brain, Axial FLAIR (C) and Axial T1 Postcontrast (D) Sequences Posttreatment, Showing No Abnormal Signal (ie, a Normal Study)Show full captionAbbreviations: FLAIR = fluid attenuated inversion recovery; MRI = magnetic resonance imaging.View Large Image Figure ViewerDownload (PPT) Abbreviations: FLAIR = fluid attenuated inversion recovery; MRI = magnetic resonance imaging. A 52-year-old man with a medical history including coronary artery disease, chronic obstructive pulmonary disease, and type 2 diabetes mellitus presented with intermittent, progressive, painful erythematous papules and plaques on the upper chest and upper extremities over 2 years (Fig. 3A). Concurrent with the skin eruption, he developed episodic but progressive weakness ultimately resulting in C5 asymmetric tetraplegia that necessitated the use of a motorized wheelchair. Before presentation at the authors' institution, he had been treated with multiple courses of high-dose pulse intravenous methylprednisolone for presumed idiopathic transverse myelitis, with temporary improvement of skin lesions and leg weakness after each treatment course. Subsequently a skin biopsy found an atypical dermal lymphoid infiltrate with an abnormal immunophenotype revealing a CD3+, CD4+ T-cell infiltrate with decreased expression of CD2 and CD7. CD25, CD30, and CD56 were negative. TCR gene rearrangement studies confirmed the presence of a T-cell clone. Brain MRI showed patchy small-volume bihemispheric parenchymal lesions in the supratentorial and infratentorial compartments. Spine MRI found extensive cervical and lumbar leptomeningeal and parenchymal enhancement and associated subarachnoid nodules (see Fig. 3B, C, D). CSF analysis found elevated glucose and protein, with the presence of atypical lymphocytes. CSF flow cytometry confirmed an abnormal T-cell population with an immunophenotype similar to that of the skin, with a low level also detected in the peripheral blood. Based on the presence of the same TCR clone in the skin, CSF, and blood, the patient was diagnosed with CTCL (peripheral T-cell lymphoma, not otherwise specified) with brain and spine parenchymal and leptomeningeal involvement. The patient was treated with pulse-dose intravenous methylprednisolone and intravenous immunoglobulin, followed by HD-MTX, 8 g/m2, for 6 cycles (each cycle administered every 2 weeks). Repeat MRI imaging showed minimal response in the brain and spine, although his neurologic examination remained stable. He was subsequently started on pemetrexed, 500 mg/m2, administered once every 3 weeks, a therapy administered on an outpatient basis. Six months after diagnosis of CTCL and with continued pemetrexed treatment, the patient remains neurologically stable with a modest clinical response and stable neuroradiographic disease. CTCL is a subtype of non-Hodgkin lymphoma with protean clinical manifestations and an estimated incidence of 1 case per 100,000 person-years.1Imam M.H. Shenoy P.J. Flowers C.R. et al.Incidence and survival patterns of cutaneous T-cell lymphomas in the United States.Leuk Lymphoma. 2013; 54: 752-759Crossref PubMed Scopus (86) Google Scholar MF, CD30+ primary lymphoproliferative disease, and Sézary syndrome are the most common subtypes of CTCL, with MF comprising the majority (> 60%) of cases of CTCL. Current World Health Organization (WHO)/European Organisation for Research and Treatment of Cancer (EORTC) classification divides the remaining subtypes of CTCL based on differing biologic and clinical characteristics; they include (among others) adult T-cell leukemia/lymphoma, subcutaneous panniculitis-like T-cell lymphoma, extranodal natural killer (NK)/T-cell lymphoma (nasal type), and peripheral T-cell lymphoma, unspecified (PTCL), an entity that encompasses several provisional diseases (primary cutaneous γ/δ T-cell lymphoma, primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma, and primary cutaneous small/medium CD4+ T-cell lymphoma). CTCL may be indolent or aggressive, with long-term survival rates ranging from 100% in stage T1 MF to 40% in stage T3 or T4 MF.2Zackheim H.S. Lebo C.F. Wasserstein P. et al.Mycosis fungoides of the mastoid, middle ear, and CNS—literature review of mycosis fungoides of the CNS.Arch Dermatol. 1983; 119: 311-318Crossref PubMed Scopus (43) Google Scholar The prognosis of PTCL, in general, is poor, with a 5-year survival rate < 20%.3Bekkenk M.W. Vermeer M.H. Jansen P.M. et al.Peripheral T-cell lymphomas unspecified presenting in the skin: analysis of prognostic factors in a group of 82 patients.Blood. 2003; 102: 2213-2219Crossref PubMed Scopus (200) Google Scholar Extracutaneous involvement in CTCL is rare in patients with limited patch- or plaque-stage disease, although it is more commonly seen in patients with tumor-stage disease or erythroderma. The most frequently involved extracutaneous sites are regional lymph nodes, visceral organs, and bone marrow. CNS manifestations in CTCL are rare. A retrospective analysis found that the overall incidence of direct neurologic complications in CTCL was 4%.4Stein M. Farrar N. Jones G.W. et al.Central neurologic involvement in mycosis fungoides: ten cases, actuarial risk assessment, and predictive factors.Cancer J. 2006; 12: 55-62Crossref PubMed Scopus (26) Google Scholar CNS involvement in MF was the least common, with only 1.3% to 1.5% of patients having neurologic involvement.4Stein M. Farrar N. Jones G.W. et al.Central neurologic involvement in mycosis fungoides: ten cases, actuarial risk assessment, and predictive factors.Cancer J. 2006; 12: 55-62Crossref PubMed Scopus (26) Google Scholar, 5Kaufman D.K. Habermann T.M. Kurtin P.J. et al.Neurological complications of peripheral and cutaneous T-cell lymphomas.Ann Neurol. 1994; 36: 625-629Crossref PubMed Scopus (39) Google Scholar PTCL has the highest CNS metastases rate, ranging from 8.5% to 10%.5Kaufman D.K. Habermann T.M. Kurtin P.J. et al.Neurological complications of peripheral and cutaneous T-cell lymphomas.Ann Neurol. 1994; 36: 625-629Crossref PubMed Scopus (39) Google Scholar, 6Yi J.H. Kim J.H. Baek K.K. et al.Elevated LDH and paranasal sinus involvement are risk factors for central nervous system involvement in patients with peripheral T-cell lymphoma.Ann Oncol. 2011; 22: 1636-1643Crossref PubMed Scopus (36) Google Scholar At present, there are approximately 80 cases of CTCL with CNS involvement reported in the literature, with the majority presented as case reports.4Stein M. Farrar N. Jones G.W. et al.Central neurologic involvement in mycosis fungoides: ten cases, actuarial risk assessment, and predictive factors.Cancer J. 2006; 12: 55-62Crossref PubMed Scopus (26) Google Scholar, 5Kaufman D.K. Habermann T.M. Kurtin P.J. et al.Neurological complications of peripheral and cutaneous T-cell lymphomas.Ann Neurol. 1994; 36: 625-629Crossref PubMed Scopus (39) Google Scholar, 6Yi J.H. Kim J.H. Baek K.K. et al.Elevated LDH and paranasal sinus involvement are risk factors for central nervous system involvement in patients with peripheral T-cell lymphoma.Ann Oncol. 2011; 22: 1636-1643Crossref PubMed Scopus (36) Google Scholar, 7Vu B.A.N. Duvic M. Central nervous system involvement in patients with mycosis fungoides and cutaneous large-cell transformation.J Am Acad Dermatol. 2008; 59: S16-S22Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 8Hallahan D. Griem M. Griem S. et al.Mycosis fungoides involving the central nervous system.J Clin Oncol. 1986; 4: 1638-1644PubMed Google Scholar, 9Lally A. Hollowood K. Whittaker S. et al.Central nervous system involvement in stage 1b mycosis fungoides.Br J Dermatol. 2007; 157: 815-816Crossref PubMed Scopus (7) Google Scholar, 10Zonenshayn M. Sharma S. Hymes K. et al.Mycosis fungoides metastasizing to the brain parenchyma: case report.Neurosurgery. 1998; 42: 933-937Crossref PubMed Scopus (24) Google Scholar, 11Peris K. Fargnoli M.C. Berardelli A. et al.Peripheral nervous system involvement in a patient with large T-cell lymphoma arising from a pre-existing mycosis fungoides.Br J Dermatol. 1998; 139: 299-301Crossref PubMed Scopus (23) Google Scholar, 12Beylot-Barry M. Dubus P. Vergier B. et al.Meningeal involvement by a transformed mycosis fungoides following Hodgkin's disease.Br J Dermatol. 1999; 141: 909-913Crossref PubMed Scopus (12) Google Scholar, 13Chua S.L. Seymour J.F. Prince H.M. Deafness from eighth cranial nerve involvement in a patient with large-cell transformation of mycosis fungoides.Eur J Haematol. 2000; 64: 340-343Crossref PubMed Google Scholar, 14Li N. Kim J.H. Glusac E.J. Brainstem involvement by mycosis fungoides in a patient with large-cell transformation: a case report and review of literature.J Cutan Pathol. 2003; 30: 326-331Crossref PubMed Scopus (18) Google Scholar The clinical features that were presented in several of the large case series of CTCL with CNS involvement are summarized in Table 1. Most studies have noted CNS involvement in patients with MF, presumably because MF is much more common than other subtypes of CTCL. The estimated clinical incidence of CNS involvement in CTCL is lower than that found in autopsy studies, with a large autopsy series estimating the incidence of CNS involvement in MF to be 14%.7Vu B.A.N. Duvic M. Central nervous system involvement in patients with mycosis fungoides and cutaneous large-cell transformation.J Am Acad Dermatol. 2008; 59: S16-S22Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar This clinicopathologic discrepancy suggests that CNS involvement in CTCL, at least in the MF type, may be insidious, without overt clinical symptoms.Table 1Summary of Large Case Series on CNS Involvement in CTCLReportCase No.Mean Age at Initial Symptoms (Years)Mean Age at Initial Diagnosis (Years)DiagnosisMean Age at CNS Involvement (Years)Diagnostic MethodaOnly the most confirmative diagnosis is listed following the sequence of autopsy, brain biopsy, CSF, and MRI/CT.TreatmentsbSome patients received multiple rounds of treatments, and the number of treatments may exceed the total case number.Median Survival Period (mo)Hallahan et al (1986)8Hallahan D. Griem M. Griem S. et al.Mycosis fungoides involving the central nervous system.J Clin Oncol. 1986; 4: 1638-1644PubMed Google Scholar9––MF–6 autopsies,2 CSF,1 MRI/CT2 irradiation,1 chemo1Stein et al (2006)4Stein M. Farrar N. Jones G.W. et al.Central neurologic involvement in mycosis fungoides: ten cases, actuarial risk assessment, and predictive factors.Cancer J. 2006; 12: 55-62Crossref PubMed Scopus (26) Google Scholar105263MF643 autopsies,1 brain bx,4 MRI/CT4 palliative,3 irradiation,2 chemo,1 ASCT,1 surgery<1Vu & Duvic (2008)7Vu B.A.N. Duvic M. Central nervous system involvement in patients with mycosis fungoides and cutaneous large-cell transformation.J Am Acad Dermatol. 2008; 59: S16-S22Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar55055MF645 MRI/CT1 palliative,1 irradiation,3 chemo,1 surgery3Yi et al (2011)6Yi J.H. Kim J.H. Baek K.K. et al.Elevated LDH and paranasal sinus involvement are risk factors for central nervous system involvement in patients with peripheral T-cell lymphoma.Ann Oncol. 2011; 22: 1636-1643Crossref PubMed Scopus (36) Google Scholar20–48PTCL49CSF or MRI/CT3 palliative,7 irradiation,12 chemo,2 ASCT3Abbreviations: – = data not available; ASCT = autologous stem cell transplant; brain bx = brain biopsies; chemo = chemotherapy; CSF = cerebrospinal fluid studies; CT = computed tomography; CNS = central nervous system; CTCL = cutaneous T-cell lymphoma; MF = mycosis fungoides; MRI = magnetic resonance imaging; PTCL = peripheral T-cell lymphoma.a Only the most confirmative diagnosis is listed following the sequence of autopsy, brain biopsy, CSF, and MRI/CT.b Some patients received multiple rounds of treatments, and the number of treatments may exceed the total case number. Open table in a new tab Abbreviations: – = data not available; ASCT = autologous stem cell transplant; brain bx = brain biopsies; chemo = chemotherapy; CSF = cerebrospinal fluid studies; CT = computed tomography; CNS = central nervous system; CTCL = cutaneous T-cell lymphoma; MF = mycosis fungoides; MRI = magnetic resonance imaging; PTCL = peripheral T-cell lymphoma. Most cases of MF with CNS involvement have been in older men with an average age of 65 years and with associated visceral organ involvement and advanced skin disease.4Stein M. Farrar N. Jones G.W. et al.Central neurologic involvement in mycosis fungoides: ten cases, actuarial risk assessment, and predictive factors.Cancer J. 2006; 12: 55-62Crossref PubMed Scopus (26) Google Scholar MF patients with large-cell transformation are at particularly increased risk of CNS involvement.7Vu B.A.N. Duvic M. Central nervous system involvement in patients with mycosis fungoides and cutaneous large-cell transformation.J Am Acad Dermatol. 2008; 59: S16-S22Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar The average interval between diagnosis of MF and development of CNS symptoms was < 3 years in one case series,4Stein M. Farrar N. Jones G.W. et al.Central neurologic involvement in mycosis fungoides: ten cases, actuarial risk assessment, and predictive factors.Cancer J. 2006; 12: 55-62Crossref PubMed Scopus (26) Google Scholar whereas patients with CNS disease in PTCL tend to present more rapidly, with an average interval of onset of 9 months.6Yi J.H. Kim J.H. Baek K.K. et al.Elevated LDH and paranasal sinus involvement are risk factors for central nervous system involvement in patients with peripheral T-cell lymphoma.Ann Oncol. 2011; 22: 1636-1643Crossref PubMed Scopus (36) Google Scholar Notably, CNS involvement may occur when skin disease is well controlled or in remission, and neurologic symptoms can develop at any stage of disease.7Vu B.A.N. Duvic M. Central nervous system involvement in patients with mycosis fungoides and cutaneous large-cell transformation.J Am Acad Dermatol. 2008; 59: S16-S22Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar The most common neurologic symptoms reported are altered mental status, cranial neuropathies, and speech difficulties. Other neurologic symptoms may include headache, fatigue, cognitive change, gait disturbance, or seizure. CNS involvement in CTCL can manifest as parenchymal metastases, leptomeningeal metastases, or both. Brain biopsy is the gold standard to confirm CNS disease, and confirmation of leptomeningeal involvement requires demonstration of atypical malignant T-cells in the CSF. In practice, brain biopsy is seldom performed. In the cases series and case reports of CNS involvement in CTCL,4Stein M. Farrar N. Jones G.W. et al.Central neurologic involvement in mycosis fungoides: ten cases, actuarial risk assessment, and predictive factors.Cancer J. 2006; 12: 55-62Crossref PubMed Scopus (26) Google Scholar, 5Kaufman D.K. Habermann T.M. Kurtin P.J. et al.Neurological complications of peripheral and cutaneous T-cell lymphomas.Ann Neurol. 1994; 36: 625-629Crossref PubMed Scopus (39) Google Scholar, 6Yi J.H. Kim J.H. Baek K.K. et al.Elevated LDH and paranasal sinus involvement are risk factors for central nervous system involvement in patients with peripheral T-cell lymphoma.Ann Oncol. 2011; 22: 1636-1643Crossref PubMed Scopus (36) Google Scholar, 7Vu B.A.N. Duvic M. Central nervous system involvement in patients with mycosis fungoides and cutaneous large-cell transformation.J Am Acad Dermatol. 2008; 59: S16-S22Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 8Hallahan D. Griem M. Griem S. et al.Mycosis fungoides involving the central nervous system.J Clin Oncol. 1986; 4: 1638-1644PubMed Google Scholar, 9Lally A. Hollowood K. Whittaker S. et al.Central nervous system involvement in stage 1b mycosis fungoides.Br J Dermatol. 2007; 157: 815-816Crossref PubMed Scopus (7) Google Scholar, 10Zonenshayn M. Sharma S. Hymes K. et al.Mycosis fungoides metastasizing to the brain parenchyma: case report.Neurosurgery. 1998; 42: 933-937Crossref PubMed Scopus (24) Google Scholar, 11Peris K. Fargnoli M.C. Berardelli A. et al.Peripheral nervous system involvement in a patient with large T-cell lymphoma arising from a pre-existing mycosis fungoides.Br J Dermatol. 1998; 139: 299-301Crossref PubMed Scopus (23) Google Scholar, 12Beylot-Barry M. Dubus P. Vergier B. et al.Meningeal involvement by a transformed mycosis fungoides following Hodgkin's disease.Br J Dermatol. 1999; 141: 909-913Crossref PubMed Scopus (12) Google Scholar, 13Chua S.L. Seymour J.F. Prince H.M. Deafness from eighth cranial nerve involvement in a patient with large-cell transformation of mycosis fungoides.Eur J Haematol. 2000; 64: 340-343Crossref PubMed Google Scholar, 14Li N. Kim J.H. Glusac E.J. Brainstem involvement by mycosis fungoides in a patient with large-cell transformation: a case report and review of literature.J Cutan Pathol. 2003; 30: 326-331Crossref PubMed Scopus (18) Google Scholar only 3 of 50 cases were confirmed with brain biopsy. Nine were confirmed by autopsy, and the remaining diagnoses were based on the clinical scenario combined with CSF studies and computed tomography (CT) or MRI findings. The International Society for Cutaneous Lymphomas (ISCL) and EORTC do not specifically address CNS involvement in the most recent staging guidelines, but they do recommend pathologic confirmation of any suspected visceral lesion outside of splenomegaly.15Olsen E. Vonderheid E. Pimpinelli N. et al.Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of [sic] Research and Treatment of Cancer (EORTC).Blood. 2007; 110: 1713-1722Crossref PubMed Scopus (1084) Google Scholar Some researchers have suggested that elevated β2-microglobulin and lactate dehydrogenase levels may be markers of CNS involvement.4Stein M. Farrar N. Jones G.W. et al.Central neurologic involvement in mycosis fungoides: ten cases, actuarial risk assessment, and predictive factors.Cancer J. 2006; 12: 55-62Crossref PubMed Scopus (26) Google Scholar, 6Yi J.H. Kim J.H. Baek K.K. et al.Elevated LDH and paranasal sinus involvement are risk factors for central nervous system involvement in patients with peripheral T-cell lymphoma.Ann Oncol. 2011; 22: 1636-1643Crossref PubMed Scopus (36) Google Scholar, 16Diamandidou E. Colome-Grimmer M. Fayad L. et al.Transformation of mycosis fungoides/Sezary syndrome: clinical characteristics and prognosis.Blood. 1998; 92: 1150-1159PubMed Google Scholar However, the use of these biomarkers remains controversial, and their significance as predicators of CNS involvement has not been confirmed.7Vu B.A.N. Duvic M. Central nervous system involvement in patients with mycosis fungoides and cutaneous large-cell transformation.J Am Acad Dermatol. 2008; 59: S16-S22Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar There are no standard guidelines regarding routine diagnostic evaluation for CNS involvement in CTCL, nor is there guidance regarding the use of CNS prophylactic treatment. Vu and Duvic7Vu B.A.N. Duvic M. Central nervous system involvement in patients with mycosis fungoides and cutaneous large-cell transformation.J Am Acad Dermatol. 2008; 59: S16-S22Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar recommended annual screening of patients with transformed MF for CNS disease with head CT and orbital cuts. Stein et al4Stein M. Farrar N. Jones G.W. et al.Central neurologic involvement in mycosis fungoides: ten cases, actuarial risk assessment, and predictive factors.Cancer J. 2006; 12: 55-62Crossref PubMed Scopus (26) Google Scholar propose prophylactic whole brain irradiation or alternatively intra-CSF chemotherapy in patients with MF and risk factors, as suggested for other aggressive non-Hodgkin lymphomas at risk for CNS metastases. Given the low numbers of cases of CNS metastases in CTCL, the efficacy of these recommendations is understandably difficult to quantitate for the general CTCL population, and such treatments should currently be applied only in special circumstances. Careful review of the history and physical examination (including attention to subtle neurologic symptoms or an early referral to a neurologist) and collaboration with multispecialty oncologists are important for the early diagnosis and management of CTCL with CNS involvement. The patient described in case 1 declined brain biopsy. Although a differential diagnosis of cerebrovascular events, infection, other brain malignancy, or other metastatic cancers could have been considered, the negative CSF evaluation for other possible entities, the clinical scenario, and the response to treatment suggested CNS involvement by MF. Without a tissue diagnosis, it was not possible to differentiate MF-related CNS metastasis from primary CNS lymphoma. There is a single case report of a patient with a history of MF who developed multifocal epithelioid glioblastoma that mimicked metastatic T-cell lymphoma,17Gasco J. Franklin B. Fuller G.N. et al.Multifocal epithelioid glioblastoma mimicking cerebral metastasis: case report.Neurocirugia. 2009; 20: 550-554Crossref PubMed Scopus (18) Google Scholar although such disease is exceedingly rare and would not be expected to respond to HD-MTX, as seen in the authors' patient. The prognosis of CNS involvement in CTCL is poor, and the majority of the patients die within 6 months after the diagnosis of CNS involvement. A delay in the diagnosis and treatment of CNS involvement of CTCL may partly contribute to the short survival time previously reported. There is a single case report of a young patient with CNS involvement of CTCL and prolonged survival after autologous stem cell transplantation.18Di Lucca-Chrisment J. Maubec E. Grossin M. et al.Long-term efficacy of autologous stem cell transplantation for stage IV mycosis fungoides.Ann Dermatol Venereol. 2009; 136: 800-805Crossref PubMed Scopus (2) Google Scholar Owing to the low incidence of CNS metastases, there are limited data evaluating or comparing different treatment regimens. Empiric treatment options include whole brain radiation therapy, intra-CSF chemotherapy, and systemic chemotherapy. Surgical resection and autologous stem cell transplantation have also been reported. Some studies have suggested that more aggressive treatment, such as the combination of brain irradiation, chemotherapy, and autologous stem cell transplantation, may be associated with better outcomes,6Yi J.H. Kim J.H. Baek K.K. et al.Elevated LDH and paranasal sinus involvement are risk factors for central nervous system involvement in patients with peripheral T-cell lymphoma.Ann Oncol. 2011; 22: 1636-1643Crossref PubMed Scopus (36) Google Scholar, 7Vu B.A.N. Duvic M. Central nervous system involvement in patients with mycosis fungoides and cutaneous large-cell transformation.J Am Acad Dermatol. 2008; 59: S16-S22Abstract Full Text Full Text PDF PubMed Scopus (17) Google Scholar, 18Di Lucca-Chrisment J. Maubec E. Grossin M. et al.Long-term efficacy of autologous stem cell transplantation for stage IV mycosis fungoides.Ann Dermatol Venereol. 2009; 136: 800-805Crossref PubMed Scopus (2) Google Scholar although the number of such cases is currently too small to support this treatment recommendation. In summary, CNS involvement in CTCL is a rare metastatic manifestation with a generally poor prognosis. Awareness of subtle neurologic symptoms, even in patients with well-controlled skin disease, is critical in identifying underlying CNS involvement. Diagnosis relies on a combination of clinical presentation, neuroimaging, CSF evaluation, and, when feasible, CNS biopsy. There is no consensus regarding standard treatment of CNS metastases, although more aggressive and timely treatment may be associated with better clinical outcomes.

BACKGROUND & AIMS:Anti-tumor necrosis factors (anti-TNF) including infliximab, adalimumab and certolizumab pegol are used to treat Crohn's disease (CD) and ulcerative colitis (UC). Paradoxically, while also indicated for the treatment of psoriasis, anti-TNF therapy has been associated with development of psoriasiform lesions in IBD patients and can compel discontinuation of therapy. We aim to investigate IBD patient, clinical characteristics, and frequency for the development of and outcomes associated with anti-TNF induced psoriasiform rash.METHODS:We identify IBD patients on anti-TNFs with an onset of a psoriasiform rash. Patient characteristics, duration of anti-TNF, concomitant immunosuppressants, lesion distribution, and outcomes of rash are described.RESULTS:Of 1004 IBD patients with exposure to anti-TNF therapy, 27 patients (2.7%) developed psoriasiform lesions. Psoriasiform rash cases stratified by biologic use were 1.3% for infliximab, 4.1% for adalimumab, and 6.4% for certolizumab. Average time on treatment (206.3weeks) and time on treatment until onset of psoriasiform lesions (126.9weeks) was significantly higher in the infliximab group. The adalimumab group had the highest need for treatment discontinuation (60%). The majority (59.3%) of patients were able to maintain on anti-TNFs despite rash onset. Among patients that required discontinuation (40.7%), the majority experienced improvement with a subsequent anti-TNF (66.7%).CONCLUSION:27 cases of anti-TNF associated psoriasiform lesions are reported. Discontinuation of anti-TNF treatment is unnecessary in the majority. Dermatologic improvement was achieved in the majority with a subsequent anti-TNF, suggesting anti-TNF induced psoriasiform rash is not necessarily a class effect.

stratum corneum TO THE EDITOR Upon revisiting our large library of archived human skin wound specimens, we observed that the stratum lucidum interfollicular parakeratotic corneocytes appear to have an active role in epidermal wound healing by expanding, migrating, and bifurcating to interact directly with and secure the wound scab in place. Our observations are based on the morphologic analysis of 240 acute, normal, full-thickness, incisional, 1- to 21-day human upper arm and lower-leg skin wounds obtained from 30 healthy volunteers, with an average age of 64±8 years (mean±SD). Wound tissue was either ½ Karnovsky's-fixed, PolyBed embedded, and Richardson's-stained or Carnoy-fixed, paraffin-embedded, and hematoxylin and eosin–stained. All wounds were obtained in accordance with the Declaration of Helsinki Principles and the University of Washington Human Subjects Institutional Review Board. In the interfollicular epidermis, terminal differentiation begins in the granular layer of the epidermis, resulting in the formation of a cornified stratum corneum (SC), often described as the "dead" outer layer of the skin (Candi et al., 2005Candi E. Schmidt R. Melino G. The cornified envelope: a model of cell death in the skin.Nat Rev Mol Cell Biol. 2005; 6: 328-340Crossref PubMed Scopus (1264) Google Scholar). The SC, however, has been shown to be a dynamic and metabolically interactive tissue acting as a biosensor to regulate metabolic responses in the underlying nucleated cell layers (Elias, 1996Elias P.M. Stratum corneum architecture, metabolic activity and interactivity with subjacent cell layers.Exp Dermatol. 1996; 5: 191-201Crossref PubMed Scopus (109) Google Scholar). The SC appears to be composed of three structurally (Brody, 1962Brody I. The utrastructure of the horny layer in normal and psoriatic epidermis as revealed by electron microscopy.J Invest Dermatol. 1962; 39: 519-528Abstract Full Text PDF PubMed Scopus (50) Google Scholar) and functionally (Richter et al., 2004Richter T. Peuckert C. Sattler M. et al.Dead but highly dynamic-the stratum corneum is divided into three hydration zones.Skin Pharmacol Physiol. 2004; 17: 246-257Crossref PubMed Scopus (74) Google Scholar) identifiable sublayers: (1) the outermost layer composed of corneocytes that undergo desquamation (stratum disjunctum); (2) an intermediary zone of uniform-sized, tightly-compacted anucleate corneocytes (stratum compactum); and (3) the zone immediately adjacent to the stratum granulosum populated with parakeratotic corneocytes (stratum lucidum) (Kligman, 1964Kligman A. The biology of the stratum corneum.in: The Epidermis. Academic Press, New York and London1964Crossref Google Scholar). Stratum lucidum parakeratotic corneocytes retain rod-shaped nuclei, ribosomes, lysosomes, mitochondria, Golgi apparatus, numerous granules, fibrillar structures (Ebling and Rook, 1972Ebling F. Rook A. Disorders of keratinization.in: Rook's Textbook of Dermatology. 3. 2. Blackwell Scientific Publications, Oxford, London, Edinburgh, Melbourne1972Google Scholar), and have "fragile" rather than "rigid" cornified envelopes identified in the upper layers of the SC (Haftek et al., 2011Haftek M. Callejon S. Sandjeu Y. et al.Compartmentalization of the human stratum corneum by persistent tight junction-like structures.Exp Dermatol. 2011; 20: 617-621Crossref PubMed Scopus (62) Google Scholar). The stratum lucidum is ∼1–2 cell layers thick in normal interfollicular skin and is more prominently visible (∼8–10 layers) in palmoplantar skin and lip (Ebling and Rook, 1972Ebling F. Rook A. Disorders of keratinization.in: Rook's Textbook of Dermatology. 3. 2. Blackwell Scientific Publications, Oxford, London, Edinburgh, Melbourne1972Google Scholar). Stratum lucidum corneocytes in interfollicular skin have been distinguished from the upper SC corneocytes by the use of unique tissue fixations and histochemical stains (Montagna et al., 1992Montagna W. Kligman A. Carlisle K. Atlas of Normal Human Skin. Springer-Verlag, New York, Berlin, Heidelberg, London, Paris, Tokyo, Hong Kong, Barcelona, Budapest1992Crossref Google Scholar) but are poorly discernable in routine hematoxylin and eosin–stained tissue. Organelles are only sporadically identifiable in corneocytes in this transition zone even using transmission electron microscopy (Montagna et al., 1992Montagna W. Kligman A. Carlisle K. Atlas of Normal Human Skin. Springer-Verlag, New York, Berlin, Heidelberg, London, Paris, Tokyo, Hong Kong, Barcelona, Budapest1992Crossref Google Scholar). Teleologically, a transient zone must exist where major cellular changes (loss of nuclei, organelles, and keratohyalin granules) take place; however, the difficulty of identifying the zone lies in the fact that this metamorphosis occurs with great speed (Kligman, 1964Kligman A. The biology of the stratum corneum.in: The Epidermis. Academic Press, New York and London1964Crossref Google Scholar). Upon injury to the skin, the clotting cascade is initiated in order to stop the hemorrhaging of damaged vessels (Singer and Clark, 1999Singer A.J. Clark R.A. Cutaneous wound healing.N Engl J Med. 1999; 341: 738-746Crossref PubMed Scopus (4638) Google Scholar). A clot filled with fibrin, blood components, wound debris (collagen and elastin fragments), and glycoproteins (Singer and Clark, 1999Singer A.J. Clark R.A. Cutaneous wound healing.N Engl J Med. 1999; 341: 738-746Crossref PubMed Scopus (4638) Google Scholar) provides a "sticky" plug that covers and fills the wound bed. As wound healing progresses, the clot appears to compartmentalize into two identifiable regions, with the upper region of the clot separated from the lower region by a "polyband" layer of polymorphonuclear leukocytes (Jonkman et al., 1988Jonkman M.F. Bruin P. Hoeksma E.A. et al.A clot-inducing wound covering with high vapor permeability: enhancing effects on epidermal wound healing in partial-thickness wounds in guinea pigs.Surgery. 1988; 104: 537-545PubMed Google Scholar). This upper clot region desiccates, forming a scab, crust, or eschar that sloughs eventually during tissue repair, whereas the lower fibrin-rich region of the clot serves as the wound bed in which granulation tissue forms (Singer and Clark, 1999Singer A.J. Clark R.A. Cutaneous wound healing.N Engl J Med. 1999; 341: 738-746Crossref PubMed Scopus (4638) Google Scholar). In this study, we show that in acute human skin wounds a unique population of parakeratotic corneocytes interacts directly with scabs, appearing to secure a temporary barrier to cover a wound until the underlying epidermis fully epithelializes, terminally differentiates, and restores a permanent skin barrier. Along the wound margin of a 6-μm tissue section of a 1-day wound immunolabeled with a pan-cytokeratin antibody (Dako, Carpenteria, CA), parakeratotic corneocytes above granular layer corneocytes expand in number and begin to migrate laterally toward the wound exudate (Figure 1a). In the 2-day wound (Figure 1b), the parakeratotic corneocyte population then bifurcates with a second population of parakeratotic corneocytes appearing to stream ventrally down along the underlying epidermis. In the 3-day wound (Figure 1c), the ventral branch parakeratotic corneocytes travel beyond the migrating tip (arrowhead) of the underlying nucleated migrating epidermis. By 7 days (Figure 1d), a mature scab has formed above an epithelialized new wound epidermis, showing parakeratotic corneocytes interacting with the upper region of the scab and undermining the base of the scab. Figure 1e shows a schematic illustration of the relationship between parakeratotic corneocytes and scabs as we observed. Forty-four percent (106/240) of the wounds appeared to have identifiable scabs (many immature wounds not yet forming scabs), of which 93% (98/106) of the wounds with scabs showed a pattern of scab/parakeratotic corneocyte interaction (Figure 1f). On occasion, scabs mechanically (either from tissue processing or from handling during tissue harvest) separated from the underlying new epithelium. These scabs appeared to be attached to the SC of the wound tissue sample (Figure 1g–i). This finding suggests that scabs adhere to the wound bed not merely by their "stickiness" but by direct interaction with the SC. The earliest observation of wound keratinocyte interaction with the scab was made by Leo Loeb in 1898, who described and illustrated in great detail that the granular and "horny" (SC) layers resolved into a homogeneous multinucleated protoplasmic layer, completely independent of the underlying epidermal tongue. This protoplasmic layer, for which he saw no cellular borders, bifurcated, with the upper "arm" quickly integrating with or covering the scab, whereas the lower "arm" more slowly migrated to undermine the scab ahead of the underlying Malphigian (nucleated) keratinocytes. These protoplasmic cells adhered tightly to the scab until the scab was sloughed (Loeb, 1898Loeb L. Über regeneration des epithels.Archiv Für Entwicklunsmechanik Der Organismen. 1898; 6: 297-364Crossref Scopus (12) Google Scholar). Zahir suggested that Loeb's "upper protoplasmic layer was either coagulated exudate forming the most superficial part of the scab or layers of collagen fibers at the surface of the scab". Zahir, 1965Zahir M. Formation of Scabs on Skin Wounds.Br J Surg. 1965; 52: 376-380Crossref PubMed Scopus (7) Google Scholar also described the branch extending over the upper surface of the scab as less well-developed cells with pyknotic nuclei. Rather than necrotic, pyknotic cells, our studies show that parakeratotic corneocytes appear to be viable, as indicated by their ability to migrate toward the wound. Viziam et al. stated that the expanded parakeratotic corneocyte population seen in wounds emanated from rapid differentiation of new wound suprabasal and stratum granulosum keratinocytes. They did not observe parakeratotic cells in the proximal portion of the migratory wound epithelial tongue, and concluded that the actively migrating epithelium had not yet undergone differentiation (Viziam et al., 1964Viziam C.B. Matoltsy A.G. Mescon H. Epithelialization of small wounds.J Invest Dermatol. 1964; 43: 499-507Abstract Full Text PDF PubMed Scopus (60) Google Scholar). In contrast to studies by Viziam et al., we observed the presence of parakeratotic corneocytes beyond the tip of the underlying, migrating, nucleated tongue of early, 1–3-day wounds. The presence of parakeratotic corneocytes not in direct association with underlying granular layer corneocytes suggests that these parakeratotic corneocytes are not derived from an accelerated keratinocyte differentiation pathway of the new wound epidermis but appear to be derived as a much earlier response to injury. It appears that keratinocytes in the granular layer in response to injury continue to produce parakeratotic corneocytes that expand in number possibly by ceasing to differentiate into anucleate corneocytes. It is this expanded population of parakeratotic corneocytes that we believe independently interacts with the scab. The expansion of the parakeratotic population appears not to be by mitosis, as there is no evidence of Ki67 immunostaining within this cell population (Usui et al., 2005Usui M.L. Underwood R.A. Mansbridge J.N. et al.Morphological evidence for the role of suprabasal keratinocytes in wound reepithelialization.Wound Repair Regen. 2005; 13: 468-479Crossref PubMed Scopus (85) Google Scholar). These unique parakeratotic corneocytes may have a role in epidermal repair separate from the role of underlying differentiated suprabasal keratinocytes (keratinocytes not yet cornified) that have been postulated to actively participate in re-epithelialization by rolling onto the wound bed (Usui et al., 2005Usui M.L. Underwood R.A. Mansbridge J.N. et al.Morphological evidence for the role of suprabasal keratinocytes in wound reepithelialization.Wound Repair Regen. 2005; 13: 468-479Crossref PubMed Scopus (85) Google Scholar). Securely attaching a scab as a temporary barrier not only protects the wound bed, but formation of an attached transitory scab may have additional benefits in protecting the host from infection. Studies have shown that 99% of the bacterial population found in wounds is sequestered in scabs and not on or within wound beds (Barnett et al., 1986Barnett A. Dave B. Ksander G.A. et al.A concentration gradient of bacteria within wound tissues and scab.J Surg Res. 1986; 41: 326-332Abstract Full Text PDF PubMed Scopus (14) Google Scholar; Zhao et al., 2010Zhao G. Hochwalt P.C. Usui M.L. et al.Delayed wound healing in diabetic (db/db) mice with Pseudomonas aeruginosa biofilm challenge: a model for the study of chronic wounds.Wound Repair Regen. 2010; 18: 467-477Crossref PubMed Scopus (168) Google Scholar). These morphologic observations necessitate additional characterization and mechanistic studies. The origin of the parakeratotic corneocytes emanating from the stratum lucidum is based strictly on our many static morphological images and is therefore hypothetical. We defined the parakeratotic keratinocytes we observed as being "corneocytes"; however, lipid membrane immaturity, fragility of cornified envelopes, and the presence of corneodesmosomes and ultrastructural components (cornified envelopes and organelles) characteristic of normal parakeratotic corneocytes must be further evaluated to clearly determine whether they are, in fact, corneocytes. In addition, studies need to be conducted to determine the mechanism by which corneocytes migrate (cytoskeletal machinery) and adhere (surface receptors) to the desiccating scab matrix. Although this was strictly a morphological, and not a mechanistic, study in which our observations show that wound parakeratotic keratinocytes interact directly with scabs, we concur with Kligman's (1964) philosophy about morphological observations: "The usual sequence of biological knowledge is from the anatomical to the physiological." This publication was made possible by grants from NIH AR43006, DK59221, EB004422, AR057115, NSF EEC9529161, VA R&D, RW Johnson Pharmaceutical Research Institute, and Advanced Tissue Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH-NIAMS, -NIBIB, -NIDDK, or NSF. We thank The George F. Odland Endowed Research Fund, Marvin and Judy Young, John and Darcy Halloran, Peter Odland, and Peter Byers for their generous support.

SIGNIFICANCE:The incidence, cost, morbidity, and mortality associated with non-healing of chronic skin wounds are dramatic. With the increasing numbers of people with obesity, chronic medical conditions, and an increasing life expectancy, the healthcare cost of non-healing ulcers has recently been estimated at $25 billion annually in the United States. The role played by bacterial biofilm in chronic wounds has been emphasized in recent years, particularly in the context of the prolongation of the inflammatory phase of repair.RECENT ADVANCES:Rapid high-throughput genomic approaches have revolutionized the ability to identify and quantify microbial organisms from wounds. Defining bacterial genomes and using genetic approaches to knock out specific bacterial functions, then studying bacterial survival on cutaneous wounds is a promising strategy for understanding which genes are essential for pathogenicity.CRITICAL ISSUES:When an animal sustains a cutaneous wound, understanding mechanisms involved in adaptations by bacteria and adaptations by the host in the struggle for survival is central to development of interventions that favor the host.FUTURE DIRECTIONS:Characterization of microbiomes of clinically well characterized chronic human wounds is now under way. The use of in vivo models of biofilm-infected cutaneous wounds will permit the study of the mechanisms needed for biofilm formation, persistence, and potential synergistic interactions among bacteria. A more complete understanding of bacterial survival mechanisms and how microbes influence host repair mechanisms are likely to provide targets for chronic wound therapy.

Cutaneous angiosarcoma of the head and neck is a rare, highly malignant neoplasm; prognosis is heavily influenced by tumor size, resectability, and stage at initial diagnosis.Most patients present with one to several erythematous to violaceous patches, plaques, or nodules.However, the clinical presentation is highly variable and leads to delayed diagnosis.We report cutaneous angiosarcoma in a 43-year-old man who presented with an 11-month history of progressive solid (non-pitting) edema involving his entire face, scalp, eyelids, and neck without characteristic clinical features of cutaneous angiosarcoma.A skin biopsy had shown non-specific findings consistent with solid facial edema or rosacea.Various etiologies were considered but there was no significant improvement after directed medical therapy.Repeat skin biopsies revealed angiosarcoma involving the dermis and sub-cutis.Computed tomography (CT) of the chest showed multiple lung nodules bilaterally and a lytic lesion in the T6 vertebra consistent with metastases.He was treated with single agent chemotherapy (paclitaxel), and had a partial response that restored his ability to open both eyes spontaneously.However, his edema has recently progressed 7 months after diagnosis.This is a rare example of cutaneous angiosarcoma presenting as progressive solid facial edema, which underscores the diverse range of clinical manifestations associated with this neoplasm.

Staphylococcus aureus biofilms are associated with chronic skin infections and are orders of magnitude more resistant to antimicrobials and host responses. S. aureus contains conserved nonribosomal peptide synthetases that produce the cyclic dipeptides tyrvalin and phevalin (aureusimine A and B, respectively). The biological function of these compounds has been speculated to be involved in virulence factor gene expression in S. aureus, protease inhibition in eukaryotic cells, and interspecies bacterial communication. However, the exact biological role of these compounds is unknown. Here, we report that S. aureus biofilms produce greater amounts of phevalin than their planktonic counterparts. Phevalin had no obvious impact on the extracellular metabolome of S. aureus as measured by high-performance liquid chromatography-mass spectrometry and nuclear magnetic resonance. When administered to human keratinocytes, phevalin had a modest effect on gene expression. However, conditioned medium from S. aureus spiked with phevalin amplified differences in keratinocyte gene expression compared to conditioned medium alone. Phevalin may be exploited as potential biomarker and/or therapeutic target for chronic, S. aureus biofilm-based infections.

Bacterial biofilm has been shown to play a role in delaying wound healing of chronic wounds, a major medical problem that results in significant health care burden. A reproducible animal model could be very valuable for studying the mechanism and management of chronic wounds. Our previous work showed that Pseudomonas aeruginosa (PAO1) biofilm challenge on wounds in diabetic (db/db) mice significantly delayed wound healing. In this wound time course study, we further characterize the bacterial burden, delayed wound healing, and certain aspects of the host inflammatory response in the PAO1 biofilm-challenged db/db mouse model. PAO1 biofilms were transferred onto 2-day-old wounds created on the dorsal surface of db/db mice. Control wounds without biofilm challenge healed by 4 weeks, consistent with previous studies; none of the biofilm-challenged wounds healed by 4 weeks. Of the biofilm-challenged wounds, 64% healed by 6 weeks, and all of the biofilm-challenged wounds healed by 8 weeks. During the wound-healing process, P. aeruginosa was gradually cleared from the wounds while the presence of Staphylococcus aureus (part of the normal mouse skin flora) increased. Scabs from all unhealed wounds contained 10(7) P. aeruginosa, which was 100-fold higher than the counts isolated from wound beds (i.e., 99% of the P. aeruginosa was in the scab). Histology and genetic analysis showed proliferative epidermis, deficient vascularization, and increased inflammatory cytokines. Hypoxia inducible factor expression increased threefold in 4-week wounds. In summary, our study shows that biofilm-challenged wounds typically heal in approximately 6 weeks, at least 2 weeks longer than nonbiofilm-challenged normal wounds. These data suggest that this delayed wound healing model enables the in vivo study of bacterial biofilm responses to host defenses and the effects of biofilms on host wound healing pathways. It may also be used to test antibiofilm strategies for treating chronic wounds.

Bacteria colonizing chronic wounds often exist as biofilms, yet their role in chronic wound pathogenesis remains unclear. Staphylococcus aureus biofilms induce apoptosis in dermal keratinocytes, and given that chronic wound biofilms also colonize dermal tissue, it is important to investigate the effects of bacterial biofilms on dermal fibroblasts. The effects of a predominant wound pathogen, methicillin-resistant S. aureus, on normal, human, dermal fibroblasts were examined in vitro. Cell-culture medium was conditioned with equivalent numbers of either planktonic or biofilm methicillin-resistant S. aureus and then fed to fibroblast cultures. Fibroblast response was evaluated using scratch, viability, and apoptosis assays. The results suggested that fibroblasts experience the same fate when exposed to the soluble products of either planktonic or biofilm methicillin-resistant S. aureus, namely limited migration followed by death. Enzyme-linked immunosorbent assays demonstrated that fibroblast production of cytokines, growth factors, and proteases were differentially affected by planktonic and biofilm-conditioned medium. Planktonic-conditioned medium induced more interleukin-6, interleukin-8, vascular endothelial growth factor, transforming growth factor-β1, heparin-bound epidermal growth factor, matrix metalloproteinase-1, and metalloproteinase-3 production in fibroblasts than the biofilm-conditioned medium. Biofilm-conditioned medium induced more tumor necrosis factor-α production in fibroblasts compared with planktonic-conditioned medium, and suppressed metalloproteinase-3 production compared with controls.

This study investigates mouse cutaneous responses to long-term percutaneously implanted rods surrounded by sphere-templated porous biomaterials engineered to mimic medical devices surrounded by a porous cuff. We hypothesized that keratinocytes would migrate through the pores and stop, permigrate, or marsupialize along the porous/solid interface. Porous/solid-core poly(2-hydroxyethyl methacrylate) [poly(HEMA)] and silicone rods were implanted in mice for 14 days, and for 1, 3, and 6 months. Implants with surrounding tissue were analyzed (immuno)histochemically by light microscopy. Poly(HEMA)/skin implants yielded better morphologic data than silicone implants. Keratinocytes at the poly(HEMA) interface migrated in two different directions. "Ventral" keratinocytes contiguous with the dermal-epidermal junction migrated into the outermost pores, forming an integrated collar surrounding the rods. "Dorsal" keratinocytes appearing to emanate from the differentiated epithelial layer, extended upward along and into the exterior portion of the rod, forming an integrated sheath. Leukocytes persisted in poly(HEMA) and silicone pores for the duration of the study. Vascular and collagen networks within the poly(HEMA) pores matured as a function of time up to 3-months implantation. Nerves were not observed within the pores. Poly(HEMA) underwent morphological changes by 6 months of implantation. Marsupialization, foreign body encapsulation, and infection were not observed in any implants.

The sinus between skin and a percutaneous medical device is often a portal for infection. Epidermal integration into an optimized porous biomaterial could seal this sinus. In this study, we measured epithelial ingrowth into rods of sphere-templated porous poly(2-hydroxyethyl methacrylate) implanted percutaneously in mice. The rods contained spherical 20-, 40-, or 60-μm pores with and without surface modification. Epithelial migration was measured 3, 7, and 14 days post-implantation utilizing immunohistochemistry for pankeratins and image analysis. Our global results showed average keratinocyte migration distances of 81 ± 16.85 μm (SD). Migration was shorter through 20-μm pores (69.32 ± 21.73) compared with 40 and 60 μm (87.04 ± 13.38 μm and 86.63 ± 8.31 μm, respectively). Migration was unaffected by 1,1' carbonyldiimidazole surface modification without considering factors of pore size and healing duration. Epithelial integration occurred quickly showing an average migration distance of 74.13 ± 12.54 μm after 3 days without significant progression over time. These data show that the epidermis closes the sinus within 3 days, migrates into the biomaterial (an average of 11% of total rod diameter), and stops. This process forms an integrated epithelial collar without evidence of marsupialization or permigration.