Critical Review-A Tribute to Louis Brocq Lymphomatoid Papulosis, the Key in Exploring the Relationship of Parapsoriasis and Mycosis Fungoides.

ABSTRACT: Both parapsoriasis and LyP appear clinically as inflammatory dermatoses with a paradoxical link to cMF. A key element in addressing the relationship of parapsoriasis and MF were the results of the French and Dutch long-term registries tracking the emergence of lymphomas in the setting of LyP. Both cMF and cALCL emerged almost equally in these long-term studies. This ultimately supports that the stem cells in both cMF and cALCL are probably derived from a common stem cell shared by CD4+/CD8+ memory stem cells defining cMF and CD30+ stem cells defining cALCL. The discovery of inducible Skin Associated Lymphoid Tissue (iSALT) mesenchymal hubs incorporating Tregs, with their pleiotropic functions represents a paradigm shift and formed a translational tool in this analysis of the paradox. LyP can be recast as activated inhibitory lymphomatoid T-cell hubs derived from inducible iTregs in iSALT and the source of the common stem cell LyP line. iSALT Treg integrated mesenchymal hubs provided an emerging translational tool in redefining integrated lymphomatoid pathways. Brocq's complex scheme defining parapsoriasis as hybrid inflammatory dermatoses with a paradoxical link to cMF became a template to preserve parapsoriasis as a clinical diagnosis. Two major iSALT Treg generated inhibitory integrated lymphomatoid hubs emerged. The major CD30+TNF lymphomatoid hub has been linked to cALCL. Clinically defined chronic regressing and relapsing parapsoriasis with the histopathology of patch stage MF can be redefined as lymphomatoid parapsoriasis. This twin inhibited oncogenic memory based hub is defined by Treg modulated, CD4+/CD8+memory linked PD-1/DL-1 cytoxic complex and lichenoid histopathology.

Myopericytomatosis: A rare entity mimicking other vascular tumours and malformations.

Myopericytoma is a rare tumour which typically presents as a benign lesion that mimics features of other more common vascular tumours and malformations. We present a case of a symptomatic diffuse myopericytomatosis of the left abdomen presenting as multiple subcutaneous vascular tumours detected on ultrasound and treated with ultrasound-guided sclerotherapy.

Keratoacanthoma, committed stem cells and neoplastic aberrant infundibulogenesis integral to formulating a conceptual model for an infundibulocystic pathway to squamous cell carcinoma.

Keratoacanthomas (KAs) are distinctive tumors that are defined by their clinical and histopathological features. Their relationship and distinction from squamous cell carcinoma (SCC), however, remain controversial. All cytogenic and immunohistochemical markers that have been applied in this quest have failed. A close relationship of KAs to hair follicles has been recognized. The descriptive term infundibulocystic or infundibular SCC was introduced to define a more broad-based pathway encompassing KAs. The follicular infundibulum roles in respect to neoplasia and wound healing are important elements in understanding the pathogenesis of KAs. Mouse models for KA have provided insights into the relationship of KA to follicles and SCCs. These advances and together with the diverse clinical and histopathological aspects of KA have contributed to the formulation of a conceptual pathway. The central element is that ultraviolet (UV)-mutated or activated committed infundibular stem cells are driven by the combination of a mutated oncogenic RAS pathway linked with the Wnt/beta-catenin pathway responsible for stem cell maintenance, hair follicle development, wound healing and driving KA proliferation and terminal keratinization. The existence and activation of this mutated pathway may form the basis of the paradoxical emergence of KAs and SCCs in patients receiving BRAF and PD-1 inhibitor therapy.

Eruptive Necrotizing Infundibular Crystalline Folliculitis: An Expression of an Abortive Sebaceous Follicular Repair Pathway Linked to Committed Infundibular Stem Cells?

ABSTRACT: Necrotizing infundibular crystalline folliculitis is a rare entity, which is a distinctive clinical and histopathological entity. Eruptive yellow waxy umbilicated folliculocentric plugs clinically correspond to pale crystalline filaments embedded in an amorphous sebum-rich material. Remarkably, only the superficial infundibular ostia remain, and the distended cavity is devoid of a follicular or sebaceous gland remnant. The pathogenesis of this enigmatic event remains to be established. The emergence of necrotizing infundibular crystalline folliculitis (NICF) as a paradoxical side effect of antitumor inhibitors epidermal growth factor receptor vascular endothelial growth factor and more recently programmed death-1 represents the expression of altered molecular pathways that underpin the pathogenesis of NICF. To explore these pathways, it is necessary to explore the hierarchy of follicular stem cells, particularly the potential role of committed infundibular stem cells that play a key role in wound healing. Committed infundibular stem cells are closely linked to the sebaceous gland stem cell axis, and this has relevance in the process of homeostatic repair of sebaceous follicles in the wake of folliculitis. The unscheduled modulation of this infundibular homeostatic sebaceous repair axis by epidermal growth factor receptor vascular endothelial growth factor, and programmed death-1 may lead to an aberrant outcome with metaplasia of infundibular keratinocytes to sebocytes. In the absence of sebaceous gland differentiation, these metaplastic infundibular sebocyte cells would lead to the consumption and loss of the infundibulum as a result of holocrine sebum production. This conceptual pathogenic pathway for NICF is constructed by incorporating recent advances in the fields of follicular stem cells, wound repair, follicular homeostasis, regulatory T cells, and molecular pathways linked to the biologicals inducing NICF.

T-Cell-Driven Fibroinflammation Inducing Follicular Dedifferentiation in Alopecia Areata and IgG4-Modified Disease.

ABSTRACT: The definition of IgG4-related diseases incorporates a broad range of systemic diseases particularly a subset dominated by fibroinflammation. CD4+cytotoxic T cells have emerged as the major driving force for the fibroinflammation, and the pathogenetic role of IgG4 still remains to be determined. Cutaneous involvement is uncommon and is not well defined as elevated tissue IgG4 plasma cells are not a specific marker and prominent cutaneous fibroinflammation is often absent in cutaneous disease. We report the case of a patient with longstanding alopecia universalis and severe atopic dermatitis who presented with diffuse induration and mottled dyspigmentation of his scalp. Multiple scalp biopsies revealed diffuse interfollicular fibroinflammation and IgG4 plasma cells with induction of distinctive dedifferentiated follicles not seen in alopecia areata. This complex case may provide insight into the role of specific subsets of T cells not only in respect to the fibroinflammation linked to IgG4-related diseases but also the capacity to modify disease, follicular stem cell activation, immune privilege, cytotoxicity in alopecia areata, and the presence of atopy that may have contributed to the pathogenesis of this case.

Atypical Disseminated Variant of Galli-Galli Disease: A Review of the Literature.

Galli-Galli disease (GGD) is a rare genodermatoses within the group of reticulated pigmentary disorders of the skin. Traditionally, its clinical presentation is identical to that of Dowling-Degos disease (DDD), with the additional feature of acantholysis on histopathological examination. We have reviewed the published cases of GGD to provide further support for the hypothesis that in fact, 2 phenotypes of GGD exist: the characteristic flexural GGD associated with KRT5 mutations and a disseminated variant with no mutation identified to date. A review of the literature revealed 53 reported cases of GGD. Fifteen atypical phenotype cases are described, and no KRT5 mutation has yet been identified. There is growing evidence that acantholysis is an underreported feature of DDD and that GGD and DDD are variations of the same disease, or in fact the same entity. This theory is supported by the identification of the c.418dupA missense mutation in both GGD and DDD. This review highlights that there is growing evidence that there are likely 2 clinical phenotypes of GGD with an associated genotypic correlation.

Onycholemmal variant of keratoacanthoma centrifugum marginatum as an expression of mutated committed stem cells in a conceptual pathway.

We describe a 43-year-old woman with a 10-year history of grossly hyperkeratotic nodules which progressively extended over the right ring finger. These involuted leaving pale, atrophic skin in their wake. At presentation, the advancing border had an arciform series of nodules in the pattern of keratoacanthoma centrifugum marginatum. The presence of filiform keratinisation that encased the nail plate, gross onychogryphotic masses of keratin on the ventral finger surface and a flat nail-like plate of keratin on the dorsal finger surface were distinctive features. Skin biopsy showed epidermal acanthosis, gross papillomatous cutaneous horn formation that had onycholemmal features. The pathology differed from keratoacanthoma and was not crateriform or infundibulocystic. Although HPV was not detected on immunohistochemistry, pathogenesis may still represent an HPV-related transfection of onycholemmal keratin committed stem cells producing an onycholemmal variant of keratoacanthoma centrifugum marginatum. A conceptual model linked to advances in follicular stem cell biology is formulated to explore this case.

Folliculitis decalvans-like pustular plaques on the limbs sparing the scalp.

Folliculitis decalvans is a neutrophilic cicatricial alopecia characterised by progressive pustular folliculitis. Folliculitis decalvans is seen as a condition usually limited exclusively to the scalp and rarely affects the limbs. We present a case of a 63-year-old man with a 3-year history of progressive pustular folliculitis with inflammatory patches and central scarring alopecia on both forearms and a circumscribed patch on his right lower leg. His presentation, clinical course and isolation of Staphylococcus aureus together with the histopathological findings all supported a folliculitis decalvans-like pustular folliculitis limited to the limbs. Biopsies revealed follicular pustules, gross interfollicular fibrosis with plasma cells and concentric perifollicular fibrosis with lymphocytes, all features seen with folliculitis decalvans. The positive response to antibiotics combined with topical corticosteroids mirrored the response seen with scalp folliculitis decalvans. In contrast to the previously reported cases, the patient had no evidence of folliculitis decalvans on the scalp.

Neurotropic T-cell lymphocytosis: a cutaneous expression of CLIPPERS.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disease of the central nervous system that predominantly involves the pons and cerebellum and that improves with immunosuppressive treatment. Only recently described, the etiology is unknown, diagnosis is difficult and long-term neurological sequelae may occur without aggressive treatment. Herein, we describe a 59-year-old woman who presented with subcutaneous nodules affecting her face, trunk, limbs and an indurated annular erythematous lesion on her forearm. This was associated with marked dysesthesia of her skin, refractory to treatment. There was a 4-year history of dysequilibrium, vertigo, truncal and gait ataxia with progressive neurological symptoms. Skin biopsy of the annular nodular lesion showed a lymphohistiocytic infiltrate in dermis and subcutis with a striking lymphocyte-dominant infiltrate that was perineural and formed a nodular collection extending along a prominent subcutaneous nerve. Immunophenotyping indicated a marked predominance of T cells that were CD3 positive with a 2 : 1 CD4 : CD8 ratio. Scattered histiocytes were present but no well-formed granulomas or vasculitis. Magnetic resonance imaging studies showed changes in the pontine, brain stem and cerebellar region, which subsequently were defined as characteristic for CLIPPERS, but no brain biopsy was pursued. The marked neural skin symptoms and the cutaneous histopathological findings indicate that the skin may be an additional target organ in CLIPPERS, and the immune response may be directed against a common neural antigen. In radiologically typical CLIPPERS, identification of clinical skin lesions particularly subcutaneous nodules and biopsy may potentially form a basis for tissue diagnosis in this syndrome.

Cutaneous adverse effects of hormonal adjuvant therapy for breast cancer: a case of localised urticarial vasculitis following anastrozole therapy and a review of the literature.

Hormonal therapy with either tamoxifen or aromatase inhibitors is commonly used to treat women with breast cancer in both the adjuvant and recurrent disease setting. Cutaneous adverse reactions to these drugs have been rarely reported in the literature. We report an unusual case of urticarial vasculitis following the aromatase inhibitor anastrozole that localised to the unilateral trunk and mastectomy scar, and review the literature on the cutaneous adverse effects of hormonal therapy for breast cancer.

Pigmentation of lower limbs: Contribution of haemosiderin and melanin in chronic venous insufficiency and related disorders.

BACKGROUND: To determine the composition of skin pigmentation in chronic venous insufficiency (CVI) and other less common vascular conditions of lower limbs. METHODS: Forty-five skin biopsies were obtained from 17 patients. Samples were taken from pigmented regions and compared with control non-lesional samples from the same patient. Perl's Prussian Blue was used to identify haemosiderin and Schmorl's for melanin. RESULTS: Seven patients presented with CVI, one with concurrent livedo vasculopathy (LV). One patient had LV only. Two patients had acroangiodermatitis (AAD). Six patients had post-sclerotherapy pigmentation (PSP), one with concurrent post-inflammatory hyperpigmentation (PIH). One patient had PIH only. The predominant pigment in CVI samples was haemosiderin. C5-C6 patients showed increased epidermal melanin. LV, AAD, and PSP samples showed dermal haemosiderin but no increase in epidermal melanin. PIH samples showed prominent epidermal melanin whilst no haemosiderin was detected. CONCLUSION: The predominant pigment in CVI and other vascular conditions was haemosiderin. Melanin was present in later stages of CVI (C5-C6) and in PIH.

Plaque-like cutaneous mucinosis: case report and literature review.

Midline mucinosis was observed in a 14-year-old man, which was confined to the midline of the back and appeared as asymptomatic, nonindurated, hyperpigmented plaques. Skin biopsies showed prominent interstitial mucinosis with perivascular lymphocytic infiltration. A literature review of plaque-like mucinosis revealed 14 previous cases with this distinct presentation that may overlap with reticular erythematous mucinosis and connective tissue disease. Midline mucinosis has been previously reported in prepubertal children but is rare.

Calcinosis cutis following contact with calcium chloride solution.

Calcinosis cutis is the deposition of insoluble calcium in the cutaneous tissue. Calcinosis cutis can be classified as metastatic, dystrophic, idiopathic or exogenous. We report a 48-year-old white man who was dismantling a portable ice skating rink when calcium chloride solution from the pipes spilt onto his clothing. Several days later, he started to develop mildly pruritic erythematous papules, some studded with white deposits and some with umbilication over the exposed areas corresponding to the spillage of the calcium chloride solution. Histological features revealed interstitial fibrohistiocytic reaction with calcium-encrusted degenerated collagen bundles in the dermis which was further confirmed by von Kossa stain. He was commenced on topical corticosteroid cream twice daily and the lesions cleared completely between 6 to 10 weeks.

Enfuvirtide injection site reactions: a clinical and histopathological appraisal.

BACKGROUND/OBJECTIVES: Enfuvirtide was the first of a new class of antiretroviral agents termed 'fusion inhibitors' used for the treatment of HIV-1 infection. Enfuvirtide is administered subcutaneously and injection site reactions (ISR) are commonplace (98%). The aim of this study was to analyse in detail the histopathological changes associated with striking ISR seen in four patients. METHODS: Biopsies were obtained at various times post-injection and were reviewed histologically. The changes in epidermal, dermal and subcutaneous connective tissue and the presence and nature of the inflammatory cellular infiltrate were noted. An immunohistochemical assessment was undertaken. RESULTS: All biopsy specimens demonstrated striking changes in the dermal connective tissue. Alteration in collagen was the most prominent feature and resembled a morphoea/scleroderma-like process. These changes persisted well beyond cessation of enfuvirtide (>1 year). The relative populations of dermal dendritic cells (DDC) (types 1 (Factor XIIIa) and 2 (CD34+)) were analysed and a reciprocal relationship between DDC subpopulations was observed akin to that observed in other sclerosing and fibrosing conditions. CONCLUSION: This study details histopathological changes associated with enfuvirtide ISR. We postulate that changes in DDC populations may contribute to the pathogenesis of the sclerotic process observed with enfuvirtide ISR.

Granuloma formation following cyanoacrylate glue injection in peripheral veins and arteriovenous malformation.

Background: Cyanoacrylate adhesive closure is a technically simple alternative to endothermal ablation of peripheral veins. N-butyl cyanoacrylate is delivered via catheters or by percutaneous injection resulting in occlusion of target veins. The local tissue reaction or the systemic immune response that may follow have not been characterised. Aim: To characterise the late local tissue reaction to N-butyl cyanoacrylate glue injected in peripheral vessels. Methods: Biopsies were obtained from two patients. In patient one, distal tributaries of the great saphenous vein were injected with VenaBlock™ glue under ultrasound guidance. Ultrasound-guided incisional biopsies were performed at one week, six weeks and 12 months. In patient two, a peripheral arterio-venous malformation was injected with Venablock™ and biopsy was performed 12 months later. Histological analysis was performed using haematoxylin and eosin and immunofixation with CD-4, CD-31, CD-34, CD-68 and D2-40. Results: Echogenic material with a strong shadow artefact consistent with the injected N-butyl cyanoacrylate was observed on ultrasound on all follow-up occasions. Biopsies taken at one week showed intravascular glue without histiocytes. Biopsies at six weeks showed isolated foreign body histiocytes coating intravascular fibrillary glue spicules but no granuloma formation. The one-year biopsies showed extravascular changes including fibrosis, lymphoid aggregates and multiple extravascular foreign body cavitated granulomas. Some vessel lumens contained residual spicules of glue but no intravascular granulomas. The extravascular granulomas were deeply located, asymptomatic and not complicated by clinical ulceration. Histologically, there was no evidence of transepidermal elimination. Conclusion: Extravascular foreign body cavitated granulomas containing spicules of glue with fibrosis and lymphoid aggregates occur as a delayed finding following the use of N-butyl cyanoacrylate.

Indurated reticulate palmar erythema as a sign of paraneoplastic palmar fasciitis and polyarthritis syndrome.

A 62-year-old woman presented with a 6-month history of polyarthritis. She had also noted a 2-month history of indurated palmar erythema and increasing bilateral hand swelling and stiffness. A biopsy from the area of palmar erythema showed interstitial fibroplasia within the dermis and subcutis representing a palmar fibromatosis. This presentation appears to belong to the spectrum of palmar fasciitis and polyarthritis syndrome. Rheumatologists have recognised this syndrome as a paraneoplastic disorder and subsequent investigations in our patient revealed an elevated cancer antigen 125 and an inoperable ovarian carcinoma. Indurated palmar erythema is a sign that is not widely recognised by dermatologists as a clue for this paraneoplastic syndrome, and skin biopsy demonstrating dermal and subcutaneous fibroplasia may help in diagnosis in the absence of advanced signs of palmar fasciitis.