Friday, 10 December 2010

Perforating granuloma annulare

Different clinical variants of granuloma annulare have been described. The most common form, as its name indicates, is an annular lesion. The annular margin is firm to palpation and may be continuous or consist of discrete or coalescent papules in a complete or partial circle. The epidermis is usually normal, but surface markings may be attenuated over individual papules whose colour may be skin coloured, erythematous, or violaceous. The lesions are usually asymptomatic. Reports of an association with diabetes mellitus are controversial. Several other associations have been reported.

There is overlap between the different variants, and more than one morphologic type may co-exist in the same patient. It must be noted that some lesions enlarge as nodules rather than having an annular morphology. A diagnosis of localized annular granuloma annulare is made on clinical examination. Histopathologic examination is necessary when the presentation is atypical. The clinical diagnosis is definitely difficult when annular lesions are absent.

Perforating granuloma annulare was named by Owens and Freeman in 1971. It exhibits transepidermal elimination of degenerating collagen histopathologically, the so called “necrobiotic collagen” hence classified as a secondary perforating disorder. Collagen is a fibre that can undergo degeneration but cannot become necrotic; only cells can undergo necrosis so the term degenerating collagen or collagenolysis is preferred. Perforating granuloma annulare starts clinically as small papules with central umbilications. Lesions may be localized (usually in an acral distribution) or generalized. Perforating granuloma annulare lesions have been present in some of the reported HIV-positive patients with granuloma annulare.

In perforating granuloma annulare there is a superficial area of the so called necrobiosis (better called degenerated collagen, as stated above) and mucin accumulation surrounded by palisading histiocytes, situated beneath a perforation in the epidermis. The so called “necrobiotic material” and mucin are extruded via the perforation. At the margins of the perforation there are varying degrees of epidermal hyperplasia. It should be noted that the epidermal changes are inconspicuous in other variants of granuloma annulare.

Mucinous degeneration of collagen appears bluish or at least shows decrease in the degree of eosinophilic (pink) staining. Mucin can be seen more readily by staining with Alcian blue or colloidal iron.

The differential diagnosis of perforating granuloma annulare includes some dermatoses such as insect bites, molluscum contagiosum, pityriasis lichenoides et varioliformis acuta, transepidermal elimination disorders such as perforating collagenosis and acquired perforating dermatosis, sarcoidosis and papulonecrotic tuberculide. Epithelioid sarcoma may masquerade as perforating granuloma annulare. It should be noted that epithelioid sarcoma that can simulate perforating granuloma annulare, as stated, may also contain mucin. Clues to epithelioid sarcoma include ulceration, cytologic atypia, necrotic foci that include necrotic epithelioid cells and possibly a history of recurrence. Immunohistochemically, epithelioid sarcoma can be distinguished from granuloma annulare by positivity for epithelial membrane antigen and (Cyto)keratin.

The tendency of granuloma annulare to remit spontaneously (but it should be noted that perforating granuloma annulare may leave a hypo- or hyperpigmented scar) complicates accurate assessment of the efficacy of any treatment (such as intralesional triamcinolone 2.5 - 3 mg/mL).

Monday, 6 December 2010

Lymphocytoma cutis

Lymphocytoma cutis is a benign lymphocyte hyperplasia (B-cell reaction to an antigen such as a red tattoo, Borrelia burgdorferi, injected drug, vaccine) that prefers the head and neck region,and can be associated with sunlight sensitivity. It presents as red or violaceous nodules or plaques and is commoner in females.

It can remain stable or regress over time. Lymphocytoma cutis can be complicated by the development of primary cutaneous B cell lymphoma. Whether the initial diagnosis in such circumstances should have been primary B-cell lymphoma and was missed, or not is uncertain. Lymphocytoma cutis has been classified as a “pseudolymphoma” but there is no need to use the term "pseudolymphoma" whenever specific diagnosis can be made.

The lymphocyte infiltrate affects the reticular dermis rather than the subcutaneous fat (In primary B-cell lymphoma the subcutaneous fat may be infiltrated); it spares the papillary dermis forming a grenz zone. It can be wedge shaped, apex of which is directed at the subcutaneous fat but it does not involve it. However, in
reactions at the site of vaccination, the subcutis is predominantly
affected with little dermal involvement. The infiltrate is considered to be bottom heavy if compared to epidermotropism of mycosis fungoides where there is no grenz zone. Some have sub-typed the lymphocytoma cutis into B-cell or T-cell, according to which lymphoid cell pattern is present on the biopsy. Further divisions within these groups are largely by its cause, if any is identified but many won't follow this classification as it will include distinct conditions under the umbrella term of pseudolymphoma which should be avoided whenever a specific diagnosis can be made. Appendages and blood vessels are spared. The infiltrate is polymorphous (lymphocytes, starry sky macrophages (with tingible/stained bodies), eosinophils and plasma cells). The infiltrate shows a mixture of kappa and lambda light chain positive B cells (polyclonal) by immunohistochemical analysis. Normally, B cells undergo gene rearrangement of one of their immunoglobulin heavy chain genes at an early stage in B-cell development. In lymphocytoma cutis, immunoglobulin heavy chain gene rearrangement polymerase chain reaction or southern blot analysis shows polyclonal rearrangement. CD1a+ dendritic cells (originally observed in the infiltrates of cutaneous T-cell lymphoma) are usually abundant by immunohistochemical analysis. It can contain lymphoid follicles (with germinal centres)[in classic cases] resembling the appearance of lymph node. Differentiation from primary B-cell lymphoma (particularly marginal zone lymphoma “MZL”) can be difficult clinically and histopathologically (presence of atypical lymphoid cells would suggest a primary cutaneous MZL).

A spectrum of B-cell neoplasia ranging from polyclonal lymphocytoma cutis (benign) via oligoclonal and monoclonal lymphocytoma cutis into primary cutaneous B-cell lymphoma (malignant) is possible.

Jessner’s benign lymphocytic infiltration (T-cell infiltrate,  predominantly in the lower dermis and concentrated tightly around blood vessels and within the lymphocytic infiltrate there is no evidence of follicle formation), tumid discoid lupus erythematosus (basal cell liquefaction degeneration with positive direct immunofluorescence), polymorphic light eruption and insect bites reactions are also among the differential diagnoses.

Treatment modalities (no treatment of proven value unless a cause is found and even then elimination of the cause does not necessarily cures the disease, sunscreens are used if there is sunlight sensitivity) include: intralesional steroid injection, topical steroids, oral hydroxycloroquine, intralesional interferon-alpha-2A, and topical tacrolimus. Observation with careful follow-up is a reasonable option.

This page was last updated in September 2014

Saturday, 4 December 2010

Linear porokeratosis

Linear porokeratosis has been classified as an epidermal naevus but it is still clinically and histopathologically indistinguishable from the lesions of generalized porokeratosis (disorder of keratinization). Linear porokeratosis probably reflects mosaicism for a gene responsible for generalized porokeratosis (autosomal dominant, but CAP syndrome “craniosynostosis – anal anomalies – porokeratosis” appears to segregate as autosomal recessive trait). This mosaicism can be explained by loss of heterozygosity for this dominant gene. Accordingly, an individual with inherited generalized porokeratosis undergoes a somatic mutation affecting the normal allele resulting in clonal loss of heterozygosity. The resultant line has ‘double the dose’ of porokeratosis. Skin cancers in porokeratosis are particularly associated with the linear variant. Overexpression of p53 [tumour suppressor protein (coded for by 17p)] has been reported in linear porokeratosis and in a superimposed squamous cell carcinoma. Many of topical agents, such as imiquimod 5% cream, an immune response modifier that induces cytokines such as interferon-alfa, used in the treatment cause initial inflammation which is followed by resolution.

Linear porokeratosis, with its ‘double the dose’ of porokeratosis, contrasts with the background skin, with its ‘one dose’ porokeratosis. Thus patients with linear porokeratosis can later develop disseminated superficial actinic porokeratosis (DSAP), the commonest presentation of porokeratoses, and children or siblings of patients with DSAP can have linear porokeratosis. Having said so, linear porokeratosis usually occurs sporadically and even many patients with generalised porokeratosis itself have no family history. Linear porokeratosis can exacerbate during episodes of liver failure, and improve following transplantation (unlike generalized porokeratosis that can be provoked by immune suppression).

Almost all epidermal naevi follow the pattern of lines documented by Blaschko from drawings of epidermal naevi. The pattern is attributed to the lines of migration and proliferation of epidermal cells during embryogenesis. The lines do not correspond to any known nervous, vascular or lymphatic structures. The bands of abnormal skin represent clones of cells carrying a mutation in a gene expressed in the skin. Mosaicism impact on the phenotype relates to the proportion of cells that harbour the mutation and their distribution. Mosaic describes an art form in which pictures are produced by joining together tiny pieces of different coloured stone or glass. The term is used in genetics to describe individuals composed of cells of different genotypes, such as patients with Turner syndrome who have both 45, XO and 46, XX cells. The pattern may vary according to cell type and timing of mosaicism. In the skin, genetic mosaicism classically appears as Blaschko's lines.

It should be noted that the term "porokeratosis" was first used by Vittorio Mibelli, Italian dermatologist, in 1893. Porokeratoses are characterised by presence of abnormal (disordered metabolism/increased cell kinetics) clone of keratinocytes showing varying degrees of dysplasia with gradual centrifugal migration of this clone resulting in a keratotic lesion that can progress to overt cutaneous neoplasm. The term “porokeratosis” is a misnomer, as porokeratosis has nothing to do with pores of sweat glands. Actually the lesions may or may not involve the eccrine sweat duct. The characteristic histopathology is seen in the edge of the lesion. The stratum corneum is hyperkeratotic, and at the raised border a column of poorly staining parakeratotic stratum corneum cells, the cornoid lamella, is seen running through the surrounding normal-staining cells. There is hypogranulosis beneath the cornoid lamella. Cornoid lamellae may also been seen in other conditions such as common warts (distinguished by presence of koilocytes), actinic keratosis (distinguished by presence of cytologic atypia) and some ichthyoses.

Main Works of Reference List (The first eight are my top favourites)

  • British National Formulary
  • British National Formulary for Children
  • Guidelines (BAD - BASHH - BHIVA - Uroweb)
  • Oxford Handbook of Genitourinary Medicine, HIV, and Sexual Health
  • Oxford Handbook of Medical Dermatology
  • Rook's Textbook of Dermatology
  • Simple Skin Surgery
  • Weedon's Skin Pathology
  • A Concise Atlas of Dermatopathology (P Mckee)
  • Andrews' Diseases of the Skin
  • Andrology (Nieschlag E FRCP, Behre M and Nieschlag S)
  • Bailey and Love's Short Practice of Surgery
  • Davidson's Essentials of Medicine
  • Davidson's Principles and Practice of Medicine
  • Fitzpatrick's Colour Atlas and Synopsis of Clinical Dermatology (Klaus Wolff FRCP and Richard Allen Johnson)
  • Fitzpatrick’s Dermatology in General Medicine
  • Ganong's Review of Medical Physiology
  • Gray's Anatomy
  • Hamilton Bailey's Demonstrations of Physical Signs in Clinical Surgery
  • Hutchison's Clinical Methods
  • Lever's Histopathology of the Skin
  • Lever's Histopathology of the Skin (Atlas and Synopsis)
  • Macleod's Clinical Examination
  • Martindale: The Complete Drug Reference
  • Oxford Handbook of Clinical Examination and Practical Skills
  • Oxford Textbook of Medicine
  • Practical Dermatopathology (R Rapini)
  • Sexually Transmitted Diseases (Holmes K et al)
  • Statistics in Clinical Practice (D Coggon FRCP)
  • Stockley's Drug Interactions
  • Treatment of Skin Disease: Comprehensive Therapeutic Strategies
  • Yen & Jaffe's Reproductive Endocrinology