David Slater

The new World Health Organization–European Organization for Research and Treatment of Cancer classification for cutaneous lymphomas: a practical marriage of two giants

Following consensus meetings of the two parent organizations, a new World Health Organization–European Organization for Research and Treatment of Cancer (WHO–EORTC) classification for primary cutaneous lymphomas has recently been published. This important development will now end the ongoing debate as to which of these was the preferred classification. The new classification will facilitate more uniformity in diagnosis, management and treatment of cutaneous lymphomas. In particular, it provides a useful distinction between indolent and more aggressive types of primary cutaneous lymphoma and provides practical advice on preferred management and treatment regimens. This will thereby prevent patients receiving high‐grade treatment for low‐grade biological disease. This review focuses on those diseases which have found new consensus agreement compared with the original WHO and EORTC classifications. In cutaneous T‐cell lymphomas, these include folliculotropic mycosis fungoides, defining features of Sézary syndrome, primary cutaneous CD30+ lymphoproliferative disorders (primary cutaneous anaplastic large cell lymphoma, lymphomatoid papulosis and borderline lesions) and subcutaneous panniculitis‐like T‐cell lymphoma. Primary cutaneous CD4+ small/medium‐sized pleomorphic T‐cell lymphoma, primary cutaneous aggressive epidermotropic CD8+ T‐cell lymphoma and cutaneous γ/δ T‐cell lymphoma are allocated provisional entry status and thereby afford better definitions for some cases of currently unspecified primary cutaneous peripheral T‐cell lymphoma. In cutaneous B‐cell lymphomas, diseases which have found new consensus agreement include primary cutaneous marginal zone B‐cell lymphoma, primary cutaneous follicular centre lymphoma, primary cutaneous diffuse large B‐cell lymphoma, leg type and primary cutaneous diffuse large B‐cell lymphoma, other. CD4+/CD56+ haematodermic neoplasm (early plasmacytoid dendritic cell leukaemia/lymphoma) now appears as a precursor haematological neoplasm and replaces the previous terminology of blastic NK‐cell lymphoma. Other haematopoietic and lymphoid tumours involving the skin, as part of systemic disease, will appear in the forthcoming WHO publication Tumours of the Skin. The new classification raises interesting new problems and questions about primary cutaneous lymphoma and some of these are discussed in this article. It is, however, a splendid signpost indicating the direction in which research in cutaneous lymphoma needs to go. In the interim, we have an international consensus classification which is clinically meaningful.

Evidence for a theory of physical fragmentation of megakaryocytes, implying that all platelets are produced in the pulmonary circulation

The mathematical description of a fragmentation mechanism which leads to log normal volume distribution is applied to platelet production from megakaryocyte cytoplasm. Large cytoplasmic fragments and whole megakaryocytes are released from the bone marrow into the circulation. Physical fragmentation of the cytoplasm occurs in the pulmonary circulation producing the observed heterogeneity of platelet volume. Experimental evidence is used to provide quantitative verification that physical fragmentation is the process which produces all platelets. With this theory the currently accepted concept of the predesignation of the platelet population by the demarcation membrane system in megakaryocyte cytoplasm becomes redundant.

Alopecia areata: alterations in the hair growth cycle and correlation with the follicular pathology

A histopathological study was performed in 17 patients with alopecia areata to elucidate the changes in hair cycle dynamics. The findings confirm the view that the initial event in alopecia areata is the premature entry of anagen follicles into telogen, although some follicles survive for a time in a dystrophic anagen state. However, after re‐entry into anagen takes place, growth appears to be halted in anagen III rather than anagen IV, as has previously been suggested. Follicles then return prematurely to telogen and these truncated cycles are repeated until the disease activity subsides. A new pathogenic hypothesis is presented which relates alterations in hair cycle dynamics to pathological changes within the anagen follicle and also provides an explanation for the formation of exclamation mark hairs and the non‐destructive nature of the disease.

Aluminium hydroxide granulomas: light and electron microscopic studies and X-ray microanalysis

Three children are described in whom painful subcutaneous nodules developed 1–2 years after the injection of adsorbed diphtheria, tetanus and pertussis vaccine. The diagnosis of aluminium hydroxide granuloma was established by ultrastructural examination with X‐ray microanalysis.

The pathogenesis of amiodarone‐induced pigmentation and photosensitivity

A new method has been used to measure tissue levels of amiodarone and its major metabolite desethylamiodarone. Amiodarone‐pigmented skin has a drug and metabolite concentration ten times that of non‐pigmented skin. Iodine‐rich amiodarone and its metabolite have been detected in secondary lysosomes by energy dispersive analysis of X‐rays. Amiodarone induces a phototoxic reaction with an action spectrum in both the UV‐B and UV‐A wavelengths.

Occupational argyria; light and electron microscopic studies and X-ray microanalysis.

Microscopic studies have been performed on skin biopsies from five patients with occupational argyria.

The relationship between platelet and megakaryocyte volumes

Planimetric megakaryocyte and nuclear areas were measured by histological techniques in rabbits subjected to 6 days of thrombocytopenia and in normal steady state function. A theoretical correction factor enables an estimate to be obtained of the actual megakaryocyte, megakaryocyte cytoplasm and nuclear volumes in these two states. The corresponding platelet volumes after 6 days of thrombocytopenia and in normal function were also measured. This enables the number of platelets produced by a single megakaryocyte (on average) to be computed directly in the two states of platelet production. The experiments showed that the volume of megakaryocyte cytoplasm increased significantly in stimulated platelet production. The number of platelets produced per megakaryocyte doubled and the mean platelet volume also increased during stimulated production. An explanation is given for the observed behaviour of platelet and megakaryocyte volumes.

Platelet and megakaryocyte changes in cholesterol-induced experimental atherosclerosis.

Rabbits were fed either 2 g cholesterol in 10 ml olive oil daily with normal diet (n = 5) or normal diet alone (n = 5). After 12 weeks, the cholesterol-fed animals had developed fatty plaques involving 24% ± 4% of the surface area of the aorta; the control animals had none. Mean platelet volume was significantly smaller (p < 0.04) in the cholesterol-fed animals (4.1 ± 0.3 fl) compared with the controls (4.8 ± 0.4 fl). The heterogeneity of the average volume distributions of the two groups, characterized by the statistical parameters of the coefficient of variation, skewness, and kurtosis, was also significantly different. Platelet count was significantly higher (p < 0.001) in the cholesterol-fed group (7.48 ± 1.06 × 1011 platelets/liter blood) compared to the control group (4.86 ± 0.60 × 1011 platelets/liter blood). Mean megakaryocyte cytoplasmic volume was significantly larger (p < 0.001) in the cholesterol-fed rabbits (12,262 ± 1485 fl) compared with controls (6,814 ± 761 fl). The range of cytoplasmic volumes was also significantly increased in the cholesterol-fed rabbits. A significant (p < 0.01) increase in mean megakaryocyte nuclear volume in the cholesterol-fed animals was accompanied by a nonsignificant increase in mean nuclear DNA content: 30.2 ± 3.7 N compared with a control value of 23.6 ± 4.0 N. This evidence indicates that a high cholesterol diet in rabbits is associated with changes in platelet production from megakaryocytes as well with as the development of atherosclerosis.

Reticular erythematous mucinosis: light and electron microscopy, irnmunofluorescence and histochemical findings

Five patients with reticular erythematous mucinosis were studied by skin biopsy and phototesting. Light microscopy showed a dermal mononuclear cell infiltrate (composed largely of lymphocytes), separation of collagen bundles and fragmentation of elastic fibres. Histochemical stains showed increased dermal mucin with a profile consistent with hyaluronic acid. In one case, the ultrastructural distribution of mucin was demonstrated using colloidal iron staining, electron microscopy and X‐ray microanalysis. In two cases, virus‐like tubular aggregates were identified in the cytoplasm of dermal cndothclial cells and pericytes. Immunofluorescent staining for immunoglobulins, fibrin and complement was negative.

ABNORMAL INTRAPULMONARY PLATELET PRODUCTION: A POSSIBLE CAUSE OF VASCULAR AND LUNG DISEASE

It is postulated that platelets are not produced by megakaryocyte budding within the bone marrow but by physical fragmentation in the pulmonary circulation. Alterations in the nature of the production site (the pulmonary vessels and their concomitant biochemical environment) or changes in the antecedent megakaryocyte cytoplasmic volumes with a concomitant alteration in protein structure can produce platelets with a mean volume larger than normal. If such platelets are more reactive then they may be involved in atherogenesis and arterial thrombosis. Furthermore several pulmonary pathological states may arise from dysfunction during pulmonary platelet production.