Napoli B., D’Arpa N., Alessandro G., Iaia A., Masellis M.

Department of Plastic Surgery and Burns Therapy, Palermo Civic Hospital, Palermo, Italy

SUMMARY. The case is described of a 62-yr-old male patient suffering from leukemized mycosis fungoides (Sézary syndrome) who was subjected to PUVA (psoralen and ultraviolet A radiation) therapy, and complicated by a serious condition of cutaneous photosensitivity. After a discussion of cutaneous T cell lymphomas, of which mycosis fungoides and the Sézary syndrome are the most frequent forms, an analysis is made of the hepatotoxic, phototoxic, and photoallergic effects of psoralen, a drug used to sensitize the skin to high-level ultraviolet rays. The criteria are described for a differential diagnosis between Lyell’s syndrome and the vesiculobullous reactions provoked by photoallergic mechanisms.

Introduction

In 1997 Speron and Gamelli reported the case of a 52-yr-old female patient suffering from a histologically demonstrated Lyell’s syndrome of pharmacological origin. Two months after recovering, the patient once again presented skin lesions, which were at first taken to be signs of recidivation. However, a new biopsy indicated mycosis fungoides, which might have made the patient more susceptible to the development of Lyell’s syndrome.

In 1995 we described a case of histologically demonstrated Lyell’s syndrome of pharmacological origin in a 50-yr-old male patient already known to be suffering from mycosis fungoides.

We report here the case of a patient suffering from leukemized mycosis fungoides (Sézary syndrome), sent to us with a diagnosis of Lyell’s syndrome, after being subjected to therapy with psoralen and UV-A radiation.

Clinical case

B.C., male, aged 62 years.

Anamnesis. In 1985, when suffering from pruriginous erythema, the patient was subjected to skin biopsy, which indicated mycosis fungoides. In February 2003 he was hospitalized after the appearance of diffuse erythema with dermal thickening plus superficial and deep adenomegaly (thorax and abdomen CT). Lab analyses showed intense leukocytosis with significant lymphocytosis (WBC 30,800/mm3 with lymphoid elements having the appearance of Sézary cells - 78% - of phenotype CD2, CD3, CD4, CD5 pos., and CD7 neg.). A diagnosis was made of Sézary syndrome, and therapy was initiated with pentostatin (6 cycles) and later with polychemotherapy (CHOP scheme, 6 cycles). This reduced the cutaneous erythema, and the adenomegaly ceased. In December 2003, the pruritus persisted and the patient had four sessions of PUVA therapy. The last of these was on 30 December 2002, i.e. five days before the onset of the clinical picture that led to the patient’s transfer to our operating unit (9 January 2003) with the diagnosis of Lyell’s syndrome. The patient was then taking two drugs: 1 tablet per day of Losaprex (losartan) and 20 drops per day of Lexotan (bromazepam).

Objective examination on entry. The patient presented erythema in the thorax and upper limbs, which were extremely oedematous and, in places, de-epithelialized. The thighs presented a coating of small vesicles and a few large phlyctenae. The genitals and perineal area were also affected by this process.

There were numerous petechiae in the legs, and it was possible to observe purple haemorrhagic vesicles in the back. The vesicles and phlyctenae were very tense, Nikolsky’s sign was negative, and the mucosae were not involved. Apart from the purpuric lesions, the picture suggested an extensive photolesive reaction at the moment of hospitalization in approximately 60% of the body surface (Figs. 1,2).

Lab tests. Lab tests indicated serious hepatic damage with a considerable increase in levels of GGT (186 UI/l), ALPH (181 UI/l), AST (245 UI/l), ALT (170 UI/l), and AMY (177 UI/l), accompanied by a serious reduction in plasma albumin (2.2 g/dl), pseudocholinesterase (2134 UI/l), and total proteins (4.8 g/dl). The low calcaemia (7.0 ng/100 ml) was evidently related to hypoalbuminaemia. A considerable increase was also found in LDH (4631 UI/l).

Leucocytes and lymphocytes. A slight reduction in leukocytes (3600/mm3) - probably related to the previous chemotherapy treatment - was accompanied by a percentage reduction in neutrophil granulocytes (38.3%), an increase in monocytes (11.5%), and, in particular, an increase in lymphocytes (50.2%; 1800 cells per mm3 in absolute terms). Examination of the lymphocyte subpopulations showed a considerable increase in CD4-T helper/inducer cells (93%; 1681 cells per mm3) and, on the contrary, a decrease in CD8-T suppressor/cytotoxic cells (3%; 56 cells per mm3). There was therefore a considerable increase in the CD4/CD8 ratio (30,10; VN 0.6-3.0), which confirmed the existence of the basic disease (Sézary syndrome) and at the same time excluded Lyell’s syndrome, in which - because of the reduction in T helper lymphocytes without any substantial modification in T-suppressor lymphocytes - the CD4/CD8 is reduced.

Histology. The skin biopsy would appear to have revealed the presence of a lymphocyte infiltrate in the superficial dermis of phenotype T, with epidermotropism, also confirming the previous pathology and excluding Lyell’s syndrome.

Course of disease and outcome. Radiography of the thorax, abdominal echography, and ECG did not reveal any important organic involvement. Haematocrit, arterial pressure, phonocardiogram, temperature, and hourly diuresis were monitored. The patient received resuscitatory treatment, albumin, ulcer and thromboembolism prophylaxis, and antibiotic and vitamin therapy. The administration of intravenous immunoglobulin (Gamma-Venin P, 5 g) was also initiated.

The main features of the patient’s clinical course were, on the one hand, a gradual improvement in hepatic function parameters but, on the other, a progressive deterioration in the condition of the skin, with the appearance of new bullae. On the third day after hospital admittance the patient died of acute myocardial infarction (cardiac vasculitis due to photoactivated losartan?).

Discussion

The abbreviation CTCL (cutaneous T cell lymphoma) is used to define a heterogeneous group of non-Hodgkin’s lymphomas that in the first instance affect the skin. Mycosis fungoides is one of the most frequent forms of CTCL. Sézary syndrome is the leukaemic variant, which may appear ex novo or (5% of cases) be a late but unpropitious development of previous lesions typical of mycosis fungoides.

Classically, there are three clinical types of mycosis fungoides:

• immediate tumours
• the erythrodermic form
• the polymorphic form

This last form, the most frequent, may have an evolution from an initial phase, defined as pre-mycosis, to mycosis proper. The characteristic feature of the first phase (“patch phase”) is the presence of polymorphic lesions (patches that may be erythematous infiltrating, psoriasiform, eczematoid, parapsoriasiform, etc.); this phase may be protracted in duration and followed by the more characteristic phase, when infiltration of the patches is more accentuated (“plaque phase”), or even by evolution towards a tumour (“tumour phase”). In about 10% of patients the disease progresses with involvement of the lymph nodes and/or viscera.

Sézary syndrome is preceded or accompanied by pruritus. The onset comes with erythematous patches that tend to combine until they occupy the entire body surface, causing exfoliative and/or infiltrating erythroderma. The erythroderma is accompanied by generalized lymphadenopathy. The haematological analysis is of special importance because it shows a condition of leukocytosis (20,000-60,000/mm3) with an increase in T lymphocytes and the CD4/CD8 ratio (Ž 10). The blood shows evidence of a cell clone T mainly composed of T lymphocytes CD4+ and CD7.

Apart from this trio of erythroderma, lymphadenopathy, and circulating atypical mononuclear cells, it is possible to find that the process spreads through the lymphatic glands to the viscera (spleen, lungs, liver) and bone marrow.

Besides the haematological finding, high LDH levels - an indication of a serious and biologically aggressive disease - are in most patients another important biological marker of Sézary syndrome.

The increase in AST, ALT, GGT, ALPH, and AMY and the reduction in PCHES, total proteins, and albumin, if these are not secondary to drug-induced iatrogenic toxicity, suggest hepatic involvement, which can be confirmed by the co-existence of an enlarged liver.

The criteria for histological diagnosis include:

• the presence of a polymorphic infiltrate of inflammatory cells that also includes atypical T cells (mycosis or Sézary-Lutzner cells with hyperchromic and characteristically irregular convoluted or cerebriform nuclei) in the superficial and medial dermis;
• the presence of an infiltrate that upwards characteristically reaches the base level of the epidermis, where nests of mononuclear cells may be present (Pautrier microabscesses), showing a marked level and characteristic epidermotropism.

The histomorphological report is similar in mycosis fungoides and Sézary syndrome.

Advanced states of the two diseases are associated with depression of cell-mediated immunity due to an aberrant production of cytokines by atypical T lymphocytes. Death in most cases is due to bacterial sepsis (Staphylococcus aureus, Pseudomonas aeruginosa) originating in the skin lesions themselves. The infective complications dictate the rationale of the treatment, which is effected with aimed antibiotics and a generous administration of intravenous immunoglobulins.

There are however other therapeutic approaches, the use and effectiveness of which vary in relation to the gravity of the disease. There are local forms of treatment (steroids, topical chemotherapics, total body electron beam radiation, PUVA), which are used to induce remission in patients suffering mainly from conditions affecting the skin, and systemic forms (extracorporeal photopheresis, recombinant A interferon, oral retinoids, chemotherapics in mono- or polytherapy, monoclonal antibodies conjugated to immunotoxins), which in advanced forms can be used sequentially for symptomatic purposes. In these last forms, topical treatment (e.g. PUVA) can be associated with systemic treatment (e.g. A interferon or retinoids).

PUVA treatment consists of photochemotherapy that combines psoralens (8-methoxypsoralen) administered per os with high wavelength ultraviolet rays (320-400 nm). Administration of the drug causes photosensitization of the skin because it becomes concentrated and is activated by the radiations.

Psoralens can however cause phototoxic reactions. After exposure to radiation, they are transformed into directly irritating compounds that provoke an inflammatory reaction in exposed regions, damaging the cell membranes and DNA (DNA synthesis is prevented by a covalent bond with the pyrimidinic bases). The result is the appearance of reddish or hyperpigmented patches and vesicles.

However, psoralens can also cause photoallergic reactions mediated by the immune system. The characteristic features of these reactions are cell-mediated responses to photoactivated components. Photoactivation leads to the development of a metabolite that can bind to protein carriers in the skin, forming a complete antigen and activating cells (and, in particular, Langerhans cells) that present the antigen, and migrating to the regional lymph nodes.

In the lymph nodes, the Langerhans cells, presenting the photoallergen to the T lymphocytes that express the antigen-specific receptors, cause them to activate, proliferate, and concentrate in the photoallergen’s deposition zone.

In the skin the T cells react with an inflammatory response that generally has the appearance of a drug-related reaction, with erythema and a vesiculobullous rash.

Table I presents the main distinguishing features between phototoxic reactions and photoallergic reactions.

Alterations of biological markers in relation to hepatic function may occur also following toxicity caused by psoralens, which are therefore phototoxic and photoallergic at cutaneous level and hepatotoxic. PUVA therapy is therefore absolutely contraindicated in patients with liver failure and, during treatment, hepatic function must be carefully monitored.

Conclusions

The main pathologies from which Lyell’s syndrome has to be distinguished are as follows:

• staphylococcal scalded skin syndrome
• linear immunoglobulin A bullous disease
• mycosis fungoides/Sézary syndrome (in erythrodermic exfoliative forms)