Granulomatous mycosis fungoides

ARTICLE

Granulomatous mycosis fungoides (GMF) was described for the first time in 1970 by Ackerman and Flaxman [1, 2]. Histological examination is caracterized by an intense granulomatous inflammatory reaction with epithelioid and large giant cells, together with a cutaneous lymphomatous proliferation.

Since then, 25 cases have been published, mostly consisting of single cases [3-12] but there are also two series of 4 and 10 cases respectively [13, 14].

Case report

T... Edmond, 60 years old, was referred to our department in January 1994 for cutaneous lesions that had been developing for 3 months.

In October 1993, non-pruritic, erythematous scaly plaques on the right arm progressively involved the trunk and left arm. The initial histology evoked the diagnosis of a drug reaction because of a lymphohistiocytic perivascular dermal infiltrate including mast-cells, necrozed eosinophilic keratinocytes and inflammatory cells in exocytosis. He was receiving at that time, chlorpropamide for diabetes mellitus, pravastatine for hypercholesterolemy, nifedipine-atenolol and sodium iodoheparinate as a result of a myocardial infarction in 1989, and omeprazol for gastritis. However, stopping treatment with chlorpropamide, sodium iodoheparinate, pravastatine and omeprazol, and replacing them with metformine, fenofibrate and ranitidine did not improve the cutaneous symptoms. So in December 1993, a second biopsy was performed on an erythematous scaly plaque on the trunk. The observation of cytonuclear atypia, led to the diagnosis of cutaneous hemopathy.

In January 1994, when the patient was examined for the first time in our department. He showed a rash consisting of large, erythemato-violaceous, annular plaques, which were scaly in places, non-infiltrated, non-pruritic and that were present at the base of the neck, the proximal part of the upper limbs and on the trunk. There was no superficial lymphadenopathy and no hepatosplenomegaly. Histological examination of a third skin biopsy from the left arm, showed a lichenified, mononuclear infiltrate of the reticular dermis which associated lymphocytes containing hyperchromatic nuclei without cytonuclear atypia, and large histiocytic cells resembling Langerhans cells. In the papillary dermis, the mononuclear infiltrate was perivascular. Immunophenotyping on deparaffined sections was non-specific for MF.

In April 1994, he was hospitalized for an aggravation of his cutaneous condition. We then observed infiltration of the previously mentioned plaques and several papulo-nodules, which were violaceous in the center and erythematous at the periphery, and situated in the axillae and on the neck (Fig. 1). There was still no pruritis. Clinical examination did not reveal any superficial lymphadenopathy or hepatosplenomegaly.

A fourth biopsy was performed on an axillary nodule. Microscopic examination (Figs. 2 and 3) revealed a dense and diffuse infiltrate, extending from the papillary dermis to the hypodermis, made up of mononuclear cells (lymphocytes, plasmocytes and some larger cells with nucleocytoplasmic atypia) with an associated epithelioid granulomatous reaction, which was tuberculoid in places (giant Langerhans-type cells) and denser in the lower parts. There was a frank epidermotropism of the mononuclear infiltrate.

Immunohistochemical phenotyping of frozen sections showed a predominantly monotypic lymphocytic population: HLA-DR II⁺, CD2⁺, CD3⁺, CD4⁺, CD5⁺, CD7⁺, CD8^­, which was intensely epidermotropic in places (Fig. 4). The phenotype of the multinucleated giant cells was CD68⁺, consistent with their histiocytic origin.

The diagnosis of granulomatous mycosis fungoides was thus made.

No circulating Sezary cells were found. The myelogram and the thoraco-abdominal CT scan were normal.

Immunological tests gave the following results: lymphopenia in the peripheral blood of 910/mm³ (CD4 528/mm³, CD8 164/mm³, CD4/CD8 ratio 3.22, CD4-CD45RA 64/mm³, CD4-CDw29 446/mm³); normal serum protein electrophoresis and serum globulins, IgE 201/mm³; negative serology for HIV1, HIV2 and HTLV1.

In May 1994, we started total body electrontherapy excluding the head, hands and feet, administering a total dose of 22 Grays during a course of 27 sessions. In September 1994, the cutaneous lesions had totally disappeared. It was decided to perform bath PUVA therapy (initial dose of 0.3 Joules, then increasing by 0.2 Joules every 2 sessions to a maximum dose of 2 Joules). Blood tests showed that lymphopenia (981/mm³) was still present, with a decrease in CD4 and CD8, but an increase in the CD4/CD8 ratio. Another thoraco-abdominal CT scan showed no changes apart from hepatic steatosis. No circulating Sezary-cells were detected.

After 43 bath PUVA therapy sessions, with a total dose of 69 Joules, the patient was still in remission. Unfortunately, he was lost to follow up in April 1995.

Discussion

The granulomatous form of MF was described in 1970 by Ackerman [1]. The observation of cutaneous epithelioid granulomas during MF had already been reported by Pautrier in 1935 [15] and Atwood in 1966 [16] but was then interpreted as an association of sarcoidosis and lymphoma.

GMF is a rare form of MF. Only 26 cases, summarized in Table I, have been published since 1970 [3-14]. Its frequency compared with classical MF has not been assessed. Recently, Wechsler et al. found 12 cases of cutaneous lymphoma with a predominant granulomatous reaction, among 353 cutaneous lymphoma reviewed. Two of these granulomatous cutaneous lymphomas were MF [17]. We noted a male predominance with a sex-ratio of 2.4, similar to that observed in classical MF (2.2) [18]. The mean age at the time of diagnosis was 51.2 years (18 to 87 years), 30% of the patients were less than 40 years old, compared to 12% for MF in general [18].

Usually, the clinical presentation does not differ from classical MF. A few case presented papulonodular lesions which were lupoid on vitropression, suggesting cutaneous sarcoids [8, 11].

In our patient, we noted a complete absence of pruritis.

Cutaneous histological examination demonstrates the characteristic features of GMF, because it shows a lymphomatous infiltrate associated with an inflammatory granuloma. The type and intensity of the granulomatous reaction do not correlate with the clinical lesions or with a progressive stage. The histological features most often reported are those of histiocytes and giant cells scattered in a lymphomatous infiltrate. Sometimes, there is the appearance of true sarcoid epithelioid granuloma [4, 9, 16] or more rarely tuberculoid granuloma [8, 10, 12]. In 5 cases [3, 10, 14], the granulomatous reaction histologically resembled an annular granuloma (AG).

The granulomatous appearance of cutaneous lymphoma is usually seen from the onset when MF is first diagnosed. In 2 cases resembling AG [3, 10], the granulomatous reaction appeared secondarily.

The diagnostic delay (9 years on average) testifies to the difficulty in diagnosing MF in its granulomatous form. In GMF, the granulomatous reaction which masks the lymphomatous proliferation, may also point to the diagnosis of different granulomatous inflammatory dermatoses. Repeat biopsy, as in our case and in those of Mainguène [9] and Schwartz [4], together with immunophenotying and molecular biology techniques are sometimes necessary to show up the tumoral component.

Immunophenotyping was performed in 6 cases including our own [8-10, 12]. In all of the cases, CD4⁺ T cells were displayed, and in one case, loss of CD7 antigen was observed [9]. The expression of the CDw29 antigen, a marker of the memory T helper phenotype, which is usually present in cutaneous T cell lymphoma [19], was sought and was present in only one case [10].

In two cases, immunophenotyping allowed the diagnosis of MF to be made [9, 10].

The diagnostic importance of molecular biology is less obvious. A study of gene rearrangement in the TCR beta-chain was performed on skin lymphocytes in 4 cases [8, 10, 12]. This was able to demonstrate a cutaneous monoclonal population in only 1 case [12].

As for the treatment of GMF, it is not different from that recommended for classical MF.

The finding of granulomas in MF raises the problem of differentiation between the other granulomatous dermatoses.

The main differential diagnosis, for the pathologist is sarcoidosis. This was the diagnosis initially made in 4 patients [4, 9, 16]. Nevertheless, the clinical presentation is rarely in favour of sarcoidosis. Tuberculosis was the initial diagnosis made in only one case [10]. AG is sometimes suggested histologically, but is rapidly eliminated because the clinical presentation is inconsistent with this diagnosis. Granulomatous slack skin disease (GSS) is a slowly progressing cutaneous T cell lymphoma whose clinical presentation is very characteristic, with bulky pendulous axilar and inguinal skin folds [14, 20]. Leboit et al. [14] emphasized the histological similarities between GMF and GSS, the latter associating a clonal T helper epidermotropic proliferation with a dense dermo-hypodermal granulomatous infiltrate, that destroys the elastic tissue.

Although the presence of a granulomatous reaction is a good prognostic factor for Hodgkin's disease [21], the prognosis of GMF is assessed differently by the authors. Ackerman [2] sees the granulomatous reaction as a defense mechanism, and so considers it as a good prognostic sign. Analysis of the latter cases to be published, does not show GMF to have a better prognosis than classical MF [12, 13]. Twelve patients died from tumoral involvement an average of 6.8 years after the diagnosis was made (survival in MF is 7.8 to 9.7 years in the larger series [18]). The mean follow up time for the 13 survivors was 7.2 years.

In our case, although the condition progressed very favorably initially, follow-up was too short to give a good indication of the true prognosis.

Some authors [14] have attempted to explain the prolonged survival of certain cases of GMF: the presence of a florid reaction with lymphophagocytosis and of mononuclear cells surrounding multinucleated giant cells, would appear to be histological criteria for a good prognosis.

The pathogenesis of GMF as the one of granulomas seen in other lymphomas such as Hodgkin's disease [22, 23], is unknown.

The hypothesis of an association of sarcoidosis with a cutaneous lymphoma has been considered [16, 24, 25].

The hypothesis of a granulomatous type of immune reaction induced by tumoral proliferation is more attractive. The CD4-lymphocyte plays a crucial role in the formation of granulomas and in the recruitment of macrophages [26]. The cytokines involved are not definitely known: IL-2, IFN-gamma, TNF-alpha and 1-25(OH)D3 seem to be important in this phenomenon [26]. Also, some authors have recently demonstrated that in MF, the CD4 lymphocytes show a Th1 phenotypic picture, this being the phenotype involved in cell-mediated immune reactions, through production of IL-2 and IFN-gamma [27, 28].

The presence in certain cases of cutaneous [14] or extra-cutaneous [5] granulomas without any associated lymphomatous proliferation, may signify that this granulomatous reaction is sometimes enough to destroy the malignant clone, or perhaps that the immune reaction is a systemic process.

On the other hand, this may also suggest that the granulomas precede and cause the lymphomatous proliferation, supporting the hypothesis of a causative association between sarcoidosis (or other type of granulomatosis) and lymphoma. Macrophage cytokines, including IL-6, may then promote the lymphomatous proliferation [29].

GMF may be a special etiological form of MF, or a type of MF that develops under immunological circumstances that remain to be defined.

REFERENCES

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