Scleromyxedematous changes in a patient with long-standing mycosis fungoides who progressed to Sézary syndrome

Abstract

Mycosis fungoides (MF) variants with different clinicopathologic and immunohistochemical features have been well-delineated. We report a case of scleromyxedematous changes arising in a patient with long-standing MF who progressed to Sézary syndrome (SS) shortly afterwards. Total skin electron beam (TSEB) radiation therapy resulted in an excellent response, controlling both the MF/SS and the scleromyxedematous lesions; however, the patient expired few months later. Although mucin deposition has been described in association with MF/SS [mainly follicular mucinosis in folliculotropic MF], there are limited reports in the literature on dermal mucinosis and scleromyxedematous changes in MF/SS. The mechanism of this association and its prognostic implications require further investigation.

Introduction

Mycosis fungoides (MF) lesions classically appear in non-sun-exposed sites, slowly progress in a stepwise fashion through patch, plaque and tumor stages¹ and may evolve to Sézary syndrome (SS). Diagnostic criteria for SS include: erythroderma, high blood tumor burden and a circulating T-cell receptor (TCR) clone identical to skin. High blood burden (stage B2) is defined as absolute Sézary cell count of at least 1000 cells/microL or one of the following two criteria: increased CD4 to CD8 ratio of 10 or more, increased CD4+ cells with an abnormal phenotype (CD4+CD7- ratio ≥40% or CD4+CD26- ratio ≥30% of total lymphocytes).^2,3

MF variants with different clinicopathologic and immunohistochemical characteristics have been well-delineated. Folliculotropic MF (FMF), granulomatous slack skin and pagetoid reticulosis are the major variants recognized by the WHO/EORTC classification of cutaneous lymphoma.^4,5 Many less well characterized clinical and pathologic variants exist, such as poikilodermatous and hypopigmented MF.⁶ Scleromyxedematous changes including histologic features of fibroblast proliferation, increased collagen and diffuse deposition of papillary and mid-reticular mucin⁷ have been rarely described in MF. We report an uncommon case of scleromyxedematous MF and discuss a possible pathogenetic link between the neoplastic lymphocytic and proliferative/depositional mucinous phenomena.

Case report

A 79-year-old male patient was followed in the cutaneous lymphoma clinic for four years after initial diagnosis with MF, clinical stage IB. The patient first presented with numerous pink papules and plaques on bilateral flanks, back, arms, shoulder, lower legs and buttocks. A shave biopsy performed at that time showed a dense band-like infiltrate of atypical lymphocytes (Fig. 1A, B). On immunohistochemical studies, most lymphocytes were CD3 positive and showed diminution of CD7 expression with a CD4 to CD8 ratio of 10:1 (Fig. 2). The Ki-67 proliferation index was 40%. The histologic and immunohistochemical findings were consistent with a plaque lesion of MF. The patient was initially treated with topical corticosteroids and topical nitrogen mustard. Oral Bexarotene was added later to achieve satisfactory disease control. Two and a half years after presentation, he developed bilateral, symmetric skin lichenification on his back, neck and axilla which gradually progressed to diffuse cutaneous thickening with skin furrowing and a cobblestone-like appearance (Fig. 3A).

Fig. 1.

Initial mycosis fungoides plaque, histopathology. (A) Low power view of a dense, band-like infiltrate of atypical lymphocytes. (B) High power magnification of atypical lymphocytes with focal areas of epidermotropism.

Fig. 2.

Initial mycosis fungoides plaque, immunohistochemical stains. Lymphocytes are positive for CD3+, CD4+ and CD8+ with a CD4:CD8 ratio of 10:1 (bottom right and left panels). There is dimuntion of CD7 expression (top right).

Fig. 3.

Scleromyxedematous changes, clinical presentation. (A) Skin thickening presenting as cobblestone-like appearance of the neck, with deep furrows involving the neck, mid-back and scapular areas. (B) Clustered pink shiny papillomatous papules on the right retroauricular area.

The patient returned to our clinic for a routine follow-up visit at that time and complained primarily of new papules involving the retro-auricular areas that were associated with a foul-smelling discharge. Physical examination revealed densely clustered shiny pink papillomatous papules on the retro-auricular areas bilaterally (Fig. 3B). The skin on the neck, back, upper chest and axillary folds was diffusely thickened. A few erythematous flat plaques on the trunk and extremities were present, clinically compatible with stable MF. A skin biopsy of the new retro-auricular papular rash showed an atypical lichenoid lymphoid infiltrate involving a papillomatous squamous proliferation with areas of epidermotropism (Fig. 4A–C). The Alcian blue stain (pH 2.5) and periodic acid Schiff (PAS) special stain preparations were positive, confirming the presence of significant increased mucin and fibroblasts (Fig. 4D). Atypical lymphocytes throughout the dermis were positive for CD3, CD4 and PD-1 with marked diminution of CD7 (90%). The Ki-67 proliferation index was at least 50% (Fig. 5). The CD4:CD8 ratio was >15:1. TIA-1 labeled scattered lymphocytes. CD25 and CD56 were mostly negative. EBER-ISH was negative. The pathologic diagnosis was cutaneous T-cell lymphoma, associated with scleromyxedematous changes. Molecular studies were performed; monoclonal rearrangements involving the TCR-beta and TCR-gamma genes were detected which were similar to those present in previous skin biopsies. Following these findings, additional blood work was performed. Immunoglobulin levels were normal and no monoclonal protein spike was seen on serum protein electrophoresis. Free T4 was slightly low, however, values were within normal range on a prior test 3.5 months earlier. Following this result, the levothyroxine dose was increased and T4 levels returned to normal. Three months later, the patient returned to the clinic complaining of intractable pruritus despite multiple anti-pruritic medications. Examination revealed diffuse plaques and scaling of his soles. Restaging of his blood showed new leukocytosis (16,000 cells/mcL) with 3,800 Sezary cells/mcL confirmed by flow cytometry study (CD4:8 ratio 23.4, CD4+CD7– 90.5%, CD4+CD26– 93.9%) and circulating TCR clonality that matched the clone in the skin. The patient was diagnosed with MF/SS. Romidepsin was initiated but the patient tolerated this treatment poorly. Subsequently, total skin electron beam (TSEB) radiation therapy was administered with excellent response in the blood and skin. He declined further systemic therapy. Several months after TSEB, the patient expired due to sepsis.

Fig. 4.

Scleromyxedematous changes, histologic sections of the right ear. (A) Hematoxylin & eosin, 100x. Atypical lymphoid infiltrate and dermal mucin involving a papillomatous proliferation. (B) Hematoxylin & eosin, 400x. Interface between dense atypical lymphoid infiltrate and mucinosis in the dermis with scattered mast cells and thickened collagen fibers. (C) Hematoxylin & eosin, 400x. Dermal mucinosis and associated fibroblasts. (D) PAS-H stain, 400x. Increased dermal mucin with dot-like mucin granules.

Fig. 5.

Scleromyxedematous changes, immunohistochemical stains of the right ear biopsy. The atypical lymphoid cells are positive for CD3 with diminution of CD7 (top right), with a CD4:8 ratio of approximately 10:1 (bottom right and left panels).

Discussion

Mucin deposition has been described in association with MF/SS, mainly follicular mucinosis in FMF.⁸ FMF cases frequently show mucinous degeneration of hair follicles, that may range from intercellular spaces expanded by mucin deposition to mucin lakes compressing epithelium with follicular rupture. In a series of 38 FMF patients, follicular mucinosis was seen in 87%.⁹ Prominent epidermal mucinosis in a spongiotic epidermis can be seen in MF and may cause difficulty in diagnosis. One study confirmed the presence of epidermal mucinosis in 30 MF cases using colloidal iron staining and showed that dermal mucin was largely proportional to the degree of epidermal mucinosis. Papillary dermal fibrosis was also seen in these cases.¹⁰ Increased dermal mucin deposition was observed in some cases of interstitial MF, a variant resembling granuloma annulare and inflammatory morphea.¹¹

Epidermal and connective tissue mucin can be detected by different pH preparations of Alcian blue and PAS. Epithelial acid mucins (sialated and sulfated) can be detected with Alcian blue at pH 2.5. Sulfated epithelial acid mucins can be detected with Alcian blue at pH 0.5 and 2.5. Myxoid material or stromal mucin and acid-complex connective tissue mucins are positive for Alcian blue, but negative for PAS. In a study of 31 patients with follicular mucinosis (both CTCL-associated and idiopathic cases), the type of mucin filling the follicles was reported to be consisted of dermal-type mucin (Alcian blue positive, PAS negative) and not epithelial-type mucin.¹² Dermal-type mucin with similar staining properties was also reported in MF with epidermal mucinosis.¹⁰ In our patient, mucin was positive for both alcian blue pH 2.5 and PAS stains suggesting epithelial-type mucin. Alcian blue pH 0.5 was not available in our lab, precluding optimal assessment of mucin type.

Scleromyxedema is a rare and distinctive variant of cutaneous mucinosis¹³ and its diagnosis is based upon the recognition of the following clinicopathologic criteria: generalized/diffuse papular and sclerodermoid eruption; microscopic triad, including mucin deposition, fibrosis and irregularly arranged fibroblast proliferation; monoclonal gammopathy and absence of thyroid disorder.^14–16 Paraneoplastic scleromyxedema has been seen with neoplastic diseases including advanced gastric cancer¹⁷ and thymic carcinoma.¹⁸ Scleromyxedema has been described in non-Hodgkin lymphoma and in patients with other hematological malignancies.¹⁹ Our case did not meet the criteria of scleromyxedema and we believe that the clinicopathologic scelromyxedematous changes were associated with the MF. The scleromyxedematous changes could conceivably be a paraneoplastic phenomenon in our patient who progressed to SS within months of his presentation, and could, by extension, portend an impending aggressive clinical course in MF/SS; however, the study of additional cases would be needed to address this issue. We identified only a single similar report of extensive dermal fibrosis and mucin deposition in a 62-year-old man with MF.²⁰

We considered the possibility that the scleromyxedematous features in our patient were related to bexarotene induced hypothyroidism, however we believe this is less likely as the lichenification and thickening of his skin were noticed before this treatment was initiated. Furthermore, in the year prior to the biopsy of the retro-auricular mucinous papule, the patient’s free T4 levels in the blood were within normal limits. Following this biopsy, we did identify that free T4 levels were slightly decreased, however the correction of the thyroid hormone level didn’t improve the scleromyxedematous clinical changes.

In scleromyxedema, mucin and fibroblasts have been hypothesized to accumulate after stimulation by circulating cytokines such as interleukin (IL)-1, TNF-alpha, and TGF-beta.⁷ Proposed mechanisms behind mucin accumulation in the hair follicle have been postulated, focusing on keratinocytes as the source of mucopolysaccharides. It has been postulated that cytokines released from perifollicular T-lymphocytes might stimulate follicular keratinocytes to secrete hyaluronate.^21,22 A study by Kaya and colleagues observed no difference in CD44 expression, currently thought to be the principal cell-surface receptor for hyaluronate, in follicular keratinocytes of follicular mucinosis cases.²¹ The mechanism of scleromyxedematous changes, immunologic properties and its role in MF cases requires further study. A plausible cause of scleromyxedema in MF/SS could be the cytokine milieu associated with the malignant T-cells²³ and activation of fibroblast and keratinocytes by the increased production of cytokines, as was suggested in follicular mucinosis in FMF. Considering this, in our case, the success of total skin electron beam (TSEB) radiotherapy (RT) might have been not only due to treatment of the MF, but also due to suppression of fibroblast proliferation or mucin production by the anti-inflammatory effect of the RT, or by the induction of apoptosis in fibroblasts.²³ Successful use of TSEB in scleromyxedema has been anecdotally reported in the literature.^24–27

Our case is remarkable for the unusual juxtaposition of MF/SS and scleromyxedematous changes with deposition of epithelial-type mucin. This case underscores the importance of tissue biopsy and histopathologic evaluation of unusual cutaneous presentations in patients with a history of MF. It highlights that MF/SS patients may present with scleromyxedematous changes, however the exact underlying mechanism of this possible association and its prognostic meaning are yet to be determined.