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Was Treatment the Trigger? Mycosis Fungoides

Published:September 30, 2013DOI:https://doi.org/10.1016/j.amjmed.2013.08.007

      Presentation

      Might a thiazide diuretic spur cutaneous lymphoma in certain vulnerable patients? That was the question when the diagnosis was determined for a 56-year-old Caucasian woman with a nonpruritic, erythematous area on her right hip. The lesion had been slowly increasing in size for 5 months. Two years earlier, the patient had undergone bilateral mastectomy and chemotherapy for breast cancer. She also had been recently diagnosed with primary hypercalciuria, which had been stable for the previous 7 months due to a regimen of hydrochlorothiazide, 12.5 mg daily. In addition, she used vitamin D and calcium supplements. A review of symptoms was otherwise unremarkable.

      Assessment

      The patient's physical examination was notable only for a nonpruritic, erythematous, well-demarcated patch on the right hip (Figure 1). Her history of malignancy, combined with the odd location of the lesion, indicated that a punch biopsy was necessary. Pathology revealed a focal infiltrate composed predominantly of small- to medium-sized T cells suggestive of mycosis fungoides (Figure 2). Follow-up polymerase chain reaction testing showed clonal rearrangement of the T-cell receptor gamma gene, confirming the diagnosis. Computed tomography scans were negative for infiltrative disease.
      Figure thumbnail gr1
      Figure 1A nonpruritic, erythematous, well-demarcated patch was located on the patient's right hip.
      Figure thumbnail gr2
      Figure 2A band-like upper dermal lymphoid infiltration consisting of mature lymphocytes and slightly larger atypical lymphocytes was evident in the pathology sample. Epidermotropism was present with an accumulation of atypical lymphocytes at the basal layer. These features are consistent with mycosis fungoides.

      Diagnosis

      Our patient had mycosis fungoides, a T-cell non-Hodgkin lymphoma that manifests in the skin but has the potential for metastasis. Staging is based on extent and type of skin involvement and presence of extracutaneous disease. Our patient had stage IA disease, which is categorized by limited patch or plaque involvement. Patients with IA disease have a 16% risk for progression to more advanced disease, but there are no known predictive factors.
      • Kim Y.H.
      • Liu H.L.
      • Mraz-Gernhard M.
      • Varghese A.
      • Hoppe R.T.
      Long-term outcome of 525 patients with mycosis fungoides and Sézary syndrome.
      Mycosis fungoides and Sézary syndrome are the most common cutaneous T-cell lymphomas. These are hypothesized to arise from a clonal expansion of memory T-cells exposed to chronic antigen stimulation.
      • Tan R.S.
      • Butterworth C.M.
      • McLaughlin H.
      • Malka S.
      • Samman P.D.
      Mycosis fungoides—a disease of antigen persistence.
      While many different antigens, including Staphylococcus aureus, the dermatophytes responsible for tinea infections, cytomegalovirus, and Epstein-Barr virus have been proposed, no single antigen has been definitively identified; this implies that the provocative antigen most probably differs between patients.
      • Jackow C.M.
      • Cather J.C.
      • Hearne V.
      • Asano A.T.
      • Musser J.M.
      • Duvic M.
      Association of erythrodermic cutaneous T-cell lymphoma, superantigen-positive Staphylococcus aureus, and oligoclonal T-cell receptor V beta gene expansion.
      • Herne K.L.
      • Talpur R.
      • Breuer-McHam J.
      • Champlin R.
      • Duvic M.
      Cytomegalovirus seropositivity is significantly associated with mycosis fungoides and Sézary syndrome.
      A recently-released study suggests that hydrochlorothiazide might be an inciting agent in some patients with cutaneous T-cell lymphomas.
      • Jahan-Tigh R.R.
      • Huen A.O.
      • Lee G.L.
      • Pozadzides J.V.
      • Liu P.
      Hydrochlorothiazide and cutaneous T cell lymphoma: prospective analysis and case series.
      In a prospective analysis of patients diagnosed with cutaneous T-cell lymphomas between 1987 and 2011, researchers found that 14.2% of the subjects were on hydrochlorothiazide. Consider that in the general population, the predicted incidence of people aged 45 years and older taking hydrochlorothiazide is only 10.3%.

      Mitchell AA. Patterns of Medication Use in the United States, 2005: A Report from the Slone Survey. Boston University Web site. Available at www.bu.edu/slone/SloneSurvey/AnnualRpt/SloneSurveyWebReport2005.pdf. Accessed May 15, 2013.

      Among patients with cutaneous T-cell lymphoma who also were being treated with hydrochlorothiazide, 63.8% either started taking the drug prior to developing disease or had a noticeable worsening in the severity of their disease upon starting it; 28.8% of these patients experienced complete or partial remission upon discontinuing the medication.
      • Jahan-Tigh R.R.
      • Huen A.O.
      • Lee G.L.
      • Pozadzides J.V.
      • Liu P.
      Hydrochlorothiazide and cutaneous T cell lymphoma: prospective analysis and case series.
      Three patients who were in complete or partial remission had a relapse of mycosis fungoides after an accidental rechallenge with the drug. Of patients who started taking hydrochlorothiazide prior to occurrence of cutaneous T-cell lymphomas, 28% began treatment within the same year that signs and symptoms arose.
      Hydrochlorothiazide is already known to cause a variety of reactions, including lichenoid dermatitis, acute generalized exanthematous pustulosis, photoallergic eruptions, and allergic vasculitis.
      • Ruscin J.M.
      • Page II, R.L.
      • Scott J.
      Hydrochlorothiazide-induced angioedema in a patient allergic to sulfonamide antibiotics: evidence from a case report and a review of the literature.
      • Atzori L.
      • Pinna A.L.
      • Ferreli C.
      • Aste N.
      Pityriasis rosea-like adverse reaction: review of the literature and experience of an Italian drug-surveillance center.
      • Pétavy-Catala C.
      • Martin L.
      • Fontès V.
      • Lorette G.
      • Vaillant L.
      Hydrochlorothiazide-induced acute generalized exanthematous pustulosis.
      • Burckhardt W.
      • Sutter T.
      Photoallergic drug exanthema caused by hydrochlorothiazide.
      • Grunwald M.H.
      • Halevy S.
      • Livni E.
      Allergic vasculitis induced by hydrochlorothiazide: confirmation by mast cell degranulation test.
      It is therefore not unreasonable to suspect that in genetically-susceptible patients, the drug could be the source of chronic antigen stimulation of memory T-cells, driving the immune system towards the development of cutaneous T-cell lymphoma.

      Management

      After discussing the case with multiple consultants, we decided that the patient should be treated with topical clobetasol propionate cream, 0.05%. She also stopped taking hydrochlorothiazide. Three months later, her rash decreased in both intensity and size.
      While the exact mechanism of disease is unknown in our patient, the time between starting hydrochlorothiazide and the appearance of the skin lesion raises the possibility that the agent played a role. This case stresses the importance of biopsy when patients with a history of malignancy present with suspicious lesions. It also underscores the role that medications can have in provoking lymphomatous processes.

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