Lymphomatoid papulosis. Development into cutaneous T-cell lymphoma

Lymphomatoid papulosis is usually considered to have a benign course, but many reports of subsequent evolution into systemic lymphoma have been reported. By measuring single-cell DNA content by flow cytometry, it may be possible to predict those cases that have the potential for the development of a malignant neoplasm. Two cases that differ from classic benign lymphomatoid papulosis had a more "malignant" clinical picture, with nodules and tumors, and the finding of aneuploidy (abnormal DNA content) from several skin lesion specimens and also from a lymph node specimen in one of the cases. Clinically evident malignant neoplasms have not yet developed in the two patients, but we suggest that the finding of aneuploidy predicts those cases that later could become malignant.     

Lymphomatoid papulosis: an update and review

Lymphomatoid papulosis (LyP) is a benign chronic often relapsing skin condition that belongs to the CD30-positive cutaneous lymphoproliferative disorders. LyP typically presents as crops of lesions with a tendency to self-resolve, and morphology can range from solitary to agminated or diffuse papules and plaques to nodules or tumours. The clinical–histological spectrum can range from borderline cases to overlap with primary cutaneous anaplastic cell lymphoma (pcALCL). Histology and immunophenotype commonly show overlap with other CD30-positive disorders and sometimes may be identical to pcALCL, making its diagnosis more difficult. Patients with LyP have an increased risk of developing a second neoplasm such as mycosis fungoides, pcALCL and/or Hodgkin lymphoma. Clinical correlation allows its proper classification and diagnosis, which is fundamental for treatment and prognosis. This review focuses on the clinical appearance, histopathological features, diagnosis, differential diagnosis and management of LyP.     

Lymphomatoid papulosis and FK 506

A 53-year-old woman underwent an orthotopic liver transplant in Pittsburgh in October 1990. She had been suffering from chronic hepatitis C that had evolved into cirrhosis with ascites, jaundice, and encephalopathy. In April 1991 she required reconstruction of the biliary anastomosis because of stricture, and in October 1991 she underwent a liver biopsy because of mild elevation of alkaline phosphatase. The biopsy revealed mild chronic rejection and changes consistent with viral hepatitis. She was on oral FK 506, 4 mg b.i.d. In November 1992 she developed recurrent self-healing erythematous, papulonodular lesions on the chest and shoulders (Pig. 1). The lesions were purplish red, mildly pruritic, and undergoing vesiculation on the top. The lesions ranged from 3 to 5 mm in size, and a few showed ulceration and necrosis and were healing with hypopigmented scars. The lesions gradually increased in number and size. A trephine biopsy specimen was obtained from the lesional skin. The tissue was prepared for light microscopic study by fixing in 10% formaldehyde solution and staining with hematoxylin and eosin. Immunohistochemistry was carried out for lymphoid markers. In February 1993, a papulonodular lesion near the left axilla enlarged to a size of 10 × 10 cm; it was ulcerated and necrotic. A biopsy was taken and sent for histopathology and immunohistochemistry. The patient continued on FK 506, 4 mg b.i.d. Many of the early lesions had become purpuric, eroded, and healed with scarring; however, fresh lesions continued to appear. A decision about modification of the patient's immunosuppressive medication was left to the Transplant Team; however, there was concern that her lymphomatoid papulosis may be a side-effect of her PK 506 treatment. Laboratory investigation revealed a normal peripheral blood film. Liver enzymes and a renal profile were within normal limits. The results of a bone marrow study, liver and spleen scan, and endoscopic examination of the gastrointestinal tract were normal. A skin biopsy revealed a nodular and wedge-shaped dermal infiltrate involving the entire dermis. The pleomorphic epidermotropic infiltrate in the upper one-third of the dermis was composed of many round or oval cells with hyperchromatic nuclei. A few nuclei were indented or kidney shaped. Mild mitotic activity was seen. The larger immunoblast-like cells were mixed with normal lymphoctyes and histiocytes. The capillaries had thickened walls with prominent endothelial cells. The second biopsy from the ulcerated axillary lesion showed a dense superficial and deep wedge-shaped infiltrate, abnormal pleomorphic cells, and a few large lymphoid cells (Fig. 2) infiltrating the dermis and extending to the subcutaneous tissue. There were scanty histiocytes, neutrophils, and a few eosinophils. Some of the large abnormal cells had kidney shaped nuclei but most had irregularly shaped nuclei with abundant cytoplasm (Fig. 3). There were many abnormal mitoses, and there were also numerous extravasated red blood cells and edema in the dermis. The epidermis was necrotic and ulcerated. The results of immunohistochemical tests showed a strong reaction for LCA and CD8, but a negative reaction for CD20. The patient's general condition and laboratory tests of hepatic and renal functions remained normal. The results of all hematologic studies, including bone marrow smear, lymph node biopsy, and liver-spleen scan, were normal. The patient continued on FK 506, 4 mg b.i.d. Serum levels of FK 506 which were never communicated to us were sent for the first time in May 1993 and showed a serum level of 39 ng/mL (normal 0.5–2 ng/mL)¹ with an instruction to repeat the test. The dose of FK 506 was immediately reduced to 4 mg/day. The patient revisited the clinic for routine check-up on June 26, 1993. The axillary lesion had disappeared leaving a hyperpigmented scar, the small lesions of lymphatoid papulosis continued to come and go.     

Lymphomatoid papulosis: a follow-up study

A follow-up study has been performed on 16 patients with lymphomatoid papulosis diagnosed at the Finsen Institute during the years 1970-81. In none of the patients did malignant lymphoma develop during the observation period (7 months to 22 years). During this period the nature of the lesions and the tendency to recurrence were unchanged in 11 patients, spontaneous remission took place in 4, and 1 patient went into complete remission after PUVA treatment (8-methoxsalen followed by UVA). The histological material (32 punch biopsies) could be divided into two major groups diagnosed as either typical (16 biopsies) or consistent with lymphomatoid papulosis (16 biopsies). Based on our present knowledge, we suggest the following classification of lymphomatoid papulosis: 1) "classical" lymphomatoid papulosis, 2) lymphomatoid papulosis associated with parapsoriasis en plaque or mycosis fungoides and 3) primary cutaneous T-cell lymphoma.     

Lymphomatoid papulosis: a cutaneous T-cell pseudolymphoma

It was the purpose of this study to further define the nature of the dermal infiltrates in lymphomatoid papulosis (LP) means of enzyme cytochemistry (acid phosphatase and esterase), immunology (rosetting techniques, immunoperoxidase technique on cryostat sections), and by semithin and ultrathin sections. The studies performed on biopsy samples with clinically and histologically typical LP indicated that most lymphoid cells display markers for T-lymphocytes, which were helper T-cells in the one case studied with monoclonal antibodies. Regarding the typical benign self-involutive clinical course, LP is considered to be a cutaneous pseudolymphoma of T-cell type.     

Lymphomatoid papulosis expresses immunophenotypes associated with T cell lymphoma but not inflammation

Twelve skin biopsy specimens of lymphomatoid papulosis from nine patients were studied immunohistologically. The large atypical cells morphologically resembled Reed-Sternberg cells in six cases and large cerebriform mononuclear cells in three cases. These cells expressed pan-T cell antigens (Leu-4 and/or Leu-5) and helper T cell antigen (Leu-3) in each case. They also expressed activation antigens: HLA (human lymphocyte antigen)-DR, HLA-DQ, Tac, and T9. Reactivity of many nuclei with Ki-67 indicated a high proliferative index. Phenotypic abnormality of the large atypical cells was evident by their deficiency of T cell antigens Leu-1 and/or Leu-9 in eight of nine cases. Neither Ki-1 nor Leu-M1 were reliable markers for lymphomatoid papulosis in this series, since large atypical cells were Ki-1-positive in only three of eight cases and were Leu-M1-negative in all eight cases tested. The remainder of the cutaneous infiltrate consisted of small T cells, macrophages, Langerhans cells, and granulocytes. The small T cells expressed a normal phenotype except in some cases associated with mycosis fungoides in which they were deficient in various T cell antigens. Comparison of concurrent lymphomatoid papulosis and mycosis fungoides skin biopsy specimens in two patients revealed that they were composed of phenotypically distinct T cell subpopulations. These results indicate that the large atypical cells of lymphomatoid papulosis are a proliferating population of activated helper T cells that are deficient in certain T cell antigens. Such abnormal T cell phenotypes are common in T cell lymphoma but are rarely, if ever, observed in cutaneous inflammation. In conjunction with the cytologic atypia, aneuploidy, and association with other lymphomas documented in this or previous reports, these data suggest that lymphomatoid papulosis represents a T cell lymphoproliferative disorder rather than an inflammatory disorder.     

Lymphomatoid papulosis terminating as cutaneous T cell lymphoma (mycosis fungoides)

The 26-year-course of a T cell dysplasia is described in a patient who during his illness showed an evolution from the clinical features of lymphomatoid papulosis to tumor-stage mycosis fungoides with dissemination to nodes and viscera.     

Lymphomatoid papulosis: remission following intravenously administered acyclovir

In a 54-year-old male patient suffering from Hodgkin's disease, lymphomatoid papulosis occurred. Complete clearing of the skin lesions was observed immediately after intravenously administered acyclovir. The patient had numerous relapses of his skin eruption with complete responses after each course of intravenously applied acyclovir. This striking therapeutic effect parallels reports of regression of mycosis fungoides and chronic generalized lymphadenopathy after acyclovir application. The mode of action of acyclovir in these disorders is not known. They all are characterized by involvement of the T cell system, and in all these diseases, a virus etiology has been proved or is suggested. Thus, a specific effect of acyclovir on T lymphocytes or selectively on helper T cells is discussed. Alternatively, the virustatic effect of acyclovir could be responsible for the therapeutic success.     

Lymphomatoid papulosis: a study of 18 cases*

Lymphomatoid papulosis (LyP) is a cutaneous eruption that is clinically benign but histologically malignant. To date, more than 300 cases have been published. About 10–20% of the patients develop a lymphoma. The purpose of this study was to make a clinicopathological study of 18 patients diagnosed with LyP in our hospital from 1973 to 1990, to characterize cellular infiltrates in the lesions, to find clonal populations of T-cells and to look for predictive factors of malignant lymphoma in LyP patients. Mean age was 48.7 years. The most frequent clinical lesions were papules (88.8%) followed by plaques (38.8%). The localizations were on extremities (100%), trunk (88%), face (22%), palms or soles (11%), perigenital (11%) and scalp (5%). Two patients have been free of disease for more than 5 years. IgA levels are increased in LyP patients. Neither HTLV I nor III can be considered as a cause of the LyP in any of our patients. Associated diseases were found in 6 cases (1 mycosis fungoides, 1 Hodgkin's disease, 2 anaplastic large-cell lymphoma and 2 large plaque parapsoriasis). Some types of parapsoriasis should be included in the ‘spectrum of Ki-1 lymphomas’. 52 skin biopsies were studied. 17% were type A of Willemze, 67% were type B and 15% were transitional. In 12 of the samples follicular or perifollicular infiltration was found. Follicular LyP should not be considered as a distinct type of LyP. Vasculitis is an uncommon finding in LyP. In all the cases studied, large atypical cells were CD30 +; 5/7 cases had lost CD5 and 4/5 cases had lost CD7. In one case, all T-cell antigens were negative. Cerebriform mononuclear cells were always recognized by T-cell antibodies and they were CD30 positive in only two cases. In one case there were more CD8 + than CD4 + cells. In 5 patients skin and blood samples for genetic rearrangement (beta-T) were taken. Only germinal line was found. We did not find any significant difference between those cases in which malignant lymphoma developed and those in which it did not.