ABSTRACT: Primary cutaneous CD30+ T-cell lymphoproliferative disorders (PCLPDs) are the second most common type of cutaneous T-cell lymphoma. These disorders comprise a spectrum of clinically benign lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large-cell lymphoma (ALCL). The peak incidence of LyP is in the 5th decade of life, and the incidence of primary cutaneous ALCL peaks in the 6th decade, but children are also affected. Both LyP and primary cutaneous ALCL have an excellent prognosis. However, LyP is associated with development of malignant lymphoma (mycosis fungoides, Hodgkin lymphoma, or ALCL) in 20% of cases, and also with an increased risk of non-lymphoid cancers. The diagnosis of LyP is difficult and often delayed. Primary cutaneous ALCL must be distinguished from secondary skin lesions in systemic ALCL, which confer a poor prognosis. Correlation of clinical findings with histopathology and immunopathology (stains for ALK kinase, epithelial membrane antigen, and cutaneous lymphocyte antigen) are important to achieve a correct diagnosis. When a diagnosis of CD30+ PCLPD is established, minimal clinical staging is required. Low-dose methotrexate(Drug information on methotrexate) (10–25 mg weekly) is the most effective therapy for PCLPD but is usually reserved for aggressive cases of LyP and multifocal lesions of cutaneous ALCL. Many patients with LyP can be followed expectantly, with special attention to changes in character of the skin lesions or development of lymphadenopathy. Patients with localized cutaneous ALCL can be treated with irradiation. Extracutaneous spread of disease is an indication for multiagent chemotherapy. Other treatment alternatives are discussed.
CD30-positive primary cutaneous T-cell lymphoproliferative disorders (CD30+ PCLPDs) comprise a spectrum of closely related disorders—lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large-cell lymphoma (ALCL) (Figure 1). LyP patients have clinically benign self-healing skin papules and/or nodules that have the unexpected histopathology of a high-grade malignant lymphoma. Primary cutaneous ALCL also has the histology of a high-grade lymphoma, but only 25% of lesions regress spontaneously. Because of their histologic appearance and frequent recurrence, patients with CD30+ PCLPD may be treated unnecessarily with multiagent chemotherapy. However, the prognosis for these patients is excellent. Disease-specific survival of LyP patients at 5 years is 100%, and overall survival at 5 years is 92%.[2,3] The disease-specific survival rate for primary cutaneous ALCL patients at 5 years is 85% to 90%.[2,3]
Oncologists should become familiar with these disorders to avoid overly zealous therapy. The purpose of this review is to familiarize oncologists with the clinical and pathologic features of this relatively rare disease spectrum. This should enable appropriate clinical management and reassurance of patients concerned about their prognosis.
LyP is often not diagnosed correctly upon presentation; it is common for symptoms to persist for 1 to 3 years before a correct diagnosis is established. A variety of diagnoses may be entertained, most commonly insect, spider, or mosquito bite. This is likely due to the common occurrence of bites with associated erythema and central necrosis, and the fact that most patients and many clinicians are unfamiliar with LyP. Indeed, LyP is more readily recognized by dermatologists trained in academic medical centers. Oncologists are unlikely to encounter LyP or PCLPD unless consulted for chemotherapy, staging, or prognosis of the disease.
Tumor cells in both LyP and primary cutaneous ALCL are derived from activated T-cells that express CD30 antigen. The CD30+ cells are larger than normal lymphocytes and have basophilic cytoplasm and large nuclei with a prominent nucleolus, resembling immunoblasts. These cells are often bi- or multinucleated, giving the appearance of Reed-Sternberg cells. Mitoses are frequent and often atypical. In LyP, tumor cells are scattered throughout the upper dermis and surrounded by small lymphocytes, neutrophils, and eosinophils. In primary cutaneous ALCL, tumor cells form large clusters or sheets that generally extend from the dermal-epidermal junction down into the subcutaneous fatty tissue. Thus the distinction of LyP from ALCL largely depends on the density of CD30+ tumor cells and the extent of dermal and subcutaneous involvement.
The frequency of LyP in male children poses an interesting differential diagnosis with pityriasis lichenoides et variolaformis acuta (PLEVA). PLEVA can present with similar cutaneous lesions but has a different prognostic significance. In particular, there is no increased risk of developing lymphoma among patients with PLEVA, while the risk of lymphoma in LyP patients approaches 20%.[3,4] PLEVA is more common in children and young adults than in older patients, so the most difficult differential diagnosis is in the age group under 30 years old.
Skin lesions in PLEVA tend to be hemorrhagic papules, whereas LyP lesions vary from papules to small nodules, often with central whitening and ulceration due to accumulation of neutrophils in the epidermis. On histology, LyP shows more frequent large bizarre cells including bi- or multinucleated cells with basophilic cytoplasm; these cells are CD30+. Such cells are infrequent or absent in PLEVA. Necrosis of individual keratinocytes (Civatte or colloid bodies) are common in PLEVA but absent in LyP. Further, immunopathology reveals a predominance of CD4+ lymphocytes in LyP but mostly CD8+ lymphocytes in PLEVA.
Nodular scabies is also in the differential diagnosis of LyP, particularly in children. Scabies also includes CD30+ cells. It is found in the inguinal and genital areas, which can be affected in LyP. In scabies, the CD30+ cells coexpress B-cell antigens, whereas CD30+ cells in LyP express T-cell antigens.
Distinction From Systemic ALCL
Oncologists need to be aware of the distinction of CD30+ PCLPD from secondary skin lesions in patients with nodal/systemic ALCL (Table 1). Skin is the most common extranodal site of disease in nodal/systemic ALCL, and skin lesions confer an increased risk of treatment failure in childhood ALCL. When skin lesions are a presenting manifestation of nodal/systemic ALCL, the distinction from CD30+ PCLPD is imperative.
The distinction of skin lesions in systemic ALCL from CD30+ PCLPD can be difficult on purely clinical grounds and may also be difficult to achieve by routine histopathology. One of the most helpful approaches is to test the tumor cells for expression of the ALK protein. This is expressed in skin lesions of most patients with nodal/systemic ALCL but not in the large majority of patients with CD30+ PCLPD. Rare exceptions occur, and in such cases a panel of immunologic markers is recommended. Epithelial membrane antigen (EMA) is expressed on tumor cells in 82% of nodal/systemic ALCL but < 5% of CD30+ PCLPD. Cutaneous lymphocyte antigen (CLA) also is more frequently expressed in CD30+ PCLPD (44%) than on tumor cells in nodal/systemic ALCL (18%). Thus, a successful immunopathologic distinction of CD30+ PCLPD from nodal/systemic ALCL can be made in most cases.
When a diagnosis of CD30+ PCLPD is established, minimal clinical staging is required. Bone marrow involvement is rare and thus bone marrow biopsy is not indicated. Lymph node involvement is uncommon and, when it occurs, does not appear to portend a poor prognosis. In my experience, peripheral lymph nodes draining areas with numerous skin lesions are the most common sites of involvement. Often this is minimal microscopic involvement with tumor cells confined to lymph node sinuses and not effacing lymph node architecture. This may be detected by immunohistochemical staining for CD30, which in combination with morphology, can reveal microscopic disease. Thoracic or abdominal lymphadenopathy is uncommon and usually occurs only as a late manifestation of disease. This is usually preceded by persistent enlarged skin tumors and accompanied by systemic symptoms (eg, fever, sweats, and weight loss). In such cases, treatment with multiagent chemotherapy and/or biologics is needed.
Although CD30+ PCLPDs are rare, all races, ages, and both genders are affected. The prevalence of CD30+ PCLPD in the United States is unknown, but an LyP patient support group includes 850 members, indicating a prevalence approaching 3 per million. Most European studies show a male predominance, whereas our US registry has a nearly equal number of males and females. The peak age incidence of LyP appears to be in the 5th decade. However, children are also affected. In our registry, females exceed males in the group over 19 years old, whereas males exceed females in the group under 20. This could be due to biased reporting of cases by women and mothers of children with LyP. Primary cutaneous ALCL has a peak incidence after age 50 but can also affect children and young adults.
CD30 signaling is known to have an effect on the growth and survival of lymphoid cells. CD30 transcription is controlled by a genetically determined polymorphic promoter. In a study published in 2005, colleagues from Western Australia and I analyzed CD30 promoter microsatellite alleles in 32 unrelated Caucasian patients diagnosed with LyP alone or LyP plus lymphoma, as well as 8 unrelated Caucasian patients with CD30+ primary cutaneous ALCL. Controls were 57 Caucasian healthy volunteers and patients with nonlymphoid malignancies. Patients and controls were gender-matched. We determined that two allelic forms of the CD30 promoter microsatellite repressive element, designated 30M377 and 30M362, are associated with the development of lymphomatoid papulosis and CD30+ lymphomas in lymphomatoid papulosis patients, respectively. These findings suggest that allele-specific differences in the control of CD30 transcription may affect the pathogenesis of the spectrum of CD30+ cutaneous lymphoproliferative disorders.
In a study from Beth Israel Deaconess Medical Center and Harvard, we reported 35 cases of LyP beginning in childhood. These patients had a significantly higher prevalence of atopy (relative risk [RR] = 3.1; 95% confidence interval [CI] = 2.2–4.3). Compared with the general population, patients with childhood-onset LyP had a significantly increased risk of developing non-Hodgkin lymphoma (RR = 226.2; 95% CI = 73.4–697.0). Fletcher and coauthors also reported an association of CD30+ PCLPD with atopic eczema beginning in childhood. Three patients had primary cutaneous ALCL, of whom two developed systemic disease and one died. A fourth patient developed LyP type A, which resolved after withdrawal of cyclosporine therapy. We conclude that LyP presents similarly in children and adults, including the risk to develop lymphoma, and that all patients should be closely monitored for the development of lymphoma throughout their lives.
The interferon regulatory factor-4 (IFR4) gene is overexpressed in multiple myeloma and some B-cell lymphomas. IFR4 translocations occur in multiple myeloma and some B-cell lymphomas. Recently, recurrent translocations involving the IFR4 locus have been reported in 8 of 14 primary cutaneous ALCLs, indicating a role for IFR4 in the pathogenesis of primary cutaneous ALCL.