Cutaneous T cell lymphoma: update on treatment

Background Cutaneous T-cell lymphoma (CTCL) is a myeloproliferative disease with pronounced epidermotropism. The major subtypes of CTCL are mycosis fungoides and Sézary syndrome. Survival is dependent on the histological subtype and clinical stage. Early CTCL has a normal life expectancy, therefore early disease recognition and stage adapted treatment might help to ensure a good prognosis. Methods This is a review of recent advances in CTCL treatment based on literature review. Results Skin targeted therapies are useful for patch and limited plaque disease with phototherapy as the cornerstone of such treatments. More advanced disease will benefit from systemic mono- or combined treatments including drug therapy, extracorporeal photopheresis, and radiotherapy. In practice combined treatments may reduce adverse events and improve response rates. For selected younger patients, stem cell transplantation seems a third-line option. Conclusions The therapeutic spectrum for CTCL has been advanced during the last years, providing the opportunity of tailored treatment for patients.     

Variable CD7 expression on T cells in the leukemic phase of cutaneous T cell lymphoma (Sézary syndrome)

CD7, a molecule normally expressed on 90% of normal CD4+ T cells, is often deficient on the malignant T cells of cutaneous T cell lymphoma. To investigate the clinical and biologic implications of CD7 expression, blood lymphocytes from 42 patients with the leukemic phase of cutaneous T cell lymphoma (CD4/CD8 ratio of 10 or more with evidence of a T cell clone in the blood) were analyzed for level of expression of CD7 by flow cytometry. CD7 expression by cells did not clearly segregate into two distinct subgroups that are either CD7 positive or CD7 negative as generally thought; however, nine of 17 patients with a predominantly CD4+CD7+ tumor population on early studies became CD4+CD7- over time whereas the converse situation was not observed. In addition, of three patients with evidence of large tumor cells in the blood coexisting with smaller cells, discordant CD7 expression was observed in one instance. In lymph node specimens, the percentage of cells expressing CD7 and other T cell markers did not correlate with histologic evidence of involvement. CD7 expression on blood lymphocytes also did not correlate with patients' survival nor to serum IgE levels or blood eosinophil counts, a finding suggesting that this marker does not identify functional cell subsets that produce serum interleukin-4 or -5, respectively. We speculate that the level of CD7 expression on malignant T cells may be the effect of sustained antigen stimulation in vivo analogous to what has been proposed to occur with normal T cells during aging.     

Anaplastic lymphoma kinase-positive primary cutaneous anaplastic large cell lymphoma--is it a new variant?

Anaplastic large cell cutaneous lymphomas are clinically and pathologically heterogeneous, CD30 + (Ki-1) lymphoproliferative disorders. The importance of anaplastic lymphoma kinase (ALK) positivity is well known in the prognosis of primary systemic anaplastic large cell cutaneous lymphomas; however, the same in primary cutaneous anaplastic large cell cutaneous lymphomas is not much clear. Herein we report a 65-year-old male with an 18-month history of minimally pruritic localized nodulo-plaque lesion over lower back. Histology revealed cutaneous large cell lymphoma and immunohistochemical staining showed positivity for CD30, CD3 and ALK. The role of ALK positivity in pcALCL is discussed in this article.     

Cutaneous T‐cell lymphoma and atopy: is there an association?

BACKGROUND: Case reports have suggested a relationship between atopic diatheses and Sézary syndrome, pre-Sézary syndrome or mycosis fungoides. However, Sézary and pre-Sézary syndromes are rare entities, and this association has never been analysed in greater detail for specific subtypes of cutaneous T-cell lymphoma (CTCL). OBJECTIVES: To evaluate the prevalence of atopy in subjects with Sézary syndrome, pre-Sézary syndrome or mycosis fungoides, and to compare the rates with the reported prevalence of atopy in the general population. METHODS: We retrospectively reviewed the records of 157 patients with the diagnosis of Sézary or pre-Sézary syndrome seen between 1965 and 2000, and 102 patients with the diagnosis of mycosis fungoides evaluated from 1994 to 2000 at Mayo Clinic. RESULTS: Of 157 subjects with Sézary or pre-Sézary syndrome and 102 subjects with mycosis fungoides, 18 and 12, respectively, were identified as having a history of atopic dermatitis, asthma or allergic rhinitis. The prevalence rates of atopy in Sézary or pre-Sézary syndrome and mycosis fungoides were 11.5% (95% confidence interval 6.9-17.5%) and 11.8% (6.2-19.7%), respectively. CONCLUSIONS: No significant difference exists in the prevalence of atopy in Sézary or pre-Sézary syndrome compared with that in mycosis fungoides (chi2-test, P = 1.00). Furthermore, the rates of atopy in Sézary or pre-Sézary syndrome and mycosis fungoides are not significantly different from the prevalence of atopy in the general population (17-40%). On the basis of these observations, no evidence currently implicates a causal association of CTCL with atopy.     

CD56 staining in Merkel cell carcinoma and natural killer‐cell lymphoma: magic bullet,diagnostic pitfall,or both?

Background: Antibodies to CD56 label natural killer (NK) cell lymphomas and neuroendocrine tumors such as Merkel cell carcinoma (MCC). In MCC altered by crush artifact or obscured by lymphocytes, the histologic features coupled with CD56 positivity can lead to an erroneous impression of NK‐cell lymphoma. Methods: Eighteen cases of MCC were stained for CD56, CK20, MNF116, and pankeratin. The results were compared to histologic features and CD56 staining pattern of three NK‐cell lymphomas. Results: Three of 18 cases of MCC histologically resembled lymphoma, and CD56 positivity with CD3 and CD20 negativity initially raised the possibility of NK‐cell lymphoma. Two additional cases were obscured by dense inflammation, again suggesting the diagnosis of lymphoma. Seventeen of 18 MCC labeled for CD56 and an equal number stained for CK20. All MCC tested were positive for CAM5.2 (14/14) and MNF116 (17/17). Antibodies to pankeratin labeled only one of 18 MCC. Staining for CD56 was stronger in MCC than NK‐cell lymphomas. Conclusions: CD56 is a sensitive marker for MCC as well as for NK‐cell lymphoma, but is not specific. Importantly, CD56 positivity in crushed or inflamed biopsies of MCC may lead to an erroneous impression of NK lymphoma. Awareness of this potential pitfall will prevent misdiagnosis.     

Epstein-Barr virus-associated primary central nervous system lymphoma in a patient with adult T-cell leukemia / lymphoma

We present a case of Epstein-Barr virus (EBV)-associated primary central nervous system lymphoma (PCNSL) arising from a patient with cutaneous-type adult T-cell leukemia/lymphoma (ATLL). Extranodal sites affected by ATLL include the skin, lung, liver, gastrointestinal tract and central nervous system (CNS). CNS involvement usually occurs as an acute and lymphoma-type ATLL. PCNSL is a rare type of tumor and the vast majority of PCNSL are of B-cell lineage. Individuals with acquired, iatrogenic or congenital immunodeficiency are at increased risk of PCNSL, which is commonly associated with EBV. In our patient, the expression of latent infection membrane protein 1 (LMP1), EBV nuclear antigen 2 (EBNA2), and EBV-encoded small RNA (EBER) in tumor cells confirmed a type III latency of EBV infection. Human T-cell lymphotropic virus type I (HTLV-I) can induce immunodeficiency before the overt development of ATLL. The HTLV-I infection led to suppression of the immune system and the development of EBV-associated PCNSL. This is the first reported case of the clinicopathological features of EBV-associated PCNSL arising from a patient with ATLL.     

Blastic natural killer‐cell lymphoma of the skin associated with myelodysplastic syndrome or myelogenous leukaemia: a coincidence or more?

We report three patients with blastic natural killer (NK)-cell lymphoma of the skin associated with myelodysplastic syndrome (MDS) (two patients) or subacute myelomonocytic leukaemia (one patient). In two patients MDS was diagnosed before skin lesions; the patient with leukaemia initially presented with skin lesions. Our patients had several clinical features in common, namely multiple skin lesions with a bruise-like appearance, involvement of the oral mucosa, and good general status at presentation but very rapid deterioration in the course of the disease. All patients died of disease 4-14 months after the diagnosis. Histopathologically, there were cutaneous infiltrates of slightly pleomorphic medium-sized cells expressing CD4, CD56, terminal deoxynucleotidyl transferase (focally) and being negative for surface CD3, cytotoxic molecules, B-cell-associated markers and myelomonocytic markers. Erythrocyte extravasation was seen in all patients. T-cell receptor genes were in germline configuration. MDS was classified as refractory cytopenia with multilineage dysplasia and ring sideroblasts and refractory anaemia with transition to refractory anaemia with excess of blasts. We reviewed similar cases reported in the literature showing coexistence of blastic NK-cell lymphoma/leukaemia and MDS or myelogenous leukaemia. We conclude that given an overall limited number of reported cases of blastic NK-cell lymphoma/leukaemia, its association with various myelodysplastic/myeloproliferative disorders seen in a subset of patients ( approximately 15-20%) is more than coincidental and may indicate their common origin.     

Distribution and maturation of skin dendritic cell subsets in two forms of cutaneous T-cell lymphoma: mycosis fungoides and Sézary syndrome

Dendritic cells (DCs) critically regulate immune responses and the "immune-surveillance" of tumours. This study retrospectively analysed the distribution and maturation status of DC-subsets in T-cell lymphoma of the skin. Mycosis fungoides and Sézary syndrome (n = 25) were investigated immunohistochemically for DC subsets, based on C-type lectin receptor expression: Langerhans' cells (langerin/CD207+, DEC-205/CD205+), dermal DCs (DC-SIGN/CD209+, CD205+) and plasmacytoid DC (BDCA-2/CD303+). Maturation status was assessed by double-labelling for CD83 and CD208/DC-LAMP. DCs were interspersed between the neoplastic infiltrate, and a marked increase in numbers of all three subsets was noted, DC-SIGN+ dermal DCs constituting the majority. Substantial numbers of plasmacytoid DCs were consistently observed. Most DCs in epidermis and dermis were phenotypically immature. Amongst the relatively few mature DCs in the dermis, langerin+ cells predominated. There was a positive correlation between the histological intensity of the tumour infiltrate and DC numbers. It is possible that mature DCs reflect ongoing anti-tumour immune responses, and immature DCs the induction of tumour tolerance.     

Screening of differentially expressed genes and predominant expression of β variable region of T cell receptor in peripheral T cells of psoriatic patients

Psoriasis is a skin disease featuring epithelial cell hyper-proliferation and T cell infiltration. Abnormal T cell immune responses play an important role in psoriatic pathogenesis. To screen differentially expressed genes in T cells of patients with plaque psoriasis, analyze the predominant expression of the β variable region of T cell receptors and discuss the role of T cells in the pathogenesis of psoriasis. High throughput RNA sequencing and Real-time PCR were used. Results: A total of 907 genes were differentially expressed in peripheral T cells of patients with psoriasis. Among them, 695 genes were mapped to the Gene Ontology database, 14 gene terms were significantly enriched, and 418 genes were involved in signaling pathways such as apoptosis, B cell receptor signaling and T cell receptor signaling. TRBV2, TRBV5-7, TRBV6-6/6-9, TRBV12, TRBV24 and TRBV29 were significantly up-regulated in psoriatic patients compared to healthy subjects, among which, TRBV6-6/6-9, TRBV12 and TRBV29 are predominantly expressed in psoriatic patients. Many genes were differentially expressed in T cells of psoriatic patients, especially the TRBV gene family, which were predominantly expressed in T cells and might play an important role in abnormal immune responses of T cells in psoriatic patients.     

A case of intraepidermal Merkel cell carcinoma within squamous cell carcinoma in-situ: Merkel cell carcinoma in-situ?

We report a case of a 79-year-old Caucasian male who presented with a wrist lesion of combined intraepidermal Merkel cell carcinoma and squamous cell carcinoma in-situ. The two tumors were tightly admixed and distinct, and both were without any dermal or invasive components. No features of transition between the two tumors were seen. We suggest the term Merkel cell carcinoma in situ for tumors that demonstrate exclusive intraepidermal proliferation of neuroendocrine cells.     

Heavy metal (monoclonal) bands: A link between cutaneous T‐cell lymphoma and contact allergy to potassium dichromate,nickel and cobalt?

It has been proposed that chronic antigenic stimulation plays a role in the pathogenesis of cutaneous T‐cell lymphoma (CTCL). By definition, antigenic stimulation triggers allergic contact dermatitis (ACD). It is therefore plausible that chronic ACD could serve as a precursor to CTCL. We report two cases of contact allergy to potassium dichromate, nickel and cobalt, where CTCL was diagnosed in one patient, and a diagnosis of CTCL is imminent in the other. We also review the literature on the diagnostic criteria for CTCL in the setting of ACD and explore potential mechanisms for the progression from ACD tos CTCL.     

Primary cutaneous Langerhans cell sarcoma without Birbeck granules: indeterminate cell sarcoma?

An 88-year-old white male presented with a rapidly growing skin nodule on the scalp. Clinically, the nodule did not appear unusual for an ordinary cutaneous neoplasm on sun-exposed skin of an elderly white male. Histopathological examination showed sheet-like epithelioid tumor cell growth with a vaguely nested pattern and frank malignant features, resembling malignant melanoma. However, the tumor cells possessed irregularly convoluted nuclei with nuclear groves, frequent multinucleation and fine vesicular cytoplasm, features highly suggestive of histiocytes. Immunohistochemistry studies showed that the tumor cells were diffusely positive for S-100 protein and CD1a and negative for HMB-45, Melan-A, cytokeratin and CD30. The provisional diagnosis of Langerhans cell sarcoma was thus favored. To confirm this diagnosis, electron microscopic examination was performed. Although classic features of histiocytes were readily identifiable, no Birbeck granules could be found upon a thorough search on repeated sections. These results are indicative of the indeterminate cell nature of the tumor. We propose a diagnosis of primary cutaneous indeterminate cell sarcoma for this unusual histiocytic neoplasm. Current classification of histiocytic neoplasms and differential diagnosis are reviewed.