Cutaneous presentation of nasal/nasal type T/NK cell lymphoma: clinicopathological findings of four cases

Epstein–Barr virus (EBV)-associated T/natural killer (NK) cell lymphoma mainly shows nasal lesions, and has recently been shown to be associated with cutaneous T-cell lymphoma (CTCL). The detailed features of CTCL nasal metastasis have yet to be elucidated. We report clinicopathological findings for four cases of cutaneous T/NK cell lymphoma with metastasis to the nose. The four patients presented progressive involvement of nasal lesions of CTCL, an aggressive course and poor outcome. Their pathological and immunohistological findings were consistent with peripheral T/NK cell neoplasm and, in three of four cases, EBER-1 were apparently detected in lymphoma cells by in situ hybridization, and two of four cases were also positive for TIA-1. The polymerase chain reaction (PCR) results showed the identical band from the skin and nasal lesions of the two patients. We also reviewed the cases of similar clinical course and attempted to elucidate clinical, pathological, immunological and genotypic features. The 10 reported cutaneous T/NK cell lymphomas with nasal metastasis revealed a poor prognosis (nine of 10 died at 3–108 months). Six cases of nine showed a positive reaction to EBV, and six cases revealed T-cell receptor β or -γ rearrangement. These findings suggest that most cutaneous T/NK cell lymphoma with nasal metastasis are similar to nasal T-cell lymphoma associated with EBV infection. This type of cutaneous T/NK cell lymphoma likely to involve nasal lesions and skin cases seemed to have a poor prognosis.     

The role of AHI1 and CDKN1C in cutaneous T‐cell lymphoma progression

Cutaneous T‐cell lymphoma (CTCL) is the most common lymphoma of the skin. Recent reports suggest that AHI1 is overexpressed in a subset of CTCL‐derived cell lines, where it downregulates the expression of CDKN1C tumor suppressor gene. In the current work, we test the expression of these genes in 60 patients with Mycosis Fungoides and Sezary Syndrome by RT‐PCR and correlate our findings with 6 years of clinical follow‐up. These findings reveal that AHI1 and CDKN1C exhibit opposite expression patterns, where AHI1 is expressed in poor and intermediate prognosis patients, while CDKN1C is expressed in favourable prognosis patients. Kaplan–Meier analysis documents that downregulation of CDKN1C is associated with poor disease outcome in patients with CTCL, while upregulation of AHI1 shows a weak association with aggressive disease course.     

Increased CCL18 expression in patients with cutaneous T‐cell lymphoma: association with disease severity and prognosis

Background CC chemokine ligand (CCL) 18 is expressed by monocytes and dendritic cells (DCs), and has potent chemotactic activity for T cells, B cells and DCs. CCL18 expression is up‐regulated in lesional skin of atopic dermatitis and bullous pemphigoid, suggesting its important roles in the development of these skin diseases. Objective To investigate roles of CCL18 in cutaneous T‐cell lymphoma (CTCL). Methods The CCL18 messenger RNA (mRNA) expression in CTCL skin (n = 21) and in normal skin (n = 7) was examined by quantitative RT‐PCR. CCL18 expression was also examined by immunohistochemistry. Serum CCL18 levels were measured in 38 patients with CTCL and 20 healthy controls by enzyme‐linked immunosorbent assay. We also analysed correlation between serum CCL18 levels and other clinical and laboratory data. Results The CTCL lesional skin contained higher levels of CCL18 mRNA than normal skin. CCL18 was expressed by dermal macrophages and DCs in CTCL skin. Serum CCL18 levels in patients with CTCL were significantly higher than those of healthy controls and correlated with types of skin lesions. They also significantly correlated with modified severity‐weighted assessment scores, serum sIL‐2R, LDH, IL‐4, IL‐10, IL‐31, CCL17 and CCL26 levels. Patients with high serum levels of CCL18 showed significantly poor prognosis compared with those with low CCL18 levels. Conclusion CCL18 mRNA is up‐regulated in CTCL lesional skin, and serum CCL18 levels are significantly increased and correlated with the severity of CTCL. These results suggest that CCL18 may be associated with the development of CTCL.     

EXPRESSION OF CLASS II MAJOR HISTOCOMPATIBILITY ANTIGENS BY KERATINOCYTES IN CUTANEOUS T CELL LYMPHOMA

Background. Expression of various class II MHC antigens by lesional keratinocytes may play an important role in the pathophysiology of a wide variety of human dermatoses including cutaneous T cell lymphoma (CTCL). Nevertheless, there is relatively little information available concerning the concurrent expression of HLA-DR, -DP, and -DO class II MHC antigens in CTCL. Therefore, our aim in this study was to determine the prevalence, localization, extent, temporal sequence, and consistency of class II MHC antigen expression by lesional keratinocytes in CTCL. Methods. We used a semiquantitative immunohistologic analysis to analyze HLA-DR, -DP, and -DO. expression by lesional keratinocytes in 66 skin biopsies obtained from 39 patients with CTCL. Results. Class II MHC antigen expression by keratinocytes was observed in 77% of cases. Expression was detected on the cytoplasmic membrane and within the cytoplasm. It varied among cases from focal to confluent. There was a hierarchy of antigen expression in terms of both extent and time course. HLA-DR was expressed first and most extensively, followed by HLA-DP and then HLA-DQ. Comparative studies of multiple serial or concurrent active lesions from 13 cases indicated that the overall pattern and extent of antigen expression was relatively constant within individual patients. Conclusions. There was no apparent correlation between class II MHC antigen expression and the clinical stage of disease, the type of CTCL skin lesion, or the overall density of the lesional T cell infiltrate. The hierarchy of keratinocyte class II MHC antigen expression observed in this study paralleled that noted in earlier studies of cultured keratinocytes exposed to recombinant interferon-γin vitro. This suggests that lesional cytokine levels may be the critical factor governing class II MHC antigen expression by lesional keratinocytes in CTCL.     

Head and neck squamous cell carcinoma skin metastases below of the diaphragm

Cutaneous metastases from carcinoma are relatively uncommon in clinical practice. Metastasis to skin sites from squamous cell carcinoma of the mucosa of the head and neck are also very rare. However, skin metastases may be the first clinical evidence of the malignant disease or its loco-regional recurrence. Early recognition of skin metastasis can lead to an accurate and prompt diagnosis and timely treatment. Patients with skin metastases have very poor prognosis. We report on four such patients, one of them with multiple skin metastases from the squamous cell carcinoma in the cervical part of the esophagus above and below the level of the diaphragm. In reviewing the literature, only two cases of solitary skin metastases below the diaphragm from laryngeal squamous cell carcinomas have been reported     

Fulminant Cutaneous T-cell Lymphoma and Sézary Syndrome

The term cutaneous T-cell lymphoma (CTCL) has recently been coined to describe a group of rare lymphoproliferative T-cell disorders classically beginning in the skin and pursuing a chronic, progressive, and indolent course eventually followed by visceral involvement. This term encompasses the spectrum of the traditional mycosis fungoides and Sézary syndrome. A unique case of CTCL that developed a fulminant course leading to death within a few months following the initial symptoms is presented. The clinical course bears a striking similarity to a group of acute T-cell malignancies, while the cytologic-pathologic findings favor the diagnosis of Sézary syndrome. Regardless of the exact classifications, this entity appears to be a highly malignant T-cell disorder, resistant to chemotherapy.     

Angiogenin levels are increased in lesional skin and sera in patients with erythrodermic cutaneous T cell lymphoma

Angiogenin is a member of the ribonuclease superfamily that is associated with the angiogenic process. Angiogenesis is regarded as an important step to support primary and metastatic tumor growth. In cutaneous T cell lymphoma (CTCL), angiogenesis in lesional skin is increased, suggesting that interaction between tumor cells and their microvasculature are likely to occur during progression of CTCL. Patients with hematological malignancies show increased serum angiogenin levels, which are related with poor overall survival. To investigate possible roles of angiogenin in development of CTCL, we measured serum angiogenin levels in 36 patients with CTCL and 21 healthy controls by enzyme-linked immunosorbent assay. We also investigated angiogenin mRNA and protein expression in lesional skin of CTCL by quantitative RT-PCR and immunohistochemistry. Serum angiogenin levels in patients with CTCL were significantly higher than those in healthy controls. When classified with types of skin lesions, serum angiogenin levels were elevated only in erythrodermic CTCL patients. Angiogenin mRNA expression levels in lesional skin were significantly elevated in erythrodermic CTCL compared to normal skin. Immunohistochemical study revealed that angiogenin was expressed by keratinocytes, endothelial cells, and infiltrating lymphocytes in CTCL. Our results suggest that enhanced angiogenin expression may be related with a poor prognosis of erythrodermic CTCL. As angiogenin acts as an inhibitor of polymorphonuclear leukocyte degranulation, angiogenin may also be linked to impaired host defense in erythrodermic CTCL.     

Cutaneous histopathology of Sézary syndrome: a study of 41 cases with a proven circulating T-cell clone

Sézary syndrome is an uncommon variant of cutaneous T-cell lymphoma (CTCL) characterized by erythroderma, pruritus, adenopathy, and circulating atypical T-lymphocytes with cerebriform nuclei. The definition of Sézary syndrome can be further refined by including only patients with a circulating peripheral blood population of clonal T-cells. We have evaluated 79 skin biopsies from such a group of 41 erythrodermic patients with circulating Sézary cells and a clonal population of T-cells detected by T-cell receptor-figene rearrangement on Southern analysis of peripheral blood mononuclear cells. Histopathologic features consistent with chronic dermatitis were observed in 26/79 (33%) skin biopsy specimens, emphasizing that a non-specific histologic appearance is common. Evidence of CTCL was lacking in 11/41 patients on biopsy of their erythrodermic skin. The survival of these patients was not significantly different from 30/41 patients in whom skin biopsies revealed changes diagnostic of CTCL, such as a dermal lymphocytic band with atypical lymphocytes (18/79, 23%) or a mycosis fungoides-like infiltrate (30/79, 38%). This study confirms that non-specific cutaneous hlstopathologic findings are common in Sézary syndrome, even when a circulating T-cell clone is present. This stresses the need for peripheral blood genetic analysis and for multiple or repeat skin biopsies in erythrodermic patients when there is high clinical suspicion of CTCL.     

Serum soluble CD26 levels: diagnostic efficiency for atopic dermatitis,cutaneous T‐cell lymphoma and psoriasis in combination with serum thymus and activation‐regulated chemokine levels

Background CD26 is a multifunctional type II transmembrane glycoprotein, which also exists as a secreted isoform, soluble CD26 (sCD26). The CD26 expression on circulating T cells is decreased in some skin diseases such as cutaneous T‐cell lymphoma (CTCL) and psoriasis. It remains to be determined whether sCD26 can be used as a marker of skin diseases or not. Objective To investigate utility of sCD26 as a diagnostic marker of skin diseases in combination with thymus and activation‐regulated chemokine (TARC). Methods Serum sCD26 levels were measured using enzyme‐linked immunosorbent assay in 130 participants including 32 patients with atopic dermatitis (AD); 45 patients with CTCL; 26 patients with psoriasis; and 27 healthy controls. Results Serum sCD26 levels in patients with CTCL and psoriasis (162.1 ± 80.2 ng/mL and 125.4 ± 82.1 ng/mL respectively) were significantly lower than those of healthy controls (392.6 ± 198.7 ng/mL; P < 0.01 and 0.01 respectively). In patients with CTCL, serum sCD26 levels of patients with advanced stage were 135.0 ± 51.5 ng/mL and they were significantly lower than those with early stage (193.1 ± 96.0 ng/mL; P < 0.05). When we used serum sCD26 and TARC levels for diagnostic criteria, sensitivity, specificity, positive predictive value and negative predictive value for AD, CTCL and psoriasis were 65.2–73.7%, 81.4–97.6%, 65.2–94.4%, and 81.4–88.9% respectively. Conclusion Serum sCD26 levels, combined with serum TARC levels, are helpful in diagnosis of AD, CTCL and psoriasis.     

Monitoring the decrease of circulating malignant T cells in cutaneous T-cell lymphoma during photopheresis and interferon therapy

BACKGROUND: The prognosis of patients with stage IV cutaneous T-cell lymphoma (CTCL) is grim and therapeutic options are limited. Treatment of advanced-stage CTCL is aimed at suppressing the dominant T-cell clone, which is typically present in the skin, peripheral blood, and lymph nodes. OBSERVATIONS: We detected the expansion of 1 T-cell clone expressing the T-cell receptor V beta 14 in the peripheral blood of a patient with stage IVA CTCL. Before initiation of combination therapy with photopheresis and low-dose interferon alpha, the dominant T-cell clone represented 84% of the total T-cell population. After successful therapy, this clone showed a dramatic decrease to 6% of the T-cell population after 6 months of treatment. This reduction in the percentage of the malignant T-cell population in response to therapy was paralleled by clinical skin improvement from initial generalized erythroderma to undetectable skin disease. CONCLUSIONS: This case demonstrates that response to combination treatment with photopheresis and low-dose interferon alpha in patients with advanced CTCL may be accurately and quantitatively followed up by monitoring the percentage of the malignant T-cell clone (when identifiable) within the total circulating T-cell population by flow cytometry.     

Overall survival in erythrodermic cutaneous T-cell lymphoma: an analysis of prognostic factors in a cohort of patients with erythrodermic cutaneous T-cell lymphoma

Background The most common cutaneous T‐cell lymphomas (CTCLs) are mycosis fungoides and Sézary syndrome. Aim To determine whether blood stage and other prognostic variables affect overall survival (OS) in CTCL. Methods We studied retrospectively 1197 CTCL patients seen at the M.D. Anderson Cancer Center since 1987. Results We identified 124 (10.3%) patients with erythrodermic CTCL (E‐CTCL), 63% of whom had positive gene rearrangements in skin and 19 of whom had no evidence of hematologic involvement. The median age at diagnosis was 63 years (range, 26–90 years); the male to female ratio was 1.3 : 1. OS curves were estimated by the Kaplan–Meier method and compared using log‐rank tests. The median OS in all 124 E‐CTCL patients was 5.1 years (range, 0.4–18.6 years) regardless of the cause of death or blood involvement. Patients were stratified by the H0–H4 staging system with manual or flow cytometric determination of Sézary cell counts (Russell‐Jones R, Whittaker SJ. Sézary syndrome: diagnostic criteria and therapeutic options. Semin Cutan Med Surg 2000; 19 : 100–108). The median OS was 7.6 years for H0–H2 (< 1000 Sézary cells/L) (n = 23), 5.4 years for H3 (≥ 1000 to ≤ 10,000 Sézary cells/L) (n = 79), and 2.4 years for H4 (≥ 10,000 Sézary cells/L) (n = 22) (P = 0.011). Treatment with systemic steroids, age, serum lactate dehydrogenase, and white blood cell count ≥ 20,000 µL were significant prognostic factors, but large cell transformation, T‐cell receptor gene rearrangement, tumor–node–metastasis stage, treatments, and CD4 : CD8 ratio were not. In multivariate analysis, advanced age and elevated lactate dehydrogenase were the strongest predictors of a poor prognosis. Conclusions Serum LDH and age were the strongest predictive factors for OS in E‐CTCL.     

Molecular staging of lymph nodes from 60 patients with mycosis fungoides and Sézary syndrome: correlation with histopathology and outcome suggests prognostic relevance in mycosis fungoides

BACKGROUND: Histological evidence of lymph node involvement is associated with a poor prognosis in patients with cutaneous T-cell lymphoma (CTCL). OBJECTIVES: To determine whether T-cell receptor (TCR) gene analysis is of prognostic relevance in CTCL. METHODS: TCR gene analysis was performed on lymph node specimens from 60 patients with mycosis fungoides (MF) and Sézary syndrome (SS) using a highly sensitive polymerase chain reaction (PCR)/single-strand conformational polymorphism analysis and results were correlated with skin, overall clinical and histological lymph node stages. RESULTS: The frequency with which a T-cell clone was detected in lymph node samples from patients with MF increased with skin stage, overall clinical stage and with the degree of histological involvement: six of 19 patients with uninvolved lymph nodes or limited histological involvement (LN0-2) and 13 of 14 patients with advanced histological involvement (LN3-4) had a detectable T-cell clone. In SS, 22 of 27 patients had a detectable lymph node T-cell clone. The clonal patients had a poorer prognosis than nonclonal patients (median survival from biopsy of > 72 months vs. 16 months for MF and 41.5 vs. 16.5 months for SS). Regression analysis confirmed that TCR gene analysis identifies a group of MF patients with a worse prognosis (P = 0.013). However, the molecular lymph node stage did not provide independent prognostic information in this cohort of patients in multivariate analysis. CONCLUSIONS: Molecular staging in MF and SS using a PCR-based method for TCR gene analysis provides additional information to histological examination. Specifically, this study identified a group of MF patients with early lymph node involvement with a poorer prognosis. However, a larger prospective study of patients with MF and early histological lymph node involvement is required to confirm whether molecular staging of lymph nodes provides independent prognostic information in a multivariate model.     

Genotraumatic T cells and cutaneous T-cell lymphoma. A causal relationship?

Mycosis fungoides, or cutaneous T-cell lymphoma (CTCL), is a T-cell mediated chronic inflammatory skin disease, which can occasionally progress with a variable time course to a fatal lymphoma or to a leukaemic form called Sézary's syndrome. Extensive research into CTCL has not yet elucidated the primary pathophysiological mechanisms. Immunohistological studies are so far less helpful than expected in establishing early diagnosis and prognosis of the disease. The proposition that an exogenous virus is the cause of CTCL has not been substantiated. Karyotypic analysis of lymphocytes from the skin and blood of patients with CTCL have shown the existence of several genetically aberrant T-cell clones in the same patient. These changes are discussed as potential primary events for the development of CTCL. The hypothesis is put forward that the development of genotraumatic T lymphocytes is involved in the progression of the disease.     

Staging and management of cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma (CTCL) accounts for two-thirds of cases of primary cutaneous lymphoma. Most variants of CTCL are indolent lymphoma, the most common being mycosis fungoides. In addition, Sézary syndrome, the leukaemic variant, has an aggressive clinical course. Accurate diagnosis and staging is critical in determining the prognosis of those with CTCL. The tumour, node, metastasis and blood stage needs to be documented and used to determine an overall stage from IA to IVB. Management of patients should be carried out by a multidisciplinary team. A full clinical examination should be made at all visits. Thorough investigations are needed at diagnosis and should be repeated during disease progression to allow initial staging and restaging. Treatment of patients with early-stage disease (IA-IIB) should be limited to skin-directed therapy. More advanced or resistant disease may be treated with systemic therapies such as extracorporeal photopheresis, immunotherapy, monoclonal antibody therapy, novel retinoids or chemotherapy, and where possible, patients should be entered into clinical trials.     

Nasal and nasal type CD56+ natural killer cell/T-cell lymphoma: a case with rapid progression to bone marrow involvement

We describe herein a case of CD56+ natural killer cell lymphoma (NKCL) that showed unusual clinical manifestations and a fulminant course of disease. A 70-year-old male patient presented with rapidly growing skin lesions and fever; a nasal lymphoma was subsequently detected and bone marrow involvement developed within a few weeks. Although the time relationship is not clear, bone marrow involvement could be dissemination from localized disease of nasal and nasal type NKCL. As seen in our case, the course can be excessively aggressive and fulminant even when it first appeared as a localized disease, and CD56 positivity, which is a specific characteristic of NKCL, may serve as a factor showing a poor prognosis for a malignant lymphoma.     

DENSITOMETRY OF PAUTRIER'S MICROABSCESS CELLS IN CUTANEOUS T CELL LYMPHOMA

Background. Epidermotropic lymphoid T cell infiltrates are part of a continuous spectrum of lesions ranging from “benign” parapsoriasis to frank cutaneous T cell lymphoma (CTCL, mycosis fungoides). Either the clinical or histologic differentiation between these entities prove often difficult and the prognosis may be difficult to assess. Patients and Methods. We studied 15 patients, men aged 50 to 81 years, mean ± SD 68 ± 12 years, with patch-plaque CTCL. Sections from punch biopsies from active lesions were stained with Feulgen reagent, coupled with a “twin” adjacent hematoxylin and eosin (H&E)-stained section and analyzed with a VIDAS Zeiss-Kontron Image Analyzer. At least 50 dermal infiltrating cells and 50 epidermotropic Pautrierian cells per specimen were counted and the biopsies were repeated periodically. Results. Nine patients with aneuploid Pautrierian cell DNA patterns did well after conventional phototherapy (dermal cell ploidy was irrelevant), whereas six patients with euploid Pautrierian cell DNA patterns had to be treated aggressively (IFN + retinoids, COP). Clinical and histopathologic aspects of the first group were comparable to those of the second group. Conclusions. The classical cytophotometric aphorism seems to be reversed in this sample: “The more abnormal the ploidy of epidermotropic Pautrierian cells, the better the prognosis.” Euploid epidermotropic cell prove more efficient in invading the skin and other areas and this efficiency may be reflected in more aggressive trends in the evolution of the lymphoma. Thus, DSM analysis of epidermotropic cells could prove very useful as an inexpensive tool for routine CTCL grading.     

T‐cell receptor gene rearrangement analysis of sequential biopsies in cutaneous T‐cell lymphomas with the Biomed‐2 PCR reveals transient T‐cell clones in addition to the tumor clone

Detection of a dominant T‐cell clone by T‐cell receptor (TCR) gene rearrangement analysis is often essential for the diagnosis of cutaneous T‐cell lymphomas (CTCL). The occurrence of T‐cell clones in addition to the diagnostic T‐cell clone during the course of CTCL has been reported, but the data of these studies have been contradictory. We retrospectively evaluated the data of 114 lesional skin biopsies from 26 patients with Mycosis fungoides and two patients with primary cutaneous anaplastic large cell lymphoma, which were analysed with the standardized Biomed‐2 PCR for the TCRγ and TCRβ locus. A dominant T‐cell clone was repetitively detected in 93% (26/28) of patients. Additional T‐cell clones appeared temporarily in 39% (11/28) of patients. Correlation with the clinical data did not show an association of the presence of additional T‐cell clones with age, number of treatments, progression of disease or survival. Our findings demonstrate that a persistent T‐cell clone, most likely the disease causing tumor clone, is detectable in almost all CTCL patients. In addition, transiently appearing T‐cell clones frequently occur during the course of disease. The biological relevance of these additional clones has still to be determined. However, it is important to take the possibility of additional T‐cell clones into account for diagnostic analyses.     

Hürthle cell adenoma of the thyroglossal duct fistula

A 41-year-old man noted the presence of a punched-out ulcer on the anterior midline of the neck. There was no previous history of trauma or radiation to the head and neck region. Physical examination showed a draining sinus surrounded by a cribriform scar on the anterior midline of the neck ( Fig. 1 ). There was no adenopathy in the neck. The head and neck were otherwise normal, as were T3 and T4, routine blood and urine tests, and chest X-rays. Thyroid scan was performed which demonstrated normal uptake and normal location of the thyroid gland. Computed tomographic scan showed a 2.5×1.0×1.0-cm-sized ovoid, hypodense cystic mass extending to the cricoid cartilage. Because there was doubt as to the extent of the fistulous tract and its ramifications, a roentgen study of the tract after injection of a contrast medium was performed. The fistulogram showed that the injected contrast medium was observed at the base of the tongue through a faintly opacified thread-like fistulous tract from the skin.

Figure 1 Open in figure viewer PowerPoint Punched-out ulcer surrounded by cribriform scar on the anterior midline of the neck     

Cutaneous T-cell lymphoma

Cutaneous T-cell lymphoma (CTCL) is a neoplasm of helper T cells whose first manifestations usually appear in the skin. The various forms of CTCL are distinguished by both clinical features and histopathology. Early on, the diagnosis may be difficult to establish because of its numerous, and often non-specific, clinical presentations. Further, the pathological findings of early lesions may lack the diagnostic features observed in well-developed or advanced disease. The diagnosis of CTCL must be considered in any patient with a chronic, therapy-resistant condition of the skin. In patients with non-specific histological findings, a high index of suspicion and multiple biopsies may eventually lead to a diagnosis of CTCL. Once the diagnosis of CTCL is established, accurate staging is essential both for its effect on treatment decisions and for its prognostic value. In general, CTCL is a chronic, slowly progressive disease with a long evolution. The development of tumours is a poor prognostic sign, as is erythroderma. The Sezary syndrome is a distinct form of erythrodermic CTCL that is characterized by exfoliative erythroderma, lymphadenopathy, lymphocytosis, intense pruritus, and circulating large, abnormal lymphocytes (Sezary cells). When death does occur, it is most often due to septicemia. Treatment of CTCL must be tailored to the individual patient. The most commonly employed treatment options are photochemotherapy and topical chemotherapy.