Primary cutaneous acral CD8 positive T‐cell lymphoma with extra‐cutaneous involvement: A long‐standing case with an unexpected progression

Primary cutaneous acral CD8+ T‐cell lymphoma (acral CD8+ TCL) is a new provisional entity characterized by acral skin lesions and an indolent course. We describe an extraordinary case characterized by relapsed nodules with CD8+ cytotoxic infiltrates on the left ear. After 35 years, the skin lesions spread to other acral sites, and a mass with the same histological features as the other skin lesions appeared on the nose. Multiple courses of chemotherapy led to stable disease. Histological examinations carried out at different times showed the gradual transformation of the neoplastic cells, with an increased proliferation index. Genomic analysis revealed losses in the regions harboring the genes involved in cell cycle control. This is the first case of an acral CD8+ TCL with a very long history of indolent nodular lesions progressing to extra‐cutaneous sites.     

Extrafacial indolent CD8‐positive cutaneous lymphoid proliferation with unusual symmetrical presentation involving both feet

Indolent CD8+ cutaneous lymphoid proliferation represents a recently described entity among cutaneous T‐cell lymphomas that typically presents with solitary skin lesions on the face or at acral sites and usually follows an indolent clinical course. Histopathologically, this entity is characterized by a dense dermal infiltrate of non‐epidermotropic, small‐ to medium‐sized pleomorphic CD8+ T‐cells of the non‐activated cytotoxic phenotype showing a clear‐cut grenz zone and a low proliferation index. Distinction from otherwise aggressive T‐cell lymphomas bearing a cytotoxic CD8+ phenotype is fundamental. We herein present an unusual case of indolent CD8+ cutaneous lymphoid proliferation presenting in bilateral symmetrical distribution on both feet and lacking the otherwise described grenz zone. Our case widens the spectrum of possible clinical and histomorphological variations of this entity. Taking into account the distinctive and unique clinical and microscopic features of all hitherto published cases of indolent CD8+ cutaneous lymphoid proliferation we suppose that this lymphoma subtype has to be included as a new and distinct entity in the World Health Organisation (WHO)‐/European Organisation for Research and Treatment of Cancer (EORTC)‐classification of cutaneous lymphomas.     

Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma with a CD15(+)CD30(-) phenotype

Primary cutaneous aggressive epidermotropic CD8(+) T-cell lymphoma (CD8(+)TCL) is an extremely rare entity with distinct clinicopathological features. While the CD15 antigen is typically associated with classic Hodgkin's lymphoma, aggressive peripheral T-cell lymphomas, including advanced stage cutaneous T-cell lymphomas, rarely express this molecule. We report a case of primary cutaneous aggressive epidermotropic CD8(+)TCL, in which lymphoma cells are CD15(+)CD30(-) with a medium-to-large pleomorphic phenotype. Although the functional characteristics of CD15 expression in the cutaneous lymphomas are not fully understood, the poor prognosis of primary cutaneous aggressive epidermotropic CD8(+)TCL might be associated with the presence of this molecule in our case.     

Composite cutaneous lymphoma of diffuse large B‐cell lymphoma‐leg type and subcutaneous panniculitis‐like T‐cell lymphoma

Composite lymphoma (CL) is a rare disease defined by the occurrence of two distinct lymphomas within a single tissue at the same time. We present the case of an 89‐year‐old male with a clinical history of immunoglobulin M monoclonal gammopathy of undetermined significance. The patient presented cutaneous eruption of nodules on the right bottom and arm. An excisional biopsy revealed cutaneous infiltration composed of two components. The first one consisted of large B‐cells with CD20+/MUM1+/BCL2+ phenotype whereas the second one involved the subcutaneous fat in a panniculitic manner, and was CD3+/CD8+/granzyme B+/TCRβF1+. The final diagnosis was CL of primary cutaneous large B‐cell lymphoma‐leg type (PCLBCL‐leg type) and subcutaneous panniculitis‐like T‐cell lymphoma (SPTCL). We report and characterize for the first time coexistent PCLBCL‐leg type and SPTCL in a patient.     

Cutaneous involvement by colonic extranodal NK/T-cell lymphoma mimicking mycosis fungoides: a case report*

We report a 51-year-old woman with cutaneous involvement by extranodal NK/T-cell lymphoma (TCL) of the colon that microscopically mimicked mycosis fungoides (MF). She had a history of fever of unknown origin for 2 months and then developed multiple erythematous papules on her trunk and extremities. A skin biopsy revealed superficial infiltration by atypical small to medium-sized lymphocytes with epidermotropism and Pautrier collections. Immunohistochemical studies showed expression of CD3 and TIA-1 with lack of expression (double negative) of CD4 and CD8. Initially, we reported the diagnosis as MF, cytotoxic variant. Thereafter, computerized tomography scan incidentally identified a colonic mass. A colonic biopsy revealed infiltration of atypical lymphoid cells with the same morphology and immunophenotype as those found in the skin. Additionally, CD56 and Epstein-Barr virus-encoded RNA in situ hybridization in both skin and colonic biopsies were diffusely positive. Thus, extranodal NK/TCL was diagnosed. Delta T-cell receptor (TCR) gene rearrangement was documented in the skin biopsy by polyacrylamide gel electrophoresis and fluorescence capillary gel electrophoresis methods. There was no TCR gene rearrangement detected in the colonic biopsy. Unfortunately, the patient died within 2 months of diagnosis.     

Cutaneous gamma/delta T‐cell lymphoma

Only 40 cases of primary cutaneous gamma/delta T‐cell lymphoma (GD‐TCL) have been described. GD‐TCL was included as a provisional entity in the WHO‐EORTC classification of cutaneous lymphomas in 2005. GD‐TCL often failed to respond to polychemotherapy and radiation therapy and have a poor prognosis with a mean survival of only 15 months. We present a patient treated with surgery, immunomodulatory therapy, and polychemotherapy. He then received hematopoietic stem cell transplantation and has been in complete remission since. Allogeneic stem cell transplantation appears to be a promising therapeutic option for aggressive and generally fatal lymphomas like GD‐TCL.     

Primary cutaneous CD8+ cytotoxic T‐cell lymphoma involving the epidermis and subcutis in a young child

CD8+ cytotoxic T‐cell lymphoma involving the skin represents a heterogeneous group of diseases that include subcutaneous panniculitis‐like T‐cell lymphoma, primary cutaneous aggressive epidermotropic CD8+ cytotoxic T‐cell lymphoma, and ‘type D’ lymphomatoid papulosis. In this report, we describe a case of CD8+ cytotoxic T‐cell lymphoma involving both the epidermis and subcutis. The patient was a 6‐year‐old girl who presented with a 3‐year history of multiple plaques on her trunk and legs. The lesions had relapsed twice but responded well to prednisone. Histopathologic examination showed the proliferation of atypical lymphocytes in the epidermis, dermis and subcutaneous tissue. On immunohistochemical analysis, the atypical lymphocytes were positive for βF1, CD3, CD8, perforin, granzyme B and TIA‐1, but negative for T‐cell receptor (TCR) γ, CD4, CD30 and CD56. It was difficult to classify this tumor in terms of the known types of cutaneous lymphoma, and this case should be differentiated with subcutaneous panniculitis‐like T‐cell lymphoma and primary cutaneous aggressive epidermotropic CD8+ T‐cell lymphoma.     

Pyogenic lymphoma of the skin: a peculiar variant of primary cutaneous neutrophil-rich CD30+ anaplastic large-cell lymphoma. Clinicopathological study of four cases and review of the literature

Systemic anaplastic large-cell lymphoma (ALCL) in human immunodeficiency virus (HIV)-infected individuals showing an extensive infiltrate of neutrophils has been reported and referred to as 'neutrophil-rich' CD30+ ALCL. Secondary cutaneous involvement has been found in a subset of these cases. We report the clinicopathological features of four immunocompetent patients with primary cutaneous neutrophil-rich ALCL and present a new histological subtype with a dissolute growth pattern of CD30+ tumour cells. Four HIV-negative patients presented with rapidly growing solitary or multiple tumours located on the face. Ulceration of the lesions with purulent discharge was a typical finding. Various inflammatory dermatoses were considered clinically in all cases. The histological hallmark was a large number of neutrophils in the infiltrate that masked neoplastic CD30+ anaplastic cells. In two cases, a dissolute growth pattern of anaplastic tumour cells was observed. In two cases, a strong correlation between tumour growth and interleukin (IL)-8 cytokine pattern as well as the production of IL-8 by tumour cells was demonstrated. The diagnosis of neutrophil-rich ALCL is challenging clinically and histologically as the tumour cell compartment is masked by an extensive inflammatory infiltrate of neutrophils and other reactive cells such as histiocytes which may be mainly due to release of IL-8 by tumour cells. The term 'pyogenic' designates the typical feature of this distinct neutrophil-rich ALCL, namely abscess formation ('pyo-') by cytokines (IL-8) produced by tumour cells ('-genic'). The clinical behaviour of this type is the same as in primary cutaneous CD30+ ALCL with classical histological presentation.     

Lymphoma or pseudolymphoma: A report of six cases and review of the literature

To explore and compare the clinical presentations and pathologic features of cutaneous pseudolymphomas (CPL) with primary cutaneous lymphomas. Review literature in order to improve the treatment of CPL. Six cases of CPLs were collected. The clinical, pathologic, and immunohistochemical features were performed and analyzed in Peking Union Medical College Hospital in 2018. Of six patients, the distributions and clinical manifestations of skin lesions are varied. The pathologic features consisted of atypical prominent lymphocytes infiltration. Of them, two cases imitated mycosis fungoides, one case mimicked primary cutaneous aggressive pidermotropic CD8+ cytotoxic T‐cell lymphoma, one case was diagnosed as Jessner‐Kanof lymphocyte infiltration and two cases primary cutaneous CD4+ small/medium T‐cell lymphoproliferative disorder. With respect to etiology, one was result from insects bite and the others were on account of drugs. All cases were treated with systemic or local glucocorticoid. The skin lesions and systemic symptoms showed notable improvement after treatment. Follow‐up visits were 2 years, half a year, and months, respectively, without relapse. These unique types of CPL were similar to cutaneous lymphomas in clinical manifestation and pathology. They were all sensitive to the treatment of externally or orally using glucocorticoid. The prognosis is generally good but needs long‐term follow‐up.     

8-Methoxypsoralen plus UVA treatment increases the proportion of CLA+ CD25+ CD4+ T cells in lymph nodes of K5.hTGFβ1 transgenic mice

Abstract: 8‐Methoxypsoralen plus UVA (PUVA) photochemotherapy is an effective treatment for many skin diseases including psoriasis. However, its exact mechanism of therapeutic action is incompletely understood. Previously, in K5.hTGFβ1 transgenic psoriatic mice, we found that PUVA induces Foxp3+ CD25+ CD4+ regulatory T cells in both lymph node and spleen. Now, in the same model, we investigated whether cutaneous lymphocyte‐associated antigen (CLA) mediates PUVA’s effect on homing of CD25+ CD4+ T cells to the lymph nodes of K5.hTGFβ1 transgenic mice. We found that a low dose of topical PUVA maximally increased the proportion of CLA + CD25+ CD4 + T cells in the lymph nodes by up to 8‐fold. We also observed an increased number of Foxp3+ CD25+ T cells in the skin of the mice after PUVA treatment. Together, these findings suggest that PUVA affects the homing of regulatory T cells.     

CD30+ lymphoproliferative disorder with spindle‐cell morphology

Lymphomatoid papulosis (LyP) is classified as a CD30+ primary cutaneous lymphoproliferative disease. The phenotypic variability along the spectrum of CD30+ lymphoproliferative diseases is highlighted by the distinct histologic subtypes of LyP types A, B, C, and the more recently described types D, E, and F. We report the case of an elderly woman with a clinical presentation and histopathologic findings consistent with LyP, whose atypical CD30+ infiltrate uniquely demonstrated a spindle‐cell morphology. To our knowledge, this is the first reported case of LyP characterized by CD30+ spindle‐shaped cells, and may represent a new and distinct histologic variant of LyP.     

Disseminated CD8‐positive,CD30‐positive cutaneous lymphoproliferative eruption with overlapping features of mycosis fungoides and primary cutaneous anaplastic large cell lymphoma following remote solitary lesional presentation

CD8‐positive, CD30‐positive cutaneous lymphoproliferative disorders constitute a rare subset of T‐cell lymphoproliferative conditions, including variants of primary cutaneous anaplastic large cell lymphoma (ALCL), mycosis fungoides, lymphomatoid papulosis type D, cutaneous gamma‐delta T‐cell lymphoma and cutaneous peripheral T‐cell lymphoma. These entities share overlapping clinical, histopathologic and immunophenotypic features, presenting both a clinical and pathological diagnostic challenge. Presented here is a 73‐year‐old man with a disseminated, indolent CD30+, CD8+ cutaneous lymphoproliferative disorder with overlapping clinical and histopathological features of both mycosis fungoides and primary cutaneous ALCL, as well as features of lymphomatoid papulosis. To our knowledge, this is the first case of a generalized CD8+, CD30+ eruption with features of both mycosis fungoides and primary cutaneous ALCL arising following an episode of solitary primary cutaneous CD8‐positive ALCL.     

Childhood mycosis fungoides with a CD8+ CD56+ cytotoxic immunophenotype

Primary cutaneous T‐cell lymphomas mostly occur in patients of middle and higher age. Their rarity and an oftentimes atypical clinical presentation in childhood as well as the reluctance of taking biopsies in children are reasons for a delayed diagnosis. We report the case of an 11‐year‐old boy with a 7‐year history of slowly progressive CD8+CD56+ mycosis fungoides of the cytotoxic immunophenotype. His trunk and extremities were affected by extensive pale‐erythematous patches and plaques with fine scaling. In addition, several poikilodermatous lesions were present on his thighs. Improvement was achieved by topical mometasone furoate treatment. On the basis of our observation, a brief review on cutaneous T‐cell lymphomas in childhood and on CD8+ subtypes in particular is given. Clinicopathological correlation is crucial for establishing the correct diagnosis and for estimation of the prognosis.     

Gamma‐delta T‐cell lymphoma arising in a long‐standing cutaneous plaque

The precise classification and characterization of primary cutaneous gamma‐delta T‐cell lymphoma (PCGD‐TCL) has been hindered by clinical and morphologic features that overlap with other lymphomas, especially subcutaneous panniculitis‐like T cell lymphoma (SPTCL). The recent World Health Organization/European Organization for Research and Treatment of Cancer (WHO/EORTC) classification distinguishes the more aggressive PCGD‐TCL from the usually indolent SPTCL, however. We report a 30‐year‐old woman with an indurated violaceous plaque on the left cheek that had been present for several years. Biopsies showed a dense lymphocytic infiltrate involving the subcutis and dermis that consisted mostly of small and medium‐sized lymphocytes, some with irregular nuclear contours and dense chromatin. These cells were positive for TIA‐1, TCR‐gamma and CD8, but negative for beta‐F1 and granzyme‐B. Staging with positron emission tomography–computed tomography (PET/CT), CBC and bone marrow with flow cytometry identified lymphadenopathy as well as blood and marrow involvement by an abnormal TCRgd‐positive T‐cell proliferation (Ann Arbor Stage IV). The patient's history of a long‐standing lesion in this case is unusual, in that gamma‐delta T‐cell lymphomas are typically rapidly progressive neoplasms. As such, it raises the possibility of ‘transformation’ of a long‐standing inflammatory process into an overt lymphoma.     

Epidermal CD8+ T cells in chronic plaque psoriasis are Tc1 cells producing heterogeneous levels of interferon-gamma

The majority of epidermal CD8+ T cells in chronic plaque psoriasis are activated Tc1 cells producing interferon-gamma and no interleukin-4, a small proportion of which express NK-T receptors. To quantitate their level of cytokine production and characterize them further, CD8+ T cells were isolated from epidermal cell suspensions of lesional biopsies from 24 patients with chronic plaque psoriasis. T-cell lines (TCL) were established by culture of CD8+ T cells with feeders and IL-2 for 11 days and expansion with PHA. Ten TCL were stained for surface markers; 6 were cloned with PHA by limiting dilution. Interferon-gamma, interleukin-4 and interleukin-10 production was measured by ELISA after PMA/anti-CD3 activation of 15 TCL and 39 CD8+ T-cell clones. The 10 TCL stained were CD8alphabeta+ (93.3%), T-cell receptor-alphabeta+ (99.5%), costimulatory molecule CD28+ (90.1%), with a small CD8alphaalpha+ population (2.3%). No NK-T-cell receptor CD158a or CD158b expression was detected, whilst CD94 was expressed on 6.2% of cells in 6/9 TCL. All the TCL and 37/39 CD8+ T-cell clones produced interferon-gamma but no or minimal interleukin-4 or interleukin-10. The TCL produced a wide range of interferon-gamma levels (138 to 15,020 pg/ml). Clones from 3 patients showed low levels (60 to 1,410 pg/ml), from 2 patients high levels (6,105 to 43,040 pg/ml) and from 1 patient a wide range (405 to 36,010 pg/ml) of interferon-gamma production. Thus epidermal CD8+ Tc1 cells in chronic plaque psoriasis produce highly heterogeneous levels of interferon-gamma, which may reflect clinical diversity.     

Histopathological aspects and differential diagnosis of CD8 positive lymphomatoid papulosis

Lymphomatoid papulosis (LyP) belongs to CD30+ lymphoproliferative disorders with indolent clinical course. Classic histological subtypes, A, B and C are characterized by the CD4+ phenotype, while CD8+ variants, most commonly classified as type D, were reported in recent years. We present 14 cases of CD8+ LyP. In all patients, self‐resolving or treatment‐sensitive papules were observed. Of 14 cases 7 produced results with typical microscopic features of LyP type D mimicking primary cutaneous aggressive epidermotropic CD8+ T‐cell lymphoma. The infiltration pattern in 4 of 14 cases were consistent with classic LyP type B, without CD30 expression in two cases, resembling mycosis fungoides (MF). The morphology of 2 of 14 cases shared a certain consistency with classic type A and C, lacking eosinophils and neutrophils. Extensive folliculotropism characteristic to type F was observed in 1 of 14 case. Significant MUM1 and PD1 expression were detected in 2 of 14 and 3 of 14 cases, respectively. We concluded that CD8+ LyP may present with different histopathological features compared with type D, similar to CD4+ LyP variants. Differential diagnoses include CD8+ papular MF, folliculotropic MF and anaplastic large cell lymphoma in addition to primary cutaneous aggressive epidermotropic T‐cell lymphoma. We emphasise that rare CD8+ LyP cases may exist with CD30‐negativity.     

Primary cutaneous follicle center lymphoma with Hodgkin and Reed‐Sternberg‐like cells: a new histopathologic variant

Primary cutaneous follicle center lymphoma (PCFCL) is the most frequent cutaneous B‐cell lymphoma. A 62‐year‐old man presented with a solitary indolent subcutaneous nodule for 3 years duration, without other abnormalities. Histological examination showed lymphoproliferation with a nodular growth pattern characterized by fibrous collagen bands surrounding nodules. The nodules were composed of medium‐sized centrocytes admixed with many large multilobulated and lacunar cells without eosinophils or granulomatous aspect. Hodgkin‐like cells were CD30+, CD15+, PAX5+, OCT2+, BOB1+, MUM1+, Ki67+, Bcl6+ and focally CD20+ and EMA?, CD79a?, Bcl2? and CD10?. The medium‐sized cells were CD20+, CD79a+, Bcl2+, Bcl6+ and CD10+, enmeshed in a network of CD21‐positive follicular dendritic cells. Epstein‐Barr virus detection was negative. Interphase fluorescence in situ hybridization showed the absence of BCL2 or BCL6 rearrangement. In such a case, the presence of Hodgkin‐like cells intermixed with the tumor population may result in a pitfall diagnosis of classical Hodgkin lymphoma (CHL). Differential diagnoses to be ruled out are secondary or primary skin localization of rather CHL, or systemic follicular lymphoma. Several clinical, radiological, histological, immunohistochemical and molecular arguments indicated the diagnosis of PCFCL. To our knowledge, this is the first report of PCFCL with Hodgkin‐like cells.     

Intermediate or chronic cutaneous leishmaniasis: leukocyte immunophenotypes and cytokine characterisation of the lesion

The American cutaneous forms of leishmaniasis include immune-responder individuals with localised cutaneous leishmaniasis (LCL) and non-responder individuals with diffuse cutaneous leishmaniasis (DCL). Patients with intermediate or chronic cutaneous leishmaniasis (ICL) have increased morbidity due to the length of their illness, atypical forms and areas of compromise. In the present study, we evaluated the expression of the leukocyte antigens (CD4, CD8, CLA: cutaneous lymphocyte antigen, CD69, CD83 and CD1a) and cytokines (IFN-gamma, IL-4, IL-10 and TGF-beta 1) in the lesions of patients with ICL (n = 18) using an immunocytochemical procedure. ICL results were compared with the information for LCL (n = 19) and DCL (n = 4). The numbers of CD4+ and CD8+ T cells in ICL were similar to those of LCL lesions, but significantly different (P < or = 0.05) from DCL lesions. LCL lesions have about half the numbers of early activated CD69+ cells as ICL, but most are CLA+ skin homing memory T cells, whereas ICL lesions have the highest number of CD69+ T cells, but about one-third of these cells expressed CLA. This suggests that the granuloma of ICL patients contains many activated T cells that are unprimed to cutaneous-launched antigens, thus contributing to an aberrant immune response. In contrast, DCL granulomas presented the lowest numbers of activated CD69+ and CLA+ cells, associated with the characteristic tolerogenic state of these patients. The immunolocalisation of cytokines showed a mixed cytokine pattern in ICL lesions with many positive cells for IL-10, TGF-beta 1, IL-4 and IFN-gamma, with a preponderance of the first two, and different from the prevalent Th1 and Th2 responses associated with LCL and DCL lesions, respectively. CD1a+ Langerhans cells were decreased (P < or = 0.05) in both ICL (271 +/- 15 cells/mm2) and DCL (245 +/- 19 cells/mm2) as compared to LCL (527 +/- 54 cells/mm2) epidermis. The percentage of IL-10+ epidermal Langerhans cells in ICL (33.69), from the total CD1a+ population, was higher than in LCL (17.45). In addition, fewer CD83+ primed Langerhans cells were present in ICL epidermis. The diminished participation of epidermal Langerhans cells, causing a defective signalling by the epidermis, in ICL lesions may account for the tissue-damaging state observed in these patients.     

Therapeutic hotline: Primary cutaneous CD4 + small/medium-sized pleomorphic T cell lymphoma coexisting with myelodysplastic syndrome transforming into chronic myelomonocytic leukemia successfully treated with cyclophosphamide

Cutaneous T cell lymphomas other than mycosis fungoides, Sezary syndrome, and primary cutaneous CD30+ lymphoproliferations constitute less than 10% of all cutaneous T cell lymphomas. Primary cutaneous small/medium CD4+ T cell lymphoma is a member of this third group of cutaneous lymphomas, separated out as provisional entity in the World Health Organization classification - European Organization for Research and Treatment of Cancer (WHO-EORTC) classification. It still awaits development of more precise diagnostic criteria and optimal therapy. We report a case of primary cutaneous CD4 + small/medium-sized pleomorphic T cell lymphoma accompanied with myelodysplastic syndrome successfully treated with cyclophosphamide. It seems that cyclophosphamide as a single-agent chemotherapy in patients with disseminated lesions might be safe and quite effective therapeutic option.     

Immunophenotypic shift of CD4 and CD8 antigen expression in primary cutaneous T‐cell lymphomas: a clinicopathologic study of three cases

Primary cutaneous T‐cell lymphomas (CTCL) comprise a heterogeneous group of neoplasms with diverse clinical behavior. Mycosis fungoides (MF) is the most common type of CTCL. Immunophenotypical shift during progression of the disease is a rare event and its significance is unknown. We present three primary CTCL cases that showed an immunophenotypical shift and poor prognosis. Conventional hematoxylin/eosin and immunohistochemical‐stained sections were examined in all the cases. Molecular analysis for rearrangement of the T‐cell receptor (TCR) gene was performed in two cases. One case was classified as MF, while the other two lacked epidermotropism, and were considered primary cutaneous peripheral T‐cell lymphoma (PTCL), NOS. Two cases were CD3+/CD4+ and one case was CD3+/CD8+ at diagnosis. The first two patients suffered many relapses and eventually, new CTCL lesions with a CD3+/CD8+ phenotype were observed. Both cases revealed identical clonal TCR rearrangements on the initial and late lesions, supporting the interpretation of a single clonal proliferation with different phenotypes. The third case progressed with skin recurrences and pulmonary lesions with a predominant CD3+/CD4+/CD8? phenotype. All cases manifested poor prognosis and two patients died of lymphoma. Immunophenotypical shift between CD4 and CD8 in CTCL seems to be a rare phenomenon that may be associated with disease progression.