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Cutaneous T-Cell Lymphoma

Primary Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphoma refers to a type of non-Hodgkin lymphoma characterized by abnormal proliferation of skin-homing T cells. Solid tumors may develop in the skin and eventually, degenerated cells may spread to lymph nodes. The two most common subtypes of cutaneous T-cell lymphoma are Mycosis fungoides and Sézary syndrome.

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Presentation

During early stages of the disease, patients may present with multiple erythematous patches and plaques that are usually well demarcated and often ring-shaped. Scaling may be noted and patients may claim pruritus. Interestingly and despite the hypothesis of CTCL being an ultraviolet light-induced tumor, these lesions typically occur on unexposed sites. They may or may not be hyperpigmented. Sun exposure, as well as topical application of corticosteroids, may induce a partial response and thus, treating physicians may be tempted to misdiagnose CTCL as a benign skin disease. Accordingly, a medical history of chronic eczema or psoriasis that fail to respond to therapy should prompt the suspicion of cutaneous lymphoma. This stage may last for years; neither hematological anomalies nor lymphadenopathy are generally encountered in these patients.

As the disease progresses, increasingly large shares of the patient's skin are compromised and full-blown erythroderma may develop. At the same time, the lesions may start to indurate and form nodular, solid tumors. Ulceration of these nodes is not uncommon and patients may start to develop systemic symptoms like malaise and weight loss.

In advanced stages of the disease, tumor cells may overcome the endothelial barrier, migrate into the dermis, and spread to regional lymph nodes via lymphatic vessels. In lymph nodes, degenerated T cells may pass through high endothelial venules, reach the cardiovascular system and viscera [10]. Systemic spread manifests in form of generalized lymphadenopathy and possibly tumor growth in other organs, although the latter may not provoke clinical symptoms.

Lymphadenopathy
  • Clinically, it is characterized by diffuse erythroderma, cutaneous edema, pruritus, nonhealing cutaneous ulcers, and lymphadenopathy.[ncbi.nlm.nih.gov]
  • The patient turned chronically subfebrile 4 months before admission, and generalized peripheral lymphadenopathy occured.[cyberleninka.org]
  • Computed tomography revealed no lymphadenopathy or metastases. No evidence of bone marrow involvement was found. The patient received a course of radiotherapy, with a good response (Panel B). Three months later, he presented with ataxia.[nejm.org]
Fatigue
  • […] of six patients in the 9 μg/kg/day cohort showed decreased appetite or fatigue.[ncbi.nlm.nih.gov]
  • We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 14, 2019[patientslikeme.com]
  • RELATED: Prolonged PFS With Brentuximab Vedotin in Cutaneous T Cell Lymphoma The most frequently reported adverse events (AE) associated with BV are anemia, peripheral sensory neuropathy, nausea, diarrhea, fatigue, and neutropenia.[cancertherapyadvisor.com]
Fever
  • A 6-year old girl presented with complaint of 3-year history of recurrent skin lesions, 3 months of fever accompanied by cough for 8 days.[ncbi.nlm.nih.gov]
  • Patients present with nodules on lower extremities and trunk and with systemic symptoms such as fever and malaise. Haemophagocytosis may be seen on histology (blood cells are found within phagocytes ).[dermnetnz.org]
  • These lesions are frequently accompanied by systemic symptoms such as fever and weight loss, and an associated hemophagocytic syndrome may be observed.[emedicine.com]
Pain
  • Abstract Eosinophilic fasciitis (EF) is a rare entity characterized by symmetrical and painful thickness and induration of the skin, especially localized on forearms and thorax and generally accompanied by eosinophilia.[ncbi.nlm.nih.gov]
  • There is no cure for CTCL, but there are a variety of treatment options available and some CTCL patients are able to live normal lives with this cancer, although symptoms can be debilitating and painful, even in earlier stages.[en.wikipedia.org]
  • He had occasional bloody discharge, without pain, and did not have constitutional or other systemic symptoms. Multiple skin biopsies eventually confirmed cutaneous T-cell lymphoma. Computed tomography revealed no lymphadenopathy or metastases.[nejm.org]
  • We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: May 14, 2019[patientslikeme.com]
Malaise
  • Disease progression was noted in both patients, after a month of cyclosporine therapy: malaise, subfebrile and febrile temperatures, and development of generalized skin nodules were evident.[content.sciendo.com]
  • Patients present with nodules on lower extremities and trunk and with systemic symptoms such as fever and malaise. Haemophagocytosis may be seen on histology (blood cells are found within phagocytes ).[dermnetnz.org]
  • Ulceration of these nodes is not uncommon and patients may start to develop systemic symptoms like malaise and weight loss.[symptoma.com]
Generalized Lymphadenopathy
  • Systemic spread manifests in form of generalized lymphadenopathy and possibly tumor growth in other organs, although the latter may not provoke clinical symptoms.[symptoma.com]
  • Acute cases may present with a high level of circulating malignant cells, generalized lymphadenopathy, hepatomegaly, and hypercalcemia with or without lytic bone lesions. Chronic and smoldering cases have a mycosis fungoides-like presentation.[rarediseases.org]
  • Sézary syndrome (SS) is defined historically by the triad of erythroderma, generalized lymphadenopathy, and the presence of neoplastic T cells (Sézary cells) in skin, lymph nodes, and peripheral blood. 78 In a recent report of the International Society[doi.org]
Overeating
  • The authors report a case of a 64-year-old man with simultaneous plaque-like lesions and disseminated nodules growing rapidly on the face, trunk, and extremities over a 6-month period.[ncbi.nlm.nih.gov]
  • Sezary syndrome is a less common type that causes skin redness over the entire body. Some types of cutaneous T-cell lymphoma, such as mycosis fungoides, progress slowly and others are more aggressive.[mayoclinic.org]
Hepatosplenomegaly
  • Patients also can present with changes to their nails, hyperpigmentation, alopecia, palmoplantar keratoderma, ectropion, and hepatosplenomegaly. The overall prognosis for patients with Sézary syndrome is poor.[ncbi.nlm.nih.gov]
  • […] non-sun-exposed areas can have telangiectasias and ulceration erythroderma ( 90% body involvement) early lesions may be confused with atopic dermatitis of psoriasis Sézary syndrome severely pruritic erythroderma with scaling alopecia lymphadenopathy hepatosplenomegaly[medbullets.com]
  • It is characterised by erythroderma, leukaemia, generalised lymphadenopathy and hepatosplenomegaly. It occurs most frequently in middle-aged males. Patients have a median survival of less than five years.[patient.info]
  • Additional symptoms include ectropion, onychodystrophy, palmoplantar keratoderma, alopecia, and hepatosplenomegaly.[rarediseases.org]
  • In the acute form, cutaneous lesions, hepatosplenomegaly, lytic bone lesions, and infections are observed, along with an elevated white blood cell (WBC) count and hypercalcemia.[emedicine.com]
Ulcer
  • A slowly enlarging arm ulcer appeared in a 61-year-old man with cutaneous T cell lymphoma. Skin biopsy revealed aseptate hyphae and nodular small/medium-sized pleomorphic CD4( ) T cell infiltration.[ncbi.nlm.nih.gov]
Dermatitis
  • [Indexed for MEDLINE] Free full text MeSH terms, Substances MeSH terms Adolescent Adult Aged Case-Control Studies Cells, Cultured Dermatitis, Atopic/blood Dermatitis, Atopic/diagnosis Dermatitis, Atopic/metabolism* Epidermis/metabolism* Epidermis/pathology[ncbi.nlm.nih.gov]
  • CTCL complicating severe atopic dermatitis. Dermatology 2009;218:168-71.[cyberleninka.org]
  • View/Print Table TABLE 2 Differential Diagnosis of the Patch and Plaque Stage of Cutaneous T-Cell Lymphoma Psoriasis Atopic dermatitis/eczema Chronic contact dermatitis Chronic, nonspecific dermatitis Drug eruption Potential precursor lesions Poikiloderma[aafp.org]
Pruritus
  • Abstract Approximately 88% of cutaneous T-cell lymphoma (CTCL) patients are affected by pruritus that responds poorly to current antipruritic therapies.[ncbi.nlm.nih.gov]
Papule
  • We describe here an indolent leukaemic patient with cutaneous T-cell lymphoma, who initially had a nodulo-tumourous eruption with a crop of solid papules, but finally presented with papuloerythroderma.[ncbi.nlm.nih.gov]
Alopecia
  • Alopecia areata-like hair loss may occur in the context of cutaneous T cell lymphoma (CTCL) and can very rarely evolve to alopecia universalis-like presentation. The dermoscopic findings of CTCL-related alopecia have not been described.[ncbi.nlm.nih.gov]
  • Skin lesions are often associated with alopecia, and sometimes with mucinorrhea (see alopecia mucinosa). Pagetoid reticulosis Localised patches or plaques with an intraepidermal growth of neoplastic T cells.[dermnetnz.org]
  • […] pruritic patches and plaques in non-sun-exposed areas can have telangiectasias and ulceration erythroderma ( 90% body involvement) early lesions may be confused with atopic dermatitis of psoriasis Sézary syndrome severely pruritic erythroderma with scaling alopecia[medbullets.com]
Sleep Disturbance
  • Other side effects include depression, sleep disturbances, anxiety, hair loss and nausea. If patients have failed to or stopped responding to interferon alfa, a synthetic form of interferon gamma may be used.[oncolink.org]

Workup

Even in patients presenting with erythematous patches and plaques, prior to manifestation of erythroderma or systemic symptoms, immunohistochemical and molecular analysis of biopsy specimens may reveal accumulations of clonal CD3+ CD4+ T cells, i.e., all cutaneous lesions contain T lymphocytes belonging to the same clonal population. Tumor cells typically lack expression of CD2, CD5, CD7 and CD8 [2]. Histopathological analyses of tissue samples are also the mainstay of diagnosis during advanced stages of the disease and should be realized for skin and lymph node biopsy specimens. In order to precisely evaluate the condition of affected tissues, excision biopsies, possibly core biopsies should be performed. Analysis of fine-needle aspirates is often a major challenge. In case of CTCL, the following may be noted:

  • Samples obtained from patients presenting with early patches and plaques affecting minor parts of the skin usually demonstrate superficial infiltration of lymphocytes and histiocytes. The majority of cells presents normal morphologic features; few cells with atypical nuclei may be observed in the epidermis.
  • As the disease progresses, neoplastic lymphocytes form Pautrier microabscesses. In order to observe the latter, multiple biopsy specimens have to be analyzed. Nevertheless, Pautrier microabscesses cannot be detected in all CTCL patients.
  • In later stages, tumor cells increasingly infiltrate the dermis. Their morphology may differ considerably from those characteristic of functional lymphocytes.
  • While the afore-described findings may apply to both MF and SS, the infiltration of lymph nodes by T cells with cerebriform nuclei and the presence of such Sézary cells in peripheral blood is characteristic of the latter.

Additionally, laboratory analyses of blood samples should be performed. Lactate dehydrogenase levels are often elevated. Leukemic features may be encountered in patients suffering from MF with secondary leukemia or in individuals who developed SS. These features comprise an increased ratio of CD4+ to CD8+ T cells (due to the proliferation of the former; in SS, >10), and possibly the presence of Sézary cells (in SS, >1,000/µl). Serological tests are recommended to ascertain whether a patient suspicious of CTCL is infected with human T-cell lymphotropic virus.

In order to determine the subtype of CTCL, clinical, histologic, immunohistochemical and molecular findings should be considered. The interested reader is referred to the respective guidelines of the World Health Organization or the European Organization for Research and Treatment of Cancer [11].

For tumor staging, computed tomography scans of the thoracic and abdominal cavities should be carried out.

Liver Biopsy
  • We report the case of a 36-year-old female patient diagnosed with cutaneous T-cell lymphoma of the mycosis fungoides variety, staged as T2N0M0B0, where a transjugular liver biopsy demonstrated the presence of nodular regenerative hyperplasia with a hepatic[ncbi.nlm.nih.gov]

Treatment

Skin-directed therapy is indicated as long as systemic involvement can be ruled out. In this context, psoralen plus ultraviolet A photochemotherapy has been applied as well as ultraviolet B, total skin electron-beam radiation and radiotherapy. Additionally, corticosteroids, nitrogen mustard, or cytostatic carmustine may be applied topically as long as the extension of skin lesions allows for this therapeutic approach. The respective benefits and disadvantages have been considered at the time of establishing treatment guidelines, which are available elsewhere [12]. Of note, recent research results indicate ultraviolet light to play a major role in CTCL pathogenesis but these findings have not yet been discussed with regards to therapeutic regimens [3] [4].

In advanced stages of the disease, i.e., upon infiltration of lymph nodes and detection of tumor cells in peripheral blood, CTCL patients require systemic therapy with biologic response modifiers (e.g., interferon-α, retinoids, rexinoids and denileukin diftitox), histone deacetylase inhibitors (e.g., vorinostat) or chemotherapeutic drugs. The latter is considered a last resort if patients fail to respond to other treatment options. In general, it is to be expected that target-oriented therapy continues to gain importance. Molecular biological techniques may reveal the precise gene defects underlying tumor development in an individual patient and those results may permit personalized treatment. For instance, CTLA-4 inhibitor ipilimumab has been used to treat CTCL due to a CTLA4-CD28 translocation [4].

Of note, immunosuppressive therapy is not generally recommended for CTCL patients. Indeed, any treatment regimen that provokes a decrease in non-malignant, tumor-infiltrating T cells may contribute to disease progression [13].

Prognosis

The likelihood of disease progression and consequent survival times depend on the tumor stage and clinical condition at the time of diagnosis. In this context, 10-year-survival rates range from almost 90% to below 20%. The detailed information regarding expected survival times dependent on the results of a risk assessment are provided elsewhere [2]. In general, advanced tumor and clinical stage, as well as increased age, are unfavorable prognostic factors. Systemic involvement is associated with a significantly worse outcome than CTCL limited to the skin. Additionally, CTCL in advanced stages is more likely to undergo large cell transformation, which has also been identified as an unfavorable prognostic factor. Finally, histological subtypes of CTCL may affect survival times [9].

Etiology

CTCL is a lymphoproliferative malignancy characterized by the abnormal proliferation of mature T lymphocytes. For a long time, the triggers of malignant T cell degeneration have remained unknown, but recently, researchers have been able to identify recurring patterns of oncogene and tumor suppressor gene mutations that are known to be induced by ultraviolet light [3] [4]. In fact, similar mutations may be encountered in melanoma and squamous cell carcinoma, both associated with exposure to ultraviolet light, but not in other types of neoplasms.

On the one hand, point mutations account for a major share of gene defects presumably involved in carcinogenesis. On the other hand, deletion of gene-spanning sequence segments renders CTCL patient hemizygous for certain tumor suppressor genes [3]. More than a dozen genes have been proposed to contribute to CTCL development, e.g., TP53 (tumor suppressor gene encoding for transcription factor p53), ZEB1 (similarly encodes for a transcription factor), and ARID1A (whose gene product is involved in chromatin remodeling). Mutations of these genes may eventually serve as biomarkers and facilitate the diagnosis of CTCL. Moreover, extended knowledge regarding the genetic basis of CTCL and alterations of signaling cascades due to gene defects may allow for a targeted therapy of this disease [5].

Epidemiology

The annual incidence of CTCL has been estimated to 2 per 1,000,000 people in Europe and 6.4 per 1,000,000 inhabitants in the United States [6] [7]. This renders CTCL an uncommon type of non-Hodgkin lymphoma. MF is most frequently diagnosed and accounts for about 53% of all cases.

Although patients of all races may be affected by the disease, the age of onset in non-Caucasians has been reported to be significantly lower. With regards to Caucasians suffering from MF, their median age at the time of diagnosis is 59 years. Patients of African or Asian descent are typically diagnosed more than 5 years earlier. A similar tendency can be observed concerning non-MF CTCL [8]. In general, highest incidence rates are reported for people aged 70 years and older. Furthermore, racial predilection has been suggested for certain subtypes and stages of CTCL. Males may develop CTCL up to two times more often than females [6] [8].

Sex distribution
Age distribution

Pathophysiology

Identification of gene defects involved in CTCL pathogenesis allowed for the determination of signaling pathways altered in degenerated T lymphocytes. In detail, alterations of JAK-STAT and NF-κB pathways, as well as T cell receptor signaling, have been related to anomalies in the following processes [1] [3]:

  • Gene expression as regulated by transcription factors
  • Chromatin modification
  • DNA damage repair
  • Cell cycle regulation and T cell differentiation
  • Proliferation and apoptosis
  • Cytokine release

Moreover, recombination activating gene endonucleases RAG1 and RAG2 have been proposed to play a role in CTCL pathogenesis. Physiologically, expression of the respective genes is restricted to immature stages of lymphocytes. RAG1 and RAG2 mediate double-strand breaks and thus allow for somatic recombination and assembly of a wide variety of T cell receptors. They may induce double-strand breaks at off-target sites, favor the expression of oncogenes and induce the deletion of tumor suppressor genes. To date, it remains unclear why those enzymes would remain active in mature T cells, which are assumed to be the origin of CTCL [3]. It has been hypothesized that RAG1 and RAG2 expression is reactivated in post-thymus T lymphocytes and that predisposing gene mutations are acquired during childhood or early adolescence [1].

Prevention

The disease occurs due to mutations in genes. It cannot be primarily prevented. However, vaccinations for Influenza can be given to the patients with the history of systemic disease or immunocompromised condition as a measure of secondary prevention.

Summary

Cutaneous T-cell lymphoma (CTCL) refers to a lymphoproliferative disorder that belongs to the group of extranodal non-Hodgkin lymphoma [1]. Its pathogenic hallmark is the uncontrolled proliferation of skin-homing T cells that subsequently accumulate in the skin. Initially, this provokes the development of erythematous patches and plaques. Disease progression is accompanied by the formation of solid skin tumors that are usually presented as visible and palpable nodular masses, and by an extension of cutaneous lesions over the patient's body. Eventually, affected individuals suffer from erythroderma. Advanced stages of CTCL are associated with the lymphogenous spread of degenerated cells that may form tumors in lymph nodes and visceral organs. Years may pass from symptom onset to manifestation of erythroderma and non-cutaneous lesions and due to the apparently benign course of the disease, prolonged diagnostic delays are common.

In order to diagnose the disease, biopsy specimens have to be obtained. Histopathologists distinguish subtypes of CTCL, with mycosis fungoides (MF) and Sézary syndrome (SS) being the two most common ones [2]. Upon confirmation of CTCL, tumor staging should be carried out. The limitation to the skin allows for the employment of skin-directed therapies and is associated with a favorable prognosis. In contrast, the extracutaneous spread may significantly worsen the outcome and possibly require systemic chemotherapy.

Patient Information

Cutaneous T-cell lymphoma (CTCL) is a rare lymphoproliferative disorder. This malignancy is characterized by an uncontrolled proliferation of T cells, a subpopulation of immune cells, in the skin. Consequently, symptoms associated with CTCL are primary cutaneous lesions. During years after symptom onset, many patients don't claim any other issue than scaling and itchy rash. Eventually, this rash may comprise the whole body. At this point, patients already suffer from advanced-stage CTCL and tumor cells may spread to lymph nodes and viscera.

Treatment options and prognosis largely depend on the tumor stage and clinical condition at the time of diagnosis. As long as CTCL is limited to the skin, skin-directed therapies like photochemotherapy, electron-beam radiation or topical application of drugs are indicated. In advanced stages of the disease, systemic therapy is required. Distinct compounds that modify T cell behavior have recently been approved to this end. Classic chemotherapeutic drugs may be used as a last resort if patients fail to respond to other treatment regimens.

References

Article

  1. Devata S, Wilcox RA. Cutaneous T-Cell Lymphoma: A Review with a Focus on Targeted Agents. Am J Clin Dermatol. 2016; 17(3):225-237.
  2. Wilcox RA. Cutaneous T-cell lymphoma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol. 2016; 91(1):151-165.
  3. Choi J, Goh G, Walradt T, et al. Genomic landscape of cutaneous T cell lymphoma. Nat Genet. 2015; 47(9):1011-1019.
  4. Damsky WE, Choi J. Genetics of Cutaneous T Cell Lymphoma: From Bench to Bedside. Curr Treat Options Oncol. 2016; 17(7):33.
  5. Sekulic A, Liang WS, Tembe W, et al. Personalized treatment of Sezary syndrome by targeting a novel CTLA4:CD28 fusion. Mol Genet Genomic Med. 2015; 3(2):130-136.
  6. Thestrup-Pedersen K. Cutaneous T-Cell Lymphoma. A hypothesis on disease pathophysiology involving deficiency in DNA repair. J Eur Acad Dermatol Venereol. 2016.
  7. Criscione VD, Weinstock MA. Incidence of cutaneous T-cell lymphoma in the United States, 1973-2002. Arch Dermatol. 2007; 143(7):854-859.
  8. Wilson LD, Hinds GA, Yu JB. Age, race, sex, stage, and incidence of cutaneous lymphoma. Clin Lymphoma Myeloma Leuk. 2012; 12(5):291-296.
  9. Agar NS, Wedgeworth E, Crichton S, et al. Survival outcomes and prognostic factors in mycosis fungoides/Sezary syndrome: validation of the revised International Society for Cutaneous Lymphomas/European Organisation for Research and Treatment of Cancer staging proposal. J Clin Oncol. 2010; 28(31):4730-4739.
  10. Girardi M, Edelson RL. Cutaneous T-cell lymphoma: pathogenesis and treatment. Oncology (Williston Park). 2000; 14(7):1061-1070; discussion 1070-1064, 1076.
  11. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood. 2005; 105(10):3768-3785.
  12. Trautinger F, Knobler R, Willemze R, et al. EORTC consensus recommendations for the treatment of mycosis fungoides/Sezary syndrome. Eur J Cancer. 2006; 42(8):1014-1030.
  13. Thomsen K, Wantzin GL. Extracutaneous spreading with fatal outcome of mycosis fungoides in a patient treated with ciclosporin A: a word of caution. Dermatologica. 1987; 174(5):236-238.

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Last updated: 2019-07-11 20:32