Primary cutaneous anaplastic large-cell lymphoma of the eyelid: report of two cases and review of the literature.

PURPOSE: Two new cases of primary cutaneous CD30+ anaplastic large-cell lymphoma (cALCL) of the eyelid are reported; these are analysed alongside existing cases to identify challenges relating to the diagnosis and management of such rare lesions. MATERIAL AND METHODS: A review of existing literature on the PubMed database is conducted using the keywords: 'eyelid lymphoid proliferations', 'lymphoma of the eyelid', and 'primary cutaneous CD30+, ALK-anaplastic large-cell lymphoma of the eyelid'. Two new cases of cALCL are reported. Cases where patients present solely with a nodular periocular lesion are analysed for recurrence and survival rate. RESULTS: Two new patients with a painless ulcerated nodule on the upper eyelid receive a confirmed diagnosis of cALCL after undergoing an excisional biopsy. The first, elderly patient has spontaneous remission; the second patient, with a concomitant chronic infection of hepatitis C virus (HCV), presents a more diffuse disease at the onset and requires radiotherapy. Together with 13 patients a primary cALCL identified from 11 previous studies, this constitutes a cohort of 15 patients. Of these, 10 present with an exclusively nodular lesion of the eyelid and four experience disease recurrence; no deaths from cALCL are reported. CONCLUSION: Differential diagnosis between primary cALCL and lymphomatoid papulosis is essential and requires careful consideration of clinical and pathologic features. Radiologic staging examination is crucial in order to exclude systemic ALCL, particularly for patients with comorbidity. Though cALCL has the pathological features of a malignant lesion, the prognosis seems favourable for patients; a relatively high percentage even experience spontaneous resolution.

Acitretin combined with NB-UVB in the treatment of cutaneous CD30-positive anaplastic large cell lymphoma.

Cutaneous CD30+ lymphoproliferative disorders represent a spectrum of skin lymphatic reticular proliferative diseases, including lymphomatoid papulosis (LYP), primary cutaneous anaplastic large cell lymphoma (PC-ALCL), and borderline lesions between them. Although they all express CD30 as a phenotypic marker and share overlapping immunophenotypic features, they differ in clinical manifestations, pathological features, treatment, and prognosis. LYP is a kind of benign disease characterized by recurrent papules and nodules, and may spontaneously regress. PC-ALCL presents with solitary tumor or local grouped nodules characterized by large T-cells and may completely or partially resolve in fewer than half of cases. We reported a case of patient with clinical manifestation and pathologic features consistent with LYP in its early stages, which later turned into PC-ALCL. This patient was treated with acitretin combined with NB-UVB and had an obvious response.

Evaluation of treatment results in multifocal primary cutaneous anaplastic large cell lymphoma: report of the Dutch Cutaneous Lymphoma Group.

BACKGROUND: There is no consensus on the treatment of multifocal primary cutaneous anaplastic large cell lymphoma (C-ALCL). Radiotherapy (RT) and methotrexate (MTX) are the current treatment options, but their efficacy is unknown. Recently, targeted therapies showed promising results in C-ALCL, and may therefore be an attractive first choice of treatment. OBJECTIVES: To assess the efficacy of conventional treatment strategies for patients with multifocal C-ALCL, and to define which patients may require novel targeted therapies. METHODS: In this multicentre study, treatment was evaluated in patients initially presenting (n = 24) or relapsing with multifocal C-ALCL (n = 17; 23 relapses). Distinction was made between patients with five or less lesions (n = 36) and more than five lesions (n = 11). RESULTS: Treatments most commonly used were RT (n = 21), systemic chemotherapy (n = 9) and low-dose MTX (n = 7) with complete response rates of 100%, 78% and 43%, respectively, and an overall response rate of 100%, 100% and 57%, respectively. Four patients showed complete spontaneous regression. In total, 16 of 24 patients (67%) first presenting with multifocal C-ALCL relapsed, including all five patients initially treated with CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin and prednisone). Compared with patients presenting with two to five skin lesions, patients presenting with more than five lesions had a higher chance of developing extracutaneous relapse (56% vs. 20%) and more often died of lymphoma (44% vs. 7%). CONCLUSIONS: Patients with five or less lesions should be treated with low-dose RT (2 × 4 Gy). Maintenance low-dose MTX (20 mg weekly) is a suitable option in patients with more than five lesions. Targeted therapies may be considered in rare patients who are refractory to MTX or patients developing extracutaneous disease.

Outcome of primary cutaneous anaplastic large cell lymphoma: a 20-year British Columbia Cancer Agency experience.

Primary cutaneous anaplastic large cell lymphoma (PCALCL) is a rare CD30+ lymphoproliferative disorder with excellent outcomes reported despite frequent cutaneous relapses. Limited information exists on the development of systemic lymphoma. The British Columbia Cancer Agency (BCCA) Lymphoid Cancer Database was searched to identify all adults diagnosed with PCALCL from 1993 to 2013. From 2005, the BCCA endorsed radiotherapy (RT) alone for limited stage with data failing to support chemotherapy. Forty-seven patients were identified with a male predominance (n = 31, 66%), median age of 64 years and predominantly limited stage (n = 40, 85%). Median follow-up was 8·4 years. The 5-year time to progression (TTP) was 58% (64% limited versus 29% advanced stage). The 5-year disease-specific survival (DSS) and overall survival was 86% and 75%, respectively. In an as-treated analysis, the 5-year DSS for limited stage patients was similar comparing RT to combined modality treatment or chemotherapy alone but the 5-year TTP favoured RT (82% vs. 33%, P = 0·004). The 5-year cumulative risk of developing systemic lymphoma was 14%. Our results confirm the favourable prognosis of PCALCL despite a high relapse rate. Limited stage patients treated with RT alone have excellent outcomes. There is a small risk of systemic lymphoma in PCALCL.

Occult Dermal Lymphatic Involvement Is Frequent in Primary Cutaneous Anaplastic Large Cell Lymphoma.

Primary cutaneous anaplastic large cell lymphoma (pcALCL) is an indolent T-cell lymphoproliferative disorder managed with low-dose radiation therapy, surgery, and/or mild chemotherapy; patients with extensive limb disease (ELD) have a more aggressive clinical course. We have previously demonstrated that histologically apparent vascular involvement in pcALCL is lymphatic. We hypothesized that histologically occult lymphatic involvement may be associated with particular patterns of disease spread that could involve lymphangitic spread including locoregional spread of disease in the form of ELD and extracutaneous spread of disease. We have therefore set out to quantitate the incidence of occult lymphovascular involvement in pcALCL and to assess for an association between lymphovascular involvement and these patterns of disease. We performed immunohistochemistry for the lymphovascular marker D2-40 on skin biopsies from 29 patients with pcALCL followed in the Stanford Cutaneous Lymphoma Clinic. Immunohistochemically evident dermal lymphovascular involvement was found in nearly half of cases examined (48%; 95% confidence interval, 29%-67%). There was a nonsignificant trend toward a higher prevalence of ELD among patients with pcALCL involving dermal lymphatics (7% vs. 29%; p = 0.12). In this small cohort, there was no indication of a significantly more aggressive disease course in patients with lymphatic involvement either in the form of disease-related mortality (one each in the lymphatic and nonlymphatic groups) or in time to extracutaneous involvement.

EORTC, ISCL, and USCLC consensus recommendations for the treatment of primary cutaneous CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma.

Primary cutaneous CD30(+) lymphoproliferative disorders (CD30(+) LPDs) are the second most common form of cutaneous T-cell lymphomas and include lymphomatoid papulosis and primary cutaneous anaplastic large-cell lymphoma. Despite the anaplastic cytomorphology of tumor cells that suggest an aggressive course, CD30(+) LPDs are characterized by an excellent prognosis. Although a broad spectrum of therapeutic strategies has been reported, these have been limited mostly to small retrospective cohort series or case reports, and only very few prospective controlled or multicenter studies have been performed, which results in a low level of evidence for most therapies. The response rates to treatment, recurrence rates, and outcome have not been analyzed in a systematic review. Moreover, international guidelines for staging and treatment of CD30(+) LPDs have not yet been presented. Based on a literature analysis and discussions, recommendations were elaborated by a multidisciplinary expert panel of the Cutaneous Lymphoma Task Force of the European Organization for Research and Treatment of Cancer, the International Society for Cutaneous Lymphomas, and the United States Cutaneous Lymphoma Consortium. The recommendations represent the state-of-the-art management of CD30(+) LPDs and include definitions for clinical endpoints as well as response criteria for future clinical trials in CD30(+) LPDs.

Primary cutaneous anaplastic large cell lymphoma with angioinvasive features and cytotoxic phenotype: a rare lymphoma variant within the spectrum of CD30+ lymphoproliferative disorders.

BACKGROUND: Primary cutaneous anaplastic large cell lymphoma (PCALCL) presents with solitary or grouped exophytic tumors and cohesive infiltrates of large CD30+ T cells. OBJECTIVE: To report an angioinvasive variant of PCALCL. METHODS: Retrospective analysis of clinicopathological features of this variant. RESULTS: The group consisted of six patients (median age 46 years) with a solitary flat necrotic lesion preferentially located on the upper extremity. Histologically, there were angiocentric and angiodestructive infiltrates of medium-sized to large pleomorphic and anaplastic cells co-expressing CD30 and CD8. Five patients were treated with surgical excision and one patient with radiotherapy. A relapse was observed in one patient with spontaneous regression of the lesions suggesting a link to the recently described angioinvasive lymphomatoid papulosis (type E). All patients were alive without evidence of disease after a median follow-up of 31 months (range 15-96), indicating an excellent prognosis. CONCLUSIONS: The angioinvasive variant of PCALCL is rare but distinctive and prone to misinterpretation as aggressive lymphoma due to its histological features.

Perils and pitfalls regarding differential diagnosis and treatment of primary cutaneous anaplastic large-cell lymphoma.

Primary cutaneous anaplastic large-cell lymphoma (PC-ALCL), belonging to the CD30+ T-cell lymphoproliferative disorders (PCLPDs), is a rare T-cell lymphoma, presenting on the skin and characterized by very good prognosis and response to treatment in the majority of cases. Nevertheless, PC-ALCL must be distinguished from secondary skin lesions in systemic ALCL, which confer a poor prognosis, and other CD30+ PCLPDs, reactive conditions, or borderline cases. Given their rarity and heterogeneity, these entities represent diagnostic and therapeutic challenges, thus requiring a multidisciplinary approach and expertise to ensure appropriate diagnosis and management. There are several perils and pitfalls that exist regarding the differential diagnosis, the possible progression, and the treatment of PC-ALCL. Careful staging, correlation of clinical findings with histopathology and immunopathology, and thorough follow-up are essential in order to achieve a correct diagnosis and proper treatment of the disease.

Anaplastic large cell lymphoma of scrotal skin.

Cutaneous T cell lymphoma (CTCL) is an uncommon diverse group of lympho-proliferative disorders involving the skin. They vary considerably in clinical presentation, microscopic features and immunophenotyping. The diagnosis is challenging, zealous, and often not easy. CD30+ve anaplastic large cell lymphoma is extremely rare. Its clinical spectrum varies from a solitary unifocal skin lesion of excellent prognosis to a multi focal systemic disease having a poor out come. The diagnosis is quite cumbersome, and often difficult. The differential diagnosis include from benign skin lesions to secondary cutaneous involvement by lymphoma. A correct diagnosis is integral with a complete metastatic/staging work up to avoid over treatment. The treatment options depend on extent of disease involvement and include surgical excision, surveillance, local radiotherapy, and systemic chemotherapy. The prognosis is good with unifocal local disease. We present here a very rare case of CD30+ ALCL of scrotal skin, in a middle aged male patient.

Primary cutaneous and systemic anaplastic large cell lymphoma: clinicopathologic aspects and therapeutic options.

Anaplastic large cell lymphoma (ALCL) is a biologic and clinically heterogenous subtype of T-cell lymphoma. Clinically, ALCL may present as localized (primary) cutaneous disease or widespread systemic disease. These two forms of ALCL are distinct entities with different clinical and biologic features. Both types share similar histology, however, with cohesive sheets of large lymphoid cells expressing the Ki-1 (CD30) molecule. Primary cutaneous ALCL (C-ALCL) is part of the spectrum of CD30+ lymphoproliferative diseases of the skin including lymphomatoid papulosis. Using conservative measures, 5-year disease-free survival rates are > 90%. The systemic ALCL type is an aggressive lymphoma that may secondarily involve the skin, in addition to other extranodal sites. Further, systemic ALCL may be divided based on the expression of anaplastic lymphoma kinase (ALK) protein, which is activated most frequently through the nonrandom t(2;5) chromosome translocation, causing the fusion of the nucleophosmin (NPM) gene located at 5q35 to 2p23 encoding the receptor tyrosine kinase ALK. Systemic ALK+ ALCLs have improved prognosis compared with ALK-negative ALCL, although both subtypes warrant treatment with polychemotherapy. Allogeneic and, to a lesser extent, autologous stem cell transplantation play a role in relapsed disease, while the benefit of upfront transplant is not clearly defined. Treatment options for relapsed patients include agents such as pralatrexate (Folotyn) and vinblastine. In addition, a multitude of novel therapeutics are being studied, including anti-CD30 antibodies, histone deacetylase inhibitors, immunomodulatory drugs, proteasome inhibitors, and inhibitors of ALK and its downstream signaling pathways. Continued clinical trial involvement by oncologists and patients is imperative to improve the outcomes for this malignancy.

[Primary cutaneous anaplastic large cell lymphoma: clinical presentation, therapy and prognosis study of 10 cases].

OBJECTIVE: To explore the clinical presentation, therapy and prognosis study of primary cutaneous anaplastic large cell lymphoma (PCALCL). METHODS: We reviewed and analyzed ten cases of PCALCL receiving treatment at our hospital from January 1999 to January 2009. RESULTS: There were 8 males and 2 females with a median age of 48 years old (range: 22 - 69). There were single subcutaneous nodule (n = 7) and multiple nodules (n = 3). And the lesions could be found on head and neck (n = 5), trunk (n = 3) and all over body (n = 2). The lesions appeared red, solid and stable subcutaneous nodules. Partial lesions had a spontaneous regression and new nodules appeared at the same or different sites. Two patients had lymphadenopathy and one had bone involvement with anaplastic lymphoma kinase (ALK) positive and high cell proliferation ratio index (ki-67 > 80%). Seven cases with single lesion received surgical excision plus radiotherapy, chemotherapy or radiochemotherapy, one case recurred, six cases survived without disease. Three cases with multiple lesions received systemic chemotherapy mainly in combination with radiotherapy or biotherapy, two cases recurred and one case survived without disease. The median follow-up was 44 months (range: 9 - 95), progression free survival 89% and overall survival 100%. CONCLUSION: PCALCL is found more commonly in males. Visceral and lymph node involvement are rare. The patients with single lesion have a longer disease-free survival than those with multiple lesions after surgical excision in combination with chemotherapy or radiotherapy. Multiple lesions can not be cured.

Primary Cutaneous Anaplastic Large Cell Lymphoma (pcALCL) in the Elderly and the Importance of Sport Activity Training.

Primary cutaneous anaplastic large cell lymphoma (pcALCL) is part of a spectrum of cutaneous CD30+ lymphoproliferative disease that also includes lymphomatoid papulosis. It often occurs in elderly patients, presenting at a median age of 60 years, although it may occur at any age. It is a CD30+ T-cell neoplasm composed of large cells with anaplastic, pleomorphic, or immunoblastic morphology, with exclusively cutaneous onset and localization. The clinical course of pcALCL is predominantly indolent. Most elderly patients with lymphoma tend to have a sedentary lifestyle, which has a negative effect on their quality of life (QoL) and survival. Several studies indicate that exercise has a positive impact on QoL because it reduces peak oxygen consumption, improves physical capacity, increases self-esteem, reduces accumulated stress, and promotes relaxation. Therefore, particularly in indolent lymphomas, it is necessary to indicate a program of physical activity to be practiced systematically. Complete surgical excision and local radiotherapy are the first line gold standard in pcALCL with a solitary lesion.

Primary Cutaneous CD30+ Lymphoproliferative Disorders: a Comprehensive Review.

PURPOSE OF REVIEW: Primary cutaneous CD30+ T-cell lymphoproliferative disorders (CD30+ LPDs) are the second most common cutaneous lymphomas after mycosis fungoides and Sezary syndrome. They include primary cutaneous anaplastic large cell lymphoma (pcALCL), lymphomatoid papulosis (LyP), and borderline lesions. The purpose of this literature review is to consolidate the available evidence on the primary cutaneous CD30+ LPD in order to define the tools for correct diagnosis and appropriate treatment. RECENT FINDINGS: The current body of knowledge regarding the clinical features, histopathologic changes, recently described genetic alterations, and therapeutic options will be covered in this comprehensive review. Primary cutaneous CD30+ LPD represent rare cutaneous lymphomas that have significant histologic overlap within the defined group as well as with other neoplastic and reactive entities. The importance of differentiating these entities is crucial, as each one has a different clinical course and prognosis.

Fatal outcome of deep-penetrating lower limb primary cutaneous anaplastic large cell lymphomas in two immunocompromised patients.

The occurrence of primary cutaneous anaplastic large cell lymphoma (PCALCL) in immunocompromised patients is rare. Only 11 cases have been reported to date, all of them in organ transplant recipients and none in patient with idiopathic CD4+ T-cell lymphocytopaenia. We describe here the original clinical pattern of deep, fascia and muscle-penetrating PCALCL of the lower limb in two immunocompromised patients, one in a renal transplant recipient, the other in a patient with idiopathic CD4+ T-cell lymphocytopaenia. Both patients experienced a negative outcome, contrasting with the usually indolent course of PCALCL in immunocompetent patients, since both died of complications related to the lymphoma 30 and 13 months later, respectively. The unusual clinical aggressiveness of these two cases of PCALCL suggests that, in this peculiar subset with a deep structures involvement hallmark, a worse prognosis could be expected, especially in immunocompromised patients. This information should be taken into consideration when making therapeutic choices.

[Primary cutaneous anaplastic large cell lymphoma: a clinicopathologic analysis of 8 cases].

OBJECTIVE: To study the clinicopathologic features, immunophenotype and prognosis of primary cutaneous anaplastic large cell lymphoma (C-ALCL). METHODS: Eight cases of C-ALCL were enrolled into the study. The clinicopathologic features, immunohistochemical findings and results of in-situ hybridization for EBER 1/2 were analyzed. RESULTS: Three of the 8 patients were males and 5 were females. The median age was 49.5 years. C-ALCL often presented with solitary skin nodule, without systemic symptoms. Histologically, the lymphoma cells infiltrated the dermis and subcutis in a sheet-like pattern. They were of large size and showed conspicuous nuclear atypia. Immunohistochemical study showed that more than 75% of the lymphoma cells were positive for CD30. All cases expressed one to three T cell markers (CD3, CD5 or CD45RO) and cytotoxic granule-associated antigens (TIA-1, granzyme B or perforin). The staining for leukocyte common antigen was positive in all cases, while the expression of CD5, CD8, ALK-1 and epithelial membrane antigen was noted in 5, 1, 1 and 3 cases, respectively. The staining for CD15, CD20, CK and HMB45 was negative. In-situ hybridization for EBER 1/2 was also negative in all the cases studied. Follow-up information was available in 6 patients. Five of them were still alive and 1 died of unclear cause. CONCLUSIONS: C-ALCL has distinctive clinicopathologic and immunophenotypic features. It is not Epstein-Barr virus-related and often carries a favorable prognosis.

Lymphomatoid Papulosis and Other Lymphoma-Like Diseases.

Pityriasis lichenoides et varioliformis acuta and pityriasis lichenoides chronica are the 2 main subtypes of pityriasis lichenoides. They represent the acute and chronic forms of the disease; both may have clonal T cells. Several treatment modalities are used, but it has been difficult to determine efficacy because of the possibility of spontaneous remission. Cutaneous CD30+ lymphoproliferative disorders constitute many cutaneous T-cell lymphomas and comprise lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma (ALCL). Both have an excellent prognosis. Lymphomatoid papulosis often only requires observation or treatment of symptoms. First-line therapies for primary cutaneous ALCL are surgical excision or radiotherapy.

Kaposi's varicelliform eruption in a patient with metastatic melanoma and primary cutaneous anaplastic large cell lymphoma treated with talimogene laherparepvec and nivolumab.

BACKGROUND: Immune-directed therapies have become front-line therapy for melanoma and are transforming the management of advanced disease. In refractory cases, multi-modal immunoncology (IO) approaches are being utilized, including combining immune checkpoint blockade (ICB) with oncolytic herpes viruses. Talimogene laherparepvec (T-VEC) is the first genetically modified oncolytic viral therapy (OVT) approved for the treatment of recurrent and unresectable melanoma. The use of IO in patients with concomitant malignancies and/or compromised immune systems is limited due to systematic exclusion from clinical trials. For example, a single case report of a solid organ transplant patient successfully treated with T-VEC for metastatic melanoma has been reported. Furthermore, the use of ICB in T-cell malignancies is limited and paradoxical worsening has been described. To our knowledge, this is the first report of dual ICB/T-VEC being administered to a patient with concurrent primary cutaneous anaplastic large cell lymphoma (pcALCL) and melanoma. CASE PRESENTATION: Here we present the case of a patient with concomitant primary cutaneous ALCL and metastatic melanoma, progressing on anti-programmed death (PD)-1 therapy, who developed Kaposi's varicelliform eruption after receiving the first dose of Talimogene laherparepvec. CONCLUSION: This case highlights the complexities of care of patients with coexistent cancers, demonstrates rapid progression of primary cutaneous ALCL on nivolumab and introduces a novel adverse effect of Talimogene laherparepvec.