Cutaneous CD30-positive lymphoproliferations: therapeutic strategies and prognostic factors

Cutaneous lymphomas originate from cancer of the lymphocytes in the skin without lymph node/organ involvement at time of diagnosis. There are many types of cutaneous lymphomas, with this thesis focusing on CD30-positive cutaneous lymphomas, consisting of a spectrum with lymphomatoid papulosis (LyP) on one side, and primary cutaneous anaplastic large cell lymphoma (C-ALCL) on the other. LyP is characterized by multiple skin lesion that resolve spontaneously, and C-ALCL by a solitary or grouped tumor that persists. This thesis shows that approximately 15% of LyP patients develop a second skin lymphoma/blood cancer, but also have an increased risk of developing other cancers (squamous cell carcinoma/melanoma/colon/lung/bladder cancer). At molecular level, a subcategory of patients was found in C-ALCL with ALK translocations, suggestive of a systemic lymphoma. It appears that these patients also have a favorable prognosis and can be treated with radiotherapy. The optimal dose of radiotherapy was also demonstrated (8 Gray). In addition, different types of mutations (PI-3-K/MAPK/G pathways) seem to occur in C-ALCL compared to more aggressive lymphomas (JAK-STAT). C-ALCL patients with ≤5 tumors are best treated with radiotherapy, and patients with >5 lesions with methotrexate. Targeted therapies remain for patients not responding to methotrexate or with systemic involvement.LUMC / Geneeskund

Frequency and prognosis of associated malignancies in 504 patients with lymphomatoid papulosis

Background: Lymphomatoid papulosis (LyP) can be associated with other haematological malignancies (HM), but reported percentages vary from 20% to over 50%. Objective: To evaluate the frequency and prognostic significance of associated HM and non-HM in LyP patients. Methods: In this multicentre cohort study, the complete Dutch LyP population was included from the Dutch Cutaneous Lymphoma Registry between 1985 and 2018. Clinical and histopathological information was retrieved from every individual patient. Results: After a median follow-up of 120 months (range, 6–585), an associated HM was observed in 78/504 (15.5%) patients. Most common associated HM were mycosis fungoides (MF; n = 31) and anaplastic large-cell lymphoma (ALCL; n = 29), while 19 patients had another HM of B-cell (n = 14) or myeloid origin (n = 5). Even after a 25-year follow-up period, percentages of associated HM did not exceed 20%. Thirty-nine of 465 patients (8.4%) without a prior or concurrent associated HM developed an associated HM during follow-up, after a median of 68 months (range of 3–286 months). Nine of 78 patients died of associated HM, including 6/22 patients developing extracutaneous ALCL, while all patients with associated MF or skin-limited ALCL had an excellent prognosis. Compared with the general population, LyP patients showed an increased risk (relative risk, 2.8; 95% confidence intervals, 2.4–3.3) for non-HM, in particular cutaneous squamous cell carcinoma, melanoma and intestinal/lung/bladder cancer. Conclusions: An associated HM was reported in 15.5% of the LyP patients, particularly MF and ALCL. Although the frequency of associated HM is lower than suggested and the prognosis of most patients with associated HM is excellent, a small subgroup will develop aggressive disease, in particular extracutaneous ALCL. Furthermore, LyP patients have a higher risk of developing other malignancies. Clinicians should be aware of these risks, and LyP patients require close monitoring

Cutaneous CD30-positive lymphoproliferations: therapeutic strategies and prognostic factors

Cutaneous lymphomas originate from cancer of the lymphocytes in the skin without lymph node/organ involvement at time of diagnosis. There are many types of cutaneous lymphomas, with this thesis focusing on CD30-positive cutaneous lymphomas, consisting of a spectrum with lymphomatoid papulosis (LyP) on one side, and primary cutaneous anaplastic large cell lymphoma (C-ALCL) on the other. LyP is characterized by multiple skin lesion that resolve spontaneously, and C-ALCL by a solitary or grouped tumor that persists. This thesis shows that approximately 15% of LyP patients develop a second skin lymphoma/blood cancer, but also have an increased risk of developing other cancers (squamous cell carcinoma/melanoma/colon/lung/bladder cancer). At molecular level, a subcategory of patients was found in C-ALCL with ALK translocations, suggestive of a systemic lymphoma. It appears that these patients also have a favorable prognosis and can be treated with radiotherapy. The optimal dose of radiotherapy was also demonstrated (8 Gray). In addition, different types of mutations (PI-3-K/MAPK/G pathways) seem to occur in C-ALCL compared to more aggressive lymphomas (JAK-STAT). C-ALCL patients with ≤5 tumors are best treated with radiotherapy, and patients with >5 lesions with methotrexate. Targeted therapies remain for patients not responding to methotrexate or with systemic involvement.</p

Cutaneous CD30-positive lymphoproliferations: therapeutic strategies and prognostic factors

Cutaneous lymphomas originate from cancer of the lymphocytes in the skin without lymph node/organ involvement at time of diagnosis. There are many types of cutaneous lymphomas, with this thesis focusing on CD30-positive cutaneous lymphomas, consisting of a spectrum with lymphomatoid papulosis (LyP) on one side, and primary cutaneous anaplastic large cell lymphoma (C-ALCL) on the other. LyP is characterized by multiple skin lesion that resolve spontaneously, and C-ALCL by a solitary or grouped tumor that persists. This thesis shows that approximately 15% of LyP patients develop a second skin lymphoma/blood cancer, but also have an increased risk of developing other cancers (squamous cell carcinoma/melanoma/colon/lung/bladder cancer). At molecular level, a subcategory of patients was found in C-ALCL with ALK translocations, suggestive of a systemic lymphoma. It appears that these patients also have a favorable prognosis and can be treated with radiotherapy. The optimal dose of radiotherapy was also demonstrated (8 Gray). In addition, different types of mutations (PI-3-K/MAPK/G pathways) seem to occur in C-ALCL compared to more aggressive lymphomas (JAK-STAT). C-ALCL patients with ≤5 tumors are best treated with radiotherapy, and patients with >5 lesions with methotrexate. Targeted therapies remain for patients not responding to methotrexate or with systemic involvement.</p

Contact allergy to a shellac-containing mouthguard

Dermatology-oncolog

Contact allergy to a shellac-containing mouthguard

Shellac is a typical cosmetic allergen that can cause reactions such as eyelid dermatitis to mascara or contact cheilitis to lipstick. However, in this case report we present shellac as a relevant contact allergen in a noncosmetic context.Dermatology-oncolog

Whole-genome profiling of primary cutaneous anaplastic large cell lymphoma

Primary cutaneous anaplastic large cell lymphoma (pcALCL), a hematological neoplasm caused by skin-homing CD30(+) malignant T cells, is part of the spectrum of primary cutaneous CD30(+) lymphoproliferative disorders. To date, only a small number of molecular alterations have been described in pcALCL and, so far, no clear unifying theme that could explain the pathogenetic origin of the disease has emerged among patients. In order to clarify the pathogenetic basis of pcALCL, we performed high-resolution genetic profiling (genome/transcriptome) of this lymphoma (n=12) by using whole-genome sequencing, whole-exome sequencing and RNA sequencing. Our study, which uncovered novel genomic rearrangements, copy number alterations and small-scale mutations underlying this malignancy, revealed that the cell cycle, T-cell physiology regulation, transcription and signaling via the PI-3-K, MAPK and G-protein pathways are cellular processes commonly impacted by molecular alterations in patients with pcALCL. Recurrent events affecting cancer-associated genes included deletion of PRDM1 and TNFRSF14, gain of EZH2 and TNFRSFB, small-scale mutations in LRP18, PDPK1 and PIK3R1 and rearrangements involving GPS2, LINC-PINT and TNK1. Consistent with the genomic data, transcriptome analysis uncovered upregulation of signal transduction routes associated with the PI-3-K, MAPK and G-protein pathways (e.g., ERK, phospholipase C, AKT). Our molecular findings suggest that inhibition of proliferation-promoting pathways altered in pcALCL (particularly PI-3-K/AKT signaling) should be explored as potential alternative therapy for patients with this lymphoma, especially, for cases that do not respond to first-line skin-directed therapies or with extracutaneous disease.Dermatology-oncolog

Clinical, histologic, and molecular characteristics of anaplastic lymphoma kinase-positive primary cutaneous anaplastic large cell lymphoma

Unlike systemic anaplastic large cell lymphoma, the vast majority of primary cutaneous anaplastic large cell lymphomas (C-ALCL) do not carry translocations involving the ALK gene and do not express ALK. Expression of ALK protein therefore strongly suggests secondary cutaneous involvement of a systemic anaplastic large cell lymphoma. Recent studies described a small subgroup of ALK-positive C-ALCL, but information on frequency, prognosis, and translocation partners is virtually lacking. A total of 6/309 (2%) C-ALCL patients included in the Dutch registry for cutaneous lymphomas between 1993 and 2019 showed immunohistochemical ALK expression. Clinical and histopathologic characteristics, immunophenotype and disease course were evaluated. Underlying ALK translocations were analyzed with anchored multiplex polymerase chain reaction-based targeted next-generation sequencing. Median age at diagnosis was 39 years (range: 16 to 53 y). All patients presented with a solitary lesion. Treatment with radiotherapy (n=5) or anthracycline-based chemotherapy (n=1) resulted in complete responses in all 6 patients. Three patients developed a relapse, of whom 2 extracutaneous. After a median follow-up of 41 months, 5 patients were alive without disease and 1 patient died of lymphoma. Immunohistochemically, 3 cases (50%) showed combined nuclear and cytoplasmic ALK expression with underlying NPM1-ALK fusions, while 3 cases (50%) showed solely cytoplasmic ALK expression with variant ALK fusion partners (TRAF1, ATIC, TPM3). ALK-positive C-ALCL is extremely uncommon, has a comparable favorable prognosis to ALK-negative C-ALCL, and should be treated in the same way with radiotherapy as first-line treatment.Dermatology-oncolog

Recommendations for the Optimal Radiation Dose in Patients With Primary Cutaneous Anaplastic Large Cell Lymphoma: A Report of the Dutch Cutaneous Lymphoma Group

Dermatology-oncolog

Outcomes of rare patients with a primary cutaneous CD30(+) lymphoproliferative disorder developing extracutaneous disease

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