features of anaplasia, pleomorphism, and kidney- and horse shaped-nuclei. These lesions are often limited to the dermis but can extend into the surrounding subcutaneous tissue and/or epidermis. Rarely, the lesions, termed pyrogenic variants, are rich in polymorphonuclear neutrophils. The neoplastic cells strongly express CD30 (100% of cases), CD2 (78%), CD4 (54–90% of cases), cytotoxicity marker proteins, and various other marker proteins that help distinguish it from other ALCL, cutaneous T-cell lymphomas, and cancers. While these cells typically are ALK-negative, they do express ALK-containing fusion proteins in rare cases. The latter cases have a relatively benign course compared to ALK-positive ALCL and are treated as variants of pcALCL rather than ALK-positive ALCL. Gene and molecular abnormalities Similar to ALK-negative ALCL, pcALCL have chromosomal rearrangements in their DUSP22 (20-30% of cases) and TP63 (5% of cases) genes and a mutation in the MSC (i.e. musculin) gene (6% of cases). Between 1993 and 2019, the Dutch registry had 6 (i.e. 2%) of 319 pcALCL cases that expressed ALK. Three of these cases were due to the NPM1-ALK chimeric gene that predominates in ALK-positive ALCL while the remaining three were due to TRAF1-ALK, ATIC-ALK, or TPM3-ALK chimeric genes. All 6 patients shared exactly the same breakpoint site in the ALK at exon 20 on the ALK gene. Treatment and prognosis Most pcALCL individuals present with isolated lesions that are effectively managed with radical surgical excision and/or radiation therapies; this approach is regarded as front-line therapy for localized disease. However, individuals with extensive disease and/or multiple tissue involvement respond poorly to front line treatment. These as well as individuals who relapse after front-line therapy need further treatment. In one study of 65 patients with pcALCL, 95% treated with surgical excision achieved complete remission but 41% of them relapsed within 22 months while 64% of patients treated with surgery plus radiotherapy developed recurrent disease within 55 months. In another study of 135 patients with this disease, 39% had relapses limited to the skin, 15% developed extracutaneous disease, and 9% ultimately died from pcALCL. Individuals with refractory, recurrent, and/or extensive disease have been treated more aggressively. In various studies, 10 of 13 such patients responded within 4 weeks to treatment with the chemotherapeutic agent, methotrexate; 10 of 16 patients obtained complete remissions of their skin lesions when treated with the anti-CD30 monoclonal antibody, brentuximab verdotin, and 48 of 53 patients treated with the aggressive chemotherapeutic CHOP regimen