Primary cutaneous anaplastic large cell lymphoma

INTRODUCTION — Primary cutaneous T cell lymphoma (PCTL) refers to cases of T cell lymphoma that present in the skin where there is no evidence of systemic (extracutaneous) disease at the time of diagnosis and after the completion of an initial staging evaluation.

Primary cutaneous CD30-positive T cell lymphoproliferative disorders are the second most common category of cutaneous T cell lymphoma in the World Health Organization (WHO) classification of lymphoid neoplasms [1]. This is a spectrum of disorders that ranges from the more benign lymphomatoid papulosis (which almost always regresses spontaneously) to the neoplastic primary cutaneous anaplastic large cell lymphoma (PC-ALCL), and includes "borderline" cases with features of each.

This topic will focus on the diagnosis and management of PC-ALCL. The diagnosis and management of systemic ALCL and lymphomatoid papulosis are presented separately.

●(See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)".)

●(See "Initial treatment of systemic anaplastic large cell lymphoma (sALCL)".)

●(See "Lymphomatoid papulosis".)

EPIDEMIOLOGY — PC-ALCL is rare and the exact incidence is not known partially because it is difficult to distinguish cases of PC-ALCL within the larger group of CD30-positive cutaneous lymphoproliferative disorders (ie, lymphomatoid papulosis and borderline cases). In an analysis of the Surveillance, Epidemiology, and End Results (SEER) database, 157 cases of primary, localized CD30-positive cutaneous lymphoproliferative disorder were documented over a 30-year timespan [2]. The median age at diagnosis was 61 years (range 5 to 98 years). There was a slight male predominance (58 percent) and most cases were diagnosed in White individuals (87 percent). Other epidemiologic reports have had similar findings [3,4].

CLINICAL AND PATHOLOGIC FEATURES — Most patients with PC-ALCL present with solitary or grouped nodules growing over weeks to months and measuring up to several centimeters. These nodules typically ulcerate with time (picture 1). The lesions regress in up to 50 percent of cases but rarely completely resolve [5]. Multifocal disease is rare at the time of diagnosis (picture 2 and picture 3) and extracutaneous spread occurs in up to 13 percent of cases, at the time of relapse [6].

Skin biopsy specimens are characterized by a dense dermal infiltrate that does not usually involve the epidermis [7,8]. The infiltrate is comprised of cohesive sheets of large CD30-positive tumor cells that morphologically resemble those of systemic ALCL (ie, large cells with abundant pale, eosinophilic cytoplasm and round or pleomorphic, often horseshoe-shaped nuclei with prominent nucleoli). Approximately one-quarter have an atypical, non-anaplastic appearance. Reactive lymphocytes, histiocytes, eosinophils, and neutrophils are commonly present in the periphery of the lesion and in ulcerating lesions in association with epidermal hyperplasia. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)", section on 'Classical variant'.)

By definition, at least 75 percent of the tumor cells express CD30 [7-9]. In addition, most cases express CD4 and have variable loss of CD2, CD3, and CD5. Most cases are positive for cutaneous lymphocyte antigen (CLA, HECA-452), but unlike systemic ALCL, they lack expression of epithelial membrane antigen (EMA) and anaplastic lymphoma kinase (ALK). (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)", section on 'Immunophenotype'.)

Most cases show clonal rearrangement of the T cell receptor (TCR) genes, although TCR proteins are often not expressed [7,8]. Unlike systemic ALCL, PC-ALCL do not have gene rearrangements involving the ALK gene on chromosome 2p23 [10].

DIAGNOSIS — The diagnosis of PC-ALCL requires a representative biopsy. Excisional biopsies are preferred to incisional biopsies. If a punch biopsy is taken, the diameter should be at least 4 millimeters. The biopsy specimen is evaluated for morphology, growth pattern, and immunohistochemical studies. The diagnosis is based upon the presence of characteristic findings on biopsy specimens in conjunction with the clinical features found on presentation. (See 'Clinical and pathologic features' above.)

All patients with a presumed diagnosis of PC-ALCL should undergo a staging assessment to confirm the absence of systemic disease. This evaluation includes a physical examination, complete blood count with differential, and radiographic staging [8,11]. For imaging, we prefer a contrast-enhanced computed tomography scan combined with positron emission tomography (PET/CT), but a CT of the chest, abdomen, and pelvis is acceptable if PET is not available. The utility of a bone marrow biopsy and aspirate in the absence of clinically or radiographically detectable disseminated disease remains debatable, but we do suggest it. Others reserve bone marrow examination for patients with multifocal tumors, unexplained cytopenias, and those with documented extracutaneous disease [8].

A clinical or radiographic suspicion of disseminated disease should be confirmed by biopsy since local or regional nodes may be abnormal due to inflammation alone. Of importance, the presence of pathologic involvement of local nodes alone does not seem to portend an adverse prognosis in patients with PC-ALCL [4].

DIFFERENTIAL DIAGNOSIS — Patients with PC-ALCL present with solitary or grouped slowly enlarging nodules that demonstrate a CD30-positive lymphoid infiltrate on biopsy. The main entities that should be considered in the differential diagnosis are lymphomatoid papulosis, systemic ALCL, transformed mycosis fungoides, and reactive causes of CD30-positive lymphoid infiltrates.

●Lymphomatoid papulosis (LyP) – LyP is a recurrent, self-healing condition characterized by a papulonodular skin eruption with histologic features of a CD30-positive lymphoid proliferation of atypical T cells. In contrast to PC-ALCL, LyP lesions are usually smaller (<2 cm) and resolve spontaneously after weeks to months, often leaving residual scars and hyperpigmentation [7,8,12]. There is considerable clinical, histologic, and immunophenotypic overlap between LyP and PC-ALCL. A waxing and waning clinical course is consistent with LyP. Skin lesions that do not spontaneously regress within eight weeks are suggestive of PC-ALCL. The term "borderline" is used for cases in which a distinction between PC-ALCL and LyP cannot be made despite careful clinical and pathologic evaluation [7]. (See "Lymphomatoid papulosis".)

●Transformed mycosis fungoides – About half of transformed mycosis fungoides and Sézary syndrome express CD30. A previous history of patch or plaque mycosis fungoides or erythroderma is suggestive of the diagnosis. (See "Clinical manifestations, pathologic features, and diagnosis of mycosis fungoides" and "Clinical presentation, pathologic features, and diagnosis of Sézary syndrome".)

●Systemic lymphoma – As described above, all patients with a presumed diagnosis of PC-ALCL should undergo a staging assessment to confirm the absence of systemic disease. Involvement of regional lymph nodes does not necessarily indicate the presence of systemic disease as pathologic involvement of local nodes alone does not impact the prognosis in patients with PC-ALCL [4]. In patients with cutaneous lesions suggestive of PC-ALCL, expression of ALK or identification of a translocation involving ALK is highly suggestive of cutaneous involvement of systemic ALCL rather than PC-ALCL. (See "Clinical manifestations, pathologic features, and diagnosis of systemic anaplastic large cell lymphoma (sALCL)", section on 'Immunophenotype'.)

Adult T cell leukemia-lymphoma (ATLL) can present with cutaneous lesions that may be difficult to distinguish from PC-ALCL. The cells can be anaplastic in appearance, express CD30, and are ALK negative. ATLL is caused by the human retrovirus HTLV-1 and the key distinguishing feature is the presence of HTLV-1 in the malignant cells of ATL. (See "Clinical manifestations, pathologic features, and diagnosis of adult T cell leukemia-lymphoma".)

Hodgkin lymphoma (HL) expresses CD30 and rarely presents with cutaneous involvement. Unlike PC-ALCL, HL expresses CD15. (See "Hodgkin lymphoma: Epidemiology and risk factors".)

●Reactive lymphoid hyperplasia – CD30-positive lymphoid infiltrates may develop in response to insect bites or infestations (eg, scabies), viral infections (eg, herpes simplex, varicella-zoster), and certain medications (eg, anticonvulsant medications) [12]. These non-neoplastic causes are usually associated with a lower percentage of CD30-positive cells on biopsy, do not have a waxing and waning clinical course, and do not show T cell receptor (TCR) gene rearrangement on molecular genetic studies. (See "Lymphomatoid papulosis", section on 'CD30+ inflammatory and infectious diseases'.)

TREATMENT — The key to the management of patients with PC-ALCL is to avoid overtreatment. Oncologists unfamiliar with the disease may recommend aggressive systemic chemotherapy including high-dose chemotherapy and autologous hematopoietic cell transplantation when such steps are unnecessary and overly toxic. (See 'Choice of agent' below.)

Most data regarding management of recurrent, multifocal, or systemic PC-ALCL come from small cohort series, case reports, and small single-center trials. Interpretation of the available evidence is further complicated by the fact that patients with relapsing disease are treated with several therapies concurrently, thereby limiting assessment of the efficacy of individual modalities.

Initial management — Most patients with PC-ALCL present with isolated lesions that can be managed with complete surgical excision (with negative margins) or radiation. Using this approach, the majority of patients will achieve a complete remission, although most will recur and require subsequent therapy.

For patients with solitary lesions without lymph node involvement, either of these modalities is acceptable. A choice is often made based on the location of the lesions and expertise available at the treatment center. For patients with pathologically confirmed, isolated involvement of local nodes, we suggest radiation to the primary lesion and the local node(s) rather than surgical excision alone or systemic therapy. In this setting, regional lymph node involvement does not appear to impart an adverse prognosis.

A retrospective cohort analysis evaluated the efficacy of surgical excision with or without radiation in 56 patients with CD30-positive cutaneous lymphoproliferative disorders [6]. Among those with solitary PC-ALCL treated with surgical excision, 95 percent achieved a complete response and 41 percent recurred within a follow-up period of 22 months. Among those treated with surgery plus radiation, 64 percent recurred during a follow-up period of 55 months. This was not a randomized trial and the patient populations likely differ between the two groups. Even so, these results suggest that there is no compelling evidence that adding radiotherapy to complete surgical excision benefits patients with localized disease.

The optimal dose of radiation for PC-ALCL is not known. Electrons are frequently used with a dose of 36 to 40 Gy and a margin of at least 2 cm, though lower doses may be equally efficacious [13].

Recurrent disease — While the vast majority of patients will attain a complete remission following initial therapy, most will recur within the first five years. The management of recurrent disease is largely dependent on the extent of disease. However, many patients will experience serial relapses and will be treated with each of the therapies described at some point during their disease course. A preferred order for their use has not been established. A choice is made based on the patient's prior treatment, the therapies' expected toxicities, and comorbid illnesses.

Localized lesions — Cutaneous recurrences after primary surgery or radiation can be treated with the same modalities again, although multiple surgeries and/or multiple radiation treatments often induce morbidity or patient inconvenience over time. Given the tendency for spontaneous regression, recurrent lesions can be observed if they are not bothersome to the patient.

Patients who experience multiple recurrences for whom repeated surgical excision and/or radiation could become excessively morbid are typically better served by systemic therapy. (See 'Multiple lesions' below.)

Case reports and small case series have described the use of topical therapies such as the immune response modifier imiquimod [14], intralesional interferon alfa [15], and topical bexarotene gel [16,17]. Topical bexarotene can cause an intense localized retinoid dermatitis that often necessitates concomitant administration of topical corticosteroids. Patients on any of these therapies should be followed in conjunction with a dermatologist experienced with their use.

Multiple lesions

Choice of agent — We offer systemic therapy to patients with more widespread disease, and to those who experience multiple recurrences for whom repeated surgical excision and/or radiation could become excessively morbid.

The choice of systemic therapy is influenced by prior therapies, likely toxicities, comorbid illnesses, physician experience, and patient preferences. We offer the following approach:

●Oral methotrexate is our preferred initial systemic therapy given its reasonable response rate, convenience, and favorable toxicity profile. (See 'Oral methotrexate' below.)

For patients who have a contraindication to methotrexate, acceptable alternatives include oral bexarotene or single agent chemotherapy. Interferon may also be used in this population, although it is often difficult to tolerate given its toxicities.

Brentuximab vedotin (BV) is another option for patients who received prior radiation therapy. (See 'Brentuximab vedotin' below and 'Bexarotene' below and 'Other agents' below and 'Interferon' below.)

●We favor BV for patients who progressed on or are intolerant of initial systemic therapy. (See 'Brentuximab vedotin' below.)

●For patients in whom BV is ineffective or causes unacceptable toxicity, we offer sequential single agent therapy with romidepsin, pralatrexate, gemcitabine, etoposide, or liposomal doxorubicin, as used in mycosis fungoides. (See 'Widespread nodal or visceral involvement' below.)

Although most data regarding these agents in PC-ALCL come from small cohort series, case reports, and small single-center trials, one randomized trial demonstrated superior efficacy (but increased peripheral neuropathy) for patients assigned to BV compared with physician's choice of bexarotene or methotrexate [18]. (See 'Brentuximab vedotin' below.)

In contrast, multiagent chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), has not proven superior to these less aggressive strategies. We reserve multiagent chemotherapy for patients with widespread nodal or visceral involvement or patients who have failed numerous single agents and skin-directed therapy. (See 'Widespread nodal or visceral involvement' below.)

Oral methotrexate — Oral methotrexate is our preferred initial systemic therapy. In one study, 10 of 13 (77 percent) patients with PC-ALCL responded to oral methotrexate [19]. Most of these patients responded within four weeks, and the median duration of methotrexate treatment was 39 months.

●Dosing – A typical starting dose for methotrexate is 15 mg in two divided doses once per week (ie, 7.5 mg orally twice per day on a chosen day of the week). We have patients take folic acid 1 mg daily on the days they are not taking methotrexate. Proton-pump inhibitors can increase methotrexate levels and should be used with caution in this population.

The methotrexate dose can be titrated up (or down) based upon efficacy or tolerance, but we do not typically use doses higher than 25 mg weekly. Dose adjustments should be made if there is no clinical improvement within eight weeks of therapy.

●Duration of therapy – Although the optimal duration of treatment is unclear, we tend to treat to best response and then decrease the frequency of methotrexate and continue as maintenance therapy for a maximum of three years. In our experience, even once monthly dosing can be effective to maintain remissions. We limit maintenance to three years because 50 percent of patients treated with methotrexate for three years had evidence of hepatic fibrosis in one series [19]. Methotrexate can be reinstituted if there is evidence of recurrence.

●Contraindications and adverse effects – Important contraindications to methotrexate therapy include liver disease, renal disease, and pregnancy or planned pregnancy (for both women and men). Before initiating long-term methotrexate therapy, screening for hepatitis B and hepatitis C virus infection is recommended. In patients with infection, this allows a decision whether to avoid the use of methotrexate, to try to eradicate the viral infection before initiating therapy, or to suppress viral replication during immunosuppressive therapy. Patients receiving low-dose methotrexate should have periodic monitoring of peripheral blood counts, aminotransaminases, and albumin.

Minor adverse effects, including nausea, stomach upset, headache, and fatigue, occur in most patients treated with low-dose methotrexate. Hepatotoxicity, pulmonary fibrosis, and myelosuppression are serious adverse effects of methotrexate treatment and may infrequently occur with low-dose therapy. (See "Major side effects of low-dose methotrexate".)

Bexarotene — Bexarotene is a systemic rexinoid (synthetic agent that binds to the retinoid "X" receptor) that is widely used in mycosis fungoides. Data regarding its use in PC-ALCL are limited to case reports and as the control arm of the ALCANZA trial where the response rate to bexarotene was low [16,17]. Therefore, we reserve bexarotene for patients who have a contraindication to methotrexate or have failed methotrexate due to disease progression or toxicity. Bexarotene must be used with caution in patients with hypertriglyceridemia, liver dysfunction, or risk factors for pancreatitis.

Although the package insert suggests a higher starting dose, we usually start at very low doses (ie, 225 mg total daily dose) with titration based on tolerance and response. In most circumstances we do not exceed 300 mg/m² daily, but doses as high as 400 mg/m² may be used in rare circumstances. Liver function, serum lipid levels, thyroid function (serum free T4), and complete blood counts should be monitored in each patient during treatment [20,21]. Given the high incidence of hyperlipidemia with bexarotene, we prescribe concomitant fenofibrate. Additional lipid lowering agents are sometimes necessary. Gemfibrozil should not be used because co-administration results in increased serum levels of bexarotene. This agent also causes central hypothyroidism and thyroid replacement must be adjusted based upon free T4 and not TSH. Further detail regarding the administration and toxicities of systemic bexarotene is presented separately. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides", section on 'Systemic retinoids'.)

Most toxicities are reversible after cessation of therapy. The most common adverse effects include weakness, myalgia, arthralgia, and headaches. Retinoids have potential hepatotoxic and hyperlipidemic effects, necessitating monitoring. Women of childbearing potential should use two reliable forms of contraception, including at least one nonhormonal form given the well-known teratogenic effects of retinoids.

Brentuximab vedotin — Brentuximab vedotin (BV) is an anti-CD30 monoclonal antibody conjugated with monomethyl auristatin E by a protease-cleavable linker that has activity in lymphomas that express CD30. BV is approved by the US Food and Drug Administration (FDA) for treatment of PC-ALCL after at least one prior systemic therapy [22].

The typical starting dose is 1.8 mg/kg (to a maximum dose of 180 mg) given intravenously every three weeks; BV can be given indefinitely until intolerance or disease progression. Infusion reactions are uncommon, but anaphylaxis has been reported. Peripheral neuropathy is the most common dose-limiting toxicity [23], and can be managed with dose reduction to 1.2 mg/kg or increasing the dosing interval. Progressive multifocal leukoencephalopathy is a rare complication of BV treatment and typically presents with subacute neurologic deficits, which may include altered mental status, visual symptoms, weakness, ataxia, and seizures. (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Brentuximab' and "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis" and "Neurologic complications of cancer treatment with molecularly targeted and biologic agents", section on 'Brentuximab'.)

An international, open-label trial randomly assigned 128 patients with CD30-expressing PC-ALCL (31 patients) or mycosis fungoides to treatment with BV versus the physician's choice (PC) of bexarotene or methotrexate [18]. BV resulted in complete resolution of skin involvement in 10 of 16 patients (63 percent) with PC-ALCL. Compared with PC, BV achieved superior rates of:

●Overall response that lasted at least four months (ORR4) among patients with PC-ALCL – 75 versus 20 percent

●Complete response (skin plus extracutaneous disease) among patients with PC-ALCL – 31 versus 7 percent

●Median progression-free survival (in all patients) – 17 versus 4 months

●Symptomatic relief (measured by Skindex-29 score, in all patients) – 28 versus 9

There were comparable rates of grade 3/4 adverse events, but higher rates of peripheral neuropathy (any grade) in patients treated with BV (67 versus 6 percent).

Other reports describe activity of BV in the setting of relapsed/refractory CD30-expressing cutaneous T cell lymphoma [24,25].

Interferon — Interferons have been used off-label for the treatment of mycosis fungoides and Sézary syndrome for decades. Data regarding the use of systemic interferon in PC-ALCL are limited to case reports, usually in combination with other agents [26,27]. Interferon alfa can be given intralesionally or subcutaneously for systemic absorption if there are numerous lesions. The usual starting dose is 3 million units three times weekly with titration up or down based upon tolerance and efficacy. Interferon can cause depression as well as liver function and thyroid abnormalities. As a result of interferon’s toxicity and somewhat cumbersome method of administration, we favor methotrexate and bexarotene and reserve interferon for patients who progress on or are intolerant of those medications.

The use of interferon alfa in mycosis fungoides and Sézary syndrome is discussed in more detail separately. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides", section on 'Interferon' and "Treatment of Sézary syndrome", section on 'Interferons (IFN)'.)

Other agents — Romidepsin, pralatrexate, etoposide, gemcitabine, and liposomal doxorubicin can be used as single agents, as they are for mycosis fungoides and Sézary syndrome [8,28,29]. The use of these agents in mycosis fungoides and Sézary syndrome is discussed in more detail separately. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides", section on 'Single agent chemotherapy' and "Treatment of Sézary syndrome", section on 'Single-agent chemotherapy'.)

Multiagent chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), has not proven superior to less aggressive strategies. In an analysis of 53 patients, multiagent chemotherapy resulted in a complete response rate of 92 percent, but 62 percent of patients relapsed at a median of four months [8]. On a subset analysis of patients treated with CHOP, the complete response rate was 85 percent and 71 percent relapsed. We reserve multiagent chemotherapy for patients with widespread nodal or visceral involvement or patients who have failed numerous single agents and skin-directed therapy. (See 'Widespread nodal or visceral involvement' below.)

Widespread nodal or visceral involvement — Widespread nodal or visceral involvement are adverse prognostic features that are uncommon at presentation, but may occur in later phases of the illness when multiple skin-directed or less toxic systemic therapies have failed [30,31]. Extensive limb disease (ELD) on the same limb and/or contiguous body areas may also be an adverse prognostic feature.

Patients with widespread nodal or visceral involvement or ELD can be treated with single agent systemic chemotherapy. We generally treat widespread systemic disease with brentuximab vedotin, if it was not previously used and there is no contraindication (eg, peripheral neuropathy). As mentioned previously, aggressive combination chemotherapy with CHOP or similar regimens is not more efficacious than single agents and should be reserved for the rare, advanced cases in which multiple single agent systemic therapies have proven unsuccessful. (See 'Choice of agent' above.)

Romidepsin [32], pralatrexate [33], gemcitabine [28], etoposide [29], and liposomal doxorubicin are also used as single agents as they are for mycosis fungoides and Sézary syndrome. The use of these agents in mycosis fungoides and Sézary syndrome is discussed in more detail separately. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides", section on 'Single agent chemotherapy' and "Treatment of Sézary syndrome", section on 'Single-agent chemotherapy'.)

Allogeneic hematopoietic cell transplantation may be considered for patients with multiple relapses progressing on systemic therapy. Data regarding its use in PC-ALCL are sparse. The use of transplantation in mycosis fungoides and Sézary syndrome is discussed in more detail separately. (See "Treatment of advanced stage (IIB to IV) mycosis fungoides", section on 'Hematopoietic cell transplantation' and "Treatment of Sézary syndrome", section on 'Hematopoietic stem cell transplantation'.)

PROGNOSIS — Most cases of PC-ALCL have an excellent prognosis with an estimated 10-year overall survival rate of 90 percent [34]. Recurrences are common with an estimated five-year failure-free survival rate of 55 percent. Leg involvement portends a worse prognosis. Patients with disease on the leg have a five-year disease-specific survival of 76 percent compared with 96 percent for other locations. Surprisingly, pathologic involvement of local nodes alone does not seem to portend an adverse prognosis [35].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary cutaneous lymphoma".)

SUMMARY AND RECOMMENDATIONS

●Primary cutaneous anaplastic large cell lymphoma (PC-ALCL) is a primary cutaneous CD30-positive lymphoproliferative disorder. Most patients present in their sixth decade with slowly enlarging solitary or grouped nodules. The nodules typically ulcerate with time and, while up to half regress, they rarely completely resolve. (See 'Epidemiology' above and 'Clinical and pathologic features' above.)

●Skin biopsy usually demonstrates a dense dermal infiltrate comprised of CD30-positive tumor cells that morphologically resemble those of systemic ALCL. Unlike systemic ALCL, PC-ALCL lack expression of anaplastic lymphoma kinase (ALK) and do not have gene rearrangements involving the ALK gene on chromosome 2p23. (See 'Clinical and pathologic features' above.)

●The diagnosis of PC-ALCL is based upon the presence of characteristic findings on skin biopsy specimens in conjunction with the clinical features found on presentation. All patients with a presumed diagnosis of PC-ALCL should undergo a staging assessment to confirm the absence of systemic disease. A clinical or radiographic suspicion of disseminated disease should be confirmed by biopsy. Involvement of regional lymph nodes does not necessarily indicate the presence of systemic disease. (See 'Diagnosis' above.)

●The main entities that should be considered in the differential diagnosis are lymphomatoid papulosis, systemic ALCL, transformed mycosis fungoides, and reactive causes of CD30-positive lymphoid infiltrates. (See 'Differential diagnosis' above.)

●PC-ALCL is an indolent disease and avoidance of overtreatment is important. Most patients present with isolated lesions that can be managed with complete surgical excision (with negative margins) or radiation. Using this approach, the majority of patients will achieve a complete remission, although most will recur and require subsequent therapy. (See 'Initial management' above.)

●The management of recurrent disease is largely dependent on the extent of disease. Many patients will experience serial relapses. The choice of therapy for relapsed disease is made based on the patient's prior treatment and the therapies' expected toxicities (see 'Recurrent disease' above):

•Many localized cutaneous recurrences can be managed with further surgery or radiation. Given the tendency for spontaneous regression, recurrent lesions can be observed if they are not bothersome to the patient. (See 'Localized lesions' above.)

•We offer systemic therapy to patients with more widespread disease and to patients who experience multiple recurrences and in whom repeated surgical excision and/or radiation could become excessively morbid. (See 'Choice of agent' above.)

•For patients requiring systemic therapy, we suggest initial treatment with single agent oral methotrexate rather than other chemotherapy regimens (Grade 2B). Methotrexate is convenient and has a reasonable response rate and favorable toxicity profile. We typically treat to best response and then decrease the frequency of methotrexate and continue as maintenance therapy for a maximum of three years. If lesions recur after treatment discontinuation, re-treatment with methotrexate can be considered. (See 'Oral methotrexate' above.)

Brentuximab vedotin is an acceptable alternative for initial systemic therapy in patients who have previously received radiation treatment. (See 'Brentuximab vedotin' above.)

•For patients who have a contraindication to, progressed on, or discontinued methotrexate due to significant toxicity, we suggest brentuximab vedotin (Grade 2B). (See 'Brentuximab vedotin' above.)

•For patients in whom the preceding therapies are ineffective or not tolerated, we offer sequential single agent therapy with systemic bexarotene, romidepsin, pralatrexate, etoposide, gemcitabine, liposomal doxorubicin, or interferon alfa. (See 'Bexarotene' above and 'Brentuximab vedotin' above and 'Interferon' above and 'Other agents' above.)

Combination chemotherapy and allogeneic hematopoietic cell transplantation should be reserved for very rare cases with disseminated disease no longer responding to the treatments listed above. (See 'Widespread nodal or visceral involvement' above.)

●Most cases of PC-ALCL have an excellent prognosis with the vast majority (90 percent) alive at 10 years after diagnosis. Recurrences are common and over half of patients will relapse within five years. (See 'Prognosis' above.)