Anaplastic large cell lymphomas (ALCLs) are distinguished from other lymphomas by their anaplastic cytology and constant membrane expression of the CD30 antigen (an activation marker for B or T cells). Striking clinical features include frequent cutaneous and extranodal involvement, young age at presentation, and male predominance. [1, 2, 3, 4]
The primary cutaneous form of ALCL (PC-ALCL), seen in the image below, is defined by skin-only involvement without systemic dissemination at presentation. However, extracutaneous involvement occurs in 5-10% of patients, mostly to the draining regional lymph nodes.
ALCL was recognized in 1985, when tumor cells consistently demonstrated labeling by the monoclonal antibody Ki-1, a marker later shown to recognize the CD30 antigen. In 1988, ALCL was added as a distinct entity to the revised Kiel classification, and in 1994, it was included in the Revised European-American Lymphoma (REAL) classification. [5, 1, 2, 6, 7, 8]
PC-ALCL is part of the primary cutaneous CD30+ T-cell lymphoproliferative disorders, a wide spectrum of disease, with lymphomatoid papulosis (LyP) at the benign end of the spectrum and PC-ALCL at the malignant end. Borderline lesions lie somewhere in between. [9, 10]
For more information, see the following:
The initial diagnostic evaluation of patients with any lymphoproliferative malignancy should include a careful history and physical examination, with close attention paid to the presence of systemic B symptoms, lymph node involvement, organomegaly, and evidence of cutaneous involvement.
Immunophenotypic and immunohistochemical studies are critical in the definitive diagnosis of ALCL. Major immunophenotypic features of ALCL include CD30+, CD15-, PAX-5-, and CD45+. Sixty percent of cases express 1 or more T-cell antigens (CD3+, CD43, or CD45RO). Anaplastic lymphoma kinase (ALK) protein may be detected in most cases (60-70%) of systemic ALCL by immunohistochemistry.
Subtypes of ALCL
The following 2 distinct clinicopathologic subtypes are described:
Systemic anaplastic large cell lymphoma (ALCL), which includes anaplastic lymphoma kinase (ALK)–positive and ALK-negative ALCL; can present as secondary involvement of the skin as part of extranodal disease
Primary cutaneous ALCL (PC-ALCL), according to the 2008 WHO classification, is part of the primary cutaneous CD30 + T-cell lymphoproliferative disorder, which is a spectrum of diseases having lymphomatoid papulosis (LyP) at the benign end of the spectrum and PC-ALCL at the malignant end
PC-ALCL has a better prognosis than the systemic type. Around 25% of patients with PC-ALCL show spontaneous regression.
Each clinicopathologic subtype can be further classified with respect to morphology, immunophenotype, and antigen markers.
Histologically, ALCL is characterized by sheets of large pleomorphic cells, abundant cytoplasm, horseshoe- or wreath-shaped nuclei, and multiple prominent nucleoli. These hallmark tumor cells may be multinucleated and can be similar to Reed-Sternberg cells in appearance
In ALK-positive systemic ALCL, the following 5 morphological patterns can be recognized  :
Common pattern (60%) - Neoplastic lymphocytes exclusively consist of large cells, frequently with hallmark appearance and at times resembling Reed-Sternberg cells
Lymphohistiocytic pattern (10%) - Characterized by tumor cells admixed with a large number of reactive histiocytes; the latter may mask the malignant cells, which are often smaller than in the common pattern and cluster around blood vessels
Small cell pattern (5–10%) - Shows a predominant population of small to medium-sized neoplastic cells with irregular nuclei; hallmark cells are always present and are often concentrated around blood vessels
Hodgkinlike pattern (3%) - Characterized by morphological features mimicking nodular sclerosing Hodgkin lymphoma
Composite pattern (15%) - More than one pattern may be seen in a single lymph node biopsy
In ALK-negative systemic ALCL, small cell pattern is not recognized. Otherwise, it has similar morphological patterns.
In WHO-European Organization for Research and Treatment of Cancer (EORTC) classification, PC-ALCL is described as having anaplastic, pleomorphic, and immunoblastic morphology. However, an inflammatory pattern has also been recognized and divided into a neutrophil-rich or a lymphohistiocytic pattern depending on the type of inflammatory cells. [12, 13]
Immunophenotype in ALCL exhibits consistently strong CD30 expression in all clinical and pathologic subtypes. Most tumor cells are of the T- or null-cell phenotype, and the demonstration of clonally rearranged TCR genes, in most cases of T-type and null-type ALCL, suggests that null-type ALCL is a variant of T-type ALCL.
B-cell antigenic expression is rare, although it is commonly observed in the HIV-related ALCL. In fact, these B-cell cases are classified separately in the Kiel, REAL, and WHO classifications and are grouped under diffuse, large, B-cell lymphoma.
In patients with t(2; 5)/NPM-ALK rearrangement, ALK staining of large cells is both cytoplasmic and nuclear. In the small-cell variant, ALK positivity is usually restricted to the nucleus of tumor cells. In cases with variant translocations, the subcellular distribution of ALK staining varies (membranous or cytoplasmic), depending on the translocation. The majority of ALK-positive ALCL is positive for epithelial membrane antigen (EMA), whereas PC-ALCL typically lacks EMA.
This is important in distinguishing between PC-ALCL with extracutaneous disease and the systemic form with skin involvement. Common leukocyte antigen has low expression in the systemic form and is variably expressed in PC-ALCL.
PAX-5 is another important marker in distinguishing between the systemic form and Hodgkin lymphoma. In Hodgkin lymphoma, virtually all tumor cells show weak PAX-5 expression which, is not reported in systemic ALCL.
Primary cutaneous ALCL is typically negative for ALK staining; however, a few cases ALK positivity in PC-ALCL have been reported.
Genetic-Molecular Characteristics and Their Effects
Most patients (60-70%) with the primary systemic anaplastic large cell lymphoma (ALCL) have translocation between chromosomes 2 and 5, resulting in a fusion protein that joins the N-terminus of nucleophosmin (NPM) to the C-terminus of anaplastic lymphoma kinase (ALK). The wild-type NPM protein demonstrates ubiquitous expression and functions as a carrier of proteins from the cytoplasm into the nucleolus. The ALK wild type has its postnatal expression limited to a few cells in the nervous system and functions as a tyrosine kinase receptor. [14, 15]
The 2;5 translocation brings the ALK gene portion encoding the tyrosine kinase on chromosome 2 under control of the NPM promoter on chromosome 5, producing permanent expression of the chimeric NPM-ALK protein (p80). This protein, an aberrant tyrosine kinase, presumably triggers malignant transformation via constitutive phosphorylation of intracellular targets. The presence of NPM-ALK serves as an additional diagnostic and subclassification tool for ALCL.
Less common ALK fusion proteins associated with ALCL include those resulting from t(1;2), t(2;3), inv(2), and t(2;22).
All variants demonstrate linkage of the ALK tyrosine kinase domain to an alternative promoter that regulates its expression.
ALK-positive systemic ALCL is relatively less aggressive and carries a better prognosis than ALK-negative systemic ALCL.
Primary cutaneous-ALCL is typically ALK negative. However, a few cases with ALK positivity have been reported with similar prognosis.
Recently, translocations involving the IRF4 (interferon regulatory factor-4) gene locus, also known as multiple myeloma oncogene-1 (MUM1), is reported in peripheral T-cell lymphoma not otherwise specified (NOS) and primary cutaneous ALCL. These translocations were rarely found in systemic ALCL and thus can be used to differentiate between these entities.
ALK-positive and ALK-negative ALCLs have been found to have different gene-expression profiles. BCL6, PTPN12, CEBPB, and SERPINA1 genes are overexpressed preferentially in ALK-positive ALCLs, whereas CCR7, CNTFR, IL22, and IL21 genes are overexpressed preferentially in ALK-negative ALCLs. [8, 16]
Incidence in the United States
Over 50,000 cases of non-Hodgkin lymphoma are diagnosed annually in the United States, which accounts for 4% of all cancers and cancer-related deaths per year.
The frequency of CD30+ anaplastic large cell lymphoma (ALCL) in the United States is not known.
Primary systemic anaplastic large cell lymphoma (ALCL) represents 2-8% of adult non-Hodgkin lymphoma cases and as many as 30% of childhood non-Hodgkin lymphoma cases. [17, 18, 19, 20] Primary cutaneous ALCL is demonstrated in 9% of cutaneous lymphomas.
ALCL constitutes approximately 2% of all lymphomas and approximately 9% of high-grade lymphomas in the Kiel registry. It represents approximately 12% of childhood lymphomas and 70% of large cell pediatric lymphomas.
AA male predominance occurs in cases of primary systemic ALCL that express the anaplastic lymphoma kinase (ALK) fusion protein and in patients whose disease is limited to the skin.
Patients with primary cutaneous-ALCL and ALK-negative systemic ALCL are generally older (median age, 61 y) than patients with the ALK-positive systemic ALCL (median age, 24 y).
When separated by extent of limb involvement, patients with extensive limb involvement had a significantly higher age at presentation (median age, 73 y) compared with those without such limb involvement (median age, 48 y).  In primary cutaneous disease, involvement of the lower extremity may be associated with a worse prognosis.
Of all cases of ALCL, 15-20% occur in persons younger than age 20 years.
As previously mentioned, in the systemic anaplastic large cell lymphoma (ALCL), the translocation t(2;5) results in a novel fusion protein, nucleophosmin (NPM)–anaplastic lymphoma kinase (ALK), which may play an important role in the pathogenesis.
The primary cutaneous form of ALCL does not commonly show the translocation t(2;5), and its etiology remains unknown.
A relationship between ALCL and insect bites has been proposed. Lamant et al studied 5 such cases.  The initial diagnosis of these lesions was consistent with nonmalignant inflammatory disease. One patient even had involvement of 1 draining lymph node, which was initially diagnosed as lymphadenitis rich in macrophages. Application of the ALK immunostain to a biopsy sample from all 5 cases showed ALK-positive cells that were also positive for CD30 and EMA, including in the lymph node. One of the 5 patients subsequently developed disseminated disease with pulmonary involvement and later died. It is proposed that the insect bite–associated antigens and inflammatory cytokines select for and encourage proliferation of T cells bearing the t(2;5) translocation. 
Most cases of HIV-related anaplastic large cell lymphoma (ALCL) are actually of B-cell origin and seem instead to be related to the anaplastic variant of diffuse large B-cell lymphoma. Many patients demonstrate infection with the Epstein-Barr virus, which is absent in those with the T-cell or null-cell types of anaplastic large cell lymphoma (ALCL).
Secondary ALCL evolves from other lymphomas, most frequently from peripheral T-cell lymphomas, mycosis fungoides, Hodgkin disease, or LyP. This form of ALCL tends to arise in older adults, usually ALK negative, and carries a poor prognosis.
Some medications have been associated with the onset of cutaneous CD30+ ALCL, including glatiramer acetate. 
Primary systemic ALCL
Primary systemic anaplastic large cell lymphoma (ALCL) is typically in an advanced stage at patient’s presentation, and the disease is rapidly progressive. These patients demonstrate an increased frequency of bone marrow involvement (30%) and extranodal involvement, including skin (21%), bone (17%), soft tissues (17%), lung (11%), liver (8%), rarely, gastrointestinal tract and central nervous system.  Extranodal involvement is more common in anaplastic lymphoma kinase (ALK)–positive ALCL than in ALK-negative ALCL. ALK-negative ALCL has a predilection for the skin, liver, lung, and GI tract. Breast ALCL is also ALK-negative. Breast ALK-negative ALCL possesses an indolent disease course, as opposed to typical ALK-negative ALCL. Systemic symptoms are observed in 75% of patients, with fever the most common symptom. Patients with infiltration into musculoskeletal tissues (eg, psoas muscle) can present with backache.
Patients with widespread systemic and cutaneous disease at first presentation should be considered to have the systemic form with skin involvement.
Primary cutaneous ALCL
Primary cutaneous anaplastic large cell lymphoma (ALCL) usually manifests as a single or localized cluster of erythematous skin nodules (as shown in the image below), some of which may demonstrate superficial ulcerations. [25, 26, 27] As many as 25% of patients have some degree of spontaneous regression of these lesions. Although most cases present with local involvement, patients may, in rare instances, present with disseminated cutaneous disease, in which case they are at higher risk of developing spread to other organs.
In one study, 30% of patients with cutaneous ALCL lesions had ichthyosiform eruptions, all of which were consistent with acquired ichthyosis. Fourteen percent of patients with mycosis fungoides also had some form of ichthyosis. No patients with cutaneous B-cell lymphoma had ichthyosiform eruptions. 
Differential diagnosis in anaplastic large cell lymphoma includes the following:
Primary CD30 - T-cell large cell lymphoma (T-LCL)
Primary cutaneous Hodgkin disease
The imaging and laboratory tests that are necessary to evaluate a patient who may have anaplastic large cell lymphoma (ALCL) are similar to those recommended in the standard evaluation of aggressive non-Hodgkin lymphomas.
Hematology, Chemistry, and ALC
Complete blood count (CBC) count, peripheral smear review, and bone marrow aspiration and biopsy are standard.
Electrolyte evaluations, renal function studies, liver function tests and liver-associated enzyme tests, and uric acid evaluations are appropriate. Serum lactic dehydrogenase (LDH), beta2-microglobulin, and albumin values are useful for prognostic categorization. The LDH and beta2-microglobulin levels also serve as indirect indicators of tumor burden and proliferative activity.
Absolute lymphocyte count
Absolute lymphocyte count (ALC) has been reported to be an independent prognostic factor.  An ALC below 1000/μL correlates with shorter survival and lower complete remission rate.
Chest Radiography, CT Scanning, and Ultrasonography
Chest radiographs are used to assess for lymphadenopathy, pleural effusions, and parenchymal lesions.
Computed tomography (CT) scans of the chest, abdomen, and pelvis should be performed for the staging of lymphoma and for differentiating the primary cutaneous form from the systemic form involving the skin.
Close attention should be paid to lymphadenopathy (the systemic form of anaplastic large cell lymphoma has systemic lymphadenopathy other than regional lymphadenopathy associated with skin lesions), pleural effusions, pulmonary parenchymal lesions, splenomegaly, and hepatic and splenic filling defects.
Ultrasonography of the liver is indicated in patients who have abnormal results from laboratory liver function tests and normal hepatic imaging findings on CT scan images.
Gallium scans, although not as useful in the initial staging workup, can be helpful for evaluating the patient’s response to treatment, because continued positive uptake in a residual mass after completion of treatment is an indicator of persistent disease.
Magnetic resonance imaging (MRI) can be useful for detecting occult bone marrow lymphoma involvement, which is displayed as patchy distribution and, thus, will be missed on bone marrow biopsy findings. A spinal study is indicated for patients with epidural involvement and possible spinal cord compression.
A bone scan is indicated if musculoskeletal symptoms are present or if the alkaline phosphatase level is elevated.
Positron emission tomography (PET) scanning is gaining wider approval as a potential staging modality at diagnosis of anaplastic large cell lymphoma (ALCL) and in cases of relapse.
Molecular Diagnostic Techniques
Most cases of cutaneous CD30+ anaplastic large cell lymphoma have clonally rearranged T-cell receptor genes.
Cytogenetics can be used to detect the t(2:5) translocation.
Reverse transcriptase-polymerase chain reaction (RT-PCR) can be used to monitor minimal residual disease.
Long-range nested PCR assay can be used to detect NPM/ALK gene rearrangements. 
Excisional biopsy of lymphadenopathy is necessary to confirm the diagnosis of anaplastic large cell lymphoma (ALCL). Critical assessments of cell morphology, lymph node architecture, immunophenotype, and molecular and cytogenetic analyses are indicated.
Bone marrow aspiration and biopsy are performed to search for occult lymphoma involvement.
However, bone marrow biopsy, a mainstay of staging by many oncologists, appears to be unhelpful at presentation. In 2008, Benner et al looked at 107 patients who presented with cutaneous manifestations of ALCL. None of the 107 patients had bone marrow involvement at presentation, despite the fact that 20 patients had simultaneous extracutaneous involvement. Only one of the 107 patients ever developed bone marrow involvement during the course of follow-up. 
The morphology of anaplastic large cell lymphoma (ALCL) is similar within its major clinical subforms, the primary systemic and cutaneous varieties. The tumor cells are usually large, with abundant cytoplasm. They manifest prominent nucleoli, display an eccentrically located and pleomorphic nucleus that is often kidney-shaped, and tend to infiltrate lymph nodes in a sinusoidal and paracortical pattern.
Cutaneous CD30+ ALCL consists of diffuse nonepidermotropic infiltrates of cohesive sheets of large CD30+ tumor cells. In most cases, the tumor cells may have the characteristic morphology of anaplastic cells, showing round, oval, or irregularly shaped nuclei; prominent (eosinophilic) nucleoli; and abundant cytoplasm. Note the image below.
Less commonly, tumor cells may have a pleomorphic or an immunoblastic appearance (see the image below). Reactive lymphocytes are often present at the periphery of the lesions. In some cases, numerous inflammatory cells (eg, T cells, eosinophils, neutrophils) and relatively few CD30+ cells may be observed (LyP-like histology). Epidermal hyperplasia may be prominent in such cases.
Immunophenotypically, most neoplastic lymphocytes have a unique CD4+, CD8-, and cytotoxic T-cell phenotype (TIA-1 and granzyme B+), with variable loss of pan–T-cell antigens (eg, CD2, CD3, CD5).  CD30 must be expressed by most (>75%) of the neoplastic cells. The neoplastic lymphocytes in the primary cutaneous form are usually EMA negative in contrast to the systemic form.
CD30+ lymphocytes can be found in certain viral infections, such as human T-lymphotropic virus type I, HIV, hepatitis B and C viruses, Epstein-Barr virus (EBV), and Parapoxvirus infection.
No clear-cut distinction exists clinically or histologically between some expressions of LyP and the primary cutaneous form of CD30+ ALCL. This discrimination may be artificial in some cases, because 10% of cases of LyP progress to the clear-cut primary cutaneous form of CD30+ ALCL.
Various infectious agents may also have CD30+ cells associated with them, including herpes simplex virus, leishmaniasis, syphilis, scabies, molluscum contagiosum virus, and parapoxvirus (milker's nodule). They may be numerous in tick bites. Lymphomatoid drug reactions may also have these same CD30+ cells.
CD30 immunostaining shows the same Golgi and membranous positivity seen in LyP and cutaneous ALCL. The positive cells are also arranged in clusters, similar to cutaneous ALCL. Thus, accurate diagnosis depends on good clinicopathological correlation and may also require detection of infectious agents. (See the image below.) 
An anaplastic lymphoma kinase (ALK) immunostain can be used to help discriminate between the primary and systemic forms of CD30+ ALCL. Primary cutaneous CD30+ ALCL is ALK positive only in extremely rare instances. Systemic CD30+ ALCL is ALK positive in 50-80% of cases. Because 10-20% of systemic ALCL eventually involves the skin, this differentiation is critical for appropriate staging and treatment.  Primary CD30- T-LCL is generally associated with a poor prognosis.
Systemic ALCL may stain negatively for ALK, and this is associated with a worse prognosis. In such cases, clinical staging has often been the determinant of whether skin involvement is primary or secondary.
In 2009, Goteri et al showed that survivin immunostaining may be helpful in this regard. Primary cutaneous ALCL, LyP, and ALK-positive systemic ALCL all stain negatively, but ALK-negative systemic ALCL has nuclear positivity. These results were found only in a cohort of 5 patients. However, if this holds true in larger studies, survivin may show great benefit in diagnosing primary versus secondary ALCL. 
Differentiation of ALCL from LyP
LyP and cutaneous CD30+ lymphoma are closely related conditions in which large atypical lymphocytes that have similar immunophenotypic features occur. In LyP, the lesions are papules and nodules that spontaneously involute. Two polar histologic patterns (type A and type B) occur in which the large atypical cells resemble those of Hodgkin lymphoma and mycosis fungoides, respectively, but in many cases, features of both types are present, either separately or in the same lesions. Type C LyP includes lesions that show sheets of atypical mononuclear cells with little admixed inflammatory cells, a histologic picture that is difficult to separate from classic CD30+ ALCL. Variants of LyP include cases with a perifollicular distribution and those with lymphocytic vasculitis or dermal mucin deposits.
LyP is associated with a long, benign course of frequent regression of papular lesions. The risk of developing a malignant lymphoma is approximately 10-20%.
A loss of response to transforming growth factor-beta, which normally dampens cellular proliferation, favors a diagnosis of CD30+ ALCL instead of LyP. One study showed that CCR3 was expressed by atypical lymphoid cells in 10 (83%) of 12 cases of ALCL but in only 5 (38%) of 13 cases of LyP. CXCR3 was expressed in 11 (85%) of 13 cases of LyP but in only 1 (8%) of 12 cases of ALCL. CCR4 was expressed in 11 (92%) of 12 cases of ALCL but in only 2 (15%) of 13 cases of LyP. RANTES was strongly expressed by lymphoma cells in ALCL (11 [92%] of 12) but was weak or sporadic in LyP (7 [54%] of 13).  The presence of CCR3 and its ligand, RANTES, suggests that cutaneous ALCL receives growth stimulation in an autocrine fashion. [36, 37] These markers may be useful to differentiate ALCL from LyP in difficult cases. Lesions of LyP typically show clonal T-cell receptor (TCR) rearrangements; therefore, this is not a useful test to differentiate between these entities.
MUM1 has been proposed as a useful marker to differentiate LyP and ALCL. It was reported to be positive in 20% of primary cutaneous ALCL, 100% systemic ALCL with secondary skin involvement, and 87% of LyP. 
Similar to MUM1, TRAF1 has shown utility, according to the authors in one study. LyP had strong cytoplasmic staining with TRAF1, and cutaneous ALCL was weakly positive or completely negative.  Another study found that TRAF1, BCL2, and CD15 showed no practical utility in the diagnosis or prognosis of CD30+ lymphoproliferative disorders. 
The term "borderline case" refers to cases in which a discrepancy exists between the clinical features and the histologic appearance. These include cases with the clinical presentation of a CD30+ ALCL but with histologic features suggestive of LyP, and, conversely, cases with recurrent, self-healing skin lesions that on histologic examination show a rather uniform proliferation of large CD30+ tumor cells with only a few admixed inflammatory cells, which is characteristic of a CD30+ ALCL. The presence of these cases indicates that CD30+ ALCL and LyP are within a spectrum of primary cutaneous CD30+ lymphoproliferative disorders.
Distinguishing between LyP and the primary cutaneous form of CD30+ ALCL is not always possible on the basis of histologic criteria. Thus, the clinical appearance and the course are used as decisive criteria for the definite diagnosis and the choice of treatment.
The Cotswold modification of the Ann Arbor staging system is the standard anatomic staging system for non-Hodgkin lymphoma and Hodgkin disease; it is used to evaluate the extent of disease in patients with anaplastic large cell lymphoma (ALCL). Accurate staging allows appropriate therapeutic selection and contributes to predicting the prognosis.
Stage I – Involvement of a single lymph node region or lymphoid structure
Stage II – Involvement of 2 or more lymph node regions on the same side of the diaphragm
Stage III – Involvement of lymph node regions or structures on both sides of the diaphragm
Stage IV – Involvement of extranodal sites beyond that designated as E (see below)
Further staging designations include the following:
Suffix A – No symptoms (any disease stage)
Suffix B – Fever (temperature >38°C); drenching sweats; unexplained weight loss (eg, 10% of body weight within preceding 6 mo) (any disease stage)
Suffix E – Involvement of a single extranodal site that is contiguous or proximal to the known nodal site (stages I-III)
Cotswold modifications are as follows:
Suffix X – Denotes bulky disease (a widening of the mediastinum by more than one third or the presence of a nodal mass with a maximal dimension of >10 cm)
Subscripts – Used to indicate the number of anatomic regions
Stage III subdivisions – May be subdivided to include III(1), with or without splenic, hilar, celiac, or portal nodes, and III(2), with para-aortic, iliac, or mesenteric nodes
Further identification – Staging identified as clinical stage (CS) or pathologic stage (PS)
Therapy for ALCL
It is imperative to rule out systemic involvement in patients with skin disease as management and prognosis is completely different. In addition, every effort should be made to distinguish primary cutaneous anaplastic large cell lymphoma (ALCL) from lymphomatoid papulosis (LyP). LyP is a benign disease with prolonged relapsing and remitting clinical course. However, patients with LyP are at increased risk of various kinds of cutaneous or systemic lymphomas, including ALCL. The presence of ALK gene rearrangement in patients with systemic disease provides both predictive and prognostic information.
Primary cutaneous ALCL
Solitary or localized primary cutaneous lymphoma is best treated with radiation therapy or surgical excision. Both approaches bring about complete remission in more than 95% of cases. Nonetheless, approximately 40% of the cases relapse within a period of a few months to a few years. Treatment with either of these modalities depends on patient preference, site of disease, and local expertise. Combined-modality treatment (surgery followed by radiation therapy) may prolong the time to first relapse.
Spontaneous regression is common. It is reported in 40% or more of patients and does not affect overall outcome.
Patients with multifocal disease require systemic chemotherapy with either a single-agent (methotrexate) or a combination regimen. Complete remission rates with combination chemotherapy are around 90%, but two thirds of these patients relapse in a few months. No particular combination is superior to CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), which is the most commonly used regimen. Given the high rate of relapse, the European Organization for Research and Treatment of Cancer (EORTC), International Society for Cutaneous Lymphomas (ISLC), and nited States Cutaneous Lymphoma Consortium (USCLC)haveproposed low-dose methotrexate as a preferred first-line treatment for multifocal disease. 
Primary systemic ALCL
Doxorubicin-based combination chemotherapy stands out as a reference regimen from the trials of peripheral T-cell lymphomas. The CHOP regimen is the most common therapy for systemic ALCL.
However, the German high-grade Non-Hodgkin’s lymphoma study group (DSH-NHL) analyzed data from 289 patients with T-cell lymphomas who either received CHOP or CHOP with etoposide in various phase II and III trials of DSH-NHL. In their analysis, 78 patients had anaplastic lymphoma kinase (ALK)–positive ALCL and 113 had ALK-negative ALCL. Statistically significant improvement in event-free survival (EFS) from 57% to 91% at 3-year was noticed in patients with ALK-positive ALCL who were young (< 60 y) and had normal lactate dehydrogenase (LDH) levels at the time of diagnosis with the addition of etoposide in combination with standard CHOP. Overall survival was not different. 
Therefore, the addition of etoposide to the standard CHOP regimen is an important consideration for young patient with ALK-positive ALCL.
More intensive chemotherapy like hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone) did not improve outcome in these patients and was more toxic. 
Patients with ALK-positive ALCL have better outcomes than those with ALK-negative ALCL. In the analysis from the DSH-NHL group, 3-year event-free survival and overall survival rates were 76% and 89.8% for ALK-positive ALCL versus 46% and 62% for ALK-negative ALCL, respectively. 
The role of high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HDC/HSCT) in first remission in patients with systemic ALCL is controversial. No randomized controlled trials have compared this strategy with incorporation of the ALK-status. Because ALK-positive patients have a better prognosis, HDC/HSCT is generally reserved for salvage and investigational therapy for upfront disease. In contrast, ALK-negative ALCL is treated like aggressive T-cell lymphomas. A phase 2 trial evaluated an upfront strategy with HSCT in peripheral T-cell lymphoma patients and included 31 patients with ALK-negative ALCL (ALK-positive patients were excluded). Patients with ALK-negative ALCL performed the best, with 5-year overall survival and progression-free survival rates of 70% and 61%, respectively. 
Radiation therapy to bulky sites of disease may be necessary after completion of chemotherapy.
In relapse/refractory settings, HDC/HSCT is an important strategy in both ALK-positive and ALK-negative patients. Allogeneic transplantation has also been tried in chemoresistant patients in small series. [46, 47]
Brentuximab vedotin is a CD30-specific antibody-drug conjugate composed of a chimeric monoclonal antibody linked by a dipeptide linker to a cytotoxic antitubulin agent, monomethyl auristatin E (MMAE). It was evaluated in a multicenter phase 2 trial as a single agent in 58 patients with relapse/refractory systemic ALCL who failed 1 or more prior multidrug chemotherapy regimens. The objective response rate (primary endpoint) was 86%, with complete and partial remission rates of 57% and 29%, respectively. ALK-positive patients had complete remission rate of 69%, while 52% patients with ALK-negative ALCL achieved complete remission. The median progression-free survival following brentuximab vedotin was significantly longer compared with the most recent previous therapy (14.3 mo vs 5.9 mo). [48, 49]
Brentuximab vedotin is approved by the US Food and Drug Administration for relapsed/refractory systemic ALCL. Currently, multiple phase 3 trial trials evaluating this agent for second-line treatment in systemic and cutaneous ALCL are ongoing.
ALK-positive systemic ALCL is also an attractive target for the small molecule ALK-inhibitor, crizotinib. It was approved for locally advanced or metastatic nonsmall cell lung cancer with ALK gene rearrangement in August 2011. A few cases of relapsed ALK-positive systemic ALCL treated with crizotinib have been reported in the literature. Significant clinical benefit was observed in these reports. [50, 51] Currently a phase 1/2 trial to evaluate crizotinib is underway for relapsed/refractory ALK-positive systemic ALCL.
Simple excision, with or without adjuvant spot radiotherapy, may be considered for solitary or localized skin lesions.  Local excision may be an alternative to radiation therapy for solitary lesions in either pregnant patients or pediatric patients.
Consultations, Diet, and Activity
Consult a hematologist/oncologist for chemotherapy evaluation.
Consult a radiation oncologist for therapy.
No limitations on diet or activity are necessary.
Although late relapses can occur, patients with diffuse aggressive lymphomas usually experience recurrence within 2 years of completion of treatment. Early detection allows identification of potential candidates for high-dose therapy and stem cell transplantation. Periodic physical examinations and re-imaging are recommended as follow-up care for patients in remission. Long-term survivors need continued surveillance for potential treatment-associated complications.
Disease and Treatment Complications
Tumor lysis syndrome (TLS) is a common complication of treatment for any high-grade, bulky, treatment-sensitive lymphoma and occurs after intracellular contents are released rapidly into the blood. The syndrome manifests as renal failure, hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia; these metabolic derangements may lead to sudden death if left uncorrected. Prophylactic and treatment measures include allopurinol, alkaline diuresis, and correction of potassium and phosphate abnormalities.
Patients with bulky or advanced-stage anaplastic large cell lymphoma (ALCL) are at high risk for TLS and should receive prophylaxis, with close monitoring of fluid status, urine output, electrolytes, and renal function.
Long-term survivors of non-Hodgkin lymphoma are at increased risk for second malignancies, including all solid tumors, melanoma, Hodgkin disease, and acute myelogenous leukemia (AML).
Rare serious complications, such as hemophagocytic syndrome, have been reported.
Chemotherapy drugs are myelosuppressive.
Generally, cutaneous CD30+ anaplastic large-cell lymphoma (cutaneous CD30+ ALCL) has a favorable clinical course (5-y survival rate of 90%), with occasional spontaneous regression (up to 25% of cases) of the skin lesions. The systemic form has a worse prognosis compared with the primary cutaneous form. However, primary cutaneous CD30- large-cell lymphoma also has worse prognosis (5-y survival rate of 15%).
Primary cutaneous disease, spontaneous regression, absence of extracutaneous involvement, and younger age at onset (< 60 y) have been suggested to be associated with better prognosis.
The expression of either NPM-ALK transcripts or ALK protein is not correlated with prognosis or age in the primary cutaneous form of CD30+ cutaneous lymphoproliferations. However, expression of either NPM-ALK transcripts or ALK protein indicates a better prognosis in the systemic form of ALCL.
Prior studies have suggested that the stage of disease may be more important than the cytologic subtype.
CD30 ligand expression is detected in regressing lesions only and indicates a better prognosis. Cutaneous CD30+ ALCLs developing from preexistent Mycosis Fungoides are often associated with a poor prognosis (5-y survival rate of 10-30%). Regional lymph node involvement is not necessarily associated with unfavorable prognosis.
P53 expression by immunohistochemistry is not associated with spontaneous regression, extracutaneous spreading, or survival.
Primary systemic anaplastic large cell lymphoma (ALCL)
The prognostic factors applied to other non-Hodgkin lymphomas are also relevant to ALCL. They include the following:
Number of extranodal sites
These features are compiled in the International Prognostic Index, which provides stratification into risk groups and serves to identify patients for whom early experimental approaches may be considered.
ALK status is also an important prognostic indicator, because ALK-positive cases have demonstrated a significantly improved 5-year overall survival rate of 70-80%, versus 15-45% reported for patients without ALK expression.
Primary cutaneous ALCL
Localized skin presentation in patients with pure cutaneous disease is associated with good, long-term survival.
This is associated with poor prognosis.
Absolute lymphocyte count (ALC) has been reported to be an independent prognostic factor.  An ALC of less than 1000/μL correlates with shorter survival and lower complete remission rate.
Morbidity in ALCL
The 5-year survival rate is typically around 90% for the primary cutaneous form of CD30+ anaplastic large cell lymphoma (ALCL).  In fact, cases of primary cutaneous CD30+ ALCL may regress without therapeutic intervention.
New data suggest that the 5-year overall survival and disease-specific survival in primary cutaneous CD30+ ALCL are affected by the extent of limb involvement. For patients without extensive limb disease, the 5-year survival remains around 90%. However, with extensive limb involvement by this disease, 5-year survival is around 50%. Patients with extensive limb involvement have also been proven to have more rapid disease progression and decreased response to treatment. 
The prognosis of the systemic form with secondary cutaneous involvement depends on the expression of the ALK protein. Patients with expression of ALK have a 5-year survival rate ranging from 70-80%. The 5-year survival rate in patients without ALK expression ranges from 15-45%.
Survival in children with systemic ALCL also depends on what sites are involved. Mediastinal involvement, visceral involvement, and cutaneous involvement portend a worse prognosis.
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- Subtypes of ALCL
- Genetic-Molecular Characteristics and Their Effects
- Differential Diagnosis
- Diagnostic Considerations
- Hematology, Chemistry, and ALC
- Chest Radiography, CT Scanning, and Ultrasonography
- Gallium Scanning
- Bone Scanning
- PET Scanning
- Molecular Diagnostic Techniques
- Therapy for ALCL
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