Anaplastic Large Cell Lymphoma 

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]}

The primary cutaneous form of cutaneous CD30-positive (Ki-1) ALCL (cutaneous CD30⁺ ALCL), seen in the image below, is defined by skin-only involvement without systemic dissemination at presentation. The involvement of draining regional lymph nodes occurs in approximately 25% of patients with only skin lesions. Whether patients showing only draining regional lymph node involvement should be considered to have a primary cutaneous form remains controversial.

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 receptor. 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.^{[3, 1, 2, 4, 5, 6]}

CD30⁺ lymphoproliferative disorders include a wide spectrum of disease, with lymphomatoid papulosis (LyP) at the benign end of the spectrum and cutaneous CD30⁺ ALCL at the malignant end. Borderline lesions lie somewhere in between.^{[7, 8]}

For more information, see the following:

• Angioimmunoblastic Lymphoma
• Cutaneous B-Cell Lymphoma
• Cutaneous T-Cell Lymphoma
• Malignant Anaplastic (Ki 1+) Lymphoma
• Lymphomatoid Papulosis

Diagnostic considerations

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.

Cutaneous CD30⁺ (Ki-1) ALCL is clinically and pathologically heterogeneous, leading to some difficulty in its diagnosis and classification.

Immunophenotyping and immunohistochemistry study of the lymphoma cells is critical in the definitive diagnosis of anaplastic large cell lymphoma (ALCL). The major features of the ALCL immunophenotype typically include, along with CD30⁺, CD15^- and CD45⁺ as well. (Hodgkin lymphoma typically expresses CD30⁺ and CD15⁺.) 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%) by immunohistochemistry.

Patient education

For patient education information, see the Blood and Lymphatic System Center, as well as Lymphoma.

Introduction

Based on clinical manifestations, cutaneous CD30⁺ anaplastic large cell lymphoma (ALCL) can be subdivided mainly into (1) a primary cutaneous form without extracutaneous involvement at presentation and (2) a systemic form with secondary skin involvement at presentation.

The primary cutaneous form generally has a better prognosis than does the latter, systemic form. Sometimes (in up to 25% of cases), spontaneous regression of the primary cutaneous form occurs despite high-grade anaplastic cytology of neoplastic lymphocytes.

Cutaneous CD30⁺ ALCL can be further classified according to histologic features (eg, pleomorphic, immunoblastic, monomorphic, small-cell predominant, Hodgkin disease–related, and other uncommon variants); immunophenotype (eg, T, null, B, rarely B and T); and other clinical features, such as whether it is arising in patients who are human immunodeficiency virus [HIV] positive or whether it is occurring after another lymphoproliferative process (eg, LyP, mycosis fungoides, Hodgkin disease).

Multiple patterns of cutaneous CD30⁺ ALCL are recognized. Three patterns of cutaneous CD30⁺ ALCL are recognized by the World Health Organization (common, lymphohistiocytic, and small cell); however, several others have been described in the literature, for example, neutrophil rich, subcutaneous, and inflammatory.^{[9, 10]}

Primary and secondary subforms of ALCL

ALCL can be divided clinically into primary and secondary subforms, with the de novo type further subclassified into systemic, cutaneous, and HIV-related forms. The primary systemic and cutaneous forms are the predominant subtypes.

All types of ALCL strongly express the CD30 antigen on cell membranes, and histologic review reveals the characteristic tumor cells.

In addition to various clinical forms, pathologic variants exist that differ with respect to morphology, immunophenotype, and other antigen markers.

Histologically, ALCL is characterized most commonly 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. The growth pattern in lymph nodes is diffuse, and for partially involved nodes, it shows a predilection for paracortical and sinusoidal regions.

Non-classic subforms

Additional morphologic subforms distinct from the above classic type do not appear to represent separate disease entities. Morphologic ALCL variants include the following:

• Monomorphic subtype
• Small cell subtype
• Lymphohistiocytic subtype
• Hodgkinlike subtype

The monomorphic subtype demonstrates a rather nonanaplastic appearance.

The small cell subtype contains a mixture of small and large lymphocytes, with the CD30 antigen expression limited mainly to the larger cells. This subtype is more common in children; it can transform into the common type and vice versa.

The lymphohistiocytic type has a predominance of histiocytes and a minority of hallmark cells. It can therefore present a diagnostic challenge. Tumor cells in the giant cell-rich type are frequently multinucleated.

The Hodgkinlike type refers to ambiguous cases in which the tumor histologically resembles both ALCL and Hodgkin disease.

Rare additional histologic types exist, including the sarcomatoid, neutrophil-rich, eosinophil-rich, and signet-ring forms. In addition, as many as 15% of patients have features of more than 1 morphologic subtype.

Immunophenotypes

Immunophenotyping in ALCL exhibits consistently strong CD30 expression in all clinical and pathologic subtypes. Most tumor cells are of the null or T-cell phenotype, and the demonstration of clonally rearranged TCR genes, in most cases of T-type and null-type ALCL, suggest 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 clinical form. In fact, these B-cell cases are classified separately in the Kiel classification, and in the REAL and World Health Organization classifications, they are grouped under diffuse, large, B-cell lymphoma.

Epithelial membrane antigen (EMA) expression is strongly positive in the most common morphologic types of ALCL, which include the classic, small cell, and lymphohistiocytic types. EMA analysis is also useful in the clinical subtype distinction, with strong expression observed in the primary systemic form and little or no expression in the other clinical forms.

Most patients with the primary systemic clinical subtype of 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 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.^{[11, 12]}

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.)

The NPM-ALK rearrangements are very specific, and within the non-Hodgkin lymphoma spectrum, they are restricted to T-cell lineage ALCL.

Various other, 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.

The other clinical subtypes of ALCL, including the primary cutaneous form, are almost never ALK positive.

ALK^- ALCLs tend to be more aggressive and are more likely to relapse than are ALK⁺ ALCLs.

ALK⁺ and ALK^- ALCLs have been found to have different gene-expression profiles. BCL6, PTPN12, CEBPB, and SERPINA1 genes were overexpressed preferentially in ALK⁺ ALCLs, whereas CCR7, CNTFR, IL22, and IL21 genes were overexpressed in ALK^- ALCLs.^[6]

Incidence in the United States

Approximately 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.

International incidence

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.^{[13, 14, 15, 16]} 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.

Sex predilection

A male predominance occurs in cases of primary systemic ALCL that express the ALK fusion protein and in patients whose disease is limited to the skin.

Age predilection

Patients with primary cutaneous forms of ALCL are generally older (median age, 61 y) than patients with the systemic form of ALCL (median age, 24 y) and, in contrast to the latter group, do not show a bimodal age distribution.

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).^[17] 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 form of cutaneous CD30⁺ anaplastic large-cell lymphoma (ALCL), the translocation t(2;5) results in a novel fusion protein, NPM-ALK, and may play an important role in the development of disease.

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. 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).

The resultant aberrant tyrosine kinase presumably triggers malignant transformation via constitutive phosphorylation of intracellular targets.

The NPM-ALK rearrangements are very specific, and within the non-Hodgkin lymphoma (NHL) spectrum, they are restricted to T-cell lineage ALCL.

The primary cutaneous form of ALCL does not commonly show the translocation t(2;5), and its etiology remains unknown.

Risk factors

A relationship between ALCL and insect bites has been proposed. A 2009 study by Lamant et al studied 5 such cases.^[18] 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 biopsy sample from all 5 cases showed positive cells that were also CD30 and EMA positive, 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.^[18]

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, is commonly ALK negative, and carries a poor prognosis.

Some medications have been associated with the onset of cutaneous CD30⁺ ALCL, including glatiramer acetate.^[19]

Primary systemic ALCL

Primary systemic anaplastic large cell lymphoma (ALCL) is typically in an advanced stage at patient 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%), and, rarely, the gastrointestinal tract and central nervous system. 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.^{[20, 21, 22]} 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.^[23]

Differential diagnosis in anaplastic large cell lymphoma includes the following:

• Hodgkin disease
• B-cell lymphoma
• Diffuse large cell lymphoma
• Lymphomatoid papulosis
• Malignant histiocytosis
• Metastatic carcinoma
• Metastatic melanoma
• Primary CD30^- T-cell large cell lymphoma (T-LCL)
• Primary cutaneous Hodgkin disease
• Granulocytic sarcoma
• Viral infection

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

Complete blood count (CBC) count, peripheral smear review, and bone marrow aspiration and biopsy are standard.

Chemistry

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.^[24] An ALC below 1000/μL correlates with shorter survival and lower complete remission rate.

Chest radiography

Chest radiographs are used to assess for lymphadenopathy, pleural effusions, and parenchymal lesions.

CT scanning

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

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.

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.

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.^[25]

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).^[26] 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.)^[27]

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.^[28] 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.^[29]

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 disease 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).^[30] The presence of CCR3 and its ligand, RANTES, suggests that cutaneous ALCL receives growth stimulation in an autocrine fashion.^{[30, 31]} 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.^[32]

However, 2 subsequent studies showed that MUM1 is expressed equally in LyP and ALCL.^{[33, 34]} Therefore, MUM1 is likely not as useful as once thought.

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.^[35] Another study found that TRAF1, BCL2, and CD15 showed no practical utility in the diagnosis or prognosis of CD30⁺ lymphoproliferative disorders.^[33]

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.

Staging for anaplastic large cell lymphoma (ALCL) is as follows^{[1, 16]} :

• 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)

General considerations

Radiation therapy is the preferred treatment for solitary or localized cutaneous CD30⁺ (Ki-1) anaplastic large-cell lymphoma (cutaneous CD30⁺ ALCL).

Generalized skin lesions may respond to methotrexate (MTX).^[36] Additionally, patients with localized lesions that are not amenable to radiotherapy or that are too large for primary excision may also benefit from MTX.

Multiagent chemotherapy, such as F-MACHOP regimen, should be considered only in patients with systemic disease.^[37] The issue of how to treat patients with local nodal disease is somewhat more controversial, and some may consider multiagent chemotherapy in these patients (see detailed information in the reference by Bekkenk et al cited in the Bibliography). Treatment with CHOP or CHOP-like regimens does not prevent future relapses or result in a higher cure rate.^[38]

Anti-CD30 monoclonal antibody (SGN-30) is being used experimentally for patients in whom multichemotherapy has failed. It has shown promise in the primary cutaneous and systemic forms of CD30⁺ ALCL.^[39] Recombinant interferon-gamma (IFN-gamma) and regimens including bexarotene with interferon alfa-2a have also shown utility. The compound 13-cis retinoic acid has also proven useful in patients with cutaneous ALCL.^[40]

Brentuximab vedotin (Adcetris) was approved by the US Food and Drug Administration (FDA) in August 2011. It is a CD30-directed antibody-drug conjugate consisting of IgG1 antibody cAC10, specific for human CD30, and the microtubule disrupting agent, monomethyl auristatin E (MMAE, or vedotin).^[41] Results from a study among patients with anaplastic large cell lymphoma who had failed a median of 2 chemotherapy regimens (n = 58) revealed an 86% response (95% CI, 77 95%), with 57% achieving complete remission (95% CI, 44-70%) and 29% a partial remission (95% CI, 18-41%). Median response duration was 12.6 months (range, 0.1-15.9 months).^[42]

Thalidomide has been reported to be useful in patients who are refractory not only to chemotherapeutic regimens, but also to IFN-gamma and 13-cis retinoic acid.

Mistletoe extract is an adjunct used in some chemotherapeutic regimens in Europe. A 2007 report shows that it is effective at eliminating lesions. Unfortunately, it was ineffective at preventing disease relapse, although it successfully treated lesions with each relapse.^[43]

In some cases, autologous or allogenic stem cell transplantation may be required, however data on efficacy are limited.

The Children's Cancer Group Study 5941 reported on a complex chemotherapeutic regimen with similar efficacy to other accepted regimens (see source for more detail). However, it had significant hematologic toxicity, producing severe neutropenia in more than 80% of patients.^[44]

Monoclonal antibodies against CD30 are being tested clinically in lymphoma and Hodgkin lymphoma. HeFi-1 and SGN-30 are 2 antibodies that are being studied in preclinical and clinical models, respectively.

Obtain a CBC in patients who are undergoing chemotherapy.

Primary systemic anaplastic large cell lymphoma

The current treatment approach for primary systemic anaplastic large cell lymphoma (ALCL) is identical to that for other types of diffuse aggressive non-Hodgkin lymphomas. Patients usually present in advanced stages, and intensive anthracycline-based chemotherapy offers a high chance of durable complete responses.

A combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) is the standard first-line treatment. If CD20 antigens are positive, rituximab should be added. Alternatively, substitution of mitoxantrone for doxorubicin (CNOP) or an equivalent third-generation regimen (eg, m-BACOD [ie, moderate-dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone], ProMACE/CytaBOM [ie, prednisone, doxorubicin, cyclophosphamide, etoposide, cytarabine, bleomycin, vincristine, methotrexate, leucovorin calcium, concomitant trimethoprim/sulfamethoxazole DS], MACOP-B [ie, methotrexate, doxorubicin, cyclophosphamide, vincristine, bleomycin], ACVB [ie, doxorubicin, cyclophosphamide, vindesine, bleomycin]) can be used.

Radiation therapy to bulky sites of disease may be necessary after completion of chemotherapy.

Compared with patients with other types of diffuse, aggressive lymphomas, patients with ALCL have increased and more prolonged response rates, with improved overall survival. The better prognosis holds particularly true for patients who are ALK positive; they have demonstrated significantly better survival rates than have patients who are ALK negative.

A prospective trial that used high-dose chemotherapy and autologous stem cell transplantation (ASCT) as front-line treatment for ALCL revealed an excellent 5-year overall survival rate of 87%, which was significantly better than for aggressive nonanaplastic lymphomas.^[45] To date, no published randomized trials have compared ASCT to conventional combination chemotherapy regimens.

Secondary forms of anaplastic large cell lymphoma

These forms are associated with a poor prognosis and also warrant treatment with a regimen containing doxorubicin.

Primary cutaneous anaplastic large cell lymphoma

As many as one fourth of patients with primary cutaneous ALCL experience spontaneous regression of skin lesions.

Patients with persistent localized disease can undergo surgical excision with or without radiation therapy and achieve excellent long-term survival. Those with disseminated skin involvement are more likely to experience progression to extracutaneous sites and thus may benefit from systemic combination chemotherapy.

The distinction of primary cutaneous ALCL from LyP, although difficult by pathologic means, should be attempted clinically, because LyP tends to run a benign clinical course despite cycles of regression followed by relapse.

Simple excision, with or without adjuvant spot radiotherapy, may be considered for solitary or localized skin lesions.^[39] Local excision may be an alternative to radiation therapy for solitary lesions in either pregnant patients or pediatric patients.

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 reimaging are recommended as follow-up care for patients in remission. Long-term survivors need continued surveillance for potential treatment-associated 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.

General considerations

Generally, cutaneous CD30⁺ (Ki-1) anaplastic large-cell lymphoma (cutaneous CD30⁺ ALCL) has a favorable clinical course (5-y survival rate of 90%) for the primary cutaneous form, with occasional spontaneous regression (up to 25% of cases) of the skin lesions. The systemic form has a worse prognosis than the primary cutaneous form. The primary cutaneous CD30^- large-cell lymphoma also has a much worse prognosis (5-y survival rate of 15%) than that of the primary cutaneous form of CD30⁺ ALCL.

Primary cutaneous disease, spontaneous regression, absence of extracutaneous involvement, and younger age at onset (< 60 y) have been suggested to be associated with a 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 an 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:

• Age
• LDH values
• Performance status
• Number of extranodal sites
• Stage

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.

Secondary ALCL

This is associated with poor prognosis.

Absolute lymphocyte count (ALC) has been reported to be an independent prognostic factor.^[24] 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).^[17] In fact, cases of primary cutaneous CD30⁺ ALCL may regress without therapeutic intervention.^[46]

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.^[17]

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. The presence of 1 of these factors decreases the 5-year survival rate from 89% to 61%.^[47] The Children's Cancer Group Study 5941 reported that only bone marrow involvement significantly changed the 5-year survival rate.^[44]