Anaplastic Large Cell Lymphoma

Overview

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]}In addition, an association between ALCL and breast implants, particularly those with textured surfaces, has been reported.^{[5, 6]}

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.

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This ulcerated nodule of localized primary cutaneous CD30+ anaplastic large cell lymphoma is relatively nonspecific in appearance. Courtesy of Dr. Ron....

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.^{[7, 1, 2, 8, 9, 10]}The World Health Organization has designated anaplastic lymphoma kinase (ALK)–negative ALCL arising in association with breast implants as breast implant–associated ALCL.^[11]

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.^{[12, 13]}

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.

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.

Patient education

For patient education information, see the Blood and Lymphatic System Center, as well as Lymphoma. US Food & Drug Administration (FDA) patient recommendations regarding breast implant–associated ALCL are as follows:

Women considering breast implants should educate themselves before agreeing to surgery, and should make sure to discuss the benefits and risks of textured-surface vs. smooth-surfaced implants with their healthcare provider.
Women with breast implants do not need to change their routine medical care and follow-up, which should include mammography screening performed by a technologist specifically trained in performing mammograms on patients with breast implants.
Women who notice any changes in their breasts should contact their health care provider promptly to schedule an appointment.

References

Subtypes of ALCL

Two distinct clinicopathologic subtypes of anaplastic large cell lymphoma (ALCL) have been described:

Systemic 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.

Morphology

Histologically, ALCL is characterized by sheets of large pleomorphic cells with 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^[14]:

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, the 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.^{[15, 16]}

Immunophenotypes

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.

References

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.^{[17, 18]}

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.

Translocations involving the IRF4 (interferon regulatory factor-4) gene locus, also known as multiple myeloma oncogene-1 (MUM1), have been 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.^{[10, 19]}

References

Epidemiology

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. As of September 30, 2017, the US Food and Drug Administration had received 414 medical device reports of breast implant–associated ALCL, including nine deaths.^[5]

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.^{[20, 21, 22, 23]}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- and age-related demographics

A 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). With breast implant–associated ALCL, the median age at presentation is 53 years (range, 25-91 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).^[24]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.

References

Etiology

In the systemic form of 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.

Risk factors

A relationship between ALCL and insect bites has been proposed. Lamant et al studied 5 such cases.^[25]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.^[25]

Most cases of HIV-related 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 usually ALK negative, and carries a poor prognosis.

Some medications have been associated with the onset of cutaneous CD30⁺ ALCL, including glatiramer acetate.^[26]

Of the 272 breast implant–associated ALCL cases reported to the FDA that described the implant surface, 242 involved textured implants and 30 involved smooth implants. Of the 413 cases with data on implant fill, 234 involved silicone gel-filled implants, and 179 involved saline-filled implants. Breast implant–associated ALCL may develop in 1 in 3,817 to 30,000 women with textured breast implants.^[5]

References

Clinical Presentation

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.^[27]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.^{[28, 29, 30]}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.

View Image

This ulcerated nodule of localized primary cutaneous CD30+ anaplastic large cell lymphoma is relatively nonspecific in appearance. Courtesy of Dr. Ron....

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.^[31]

Breast implant–associated ALCL

Breast implant–associated ALCL usually presents as an accumulation of seroma fluid between the implant itself and the surrounding fibrous capsule. Patients typically report persistent swelling or pain in the vicinity of the implant. A palpable mass or capsular contracture may be present.^[11]The median time from implant placement to ALCL diagnosis is 7 to 8 years (range, 0 to 40 y).^[5]

References

Differential Diagnosis

Differential diagnosis in anaplastic large cell lymphoma includes the following:

Hodgkin lymphoma
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 lymphoma
Granulocytic sarcoma
Viral infection

References

Diagnostic Considerations

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.

Testing for breast implant–associated ALCL involves collecting fresh seroma fluid and representative portions of the capsule. Diagnostic evaluation should include cytological evaluation of seroma fluid with Wright-Giemsa–stained smears and cell block immunohistochemistry testing for cluster of differentiation (CD) and anaplastic lymphoma kinase (ALK) markers.^[5]

References

Hematology, Chemistry, and ALC

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.^[32]An ALC below 1000/μL correlates with shorter survival and lower complete remission rate.

References

Chest Radiography, CT Scanning, and Ultrasonography

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.

References

Gallium Scanning

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.

References

MRI

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.

References

Bone Scanning

A bone scan is indicated if musculoskeletal symptoms are present or if the alkaline phosphatase level is elevated.

References

PET Scanning

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.

References

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.^[33]

Biopsy

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.^[34]

Histologic Findings

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.

View Image

Sheets of atypical cells are seen infiltrating through the superficial and deep dermis. The epidermis is hyperkeratotic (hematoxylin and eosin, 40X).

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.

View Image

The markedly atypical, large, and pleomorphic epithelioid cells have frequent mitoses. Prominent nucleoli are present (hematoxylin and eosin, 400X).

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).^[35]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.)^[36]

View Image

CD30 strongly stains all the malignant cells in the characteristic membranous pattern (CD30 immunostain, 100X).

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.^[37]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.^[38]

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).^[39]The presence of CCR3 and its ligand, RANTES, suggests that cutaneous ALCL receives growth stimulation in an autocrine fashion.^{[39, 40]}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.^[41]

However, 2 subsequent studies showed that MUM1 is expressed equally in LyP and ALCL.^{[42, 43]}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.^[44]Another study found that TRAF1, BCL2, and CD15 showed no practical utility in the diagnosis or prognosis of CD30⁺ lymphoproliferative disorders.^[42]

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.

Staging

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, 23]}:

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)

References

Therapy for ALCL

General considerations

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 United States Cutaneous Lymphoma Consortium (USCLC)haveproposed low-dose methotrexate as a preferred first-line treatment for multifocal disease.^[45]

Retinoids (bexarotene), interferon-alfa, interferon-gamma, topical imiquimod, and thalidomide have also been shown to have activity against cutaneous ALCL in case reports or small series.

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.^[46]

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.^[47]

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.^[46]

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.^[48]

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.^{[49, 50]}

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 in whom 1 or more prior multidrug chemotherapy regimens had failed. 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% of 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).^{[51, 52]}

Brentuximab vedotin is approved by the US Food and Drug Administration for relapsed/refractory systemic ALCL. In 2018, the FDA approved brentuximab vedotin for treatment of adult patients with previously untreated systemic ALCL or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone (CHP). Approval as frontline therapy was based on the ECHELON-2 phase 3 clinical trial (n = 452), in which brentuximab plus CHP was superior to CHOP with respect to progression free survival (P = 0.011) and overall survival (P = 0.024).^[53]

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.^{[54, 55]}Currently a phase 1/2 trial to evaluate crizotinib is under way for relapsed/refractory ALK-positive systemic ALCL.

Proteosome inhibitors and lenalidomide have also shown activity in small case series of relapsed refractory T-cell lymphomas, which included few cases of systemic ALCL.^{[56, 57]}

Breast implant–associated ALCL

In most cases, the neoplastic cells are confined to the seroma fluid, without invasion of the capsule, and the recommended therapy is removal of the implant and capsule.^[5]A review of 87 patients by Clemens et al reported better event-free and overall survival in patients who underwent total capsulectomy with breast implant removal than in those who received partial capsulectomy, systemic chemotherapy, or radiation therapy.^[58]Systemic chemotherapy is warranted if invasion through the capsule through the capsule has occurred, as these patients are at risk for lymph node involvement and systemic spread.^[59]

The US Food & Drug Administration (FDA) does not recommend prophylactic breast implant removal for prevention of implant-associated ALCL in patients without symptoms or other abnormality.^{[5, 6]}

The FDA does recommend that clinicians report all confirmed cases of ALCL in women with breast implants to its MedWatch system. In addition, the FDA recommends submitting case reports of breast implant–associated ALCL to the PROFILE Registry, to contribute to better understanding of the causes and treatments of the disease.^{[5, 6]}

Surgical Care

Simple excision, with or without adjuvant spot radiotherapy, may be considered for solitary or localized skin lesions.^[45]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.

Follow-up Monitoring

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.

References

Prognosis

General considerations

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:

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.^[32]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).^[24]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.^[24]

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.

References

What is anaplastic large cell lymphoma (ALCL)?How is anaplastic large cell lymphoma (ALCL) diagnosed?What is included in patient education about anaplastic large cell lymphoma (ALCL)?What are the subtypes of anaplastic large cell lymphoma (ALCL)?What are the morphological patterns of anaplastic large cell lymphoma (ALCL)?What are the immunophenotypes of anaplastic large cell lymphoma (ALCL)?What are the genetic-molecular characteristics of anaplastic large cell lymphoma (ALCL)?What is the prevalence of anaplastic large cell lymphoma (ALCL) in the US?What is the global prevalence of anaplastic large cell lymphoma (ALCL)?What are the sexual predilections of anaplastic large cell lymphoma (ALCL)?Which age groups have the highest prevalence of anaplastic large cell lymphoma (ALCL)?What causes anaplastic large cell lymphoma (ALCL)?What are the risk factors for anaplastic large cell lymphoma (ALCL)?Which clinical history findings are characteristic of breast implant–associated anaplastic large cell lymphoma (ALCL)?Which clinical history findings are characteristic of primary systemic anaplastic large cell lymphoma (ALCL)?Which clinical history findings are characteristic of primary cutaneous anaplastic large cell lymphoma (ALCL)?Which conditions are included in the differential diagnoses of anaplastic large cell lymphoma (ALCL)?Which tests are performed in the workup of anaplastic large cell lymphoma (ALCL)?What is the role of complete blood count (CBC) in the workup of anaplastic large cell lymphoma (ALCL)?What is the role of blood chemistries in the workup of anaplastic large cell lymphoma (ALCL)?What is the role of absolute lymphocyte count (ALC) in the workup of anaplastic large cell lymphoma (ALCL)?What is the role of chest radiography in the workup of anaplastic large cell lymphoma (ALCL)?What is the role of CT scanning in the workup of anaplastic large cell lymphoma (ALCL)?What is the role of ultrasonography in the workup of anaplastic large cell lymphoma (ALCL)?What is the role of gallium scanning in the workup of anaplastic large cell lymphoma (ALCL)?What is the role of MRI in the workup of anaplastic large cell lymphoma (ALCL)?What is the role of bone scanning in the workup of anaplastic large cell lymphoma (ALCL)?What is the role of a PET scan in the workup of anaplastic large cell lymphoma (ALCL)?How is anaplastic large cell lymphoma (ALCL) differentiated from lymphomatoid papulosis (LyP)?Which molecular techniques are used in the workup of anaplastic large cell lymphoma (ALCL)?What is the role of biopsy in the workup of anaplastic large cell lymphoma (ALCL)?Which histologic findings are characteristic of anaplastic large cell lymphoma (ALCL)?How is anaplastic large cell lymphoma (ALCL) staged?What must be excluded in patients with anaplastic large cell lymphoma (ALCL) prior to initiation of treatment?How is primary cutaneous anaplastic large cell lymphoma (ALCL) treated?How is primary systemic anaplastic large cell lymphoma (ALCL) treated?How is breast implant–associated anaplastic large cell lymphoma (ALCL) treated?What is the role of surgery in the treatment of anaplastic large cell lymphoma (ALCL)?Which specialist consultations are beneficial to patients with anaplastic large cell lymphoma (ALCL)?Which diet and activity modifications are used in the treatment of anaplastic large cell lymphoma (ALCL)?What is included in the long-term monitoring of anaplastic large cell lymphoma (ALCL)?What are the possible complications of anaplastic large cell lymphoma (ALCL) treatment?What is the prognosis of anaplastic large cell lymphoma (ALCL)?What are the prognostic factors for primary systemic anaplastic large cell lymphoma (ALCL)?What is the prognosis of primary cutaneous anaplastic large cell lymphoma (ALCL) with a localized presentation?What is the prognosis of secondary anaplastic large cell lymphoma (ALCL)?What are the mortality rates of anaplastic large cell lymphoma (ALCL)?

References

Author

Delong Liu, MD, PhD, Professor of Medicine, Division of Oncology/Hematology, New York Medical College; Chief of Hematology, Phelps Memorial Hospital Center; Director of Non-ablative Allogeneic Stem Cell Transplantation Program, Westchester Medical Center; Editor-in-Chief, Journal of Hematology and Oncology