Continuing Education Activity

Anaplastic lymphoma kinase positive (ALK+) anaplastic large cell lymphoma (ALCL), is a T-cell lymphoma characterized by large, pleomorphic lymphoid cells with abundant cytoplasm and horseshoe-shaped nuclei, positive for CD30. ALK+ ALCL has associated recurrent t(2;5) fusion translocation involving the ALK gene and nucleophosmin (NPM1) gene. This CME activity outlines the evaluation and management of ALK+ ALCL while highlighting the role of the interdisciplinary healthcare team in the management of this condition.

Objectives:

• Review the etiology and epidemiology of ALK+ ALCL.
• Describe the histopathology and clinical presentation of ALK+ ALCL.
• Summarize the treatment and prognosis of ALK+ ALCL.
• Discuss modalities to improve care coordination among interprofessional team members in order to improve outcomes for patients affected by ALK+ ALCL.

Introduction

Anaplastic lymphoma kinase positive (ALK+) anaplastic large cell lymphoma (ALCL) is a peripheral T-cell lymphoma (PTCL) that consists of characteristic large pleomorphic lymphoid cells with abundant cytoplasm and horseshoe-shaped nuclei, strongly positive for CD30 immunohistochemical staining. ALK+ ALCL has associated recurrent t(2;5) fusion translocation involving the ALK gene and nucleophosmin (NPM1) gene. Ki-1 lymphoma is the old terminology that refers to the CD30 (previously designated as Ki-1 antigen) positive lymphomas, exhibiting a morphology resembling malignant histiocytes, but having overlapping immunohistochemical features of classic Hodgkin's lymphoma.

The 2016 revised World Health Organization (WHO) lymphoma classification includes four distinct entities under ALCL: systemic ALK-positive ALCL (ALK+ ALCL), systemic ALK-negativeALCL (ALK- ALCL), primary cutaneous ALCL (pC ALCL), and the provisional entity breast implant-associated ALCL (BI-ALCL).[1]

Etiology

ALCL (ALK-positive) usually is of T cell origin. ALCL (ALK-positive) may be primary or secondary. The disease is associated with HIV, mycosis fungoides, pulmonary and inflammatory pseudotumors.  ALCL (ALK-positive) has not been shown to be related to EBV infection.[2]

Epidemiology

ALK+ ALCL is more common in children and adolescents as compared to adults. It is notably more common in the first three decades of life and shows an overall male predominance (male to female ratio of 1.5:1).[2][3] Majority of patients present with advanced-stage III or IV disease, and exhibit B symptoms (persistent fevers, weight loss, and profuse night sweats).[2]

Histopathology

ALCL (ALK-positive) shows a diverse morphologic spectrum. Most cases show infiltration of interfollicular T zones and nodal sinuses by anaplastic large cells that have horseshoe ("hallmark") cells, wreath-like or multiple nuclei, multiple nucleoli, perinuclear eosinophilic region, occasional nuclear pseudoinclusions ("doughnut" cells), and rare mitotic activity. These cells have been referred to as hallmark cells because they are present in all morphological variants. The anaplastic large cells can sometimes mimic Reed-Sternberg cells, metastatic carcinoma cells, or megakaryocytes. Bone marrow forms of infiltration vary from extensive involvement by anaplastic large cells to only rare scattered anaplastic large cells that may elude detection. The classic ALCL (ALK-positive) is known as a common pattern, and this pattern presents in up to 60% of cases. The following morphologic variants have been described: Lymphohistiocytic, small cell, Hodgkin-like, hypocellular, neutrophil-rich cutaneous T cell, sarcomatoid, and composite pattern.[4][5]

History and Physical

ALCL (ALK-positive) patients can present with variable symptoms. Most cases present with advanced stage (III-IV). Symptoms include peripheral or abdominal lymphadenopathy, extranodal infiltrates, bone marrow involvement, and B symptoms (such as fever and weight loss). In cases of BM infiltration, the patients can present with anemia or pancytopenia, eosinophilia, and high LDH. The small cell variant of ALCL (ALK-positive) may show a leukemic presentation with peripheral blood involvement.[4][5]

Evaluation

Immunohistochemistry (IHC) is necessary to confirm ALCL (ALK-positive). Positive stains supporting ALCL (ALK-positive) diagnosis include:  CD30 (cytoplasmic), EMA, CD2, CD4, CD5, TIA1, granzyme B, perforin, CD45, CD45RO, CD61, CD25 (strong), BNH9. Negative stains include: CD15, CD20, CD79a, cytokeratin, bcl2, PAX5 / BSAP, PGM1, EBV (EBER & LMP1).  ALCL (ALK-positive) can show loss of several pan-T- cell antigens, referred to as null-cell phenotype. However, these cells still show evidence of a T-cell lineage at the genetic level. No clinical or prognostic difference between T-cell versus a null-cell phenotype has been found. ALK immunohistochemistry (ALK IHC), fluorescence in situ hybridization (FISH), and reverse-transcription polymerase chain reaction (RT-PCR) results have been shown to be comparable diagnostic tools. FISH using an ALK break-apart probe or karyotyping is not mandatory in clinical practice if ALK staining is positive. RT-PCR is usually used for the detection of minimal residual disease in blood or bone marrow. Genetic testing is useful in confirming ALCL (ALK-positive) diagnosis. T cell receptor (TCR) gene rearrangement is seen in most cases and can be assessed by PCR or flow cytometry. There are different distinct translocations all of which result in upregulation of ALK protein. The most common translocation is t(2;5)(p23;q35). Other translocations/rearrangements include: t(1;2)(q25;p23), inv(2)(p23;q35),  t(2;3)(p23;q21),  t(2;17)(p23;q23), t(2;X)(p23;q11-12), t(2;19)(p23;p13.1), t(2;22)(p23;q11.2) and t(2;17)(p23;q25). Other secondary genetic alterations include: -4, del11q, del13q, +7, +17p, +17q). Gene expression profiling comparing ALCL (ALK-positive) and ALCL (ALK-negative) has shown significant differences, although the two tumors show similarities.  ALCL (ALK-positive) shows unique overexpression of BCL6, PTPN12, SERPINA1and CEBPB.[4][6]

Differential Diagnosis

• ALCL (ALK-negative)
• ALK-positive diffuse large B cell lymphoma with immunoblastic/plasmablastic features
• Pleomorphic carcinoma
• Hodgkin lymphoma
• Lymphomatoid granulomatosis
• Histiocytic sarcoma
• Nonneoplastic disorders with atypical CD30+ cells
• Rhabdomyosarcoma
• Inflammatory myofibroblastic tumor

Treatment Planning

ALCL patients receive treatment with an anthracycline-based chemotherapy regimen with the goal of achieving a complete remission (CR). The anthracycline-based chemotherapy regimen CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) with or without etoposide is the standard treatment approach. Patients less than 60 years should receive six cycles of CHOEP for induction and patients greater than 60 years should receive six cycles of CHOP for induction. Patients should then undergo CT/PET imaging one month after completion of treatment to assess the response. If the patient is more than 40 years and has an International Prognostic Index greater than 3, autologous hematopoietic cell transplantation should is an option to be offered. Otherwise, patients should be observed until progression. High-risk patients should go through high-dose consolidation chemotherapy and autologous hematopoietic cell transplantation (HCT). Refractory ALCL (ALK-positive) patients may benefit from clinical trials utilizing small-molecule inhibitors of ALK kinase or CD30 antibody-drug conjugates.[7]

Prognosis

ALCL (ALK-positive) is a moderately aggressive T cell lymphoma. The overall prognosis is better than other peripheral T-cell lymphomas. ALCL (ALK-positive) has a better prognosis than ALCL (ALK-negative) with a 5-year overall-all (OS) of 80% compared to 48%. International Prognostic Index (IPI), is a useful prognostic tool in ALCL (ALK-positive). The index assigns one point for each of the following variables:

• Age >60 years
• Serum lactate dehydrogenase concentration greater than normal
• ECOG performance status of 2 or greater
• Clinical stage III or IV disease
• >1 involved extranodal site

MYC gene rearrangement is associated with an unfavorable prognosis. The morphological variants small-cell and lymphohistiocytic variant also confer inferior prognosis compared to the common type histology.  The IPI has shown significant prognostic value, compared to other lymphomas. Research has shown no prognostic difference between classic and variant translocations. Relapses of ALCL (ALK-positive) usually remain sensitive to chemotherapy; allogeneic bone marrow transplantation is usually only for refractory cases.[5]

Complications

ALCL (ALK-positive) complications include BM suppression, organ dysfunction or adverse effects related to high dose chemotherapy.

Deterrence and Patient Education

Patients with newly diagnosed ALCL (ALK-positive) receive treatment with an anthracycline-based chemotherapy regimen with the goal of achieving a complete remission (CR).

Enhancing Healthcare Team Outcomes

The diagnosis of ALCL (ALK-positive) has its basis in the pathologic features of lymph node biopsy in combination with a clinical evaluation. Patients with newly diagnosed ALCL (ALK-positive) receive therapy with CHOP or CHOEP regimens for six cycles. Evaluation post-induction is crucial to assess future treatment options.