Primary ALCL Research Articles

Clinicopathologic features of primary central nervous system anaplastic large cell lymphoma: a multicenter study identifies age and ALK status as prognostic factors.

Anaplastic large cell lymphoma with primary presentation in, and disease limited to, the central nervous system (primary CNS ALCL) is a rare and aggressive lymphoma found in a sensitive anatomic site. We report the clinical and pathologic characteristics of 17 primary CNS ALCL cases that are newly reported from six academic medical centers. We are investigating the characteristics of these cases, alongside their commonalities and differences from systemic ALCL arising at conventional anatomic sites. Clinical, pathologic, and outcome data were extracted by medical record review. The median patient age was 32years with a male-to-female ratio of 2.4:1. Cases presented with either localized or multifocal central nervous system (CNS) disease without coinciding systemic disease. Histologically, the common pattern prevailed, and loss of pan-T-cell markers was frequent. There was a similar proportion of anaplastic lymphoma kinase (ALK) positivity in primary CNS ALCL (12/17, 71%) compared to that reported in systemic ALCL (70-80%). Our data indicate a 5-year overall survival (OS) rate of 65% and a 5-year progression-free survival (PFS) rate of 48%. Five patient deaths occurred in this study of which all were in the ALK-negative group, and all were patients over 40years old. ALK-positive patients were significantly younger than ALK-negative patients, and survival analyses showed that both ALK-positive and younger age (≤ 40years) were favorable prognostic factors. This is the largest series of primary CNS ALCL reported to date, which demonstrates a high proportion of ALK-positive cases and favorable outcomes for both younger and ALK-positive patients despite the involvement of a sensitive anatomic site.

Establishment and characterization of TK-ALCL1: a novel NPM-ALK-positive anaplastic large-cell lymphoma cell line.

TK-ALCL1, a novel anaplastic lymphoma kinase (ALK)-positive anaplastic large-cell lymphoma (ALK+ ALCL) cell line, was established from the primary tumor site of a 59-year-old Japanese male patient. The immune profile of TK-ALCL1 corresponds to that seen typically in primary ALCL cells, i.e., positive for ALK, CD30, EMA, and CD4, but negative for CD2, CD3, CD5, CD8a, and EBV-related antigens. The rearrangement of the T cell receptor-gamma locus shows that TK-ALCL1 is clonally derived from T-lineage lymphoid cells. FISH and RT-PCR analysis revealed that TK-ALCL1 has the nucleophosmin (NPM)-ALK fusion transcript, which is typical for ALK+ ALCL cell lines. When TK-ALCL1 was subcutaneously inoculated into 6-week-old BALB/c Rag2-/-/Jak3-/- (BRJ) mice, it formed tumor masses within 4-6weeks. Morphological, immunohistochemical, and molecular genetic investigations confirmed that the xenograft and the original ALCL tumor were identical. The ALK inhibitors Alectinib and Lorlatinib suppressed proliferation in a dose-dependent manner. Thus, TK-ALCL1 provides a useful in vitro and in vivo model for investigation of the biology of ALK+ ALCL and of novel therapeutic approaches targeting ALK.

Primary Central Nervous System Anaplastic Large Cell Lymphoma, ALK Positive.

Primary central nervous system anaplastic large cell lymphoma, anaplastic lymphoma kinase positive (primary CNS ALCL, ALK+) is a rare CNS lymphoma whose description is limited to case reports. These tumors have a variable clinical course, and prognosis is primarily determined by age. We present the largest case series to date of primary CNS ALCL, ALK+, with observational data. A retrospective search of multiple academic centers was performed to identify cases of primary CNS ALCL, ALK+. We also performed a review of published cases of primary CNS ALCL, ALK+. Clinical history, radiography, pathology, and genetic testing data were obtained to determine the prognostic implications in the context of clinical course. We identified three cases of primary CNS ALCL, ALK+ from our databases. A literature review identified 30 published reports of 31 individual cases. Clinical features for the combined 34 cases included a median age of 18.5 years, with a male to female ratio of 4.7:1, and the most common symptom was headache. Genetic studies demonstrated an ALK rearrangement by fluorescence in situ hybridization, and a gene fusion assay confirmed an NPM1-ALK gene fusion in one case. We present the largest case series to date of a rare primary CNS lymphoma with additional diagnostic and clinical information.

Incidence of Anaplastic Large Cell Lymphoma and Breast-Implant-Associated Lymphoma-An Analysis of a Certified Tumor Registry over 17 Years.

Background: Breast-implant-associated anaplastic large cell lymphoma (BI-ALCL) and primary breast ALCL are rare extranodal manifestations of non-Hodgkin lymphoma. The rarity of both diseases, along with unreleased sales data on breast implants and constant updates of classification systems impede the calculation of an exact incidence. Methods: The database of the Tumor Center Regensburg in Bavaria was searched for patients with CD30-positive and ALK-negative anaplastic large cell lymphoma between 2002 and 2018. These lymphomas were identified by the ICD-O-3 morphology code “97023” and were cross-checked by searching the diagnosis by name the and ICD-10 code C84.7. Furthermore, we tried to calculate the incidence rates and corresponding 95% confidence intervals, standardized to 1,000,000 implant years of breast-implant-associated anaplastic large cell lymphoma and primary breast anaplastic large cell lymphoma. Results: Twelve ALK-negative and CD30-positive anaplastic large cell lymphomas were identified out of 170,405 malignancies. No case was found within the breast tissue and none of the patients had a previous history of breast implant placement. In five cases, lymph node involvement in close proximity to the breast was observed. Conclusion: We found a low incidence of anaplastic large cell lymphoma and no association to breast implants in these patients. A review of the current literature revealed inconsistent use of classification systems for anaplastic large cell lymphomas and potential overestimation of cases.

A Rare Case of Primary Pulmonary Anaplastic Large Cell Lymphoma.

Non-Hodgkin lymphomas are rare causes of primary lung neoplasms and most are B-cell in origin. Anaplastic large cell lymphoma is an exceedingly rare type of primary pulmonary lymphoma, with an aggressive clinical course.We present the case of an 85-year old male patient who attended our Emergency Department complaining of respiratory and constitutional symptoms, and who was found to have a bronchial mass causing subtotal atelectasis of the left lung. Histological examination showed an anaplastic large cell lymphoma and further investigation revealed that it was limited to the lung. To our knowledge, very few similar cases have been reported in the literature.LEARNING POINTSNon-Hodgkin lymphomas are rare causes of pulmonary lung neoplasms, with the majority of cases being marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue or diffuse large B-cell lymphoma.Anaplastic large cell lymphoma (ALCL) usually involves the lymph nodes, skin and soft tissue. It follows an aggressive clinical course and constitutional symptoms are frequent at presentation. Lung involvement may occur as a result of dissemination in up to 12% of cases. Primary ALCL of the lung is extremely rare.Anaplastic lymphoma kinase (ALK) expression is an important prognostic factor, with ALK+ ALCL patients experiencing better outcomes. Adverse prognostic factors also include advanced age, serum lactate dehydrogenase levels and early relapse after therapy.

Epidemiology and Survivorship of Anaplastic Large Cell Lymphoma

Background:Anaplastic Large Cell Carcinoma (ALCL) is a rare form of Non-Hodgkin Lymphoma. The incidence of ALCL, especially of breast implants, has been increasing over the years. We utilized the NCDB database to study prognostic variables for ALCL, to create the largest and most comprehensive cohort of patients with primary ALCL, to analyze primary anatomical site and other prognostic variables and how they affect survival so as to help improve clinical outcomes across the world.Methods: Utilizing the National Cancer Database, 3,298 patients with primary T-cell anaplastic large cell lymphoma were identified by the histology code 9714 and grade code 5. Kaplan-Meier curves and survival tables were created to calculate 1-, 5-, and 10-year survival probabilities for variables including stage, race, sex, facility type, age, insurance, primary site, year of diagnosis, and adjuvant therapy. Log-rank analysis was used to compare the groups within each variable.Results: The cohort consisted of 61.2% male patients and 77.9% Caucasian patients with a median age of diagnosis of 51 years old. Approximately 67% of the patients were diagnosed with ALCL between the years of 2010 and 2015. The most common type of insurance was private insurance with 49.4% of the cohort followed by Medicare with 27%, Medicaid with 12.8% and not insured with 6.3%. Most patients (27.3%) were treated at academic or research facilities, closely followed by comprehensive community cancer programs with 26.4% of the cohort. The most common primary anatomical site was lymph nodes of multiple sites consisting of 34.4% of the cohort. Stage IV was the most common stage consisting of 31.8% of the cohort.Overall 1-, 5-, and 10-year survival probabilities for patients with ALCL were 71.5%, 59.7%, and 51.8%, respectively. As age increased, overall survival decreased, with the ≥75 age group having the worst 1- and 5-year survival probability of 43.6% and 23.5%, respectively. Patients diagnosed between the years of 2004-2009 (1-year:66.4% and 5-year:52.7%) had much worse survival probabilities when compared to patients diagnosed between the years of 2010-2015 (1-year:74.5% and 5-year:68.1%). Caucasian patients had better 1-,5- and 10-year survival outcomes when compared to African Americans with 1-year survival probabilities of 72.2% and 64.9%, respectively. Facilities other than research or academic centers and Medicare or Medicaid insurance had worse 1-,5-, and 10-year survivals when compared to research or academic centers and private insurance. As stage increased, overall survival probabilities decreased. The lower limb and hip anatomical site had the best survival outcomes with 1- and 5-year survival probabilities of 84.7% and 78.3% respectively. Adjuvant hematologic transplant patients did best with a 1- and 5-year survival probabilities of 94.8% and 87.4%, respectively, followed by an adjuvant combination of both radiation and hematologic transplant (1-year:85.2% and 5-year:81.5%), adjuvant radiation (1-year:83.3% and 5-year:74.2%), and chemotherapy alone (1-year:73.7% and 5-year:65.0%). DISCUSSIONThis is the largest and most comprehensive study to date on the epidemiology and prognostic factors of Anaplastic Large Cell Lymphoma. The results of our analysis bring up several interesting trends, the most interesting one being the marked increase in survival rates between 2010- 2015 compared to 2004-2009. This is likely attributed to better treatment modalities. With regards to treatment modalities, patients who underwent chemotherapy followed by adjuvant transplant had better 1, 3, 5 and 10 year survival rates compared to all other treatment modalities. As previously established, younger age at diagnosis is a good prognosis factor. Other major factors influencing survival, previously unstudied, are facility type, race, insurance status, stage, adjuvant therapy, and primary site. Asians and those with private insurance had better survival rates. Primary site involving multiple lymph nodes carried the worst prognosis, while lower limb and hip as primary sites carried the best prognosis. Patients treated at academic and research center had better prognosis compared to those treated at non- academic centers. Performing a multi-variate analysis and further studies to elucidate the causes of improved survival associated with some of these factors will help improve quality of care for patients with ALCL. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

ALK Expression is a Rare Finding in Mycosis Fungoides.

Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma. Although indolent in its early stages, MF is more aggressive in advanced stages, particularly if large cell transformation occurs. Histologically, transformed MF is similar to primary cutaneous anaplastic large cell lymphoma (pcALCL) and nodal ALCL (nALCL). MF had not been associated with immunohistochemical expression of anaplastic lymphoma kinase (ALK) until we previously reported a case documenting the presence of ALK by immunohistochemistry in a patient with stage IA MF and concurrent nALCL. This is a unique finding due to the fact that ALK positivity is usually found in nALCL. The goal of this study is to examine the extent to which ALK may be expressed in the different morphologic lesions of MF. One hundred three biopsies from 96 patients, including the patient from the original case, with confirmed MF representing various lesion stages and subtypes, were tested for ALK by immunohistochemical staining. Out of the 103 biopsies, only the original index case of Stage IA MF with concurrent nALCL expressed ALK. From these results, we conclude that ALK is not routinely present in MF in any lesion stage or variant type. Routine staining of ALK is therefore of no additional benefit for the workup of known early stage MF; however, its use may be beneficial in the initial workup of unspecified large cell lymphomas of the skin.

Primary Anaplastic Large Cell Lymphoma of the Lung in a Child

Anaplastic large cell lymphoma [ALCL] is a rare disease in children accounting for 10-15% of all childhood non-Hodgkin lymphomas. Primary ALCL characteristically involves the lymph node/skin and is a rare malignancy in the lung accounting for only 0.3% of primary lung neoplasms. A case of primary ALCL of the lung in a 5-year old boy is discussed detailing …

Bortezomib Induces Caspase-9-Mediated Apoptosis through Activation of the BH3-Only Proteins Noxa, Bik and Puma In Both ALK-Positive and ALK-Negative Anaplastic Large Cell Lymphoma Cells

AbstractAbstract 2847Anaplastic large cell lymphoma (ALCL) is a CD30 positive T-cell lymphoma that can be divided into a systemic and a primary cutaneous type. Systemic ALCL can be further divided into an anaplastic lymphoma kinase (ALK) expressing type and an ALK-negative type. Despite intensive treatment regimens, the disease will be fatal in 20–30% of the systemic ALK-positive and 50–70% of the systemic ALK-negative ALCL patients. A recent study in primary ALCL samples has demonstrated an increased expression of a fraction of NF-κB target genes, suggesting upregulation of NF-κB activity in ALCL tumor cells. NF-κB activity can be inhibited by the proteasome inhibitor bortezomib resulting in induction of apoptosis. In this study, we therefore investigated if bortezomib can induce apoptosis of cultured lymphoma cells of three systemic ALK-positive and three ALK-negative ALCL patients and seven ALCL cell lines and we examined the mechanisms by which bortezomib induced cytotoxicity in these ALCL cells.Treatment with bortezomib resulted in induction of apoptosis in all ALK-positive and ALK-negative ALCL patient samples and ALCL cell lines tested, when we compared the percentage cell death with the non-neoplastic CD4- and CD8-positive PBMC and tonsil T-cells from healthy donors. The lethal dose (LD50) varied between 54nM and more than 100nM after 24 hours and varied between 21nM and 52nM after 48 hours of exposure. ALK-negative ALCL cases were more sensitive to bortezomib and showed significant lower LD50 values than ALK-positive ALCL cells. We show that bortezomib-induced cell death in ALK-positive and ALK-negative ALCL is dependent on caspase-9 and/or caspase-8 mediated apoptosis and that bortezomib induces depolarization of the mitochondrial membrane. mRNA-expression and protein analysis revealed clearly upregulation of the BH3-only proteins Noxa, Bik and Puma, resulting in Bak and Bax release from the anti-apoptotic proteins Mcl-1 and Bcl-2. We also demonstrated that ALCL cells relatively resistant to bortezomib were characterized by high expression of Bcl-2A1, suggesting the possibility of pre-defining patients most likely to benefit from bortezomib therapy.Our preclinical data support the therapeutic application of bortezomib as potential drug in the treatment of ALCL, especially ALK-negative ALCL patients to improve their prognosis. Disclosures:No relevant conflicts of interest to declare.

Primary cutaneous neutrophil-rich CD30+ anaplastic large-cell lymphoma: a report of two cases

Primary cutaneous ananplastic large-cell lymphoma(C-ALCL) has been well known, but the primary cutaneous neutrophil-rich ALCL, a morphological variant of C-ALCL, has unusual clinicopathologic features. Two cases of primary cutaneous neutrophil-rich ALCL without systemic involvement are reported.The patients showed erythema and nodules with purulent discharge. Histopathologically, the dermal infiltrate composed of not only numerous CD30-expressing pleomorphic cells but also a large quantity of neutrophils. Key words: Lymphoma; Anaplasia; Antigens, CD30+; Neutrophil infiltration

ANAPLASTIC LARGE CELL LYMPHOMA WITH PRIMARY INVOLVEMENT OF SKELETAL MUSCLE: A Rare Case Report and Review of the Literature

Primary skeletal muscle ALCL is very rare. Here the authors report a case of skeletal muscle ALCL that was proven pathologically. A 14-year-old boy presented with a persistent fever, chills, night sweats, headache, and significant weight loss. A CT scan of the abdomen showed a hazy mass about 3.2 × 1.2 cm in his left sacrospinalis. Ultrasonography revealed a low-echo and irregular mass in the left lumbar muscle measuring 8 × 1.4 × 3.6 cm in size and a similar mass 8 × 3.5 × 3.7 cm in size in the femoral muscle of the left thigh. MRI demonstrated an abnormal mass signal 4 × 3 × 9 cm in size infiltrating the left sacrospinalis muscle. The biopsy specimen was taken from the femoral muscle of the left thigh at surgery. Histopathological examination revealed a diffuse infiltration of large and atypical cells with pleomorphic nuclei and abundant cytoplasm. Immunohistological staining showed these atypical cells were positive for CD30 (Ki-l), anaplastic lymphoma kinase (ALK), epithelial membrane antigen (EMA), CD3, CD45RO, and CD68. The morphology and immunophenotype were consistent with CD30-positive, ALK-positive, and ALCL of T-cell lineage. The patient's condition was diagnosed as CD30-positive primary skeletal muscle ALCL.

Primary Anaplastic Large Cell Lymphoma of the Pancreas

Most solid pancreatic tumors are exocrine adenocarcinomas. We presented a patient with primary ALCL of the pancreas masquerading as a carcinoma of the head of pancreas. She was scheduled for a Whipple's operation and the intra-operative frozen section showed anaplastic carcinoma. The proper diagnosis was only derived later with CD30 immunohistochemical study. This carries important implications on the management, as radical surgery is indicated in resectable carcinoma but not for a chemosensitive lymphoma.

Uniform expression of cytotoxic molecules in anaplastic large cell lymphoma of null/T cell phenotype and in cell lines derived from anaplastic large cell lymphoma.

We recently provided ample evidence that anaplastic large cell lymphomas of T/null phenotype (T-/null-ALCL) genotypically represent peripheral T cell lymphomas which in up to 90% have a phenotype of cytotoxic cells with expression of granzyme B protein and perforin transcripts. However, the issue of granzyme B expression in T-/null-ALCL is still controversial due to differing results from another laboratory. To verify our earlier immunohistochemical stainings for granzyme B, we looked for granzyme B transcripts by in situ hybridization (ISH). In addition, we investigated our previously analyzed cases by immunohistology (IH) with another antibody (2G9), which reacts with two molecules known to be expressed in cytotoxic cells: T-cell-restricted intracellular antigen (TIA)-1 and granule membrane protein-17 (GMP-17). We also extended our studies to homogenous tumor cell populations provided by ALCL-derived cell lines. As evidenced by ISH, transcripts for perforin, TIA-1 and granzyme B were found in all ALCL-derived cell lines. Similarly, proteins of TIA-1/GMP-17, granzyme B and perforin were expressed in all of these lines as shown by IH. In biopsy specimens, TIA-1/GMP-17 were detected by IH in 14/16 cases of T-/null-ALCL, and granzyme B transcripts were found in 13/13 T-/null-ALCL cases, but not in 6 B-ALCL cases. The detection of granzyme B transcripts yielded results largely identical to those of IH for granzyme B protein, thus confirming our earlier data and suggesting that the regulation of the expression of this molecule largely occurs at the transcriptional level. Our data further confirm the almost uniform expression of cytotoxic molecules in both primary ALCL cases and ALCL-derived cell lines and therefore suggest that the derivation from cytotoxic T cells may be the unifying characteristic for T-/null-ALCL.