Anaplastic Large Cell Type Research Articles

ACT-05 Present and future of precision-based medicine using cancer genome panels

Background: Two cancer genome panels were approved for use in Japan in 2019, and their application in brain tumors are awaited. We have used CANCERPLEXR and FoundationOne CDx (F1) panels for the realization of precision-based medicine in brain tumors. Patients and methods: From August 2017 to present, we have applied cancer genome panels in 11 times to tumors in 9 patients. We assessed patient data including age, sex, pathology, reason for using the panel and actionability. Results: The range of age of 4 to 69 years (mean 45.2 years), and 5 men and 4 women were studied. Pathological diagnosis was epithelioid glioblastoma (GBM), giant cell GBM, anaplastic ependymoma, anaplastic meningioma, anaplastic large cell type lymphoma, meningeal melanomatosis, enterogeneous carcinoma, choroid plexus carcinoma and pineoblastoma. CANCERPLEXR was performed 7 times and F1 panel 4 times and the reasons included confirmation specific gene mutations such as BRAF V600E and TP53, young (pediatric) age and patient request. In one patient, by analyzing primary and recurrent tissue, we were able to assess genetic hits involved in malignant transformation. Actionable targets were found in 4 (44%) of cases, and action was taken in only 1 epithelioid GBM patient with BRAF V600E mutation, albeit with dramatic response (Kanamaru et al., Acta Neuropathol Commun, 2019). All tumors were microsatellite stable. Conclusions: We were able to understand tumor biology in rare brain tumors using 2 genome panels. We need to increase the percentage of patients actually treated. I will also like to touch briefly on how use genome panels for translational research on brain tumors.

WS3-2 - Pathological Features and Microenvironment of Atll

Histopathology of ATLL usually shows a pleomorphic type. Some cases show a pleomorphic small cell, or anaplastic large cell type. In addition, some patients with pre-overt ATLL show a Hodgkin's disease-like and lymph nodes in non-neoplastic carriers with features of lymphadenitis. Lymphoma cells express T-cell-associated antigens (CD2, CD3, CD5, CD4), and CD25. CCR4 of the chemokine receptor is frequently expressed, and FoxP3 of the regulatory T-cell marker also. Half of ATLL cases express HTLV-1 Tax which is a target of HTLV-1-specific cytotoxic T lymphocyte (CTL). And there was inverse correlation between Tax-specific CTL and FoxP3. In addition, the increased CD163+ tumor associated macrophages were associated with worse prognosis. Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) with genomic aberrations has been shown to resemble ATLL in terms of its genomic aberration patterns, histopathology, phenotype and prognosis.

Prognostic Analyses on Anatomical and Morphological Classification of Feline Lymphoma

ABSTRACTThe present study was carried out to analyze the prognosis of 163 cats with lymphoma classified anatomically and cytomorphologically. Anatomically, alimentary lymphoma was the most common form and showed significantly shorter survival than mediastinal and nasal lymphomas in cats. Cytomorphologically, there was no predominant subtype in feline lymphomas. Immunoblastic type (18%), centroblastic type (16%), globule leukocyte type (15%), lymphocytic type (12%), lymphoblastic type (12%), pleomorphic medium and large cell type (10%) and anaplastic large cell type (7%) were relatively common subtypes. Most of the cats with globule leukocyte lymphoma had the alimentary form. Comparing median survival time among classifications, cats with globule leukocyte lymphoma showed significantly shorter survival than those with high-grade and other low-grade lymphomas. Furthermore, cats with high-grade lymphomas showed significantly shorter survival than cats with other low-grade lymphomas. The present study indicated the clinical significance of anatomical and cytomorphological evaluation in feline lymphomas.

Favorable Outcome In ALK-Negative Anaplastic Large-Cell Lymphoma Following Intensive Induction Chemotherapy and Autologous Stem Cell Transplantation (ASCT): a Prospective Study by the Nordic Lymphoma Group (NLG-T-01)

AbstractAbstract 3566Primary systemic T-cell lymphoma of anaplastic large cell type (ALCL) is an aggressive and predominantly nodal subtype of lymphoma, further subdivided based on expression of the ALK-protein, with ALK-pos ALCL occurring predominantly in younger patients and associated with a favourable prognosis. ALK-neg ALCL is believed to carry a prognosis similar to that of other nodal peripheral T-cell lymphomas and previous studies have shown long-term survival rates below 50%. There is retrospective data suggesting a benefit from ASCT in first-line treatment of this lymphoma subtype. We analyzed the outcome of ALK-neg ALCL patients included in a prospective phase II trial, NLG-T-01, conducted by the Nordic Lymphoma Group. The NLG T-01 trial enrolled 160 patients aged 18–67 years from the Nordic countries with systemic ALK-neg peripheral T-cell lymphoma within the period 2002–2007. The treatment schedule consisted of 6 courses of CHOEP-14 followed by ASCT (BEAM or BEAC) in responding patients. Patients >60 years received CHOP-14 as induction. Altogether, the trial included 31 patients with ALK-neg ALCL (19% of the study population). Median age was 56 years (22-65) with a male:female ratio of 2.4. Stage III-IV was found in 18 patients (58%), B-symptoms in 19 patients (61%) and 6 patients (19%) had a bulky lesion (>10cm). Pre-therapeutic serum lactate dehydrogenase was elevated in 18 patients (58%) and performance score was 2–4 in 10 patients (32%). After 3 and 6 courses of chemotherapy, response status was CR or CRu in 29% and 58% of the patients, respectively. In total, 24 out of 31 patients (77%) underwent BEAM/BEAC therapy followed by ASCT. Four patients did not respond or had disease progression during induction chemotherapy. The remaining 3 patients did not undergo ASCT for other reasons (mobilization failure, lung insufficiency, patient decision, respectively). Overall response rate after ASCT was 74% for the entire initial population and 96% for those undergoing ASCT. Median follow-up was 45 months. Six patients relapsed after ASCT. There was a total of nine deaths (29%): six due to lymphoma, two due to toxicity and one from second malignancy (colon cancer). With a median follow-up of 45 months, 3-year overall and progression-free survival values were 73% and 64%, respectively. Intensive chemotherapy followed by ASCT was feasible in the majority of the patients included in this prospective trial. Long-term outcome appears promising when compared to previously published data, with the survival curve suggesting a plateau. In ASCT eligible patients, intensive induction chemotherapy consolidated by upfront ASCT is an effective treatment that yields outcome results at least as good as those obtained in age-comparable patients with diffuse large B-cell lymphoma. Disclosures:No relevant conflicts of interest to declare.

Frequent expression of gp46 in adult T-cell leukemia/lymphoma: An immunohistochemical study of 40 cases

Adult T-cell leukemia/lymphoma (ATLL) is a lymphoproliferative disease caused by human T-cell lymphotropic virus type 1 (HTLV-1) infection. HTLV-1 is spread by cell-to-cell transmission via the gp46-197 region, from Asp197 to Leu216, in the envelope protein gp46. A correlation exists between the prevalence and titer of the antibody recognizing the gp46-197 region (anti-gp46-197 antibody) and the severity of ATLL. In the present study, immunohistochemical staining was performed on samples of paraffin embedded lymph nodes of three different histological types of ATLL (anaplastic large cell type, n = 10; pleomorphic type, n = 10; and Hodgkin's-like type, n = 10) from 30 cases and 10 cases of HTLV-associated lymphadenitis. Of the three ATLL subtypes, gp46 expression was highest in the anaplastic large cell type, followed by the pleomorphic type and Hodgkin's-like type (mean: 53.4%, 34.9% and 16.0%, respectively; P= 0.0003). In HTLV-1 associated lymphadenitis cases, gp46 positive cells were rarely seen (4.0%). These results suggest that gp46-197 immunohistochemical staining can be a useful histological indicator for prediction of the aggressiveness of ATLL and prognosis for ATLL patients.

Extranodal adult T-cell leukemia/lymphoma of the head and neck: a clinicopathological study of nine cases and a review of the literature

Extranodal adult T-cell leukemia/lymphoma (ATLL) of the head and neck is a rare disease. We studied the clinicopathological features of nine patients with ATLL involving extranodal head and neck sites and conducted a literature review. Six patients presented with extranodal mass of the head and neck, whereas three had disseminated diseases. Tumors involved the parotid gland, sinonasal tract, masseter muscle, mandible and skull. Histopathology included diffuse pleomorphic-type (with angiocentric features), Hodgkin-like and anaplastic large cell-type. Five patients with localised disease showed prolonged survival regardless of unfavourable histology and/or aberrant provirus status, including integration of multiple copies or defective provirus. Patients with localised disease documented in the literature, including our study series, had a reduced frequency of elevated lactate dehydrogenase, no hypercalcemia and longer survival. ATLL should be included in the differential diagnosis of extranodal head and neck lymphoma. Localised extranodal ATLL of the head and neck may exhibit indolent clinical behaviours.

Whole-Genome Analysis and HLA Genotyping of Enteropathy-Type T-Cell Lymphoma Reveals 2 Distinct Lymphoma Subtypes

Enteropathy-type T-cell lymphoma (ETL) is an aggressive extranodal T-cell non-Hodgkin lymphoma assumed to arise in the setting of celiac disease. To precisely define the genetic alterations underlying the pathogenesis of ETL, 30 ETL samples were profiled for genetic copy number alterations using high-resolution whole-genome tiling path array comparative genomic hybridization. To investigate the potential association of genetic alterations in ETL with celiac disease, HLA-DQB1 genotyping was performed. By array comparative genomic hybridization, 13 novel recurrent minimal regions of chromosomal alteration were identified on multiple chromosome arms. ETL is characterized by frequent complex gains of 9q31.3-qter (70% of cases), or by an almost mutually exclusive 2.5-megabase loss of 16q12.1 (23% of cases). Two distinct groups of ETL could be delineated morphologically and genetically: type 1 ETL is characterized by nonmonomorphic cytomorphology, CD56 negativity, and chromosomal gains of 1q and 5q. Type 1 ETL also appears to be linked pathogenetically to celiac disease, sharing genetic alterations and HLA-DQB1 genotype patterns with (refractory) celiac disease. Type 2 ETL shows monomorphic small- to medium-sized tumor cell morphology, frequently shows CD56 expression, MYC oncogene locus gain, and rare gains of chromosomes 1q and 5q. In contrast to type 1 ETL, type 2 ETL shows a HLA-DQB1 genotype pattern more resembling that of the normal Caucasian population. Contrary to current clinical classification, ETL comprises 2 morphologically, clinically, and genetically distinct lymphoma entities. In addition, type 2 ETL may not be associated with celiac disease.

FoxP3, a Key Molecule in CD4+CD25+ Regulatory T Cells, Express in Adult T Cell Leukemia/Lymphoma Cells and Relates to Clinicopathological Features.

AIMES: Adult T cell leukemia/lymphoma (ATLL) is an aggressive neoplastic disease and opportunistic infections often occur in patients with ATLL. However, the underlying mechanisms of such infections remain unknown. Recently, regulatory T cells (Treg), characterized by coexpression of CD4 and CD25, are proposed as a new T cell group with definite function. Treg suppresses normal T cells proliferation in vitro and play an important role to suppress autoimmune disease in vivo. But the deregulated proliferation such immunosuppressive T cells may induce immunodeficient status. We analyzed the expression of forkhead/winged helix transcription factor (FoxP3), known to be important for the function and specific marker of Treg cells, on ATLL cells.METHODS and RESULTS: FoxP3 expression was detected in both peripheral blood and lymph nodes in part of ATLL cases by real-time PCR and immunostaining (Figure). Next, we immunostained lymph node sections from 112 cases and 36 cases showed positivity for FoXP3. Morphologically, 112 ATLL cases were divided into three variants, namely pleomorphic cell type (61 cases), large cell type (45 cases), and anaplastic large cell type (16 cases). FoxP3 was expressed (more than 30% of the lymphoma cells) in a proportion of pleomorphic cell type (24 cases, 39.4%) and large cell type (12 cases, 26.7%) but no cases of anaplastic type showed positivity. Especially, strong expression (more than 50% of the lymphoma cells) was observed in 15 cases and 12 cases were pleomorphic cell type (Table). A proportion of FoxP3 positive ATLL cases showed intermingled EBV-infected transformed lymphocytes, suggesting local immunodeficient condition (Very few FoxP3 negative cases showed EBV-infected lymphocytes)(Table). Clinically, more proportion of FoxP3 positive ATLL cases showed opportunistic infection, for example Pneumocystis Carinii infections, Herpes zoster virus infection, antibiotics-refractory abscesses (Table).CONCLUSION: A proliferation of FoxP3 positive lymphoma cells may contribute to the tumor invasion and opportunistic infection by inducing local and diffuse immunodeficient status respectively. [Display omitted]

Primary Anaplastic Large Cell Lymphoma of the Breast Occurring in Patients with Silicone Breast Implants.

Primary breast lymphoma (PBL) accounts for up to 1% of all primary breast tumors, and 2.2% of all extranodal lymphomas. The vast majority of PBL are of B-cell origin, most commonly of the diffuse large cell histology. Fewer than 20 cases of T-cell PBL have been reported. We report 6 cases of T-lineage PBL occuring in patients who had previously received silicone breast implants for purposes of breast augmentation. None of the patients had a previous diagnosis of malignancy or unrelated prior breast surgery. In each case, the implants had been placed between 5 and 20 years previously. In each case, lymphoma was confined to breast by staging, and met previously defined criteria for PBL. In 5 cases, the lymphoma was identified as a solid mass involving the breast tissue. In one case, lymphoma cells were identified by flow cytometry in a fluid collection surrounding the implant. The implant was replaced, and the patient has subsequently treated with systemic chemotherapy despite negative PET scan. Thus far, reaccumulation of fluid has not occurred several months following replacement of the implant. In patients for whom follow-up information is available, two recurred following initial therapy and received autologous stem cell transplantation in second complete remission, and remain disease free at 2 years post-transplantation. Since 1995, six cases of PBL associated with breast implants have been reported in the literature, all of which are of T-cell lineage. The majority are of anaplastic large cell type. None of these cases have been previously reported, and this is the largest collection of such reported from a single institution. While previous reports have discounted any link between breast implants and lymphoma, this appears to be a specific association of an unusual lymphoma subtype occuring after a significant time period. Given the increasing number of silicone implant procedures recorded each year in the U.S., this represents an environmental association ripe for further investigation. Establishment of a national database would be appropriate to monitor any potential trends in this entity.PBL Anaplastic Lymphoma, ImmunohistochemistryAge at DiagnosisALK-1CD2CD3CD20CD30CD43CD4532−+−++41++++40−+−−+−54−−−−++−49+−+++62−−−+−+31+−−−+−+

Non-HTLV-1-associated primary gastric T-cell lymphomas show cytotoxic activity: clinicopathological, immunohistochemical characteristics and TIA-1 expression in 31 cases.

Most primary gastrointestinal lymphomas are of B-cell origin and T-cell origin is very rare. Recent studies have suggested that human T-cell lymphotrophic virus type 1 (HTLV-1) may be involved in the development of primary gastric T-cell lymphoma. We analysed 31 patients with primary gastric T-cell lymphoma in south-west Japan, an area endemic for HTLV-1, and determined their phenotypes, genotypes, and HTLV-1 status. Here we present 31 cases of primary gastric T-cell lymphoma in a HTLV-1-endemic area in Japan and analyse the clinical status, histology, phenotype and virus status. The median age at onset of primary gastric T-cell lymphoma was 57 years with a gender ratio of M:F = 1.58:1. Six of the 31 primary gastric T-cell lymphoma cases had HTLV-1 proviral DNA (five males, one female), nine of the 31 cases were positive for anti-adult T cell leukaemia antibody, without examination of HTLV-1 proviral DNA (five males, four females), eight were non-HTLV-1-associated primary gastric T-cell lymphoma (four males, four females) and the other eight cases were unknown. Primary gastric T-cell lymphoma usually presented as a large ulcerated tumour at the corpus to the antrum and histologically consisted of anaplastic large cell type (n = 2), pleomorphic large cell type (n = 3), pleomorphic medium and large cell type (n = 14), pleomorphic medium cell type (n = 11), and angioimmunoblastic T-cell lymphoma type (n = 1). There were no clear macroscopic and microscopic differences between HTLV-1-associated and non-HTLV-1-associated primary gastric T-cell lymphoma. Most patients died within 2 years of diagnosis, and both types of primary gastric T-cell lymphoma (with and without HTLV-1) were associated with poor prognosis. Cytotoxic marker analysis showed that HTLV-1-associated lymphomas were negative for TIA-1, while non-HTLV-1-associated lymphomas were positive for TIA-1. Our results suggest that in HTLV-1-endemic areas, patients with HTLV-1-associated primary gastric T-cell lymphoma should be managed carefully and that TIA-1 seems to be useful for identifying the aetiology of this lesion.

Survival of patients with HTLV-I-associated lymph node lesions

Adult T-cell leukaemia/lymphoma (ATLL), is a malignant condition associated with human T-cell leukaemia virus type I (HTLV-I). Usually, although not uniformly, histopathological examination of the lymph nodes shows a pleomorphic type. In addition, some patients with pre-overt ATLL show a Hodgkin's disease-like morphology and lymph nodes in non-neoplastic carriers show features of lymphadenitis. To characterize further the clinicopathological features of HTLV-I-associated lymphadenopathy, the histopathological features of the lymph nodes of 289 patients were classified into five types: lymphadenitis ( n=14), Hodgkin's-like (Hodgkin's) ( n=18), pleomorphic (medium and large cells) ( n=219), pleomorphic small cell ( n=11), and anaplastic large cell (ALC) ( n=27). Survival data were analysed according to the histopathological features of the lymph nodes. The pleomorphic type, which showed typical features of ATLL, was associated with a highly aggressive course and an initially high mortality, followed by a rapid decrease in survival. This pattern was also observed in patients with the ALC type. All cases with lymphadenitis were still alive at the end of the study, while survival progressively decreased in the Hodgkin's type. The small cell type showed an initial rapid decrease in survival followed by a plateau. These results show that the survival trends of patients with pleomorphic and anaplastic lymph node lesions are similar to those with ATL lymphoma, while patients with the lymphadenitis type of lesion were considered to have a non-neoplatic status. There is at present no effective therapy for ATLL, but in the future, these classification and survival data might be useful for the selection of appropriate chemotherapeutic regimens for patients with ATLL.

Nodal T-cell lymphoma in an HTLV-I-endemic area: proviral HTLV-I DNA, histological classification and clinical evaluation.

Adult T-cell leukaemia/lymphoma (ATLL) is a human malignancy associated with human T-cell leukaemia virus type I (HTLV-I). The histology usually indicates a pleomorphic type, but is not consistent. To clarify the relationship between the histological classification and prognosis in ATLL, and to confirm the significance of clonal HTLV-I integration, we reclassified 572 cases with nodal T-cell lymphoma in which the T-cell phenotype and/or genotype was confirmed. In all cases the clonal integration of HTLV-I proviral DNA in the lymph nodes was examined by Southern blot analysis. In addition, anti-ATL antigen (ATLA) determination in the serum or PCR analysis of HTLV-I pX amplification in lymph nodes was also performed. 66/313 (21%) cases with ATLA had no evidence of clonal HTLV-I integration. 572 cases were classified into three groups: (A) cases with clonal integration (247 cases), (B) cases with ATLA without clonal integration of HTLV-I proviral DNA (66 cases), (C) cases without ATLA (259 cases). Histologically, groups B and C frequently demonstrated large cell type and angioimmunoblastic lymphadenopathy with dysproteinaemia (AILD) type; however, group A tended to show a pleomorphic type. Clinically, group A showed a poorer prognosis than groups B and C. In conclusion, group A cases were defined as ATLL (HTLV-I-associated T-cell lymphoma), whereas group B was classified as T-cell lymphoma, which had coincidently occurred in HTLV-I infected carriers. The simplified classification of REAL indicated clinical outcome: the prognosis of ATLL was poor, the unspecified type was intermediate, whereas the other types of lymphoblastic, AILD and anaplastic large cell type were all relatively favourable.

Peripheral T-cell lymphoma in childhood and adolescence a clinicopathologic study of 22 patients

Peripheral T-cell lymphoma (PTCL), although the most common T-cell lymphoma in adults, is relatively rare in childhood, and only small series have been reported. Twenty-two cases of PTCL were studied that occurred in patients 18 months to 20 years of age. Nine were seen when the condition was diagnosed, and the other 13 were referred after they had relapses. The stage at diagnosis was I or II (45%), III (41%), and IV (14%). Patients with Stage IV disease were younger than those with Stage I or II disease (2.5 versus 14.8 years, P = 0.04). Twelve patients had extranodal disease when the diagnosis was made; the skin was the most common site. Ten tumors were classified as diffuse large cell type; five, as diffuse anaplastic large cell type; and seven, as diffuse mixed cell type. Twenty of the 21 tumors tested were CD30 (Ki-1 or Ber-H2) antigen positive. Of the nine patients seen when the diagnosis was made and treated by the authors, three had a relapse (median, 12 months), a 2-year relapse-free survival (RFS) rate of 61%. For the total group, the RFS was longer for patients older than 12 years of age compared with those who were younger (20 versus 12 months, P = 0.05). Overall, six patients remained in their first complete remission. Sixteen patients had a relapse, and 13 of these underwent bone marrow transplantation (BMT). Six of these remained in complete remission (median, 18 months after BMT). Overall, only 6 of 22 patients died (median survival, > 60 months). It was concluded that aggressive therapy, including BMT for relapses, can provide prolonged disease control in most children with PTCL.

The pathogenesis of eosinophilic endomyocardial disease in patients with carcinomas of the lung

Studies were done on a patient with a carcinoma of the lung induced by hypereosinophilia who was thought to be at risk from developing eosinophilic endomyocardial disease to see whether the development of heart disease could be related to abnormalities in the morphology or kinetics of blood eosinophils. The patient was a 61-year-old man who had a partial resection of a squamous cell bronchial carcinoma of anaplastic large cell type which has spread locally. Seven months later, he developed a blood eosinophil count of 33.9 x 10(9)/1. There were only transient responses to treatment with steroids and tumor irradiation, and he died 15 weeks later. Up to 3 x 10(9)/1 blood eosinophils were degranulated, correlating with serum levels of eosinophil cationic protein. The blood half-life of 111indium-labeled eosinophils was prolonged to 53 h, but their distribution was normal. Although an unsuccessful search was made during life for the development of endomyocardial damage, at postmortem the left ventricle had features of eosinophilic endomyocardial disease in the acute necrotic stage. Among 13 other reported patients with carcinoma of the lung and hypereosinophilia, three also had endomyocardial disease or myocardial lesions. These findings confirm the suggestion that the presence in the blood of greater than 1 x 10(9)/1 degranulated eosinophils can be used to predict the development of eosinophilic endomyocardial disease before it becomes apparent clinically, and they also add weight to the hypothesis that blood eosinophil degranulation causes this complication of hypereosinophilic states.