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The Time to Target and Terminate the Threat of Ptcl

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The Time to Target and Terminate the Threat of Ptcl THE TIME TO TARGET AND TERMINATE THE THREAT OF PTCL Oliver Karanfilski University Hematology Hospital, Medical Faculty, University “Ss.Kiril and Metodij”, Skopje, Republic of Macedonia Whenever professional interest is directed The final word in labeling these neoplasms towards this particular type of lymphoma, some belongs to the pathologist, regardless whether only terms are evidently present more than others: morphology is going to be decisive, or immunophe- heterogeneous, aggressive, dismal prognosis, stan- notyping, molecular analyses and/or genetics are dard treatment not established, poor outcome ..., going to be included in the process of establishing something that does not make any hematologist the diagnosis. Many problems lie in the path for very happy. If some breakthroughs in hematolo- the pathologists. Firstly, due to the not clearly dis- gy in the past two decades brought smiles to our tinct clinical manifestations, parallel to the aggres- faces, this area of expertise is certainly not among sive and rapidly advancing disease course, the those. pathologist might not even receive any substrate Let’s have a look at the definition of Peripheral for examination, only leaving the opportunity for T cell Lymphomas. establishing the diagnosis following autopsy. When substrate is available, the problems arise from the Although the term “peripheral” could associate growing number of entities that are introduced to to “not central”, or “distal”, in means of occurrence, this segment of pathology in the successive clas- localization of the disease, or eventually to the sifications of lymphoproliferative disorders, which zone in the lymph node where it develops and/or becomes the basis for naming this group of disor- grows, that is not what it refers to. Peripheral is an ders heterogeneous, diverse and complex. In such attribute for the T cells, aiming to explain that the a situation, when not so many cases of PTCL are essence of these lymphomas is the mature T cell, scattered around the World, and are being classi- one that has been introduced to its destined func- fied in a growing number of distinct categories, the tions in the human organism. If it had been still suffering end is the level of concordance in pathol- immature, and taken a turn towards malignant ogist’s opinions. Even in the vast field of B-cell proliferation, the result would be a lymphoblastic lymphoma (only approximately 10% of these are lymphomas pathologists have a certain level of of B lineage origin), or an ATLL. In a smaller pro- disagreement regarding final diagnoses, but it has portion, these lymphomas can have their origin in been observed that the accord, confidentiality and a subset of lymphocytes of the natural killer type. reproducibility levels decline for around further 10% in the area of PTCL. Utilizing contemporary In explaining the previous, we have also estab- available lab techniques gives rise to the possi- lished that the pathognomonic substance of these bilities for precise diagnosis of a certain type of neoplasms are the T lymphocytes. PTCL, but characteristics obtained by these are not The last of the terms simply delineates that attributable to all subtypes. Therefore, for some these disorders are inevitably of malignant nature, types of PTCL, molecular analyses of immunophe- lymphoproliferative neoplasms, very aggressive, notype or genetic distinctions can be the decisive fast growing, quite resistant to known therapies, factor, but for others it will still remain a matter of and very frequently fatal. professional opinion. 23-26 Ekim 2013, Antalya 125 Table 1. Classification and characteristics of T/NK-cell lymphoproliferative disorders Entity Immunology Genetics Cutaneous Mycosis fungoides Sezary syndrome CD4+, CD5+, CD7- Primary cutaneous CD30+ T-cell lym- phoproliferative disorders Primary cutaneous ALCL Primary cutaneous γδ TCL Primary cutaneous CD8+ aggressive epider- motropic lymphoma (provisional) Primary cutaneous CD4+ small/medium TCL (provisional) Nodal TCR αβ; AITL (18.5%) CD10+ Gains 2 5 13q22; TCR αβ; Translocation (2;5); Gain 1q; Loss ALCL ALK+ (6.6%) CD30+, CD4+/CD8-. 6q 13q; ALCL ALK- (provisional) (5.5%) CD15- ; Pax5-; TCR αβ; TCR αβ; PTCL NOS (25.9%) Loss of CD5/CD7 Loss 13q22; Gains 8q 9p 19q; Loss 3q 9p; Extranodal Systemic EBV+ T-cell childhood lymphoproliferative disorder Hydroa vacciniforme-like lymphoma Extranodal NK/T-cell lymphoma, nasal type CD56+, cytoplasmic CD3+ TCR αβ: CD3+, CD7+, CD56-, may be Gains Enteropathy associated TCL CD8+, CD56+ (monomorphic) 9q33-q34 TCR γδ; CD2+, CD3+, CD4-, CD5-, Hepatosplenic TCL CD7+, CD8+ or CD8-, Isochromosome 7q CD56 may be + TCR αβ: CD3+, CD4-, CD8+, CD56- 5q Gains Subcutaneous panniculitis-like TCL TCR γδ; CD3+, CD8-, CD56+/- 13q Gains Leukemic T-cell prolymphocytic leukemia CD2+, CD5+, CD7++, CD52+ T-cell LGL leukemia CD3+, CD8+, CD16+, CD57+ Adult T-cell leukemia/lymphoma precursor CD4+/CD25+ Aggressive NK-cell leukemia CD3-, CD16+, CD56+ Indolent large granular NK-cell lymphopro- CD3-, CD16+, CD56+ liferative disorder (provisional) *bold frame marks the most frequent subtypes The relatively small overall number of PTCL rising number of agents that are introduced as cases definitely handicaps progress in managing therapeutic possibilities for PTCLs. In summary: this area of hematology. Prospective randomized too few cases, too many centers, too many treat- studies have since long ago become the verified ment alternatives ... not a fruitful field for random- basis for advances in the field of establishing suc- ized studies. The conclusion is inevitable: progress cessful treatment options for any kind of disease. When PTCLs are in question, not much success can be achieved only through multicentre inves- is observed. According to different reports, the tigational programs and protocols, such as is the whole segment of PTCLs account for not more than International PTCL project. 12-15% of all lymphomas, which, when distributed To make the issue even worse, PTCL patients to the existent and growing number of hematol- ogy centers, hardly comprise patient populations tend to relapse very often, and within a short mar- sufficient for randomized studies. Even more, this gin of time, in which situations their prognosis option is made more implausible, because of the becomes even more dismal. 126 XXXIX. Ulusal Hematoloji Kongresi At present, the number of entities comprising the designated treatment approach for all of those the circle of PTCLs is a result of joint efforts of the would be the same. WHO classification and the International PTCL When we come to the point of treatment, we project consortium. Some of the entities are better must once more emphasize that a total relative- characterized and firmly established, and a minor ly small number of cases denies possibilities for number are labeled as provisional entries. There performing successful randomized studies. Small is a total of 22 entities, T-cell and NK-cell derived numbers deny the analyzes the statistical power to neoplasms, distributed in several groups (Table 1). prove a hypothesis, and they also demand greater A few of the entities are diagnosed with great differences in order to assign the attribute of signif- confidentiality, based solely on morphology, espe- icance to the findings. cially the cutaneous types of PTCL, since clinical Nevertheless, clinical experience has come to presentation patterns and characteristics contrib- some revelations. It is now well established that ute considerably to the process. Immunopheno- the subset of anaplastic lymphoma kinase protein typing, whether performed by immunohistology (ALK) positive ALCL (which can be T-cell or NK-cell or flow cytometry, can aid the categorization, but derived) have a better prognosis with today’s “stan- also of a certain number of entities, and maybe dard” treatments, i.e. with chemotherapy alone, help in distinction of certain subtypes. Since we even better than cases with DLBCL: ~70% for 5-y have largely entered the era of genomics, efforts OS. Also, it is almost without exceptions shown are introduced to utilize this methodology in better that the cutaneous forms of PTCLs tend to have a characterizing the PTCL’s also, but definite genetic better outcome and vital statistics. associations in the area of PTCLs are still anecdot- al. This is why most of the diagnosed PTCLs are Worldwide, CHOP chemotherapy regimen is framed in the category of “not otherwise specified”. still recognized as the “standard” first line treat- ment option for all PTCLs, everywhere quoted as Some of the entities are definitely associated producing results that are not even close to those with the presence of the HTLV-1 virus, in partic- obtained in B-cell neoplasms. With the exception of ular the Adult T-cell leukemia/lymphoma type. ALK+ ALCL, all other PTCL subtypes have OS rates Since this virus is much more frequently present below 50%, some expressed as 5-y rates, but some in the population of the Far East, the Caribbe- as only 2- or 3-y rates. In some types, PFS and/ an and the Middle East, chances for acquiring or OS are expressed only in months, when first- a consequent PTCL of this particular type range line treatment is analyzed. The dismal prognosis from 2-4%, but by no means does it state that becomes even shorter, and finally inevitably fatal, a person with the HTLV-1 will certainly develop in virtually all relapsed patients. a PTCL. Considering the Asian region again, the intestinal PTCLs on that continent are far more When one tries to improve on treatment results, frequently associated with an EBV infection. On there are two basic options: a. increase treatment the other hand, some PTCLs are associated with intensity by elevating drug dosage or by shorten- other disorders, as is the enteropathy associated ing the intervals of chemotherapy administration, TCL, which arises more frequently in individuals or b. expand the “coverage” area of chemotherapy with celiac disease, making it more prevalent in by adding drugs to the regimen.
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