Multimodal image analysis of chronic leukemic lymphoproliferative disorders and the hypothesis of "single" and "multiple" programmed stops in the development of typical and atypical forms of leukemias and lymphomas [Multimodalna stanična analiza u kroničnim leukemijskim limfoproliferativnim bolestima i hipoteza "jednostrukih" i "višestrukih" programiranih stopova u nastanku tipičnih i atipičnih oblika leukemija i limfoma]

Kardum-Skelin, Ika and Jelić Puškarić, Biljana and Radić-Krišto, Delfa and Jakšić, Ozren and Kardum, Matko and Jakšić, Branimir (2010) Multimodal image analysis of chronic leukemic lymphoproliferative disorders and the hypothesis of "single" and "multiple" programmed stops in the development of typical and atypical forms of leukemias and lymphomas [Multimodalna stanična analiza u kroničnim leukemijskim limfoproliferativnim bolestima i hipoteza "jednostrukih" i "višestrukih" programiranih stopova u nastanku tipičnih i atipičnih oblika leukemija i limfoma]. Collegium Antropologicum, 34 (2). pp. 367-376. ISSN 0350-6134

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Abstract

The study consisted of morphometric analysis, assessment of the argyrophilic nucleolar organization region (AgNOR) characteristics, and image cytometry (ICM) in different tumor mass compartments: bone marrow (BM), peripheral blood (PB) and lymph nodes (LN) from patients with chronic leukemic lymphoproliferative disorders. A total of 71895 cells were analyzed on SFORM PC (VAMSTEC, Zagreb). Correlation between morphometric, AgNOR and ICM characteristics revealed the cells with low proliferative activity to possess small, homogeneous AgNOR, with the majority of cells in the peak of DNA histogram. The cells with high proliferative activity had inhomogeneous AgNOR, mostly containing greater DNA content than peak cells, pathologic mitoses (DNA > 4N), or the majority of cells were in the S-phase of the cell cycle. Cells with medium proliferative activity and annular AgNOR were in-between. Analysis of different tumor mass compartments showed that lymphatic cells with the affinity to accumulate in BM regularly exhibited low proliferative activity (a lower percentage of cells in SFC and highest percentage of cells in the peak of the G0/G1 phase). The cells in LN exhibited the characteristics of proliferative cells (an increased number of AgNOR, larger and more proliferative inhomogeneous AgNOR, and lowest percentage of cells in the G0/G1 phase). The migration of cells from BM to LN and between lymph nodes occurred through PB (there were cells with low and high proliferative activity: a higher proportion of cells in SFC and at the same time in the G0/G1 phase of the cell cycle). Analysis of cell size and proliferative activity in different compartments of tumor mass revealed that the cells in BM and PB did not differ substantially according to size and proliferative activity, while an inverse pattern was observed between PB and LN. As small cells are inactive and larger cells more proliferative, the analysis quite unexpectedly showed the PB cells to be largest and most inactive, in contrast to LN where the cells were smallest and most active. The "single" and "multiple programmed stops" have been hypothesized in the development of typical forms of leukemias and lymphomas and atypical forms of subacute and subchronic leukemias. Differentiation impairment may occur at any stage, and different "stop" locations result in different morphology and affinity to accumulation in bone marrow, peripheral blood and lymph nodes.

Abstract in Croatian

Studija je obuhvatila morfometrijsku analizu, analizu osobina regije nukleolarne organizacije (AgNOR) te statičku DNA citometriju u različitim odjeljcima tumorske mase: koštanoj srži (KS), perifernoj krvi (PK) i limfnim čvorovima (LČ) u bolesnika s kroničnim leukemijskim limfoproliferativnim bolestima. Ukupno je analizirano 71895 stanica, na osobnom računalu »SFORM« tvrtke VAMSTEC, Zagreb. Međusobnom analizom morfometrijskih, proliferacijskih i kinetičkih pokazatelja vidjelo se kako nisko proliferativne stanice imaju male homogene AgNOR-e te većinu stanica u vršku DNA histograma. Visoko proliferativne stanice su s inhomogenim AgNOR-ima, od kojih većina sadrži količinu DNA veću od stanica u vršku; patološke mitoze (DNA>4N) ili veći broj stanica u S-fazi staničnog ciklusa. Negdje u sredini su srednje proliferativne stanice s prstenastim AgNOR-ima. Analizom u različitim odjeljcima tumorske mase vidljivo je kako limfatične stanice koje imaju afinitet prema akumulaciji u KS, u pravilu imaju malu proliferativnu aktivnost (najveći postotak stanica u vršku Go/G1 faze). Stanice s afinitetom prema akumulaciji u LČ imaju veći broj ukupnih AgNOR-a, veću površinu proliferativnijih, inhomogenih AgNOR-a i najmanji postotak stanica u Go/G1 fazi. Sama migracija stanica iz KS prema LČ kao i između LČ događa se u PK gdje su prisutne stanice s nižom i višom proliferativnom aktivnosti (viši postotak stanica u S-fazi i istodobno u Go/G1 fazi staničnog ciklusa kao i prisustvo većih stanica, ali manjih jezgara, s prstenastim AgNOR-ima intermedijalnog stupnja proliferativnosti). Izgleda kako PK ima samo transportnu ulogu. Analizirajući veličinu stanica i njihovu proliferativnu aktivnost u različitim odjeljcima tumorske mase uočeno je da se stanice u KS i PK ne razlikuju bitno po veličini i proliferativnoj aktivnosti, dok je obrnuta situacija ako se gleda PK i LČ. Nasuprot očekivanju, kako su male stanice mirnije, a veće proliferativnije, analiza je pokazala da su u PK stanice najveće i najmirnije, za razliku od LČ gdje su najmanje i najaktivnije. Postavljena je hipoteza jednostrukih i višestrukih »programiranih stopova» u nastanku tipičnih oblika leukemija i limfoma te subakutnih i subkroničnih leukemija. Poremećaj diferencijacije može nastati na bilo kojem stupnju, a različito mjesto »stopa« rezultira različitom morfologijom te različitim afinitetom prema akumulaciji u KS, PK I LČ.

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