Pragmatische Lösung eines komplexen Problems Schweizer ...

Der seltene Fall
ATRA, a vitamin A metabolite, takes part in the control
of normal cell growth, cell differentiation, and cell death
during embryonic development and in certain tissues later
in life. For example the induction of glandular differentiation
of the oesophagus was demonstrated [20]. In vertebrates,
ATRA has a relevant role in the early development
of the nervous system, stimulating neuronal differentiation
and inducing the expression of neuronal proteins [21,
22]. In the embryo, ATRA is essential in the support of
neuronal survival, migration, and differentiation [21].
ATRA acts by binding to nuclear retinoic acid receptors
(RARs), which alter gene transcription, however, the
genes that lie downstream of ATRA and its receptors in
neuronal cells are largely unknown [21]. Neuroblastoma
cell lines can be induced to differentiate along many neural
crest cell lineages like chromaffin cells, Schwann cells,
melanocytes and neurons [23, 24] and ATRA has been
thoroughly described in vitro to act as a neuronal differentiation
inducer [25].
Whether the long term administration of ATRA in vivo
has played a role in promoting the growth of the stromal
and peripheral nerve sheath tumors remains arguable. We
found no reports in the literature.
In a recent efficacy and safety study of ATRA in combination
with arsenic trioxide in newly diagnosed APL, the
toxicity profile was mild and reversible and no secondary
carcinoma was observed, but the follow-up was limited
to 24 months post-treatment [26]. Rare therapy-related
myelogenous leukemias and myelodysplastic syndromes
in APL patients have been described [27] but the development
of stromal and peripheral nerve sheath tumors is not
a known long term effect of anthracycline or cytarabine
treatment. An increased risk of developing acute myeloid
leukemias [28], as well as other solid cancers [29], has
recently been reported in patients with GIST; but, on the
other hand, a predisposition for developing gastrointestinal
mesenchymal tumors in patients presenting APL has
not yet been reported. A few cases of schwannoma developed
following treatment for Hodgkin disease have been
reported [30, 31], and we found only one case report of
concomitant GIST and APL in the literature [32]. Nevertheless,
in this patient, the maintenance treatment with
ATRA was extended for about 12 years and the synchronous
occurrence of a gastric schwannoma and small bowel
GIST some years later seems worth to be reported.
References
1. Fey, MF, Dreyling, M. Acute myeloblastic leukaemias and
myelodysplastic syndromes in adult patients: ESMO Clinical Practice
Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2010; 21
Suppl 5: v158-161.
2. Arber, DA, Brunning, RD, LeBeau, MM, Falini, B, Vardiman,
JW, Poerwit, A et al. Acute myeloid leukemia with recurrent genetic
abnormalities. In: WHO Classification of Tumours of Haematopoietic
and Lymphoid Tissues S. Swerdlow, E. Campo, N.L. Harris, E.S. Jaffe,
S.A. Pileri, H. Stein, J. Thiele & J.W. Vardiman (eds). IARC: Lyon,
2008; 110-123.
3. Hillestad, LK. Acute promyelocytic leukemia. Acta Med Scand 1957;
159: 189-194.
4. Bernard, J, Weil, M, Boiron, M, Jacquillat, C, Flandrin, G ,
Gemon, MF. Acute promyelocytic leukemia: results of treatment by
daunorubicin. Blood 1973; 41: 489-496.
5. Crowther, D, Powles, RL, Bateman, CJ, Beard, ME, Gauci, CL,
Wrigley, PF et al. Management of adult acute myelogenous leukaemia.
Br Med J 1973; 1: 131-137.
6. Breitman, TR, Collins, SJ , Keene, BR. Terminal differentiation of
human promyelocytic leukemic cells in primary culture in response to
retinoic acid. Blood 1981; 57: 1000-1004.
7. Rowley, JD, Golomb, HM , Dougherty, C. 15/17 translocation, a
consistent chromosomal change in acute promyelocytic leukaemia.
Lancet 1977; 1: 549-550.
8. de The, H, Chomienne, C, Lanotte, M, Degos, L , Dejean, A. The
t(15;17) translocation of acute promyelocytic leukaemia fuses the
retinoic acid receptor alpha gene to a novel transcribed locus. Nature
1990; 347: 558-561.
9. Kakizuka, A, Miller, WH, Jr., Umesono, K, Warrell, RP, Jr.,
Frankel, SR, Murty, VV et al. Chromosomal translocation t(15;17) in
human acute promyelocytic leukemia fuses RAR alpha with a novel
putative transcription factor, PML. Cell 1991; 66: 663-674.
10. Alcalay, M, Zangrilli, D, Pandolfi, PP, Longo, L, Mencarelli, A,
Giacomucci, A et al. Translocation breakpoint of acute promyelocytic
leukemia lies within the retinoic acid receptor alpha locus. Proc Natl
Acad Sci U S A 1991; 88: 1977-1981.
11. Pandolfi, PP, Grignani, F, Alcalay, M, Mencarelli, A, Biondi,
A, LoCoco, F et al. Structure and origin of the acute promyelocytic
leukemia myl/RAR alpha cDNA and characterization of its retinoidbinding
and transactivation properties. Oncogene 1991; 6: 1285-1292.
12. Huang, ME, Ye, YC, Chen, SR, Chai, JR, Lu, JX, Zhoa, L et al.
Use of all-trans retinoic acid in the treatment of acute promyelocytic
leukemia. Blood 1988; 72: 567-572.
13. Tallman, MS, Nabhan, C, Feusner, JH , Rowe, JM. Acute
promyelocytic leukemia: evolving therapeutic strategies. Blood 2002;
99: 759-767.
14. Tallman, MS, Altman, JK. Curative strategies in acute promyelocytic
leukemia. Hematology Am Soc Hematol Educ Program 2008; 391-399.
15. Agaimy, A, Markl, B, Kitz, J, Wunsch, PH, Arnholdt, H, Fuzesi,
L et al. Peripheral nerve sheath tumors of the gastrointestinal tract:
a multicenter study of 58 patients including NF1-associated gastric
schwannoma and unusual morphologic variants. Virchows Arch 2010;
456: 411-422.
16. Melvin, WS , Wilkinson, MG. Gastric schwannoma. Clinical and
pathologic considerations. Am Surg 1993; 59: 293-296.
17. Goh, BK, Chow, PK, Kesavan, S, Yap, WM, Ong, HS, Song, IC
et al. Intraabdominal schwannomas: a single institution experience. J
Gastrointest Surg 2008; 12: 756-760.
18. Yoon, HY, Kim, CB, Lee, YH , Kim, HG. Gastric schwannoma.
Yonsei Med J 2008; 49: 1052-1054.
19. Bees, NR, Ng, CS, Dicks-Mireaux, C , Kiely, EM. Gastric
malignant schwannoma in a child. Br J Radiol 1997; 70: 952-955.
20. Chang, CL, Lao-Sirieix, P, Save, V, De La Cueva Mendez, G, Laskey,
R , Fitzgerald, RC. Retinoic acid-induced glandular differentiation of
the oesophagus. Gut 2007; 56: 906-917.
21. Merrill, RA, Plum, LA, Kaiser, ME , Clagett-Dame, M. A
mammalian homolog of unc-53 is regulated by all-trans retinoic acid
in neuroblastoma cells and embryos. Proc Natl Acad Sci U S A 2002;
99: 3422-3427.
22. Clagett-Dame, M, McNeill, EM , Muley, PD. Role of all-trans
retinoic acid in neurite outgrowth and axonal elongation. J Neurobiol
2006; 66: 739-756.
Schweizer Krebsbulletin • Nr. 3/2010 283