|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3475-3477
CORRESPONDENCE
Chediak-Higashi-Like Granules in Acute Promyelocytic
Leukemia
 |
LETTER |
To the Editor:
Hematologic morphology is loosing grounds, particularly in this
country. This is because of the emergence of new technologies (eg,
molecular biology, flow cytometry, and polymerase chain reaction in
situ), and the failure of cell image analysis to provide practical means for objective assessment of morphological characteristics. However, for many hematologists trained in hematopathology, the Romanowsky (Wright, Giemsa)-staining-based morphology has been, and
still is, a powerful tool for better understanding of happenings inside
cells, and showing different processes affecting blood and bone marrow
cells. Two years ago Blood honored my devotion to this morphology by publishing one picture of a cytoplasmic bridge
between basophilic normoblasts. (Delayed Cytokinesis of Erythroblasts.
Blood, May 15, 87:4254, 1996). This is another example in
support of the old values.
In 1973, I was a coauthor of a report describing morphological features
of gigantic azure granules seen in two cases of acute promyelocytic
leukemia.1 One case of acute promyelocytic leukemia (APL)
with Chediak-Higashi (CH)-like granules diagnosed at the Division of
Hematology, Department of Internal Medicine (Medical Faculty Hospital,
Skopje, Macedonia) in 1973 prompted this report. Indeed, it was my
second case. In 1972, while investigating the archives of the Leukemia
Service, National Cancer Institute, NIH, Bethesda, MD (Chief Dr Edward
Henderson) and the collection of old bone marrow smears from the
Laboratory of Hematology, Clinical Pathology, Clinical Center, NIH
(Head Dr Harvey Cralnick), I found those gigantic granules in one case
of APL. In 1973, Markovic and Henderson2 reported the
abnormal cytoplasmic inclusions resembling Chediak-Higashi granules
amid other rare morphologic characteristics of acute leukemia. The name
CH-like granules came later, after Dr Olivera Markovic demonstrated
myeloperoxidase activity in those granules (macedonian case), and
proved their lysosomal character. Ultrastructural analysis was not
provided in both cases and, therefore, we did not submit the report for publication to major journals.
Presently, when ultrastructural analysis has confirmed the nature of
those granules, this following example of a light microscope morphological analysis could remind us not to underestimate the power
of hematologic morphology. In both cases described in 1973, we saw the
gigantic granules only in cells resembling abnormal promyelocytes
(large cells, cytoplasm/nuclear [C/N] ratio ~1.5), kidney-shaped
nucleuses with one or two large nucleoli, chromatin structured in a net
of fine granular material, the abundance of immature azure granules
(scattered through the cytoplasm), lacking mature (dark purple to blue,
about 2 µm in diameter) azure granules, and two types of abnormal
pink inclusions: the multiple Auer body-like inclusions, or CH-like
gigantic granules (Fig 1). We did not see these two distinctive features (Auer body and CH-like granules) together in single cells. Individual cells containing CH-like granules
showed many aggregates of azure granules of different sizes, suggesting
a continuous process of granular growth and fusion. In normal
promyelocytes, this process is limited. When an azure granule reaches a
size of approximately 2 µm, further growth ceases, the granule
"matures" and its color changes from pink into dark purple or
blue (May-Grünwald Giemsa staining). We saw none of these mature
granules inside the leukemic promyelocytes. CH-like granules varied in
shape and content. When filled with a pink, uniformly distributed
material, they had a polygonal shape, which was similar to the form of
the granules seen in the congenital CH disease. Flat, nonstructural
pinkish content was seen in round granules, and in
granules with a colorless halo (a pinkish, nonstructural center and
vacuole-like periphery). We saw different relations between the central
and peripheral part of these granules. There were also vacuoles with a
very small amount of or with no tinted content inside. Few cells showed
"rupture" of cell membrane and vacuoles open to exterior (Fig 1).
In the Macedonian case, few cells resembling "small" macrophages,
or destroyed abnormal promyelocytes, were seen "engulfing" large
individual vacuoles with some pinkish content. In CH disease, gigantic
granules do not show growth and evolution toward vacuolization.
View larger version (86K):
[in this window]
[in a new window]
View larger version (107K):
[in this window]
[in a new window]
View larger version (113K):
[in this window]
[in a new window]
View larger version (86K):
[in this window]
[in a new window]
View larger version (90K):
[in this window]
[in a new window]
View larger version (114K):
[in this window]
[in a new window]
View larger version (94K):
[in this window]
[in a new window]
View larger version (93K):
[in this window]
[in a new window]
View larger version (116K):
[in this window]
[in a new window]
View larger version (100K):
[in this window]
[in a new window]
View larger version (86K):
[in this window]
[in a new window]
View larger version (122K):
[in this window]
[in a new window]
| Fig 1.
(A1) Two neutrophils from a case of APL with CH-like
granules. The promyelocytes looks normal in all parameters except in
the primary granules. They are more abundant than normally seen; they
are immature, different sized, and there is no dark purple of blue
mature azure granules. The PMN looks normal except for increased number
of primary (azure) immature granules. (B1) A promyelocyte
from the same case of APL. Abundance of immature azure granules of
different sizes. None of them mature and none are of abnormal sizes.
There is one vacuole and the Golgi apparatus is clearly visible. (C1)
Two promyelocytes similar to B1. Some azure granules undergo
aggregation. (A2) Two promyelocytes in the same bone marrow smear.
Split of maturational direction. One cell shows numerous Auer
body-like inclusions and clear cytoplasm. The other shows numerous
aggregates of azure granules. Some of them suggest fusion of smaller
granules. (B2) Typical appearance of a bone marrow high-power field.
Several leukemic promyelocytes. One shows Auer body-like inclusions.
Others show immature azure granules at different levels of aggregation.
The typical CH-like granules are not present. (C2) One
large leukemic promyelocyte. A gigantic, pink, polygonal granule if
formed. Many polygonal aggregates of small azure granules. Some
clearing of cytoplasm (reduced total number of granules) can be seen.
(A3) Fully developed CH-like granule in a leukemic promyelocyte. Other
azure granules and, particularly, aggregates are not part of this
granule. They follow their own development. Clearing of cytoplasm is
also present. (B3) Several large and one gigantic, fully developed,
pink-color and polygonal-shaped azure granules. Clear cytoplasm. This
is a picture of a typical cell. (C3) A promyelocyte with three gigantic
CH-like granules. All three are round, and all show structural changes.
Onion- or myelin-like figures appear inside granules. They are
apparently composed of the same material as other CH-like granules.
Changes indicate hyalinization and autolysis. (A4) Two promyelocytes:
one with Auer body-like inclusions, and the other with two small
CH-like granules undergoing autolysis and one huge vacuole containing
residual hyaline material of a CH-like granule, and a transparent,
watery content. (B4) Two promyelocytes with gigantic, autolytic
granules-vacuoles. Both resemble macrophages and phagocytosis. Only the
presence of other azure granules in one of them suggest neutrophilic
origin of this cell. (C4) A leukemic promyelocyte with many vacuoles.
Few show some content. One (at 2 o'clock) is opened toward the cell
exterior and some cytoplasmic ridges can be seen around the
"rupture." Two nucleoli identify the immaturity of the cell.
|
|
The investigators tried to organize these different features in a
logistic way. They postulated that an unknown force or agent (eg,
malignancy, perhaps) has altered the genetic code controlling the
maturation of azure granules. Without this control mechanism, azure
granules continue to grow until self-destruction caused by accumulated
and probably freed hydrolytic enzymes. In the past, it was pure
speculation based on morphology alone. Today, I wonder was it only
speculation, or a power of morphology to provide strong information for
undergoing processes?
Almost 20 years later, in 1992, Akashi et al3 described
appearance of pseudo-CH granules and prominent vacuoles in biphenotypic blasts of a case of acute leukemia. About the same time, Irimajiri et
al4 studied light and electron microscopic images of these granular structures. They concluded that the giant granule is azurophilic, it is a circular structure with a homogenous matrix, the
content changes by autolysis, and the vacuole formation appears. They
have also described the Auer body-like granules with crystalline formation.
In 1993, Symes et al5 described a case of acute
promyelocytic leukemia with pseudo-CH anomaly and molecular
documentation of t(15;17) chromosomal translocation. The same year,
Hamanaka et al6 confirmed the presence of noncrystalloid
azure granules in eozinophils of two patients with congenial CH
disorder.
In 1994, Cervero et al7 conducted an ultrastructural study
of CH-like inclusions in acute myeloblastic leukemia and showed that
granules contain a dense matrix and fingerprint structures at the
periphery. In some inclusions they saw fibrillar structures and
myelinic figures. The matrix was reactive to peroxidase and small
vesicles were prominent in the cytoplasm near the granules. They
concluded that the granules could have been formed by the fusion of
primary granules and/or by fusion of these small dense vesicles.
Recently, I compared the report published in the Proceedings of the
9th Congress of Macedonian Physicians1 and the
contemporary interpretation of the appearance of the CH-like granules
in acute promyelocytic leukemia.3-7 The same features seen
on light microscopy were confirmed and probably better defined on the
ultrastructural level (electron microscopy). The interpretation was
similar, too. However, the ultrastructuralists did not develop any
attractive "fairy tale" such as the light microscopists did.
I believe that this letter supports my devotion to hematologic
morphology and, hopefully, will challenge other hematologists to share
their experiences.
Nenad Markovic
BioSciCon,
Inc
Rockville, MD
| |
REFERENCES |
1. Markovic O, Markovic N: Chediak-Higashi similar granules in acute
promyelocytic leukemia. Proceedings of The 9th Congress of
Macedonian Physicians 2:1191, 1974
2. Markovic N, Henderson E: Subcellular morphology and prognosis of
acute leukemia. Proceedings of The 4th Congress of Yugoslavian
Internists 1:375, 1973
3.
Akashi K,
Shibuya T,
Harada M,
Oogami A,
Teshima T,
Takamatsu Y,
Kikuchi M,
Niho Y:
Interstitial 9q deletion in T-lymphoid/myeloid biphenotypic leukemia.
Br J Haematol
80:172,
1992[Medline]
[Order article via Infotrieve]
4.
Irimajiri K,
Iwamoto I,
Kawanishi K,
Tsuji K,
Morita S,
Koyama A:
Studies on pseudo Chediak-Higashi granules formation in acute promyelocytic leukemia.
Rinsho-Keusueki
33:1057,
1992
5.
Symes PH,
Williams ME,
Flessa HC,
Srivastava AK,
Swerdlox SH:
APL with pseudo Chediak-Higashi anomaly and molecular documentation of t(15;17) chromosomal translocation.
Am J Clin Pathol
99:622,
1993[Medline]
[Order article via Infotrieve]
6.
Hamanaka SC,
Gilbert CS,
White DA,
Parmley RT:
Ultrastructural morphology, cytochemistry, and morphometry of eosinophil granules in Chediak-Higashi syndrome.
Am J Pathol
143:618,
1993[Abstract]
7.
Cervero C,
Heinrichs B,
Villarubia J,
Velasco JL,
Ferro MT,
Lopez J,
Escribano L:
Chediak-Higashi-like inclusions in acute myeloblastic leukemia (ultrastructural study).
Sangre
39:136,
1994
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
|
|
