Leukemia occurring in treated Hodgkin's disease: Two neoplasms or one? - Cleveland ...
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Leukemia occurring in
treated Hodgkin's disease:
Two neoplasms or one?
T h e origin o f the malignant cell in Hodgkin's
disease and the increased incidence o f second ma-
lignancies in patients with Hodgkin's disease re-
Khalil Sheibani, M . D . main unsolved problems. 1 " 4 T h e results o f cyto-
chemical, immunomicroscopic, immunologic, and
Division of Laboratory Medicine
ultrastructural studies of the neoplastic cells 5-1
have failed to identify their origin, but suggest
R a y m o n d R . Tubbs, D . O .
either a histiocytic or B-lymphocytic derivation.
Department of Pathology Similar studies in acute leukemias 18,19 arising in
patients with Hodgkin's disease have suggested dif-
Richard A. Savage, M . D . ferences between the leukemic cells and the cells of
Department of Laboratory Hematology and
Hodgkin's disease. W e report a case o f Hodgkin's
Blood Banking disease in which an apparent second neoplasm
developed. Sequential studies o f the neoplastic cells
Rafael Valenzuela, M . D . suggest that radical changes occurred in the cell
type during evolution o f the disease. Such changes
Department of Immunopathology
may reflect treatment-mediated or naturally occur-
ring evolution o f the neoplastic cell lines o f H o d g -
Bruce A. Sebek, M . D .
kin's disease, rather than a second neoplasm origi-
Department of Pathology nating from a different cell line.
James S. Hewlett, M . D . Clinical summary
Department of Hematology and Medical A 44-year-old white male was well until Septem-
Oncology ber 1974 when progressive shortness of breath de-
veloped. A diagnosis of nodular sclerosing H o d g -
kin's disease, Stage I, involving a left scalene lymph
node was made at another hospital (Fig. I). T h e
patient received 4000 rads to the right and left
39
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Fig. 1. Left scalene lymph node containing a polymorphous infiltrate with atypical lacunar cells and
occasional Reed-Sternberg cells (hematoxylin and eosin stain, X640)
supraclavicular lymph node areas. He Chemotherapy was continued. In
was referred to the Cleveland Clinic 8 March 1976 the W B C was 6.7 X 10 9 /1
months later for consideration of chem- with a normal differential count, but
otherapy. At this time there was evi- the hemoglobin level was 5.3 g / d l . A
dence o f radiation pneumonitis. T h e bone marrow aspirate revealed com-
blood count showed hemoglobin, 8.7 g / plete replacement with primitive cells
dl and white blood cell count ( W B C ) , having pleomorphic folded nuclei
8.3 X 10 9 /1 with a normal differential suggestive of histiocytic lymphoma or
count. A biopsy specimen of the left monocytic leukemia (Fig. 2); similar
posterior iliac crest revealed a marrow cells were present in a bone marrow
o f normal cellularity containing small biopsy performed at the same time (Fig.
foci of undifferentiated cells suggesting 3). T h e patient was readmitted to the
the possibility of acute monocytic leu- hospital one month later with a temper-
kemia; the remainder o f the biopsy spec- ature o f 39 C and severe acute respira-
imen appeared normal. He was treated tory distress. Pneumonia with a mixed
with M O P P (nitrogen mustard, vincris- gram-negative and gram-positive bac-
tine, prednisone, and procarbazine). terial flora was present, and his course
Five weeks later the W B C was 3.4 X was marked by deteriorating respiratory
10 9 /1 with a normal differential count; function. He died 9 days after admis-
hemoglobin level, 7.9 g / d l ; hematocrit, sion. At no time during the course of his
21.9%; and platelet count, 165 X illness were malignant cells identified in
the peripheral blood.
io9/i.
Downloaded from www.ccjm.org on November 12, 2021. For personal use only. All other
uses require permission.Fig. 2. Bone marrow aspirate specimen obtained concomitantly with the biopsy illustrated in Figure 3.
Malignant cells are characterized by folded nuclei and prominent nucleolation (Wright's stain, X640).
Individual neoplastic cells demonstrate NaF-resistant alpha naphthyl acetate esterase positivity (inset,
X 1600).
Autopsy findings merous round gray-white nodules mea-
suring 0.5 cm in maximum diameter
At autopsy, each pleural cavity con- were scattered diffusely throughout the
tained approximately 500 ml of straw- gastric mucosa. T h e gastrointestinal
colored fluid. T h e lungs were congested tract was otherwise normal. A small sub-
and weighed 1630 g. Multiple firm dural hematoma was present over the
white nodules 0.5 to 1.5 cm in diameter left frontal lobe.
were scattered throughout the visceral Microscopic examination of lymph
pleura. A firm, centrally cavitating nodes, the intercostal mass, gastric mu-
gray-white mass measuring 7 x 5 x 2 c m cosa, pancreas, and thyroid gland re-
was present below the right clavicle. A vealed a nodular infiltrate consisting of
firm gray-white spherical nodule was small lymphocytes, mature plasma cells,
present in the left posterior eighth inter- mature histiocytes, and occasional
costal space. T h e liver and spleen were Reed-Sternberg cells diagnostic of no-
enlarged and congested, but no neo- dular sclerosing Hodgkin's disease. This
plasm was identified grossly or micro- morphologic picture was virtually iden-
scopically in these organs. tical to that seen in the original scalene
Peribronchial, mediastinal, periaor- lymph node biopsy. A morphologically
tic, and peripancreatic lymph nodes different neoplasm was identified in the
were enlarged with fleshy gray-white bone marrow and in the pleural nod-
nodules grossly visible within them. Nu- ules. T h e infiltrate in these tissues con-
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S i « ? ® * '
Fig. 3. Marrow biopsy demonstrating infiltration by cytologically malignant mononuclear cells with
irregular folded nuclei (hematoxylin and eosin stain, X640).
sisted o f large pleomorphic mononu- paque gradient. These cells were washed
clear cells with vesicular nuclei and with Hank's solution without calcium
prominent basophilic nucleoli; binu- and magnesium (Grand Island Biologi-
cleate and multinucleate variants were cal C o m p a n y ) , and consisted principally
also found, but typical Reed-Sternberg of viable, cytologically malignant forms.
cells were not identified. Surface markers were evaluated using
techniques previously described. 22 Tis-
Materials and methods sue immunomicroscopy was performed
Tissues fixed in buffered formalin and for cytoplasmic immunoglobulins (CIg)
in Zenker's solution were stained with using unlabeled'' peroxidase-antiperoxi-
hematoxylin and eosin, and methyl- dase (PAP) and direct techniques, 2 ' 5 and
green pyronine. Air-dried bone marrow for cytoplasmic muramidase (CM) 2 4 us-
aspirate preparations were stained with ing the P A P technique. Controls con-
Wright's stain, periodic acid-Schiff sisted of the substitution of normal goat
(PAS) stain and alpha naphthyl acetate or rabbit serum for the primary or con-
esterase with and without fluoride inhi- jugated antibody without changes in
u-.-
bition. 20,21 subsequent steps of the procedures.
Cell suspensions were prepared at au-
topsy from a lymph node showing Results
Hodgkin's disease and from the bone Results of comparative studies per-
marrow containing the morphologically formed on the two morphologically dis-
different neoplasm using a Ficoll-Hy- tinct neoplasms are summarized in the
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Table. T h e tumor cells in the original T h e suspension of Hodgkin's tumor
lymph node biopsy and in autopsy tissue cells obtained at autopsy did not form
showing Hodgkin's disease were a significant number (less than 5%) of
strongly reactive with methyl-green py- spontaneous rosettes with sheep red
ronine and contained polyclonal cyto- blood cells (Srbc). However, 78% of the
plasmic immunoglobulin identified by cells formed rosettes with Srbc coated
both PAP and direct techniques (Fig. with antibody and complement (IgM-
4A and B). The cytoplasmic staining for EAC) (Fig. 5B) reflecting a preponder-
CIg in these cells, although strong, was ance of complement receptors on the
somewhat less intense and delayed com- Hodgkin's tumor cells. T h e malignant
pared to the staining observed in mor- cells aspirated from the bone marrow at
phologically typical plasma cells in the autopsy formed 9% spontaneous Srbc
tissue adjacent to the neoplastic cells. rosettes and 15% I g M E A C rosettes.
C M was not identified in neoplastic cells
in the original or residual Hodgkin's Discussion
disease. Similar results have previously T h e initial concept of either a T-cell
been reported in Hodgkin's disease. 5,9 or true histiocytic origin for Hodgkin's
T h e neoplastic cells in the bone mar- disease was based on a variety of indirect
row biopsy obtained in March 1976 evidence. 7 Some investigators have sug-
were devoid of significant pyroninophi- gested that the malignant cells of Hodg-
lia and contained no cytoplasmic im- kin's disease are of B-cell origin, since
munoglobulins (Fig. 5A), but C M was they are characterized by cytoplasmic
present. These findings suggest a histio- immunoglobulin, receptors for comple-
cytic origin. 24,25 The marrow aspirate ment components, prominent pyroni-
performed simultaneously contained nophilia in the cytoplasm, many poly-
cells showing strongly positive cytoplas- ribosomes, and a varying amount of
mic staining for alpha naphthyl acetate cytoplasmic microfibrils. 8-14,26 How-
esterase; the strength of this reaction ever, tissue culture studies of spleen in-
was not inhibited by sodium fluoride 21 volved by Hodgkin's disease that have
(Fig. 2, inset). These findings also suggest shown cell lines morphologically accept-
a histiocytic origin. No significant stain- able as Reed-Sternberg cells or their
ing with PAS was observed. mononuclear variants have met the cri-
Table. Summary o f comparative studies
Patient's origi- Histiocytic malig- Patient's subse-
NSHD nal neoplasm nancies quent neoplasm
Cytochemistry
Pyronine + + + +
+ +
a-N A E V ND
Immunocytochemistry
CIg + NWE
+
CM V +
Surface markers
SIg V ND V ND
+ +
IgMEAC V
NSHD = nodular sclerosing Hodgkin's disease; a N A E = alpha naphthyl acetate esterase; CIg =
cytoplasmic immunoglobulin; C M = cytoplasmic muramidase; SIg = surface immunoglobulin; I g M E A C
= immunoadherence study using sheep red blood cells coated with rabbit IgM and guinea pig complement;
V = variable; N D = not done; N W E = not well established.
Downloaded from www.ccjm.org on November 12, 2021. For personal use only. All other
uses require permission.Fig. 4. A , (to/i) Comparative immunomicroscopy of the original node involved with Hodgkin's disease. The
malignant mononuclear cells of the original neoplasm contain cytoplasmic immunoglobulin, identified as
black staining of the cytoplasm o f these cells ( X 1 6 0 ) . B, (bottom) Cytoplasmic immunoglobulin present
within the residual Hodgkin's tumor cells (direct technique using anti-IgG peroxidase conjugate, X640).
teria for histiocytes. 15 ' 16 T h e CIg and phagocytic activity. 17 Other investiga-
SIg present in the malignant cells of tors have suggested that the presence of
Hodgkin's disease are not endogenous CIg in Reed-Sternberg cells is the result
and probably are a consequence of of a defective cell membrane. 2 ' Both
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uses require permission.Summer 1979 Leukemia in treated Hodgkin's disease 45
Mrl b
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Fig. 5. A, (top) The tumor cells in the bone marrow do not have cytoplasmic immunoglobulin; red blood
cells are stained due to the pseudoperoxidase activity of hemoglobin (X400). B, (bottom) IgMEAC rosette
formed by a nucleolated tumor cell in the cell suspension prepared from residual Hodgkin's disease at
biopsy (X 640).
these findings suggest an exogenous or- not resolve the question o f the ultimate
igin for the C I g in the malignant cells origin o f the malignant cell in Hodgkin's
o f Hodgkin's disease. disease. However, they d o suggest that
T h e cytochemical and immunomi- the malignant mononuclear cells in the
croscopic marker studies o f the neoplas- scalene lymph node were different from
tic cells from various sites in this case do those in the bone marrow. Differences
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were also demonstrable between differ- progress in this laboratory and in other
ent sites of tumor in the autopsy speci- institutions to determine if indeed such
mens. Cytoplasmic immunoglobulin a phenomenon does occur.
was detected in the original and residual
Hodgkin's disease tissue, but not in the Summary
bone marrow biopsy specimen; the re- Investigators have suggested either a
verse was true for cytoplasmic murami- B-lymphocytic or a histiocytic origin for
dase. T h e neoplastic cells in the bone the malignant cell in Hodgkin's disease.
marrow were positive for fluoride-resist- The results of cytologic, cytochemical,
ant alpha naphthyl acetate esterase, a and immunologic studies of two mor-
cytochemical marker expressed by phologically different neoplasms en-
phagocytic histiocytes and epitheloid countered sequentially in a patient with
cells. 20 ' 21 ' 28 Results reported for this en- nodular sclerosing Hodgkin's disease are
zyme in Reed-Sternberg cells in touch reported. These results could suggest
preparations 20 ' 28 and in tissue cul- either B-lymphocytic or histiocytic ori-
ture15' 16 have been variable. Differences gin for cytologically malignant cells in
in the distribution of CIg and SIg in different sites. However, these results
fresh cell suspensions from Hodgkin's probably reflect differential expression
disease have been documented previ- of properties possessed by all Reed-
ously. 17 However, we are unaware of Sternberg cells. These differences may
any previous demonstration of the se- have been induced by therapy. Thus,
quential variability in cytochemical and monocytic leukemia arising in a post-
immunologic parameters seen in this pa- therapeutic setting may represent an ov-
tient. ergrowth of one component of a single
W e propose that our observations, as neoplasm rather than a new malig-
well as those of others,1 indicate that nancy.
the evolution of treated Hodgkin's dis-
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