Download Effect of Colchicine on Human Tissues.

EFFECT OF COLCHICINE ON HUMAN TISSUES
W. 0. BROWN, M.D.*
AND L T . COL. LINDON SEED, M.C.,
A.U.S.
From the Department of Pathology and Surgery, University of Illinois, College of Medicine, Chicago, Illinois
T h e effect of colchicine on normal and cancerous
tissues in laboratory animals has received considerable study, and some observers have been
able to produce, a regression in experimental
tumors under colchicine therapy. This action
has been attributed to an arrest of mitosis by the
drug. 1 Ludford 2 and Brues 3 have studied cells
arrested by colchicine and found an absence of the
mitotic spindle with clumping and bizarre configurations
of the chromatin material. Mild
changes are apparently reversible, b u t the more
severe ones result in abnormal mutations in t h e
nuclei of the daughter cells, or in cell death.
T h e number of the cells affected and the severity
of the changes vary with the size of the dose, b u t
are not directly proportional. T h e literature
pertaining to colchicine has been reviewed b y
Lits. 4 T h e cells arrested b y colchicine frequently
have been referred to as "colchicine figures" and
for the sake of brevity this term will be used here
to designate similar cells.
mm. to 1950, with 40 per cent stab forms. Death occurred on the seventh day after the first dose of colchicine.
Necropsy was performed seven hours after death.
The right breast was small, firm, and surmounted by
several ulcerated tumor nodules. The breast tissue
was almost completely replaced by firm pale tumor tissue, and there were several firm axillary metastases
measuring up to 2 cm. in diameter. The left breast
appeared normal except for an inverted nipple. The
lungs contained numerous miliary subpleural metastases. The gastro-intestinal mucosa showed areas of
edema and hemorrhage. The heart, liver, kidneys,
spleen, pancreas, adrenals, thyroid, internal genitalia,
and brain showed no distinctive changes.
Microscopically, the tumor of the right breast was a
scirrhous duct carcinoma composed of small groups or
columns of cells separated by an abundant dense
stroma. Colchicine figuresf were numerous, and no
normal mitoses were seen. The central portions of the
larger tumor islands occasionally showed ischemic
necrosis, which was not attributed to colchicine. The
metastases to the lungs and axillary lymph nodes
had a similar appearance. The left breast showed
the usual appearance of cystic disease. There were
also numerous colchicine figures in the epithelium
of the gastro-intestinal mucosa and in the liver cells
(fig. 1). There was degeneration of the basal layer
of the epidermis and the inner root sheath of the
hair shafts. The stratum granulosum contained a
multitude of colchicine figures. The sternal bone marrow was made up almost completely of fat and erythrocytes, with a few normoblasts and lymphoid cells, but
the myeloid elements were decreased to the point of
extinction. Sections of the popliteal nerve stained
T h e report of several cases of inoperable cancers
treated with colchicine has appeared previously. 5
I t is the purpose here to present the necropsy
findings and histologic studies on three cases of
this series in which death occurred during t h e
course of treatment. Since the clinical findings
have been presented in detail before, 5 only t h e
pertinent facts are mentioned here.
CASE REPORTS
Case 1. D. C , a white female, aged 65, was admitted with an inoperable carcinoma of the right
breast. Except for the primary tumor and axillary
metastases, the physical examination was negative.
She was given a total of 13 mg. of colchicine over a
period of four days, and on the fourth day vomiting,
diarrhea, and prostration appeared, with an elevation
of temperature to 101°F. By the sixth day the leucocyte count of the blood had dropped from 6800 per cu.
* Present address, Kern General Hospital, Bakersfield, California.
t The term "colchicine figures" is taken to indicate
cells from patients treated with colchicine in which the
nuclei show abnormal configurations or mitotic patterns
that could not readily be interpreted on any other
basis. The nuclear changes of cell death which are normally encountered in any rapidly growing tumor or
tissue were excluded as far as possible. This cannot
always be done accurately on a morphologic basis and
the factor of normal expectancy must be considered as
well.
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190
W. O. BROWN AND LINDON SEED
with Sudan III and osmic acid showed a slight fatty
degeneration of the myelin sheaths, but silver stains
revealed no axonal changes. '
There were also numerous colchicine figures in the
large lymphocytes, or "lymphoblasts" of the lymph
nodes, the epithelium of the fallopian tubes, endometrium, and the epithelium of the renal tubules. In the
latter instance, an occasional multinucleated cell could
be found (fig. 6).
Diagnosis: Colchicine poisoning, scirrhous duct carcinoma of the right breast, hypoplasia of the bone marrow.
Case 2. R. B., a colored male, aged 44, was admitted
with an advanced carcinoma of the rectum. Physical
findings were negative except for the rectal tumor.
Serologic tests for syphilis in blood were positive. He •
received a total of 29 mg. of colchicine over a period of
seven days. On the tenth day he was obviously
"toxic," the leucocyte count had fallen to 1200 per cu.
mm., and there was evidence of consolidation in the
right pulmonary base. The patient died on the fourteenth day after colchicine was started with a terminal
leucocy tosis of 10,450.
Necropsy was performed eight hours after death.
Seven and a half centimeters above the anal sphincter
was an annular constricting carcinoma which infiltrated
the surrounding soft tissues and studded the peritoneum
of the recto-vesical fold with metastases. In the cecum
and ascending colon were several ulcers measuring up to
1.5 cm. in diameter with edematous hemorrhagic bases.
There were confluent areas of bronchopneumonic consolidation in the base of each lung. The gross appearance of the other organs was not significant.
Microscopically the tumor was a colloid carcinoma
which showed few if any colchicine figures. On the
other hand numerous colchicine figures were found in
the epithelium of the intestinal mucosa, liver, lymph
nodes, and in undifferentiated mesenchymal cells of
the intestinal submucosa. None were found in the
skin. The bone marrow was markedly hyperplastic,
in contrast to the hypoplasia which had undoubtedly
been present a few days before. The other organs resembled those of case 1.
Diagnosis: Colchicine poisoning, colloid carcinoma
of rectum, hypostatic bronchopneumonia.
Case 3. A. W., a white male, aged 54, was admitted
with a large carcinoma of the left lateral side of the
neck. The patient received a total of 28 mg. of colchicine over a period of 64 days with several rest intervals.
The first course of treatment caused a marked diminution in size of the tumor, but in the following rest
period, growth was resumed with unprecedented rapidity, and after this the tumor was little affected by
the drug. Death occurred 19 days after the last dose of
colchicine.
Necropsy was performed 9 hours after death. There
was a large cauliflower-like tumor occupying the greater
part of the left lateral aspect of the neck, and produced
by broken down lymph node metastases from, a primary
tumor of the left faucial tonsil. There were also metastases to the pleura, pharynx, liver, and jejunum. The
other organs showed no distinctive changes.
Microscopically the tumor was a transitional cell
carcinoma, and showed numerous colchicine figures,
as well as numerous other cells having several small
round micronuclei. Colchicine figures were also present in large numbers in the esophageal mucosa, but
were not found in any other tissue. The liver contained
numerous normal mitotic figures.
Diagnosis: Transitional cell carcinoma of the left
faucial tonsil.
COMMENT
Colchicine does not produce distinctive gross
changes in the organs, and the effects of the drug
are visible only on microscopic examination.
Numerous references were made to "colchicine
figures" and in general these were most numerous
in the epithelial elements of parenchymatous
organs and in lymphoid structures. The cells
showing the earliest effects were invariable in the
metaphase, and earlier stages could not be detected.
The cells showing the least severe changes were
usually found in the liver, and these consisted of
absence of the mitotic spindle, and a shortening
and tendency to clumping of the chromosomes,
although the aster arrangement of the metaphase
was preserved (fig. 1). A curious observation in
connection with the liver was that from this stage,
the chromosomes became contracted to minute
granules which then were scattered indiscriminately through the cytoplasm, while the cell
became swollen by hydropic degeneration and
disintegrated (fig. 2). Almost all the liver cells
showing colchicine effects were in various stages
of this process and very infrequent deviations
from this sequence of events could be found.
This particular chain of events was prominent in
only one other organ, viz.—the skin. Here,
however, there was a great variety of chromatin
patterns (fig. 3). A common abnormality, and
one that was frequently seen in the lymph nodes
and intestinal epithelium, was a clumping of the
chromosomes into a pyknotic bar (fig. 4). The
mitotic spindle was absent, and unlike the normal
equatorial plate of the metaphase, this showed no
definite orientation to the long axis of the cell, but
lay in various positions. Other chromosomal
deformities consisted of clumping into a small
intensely pyknotic mass in which no detail could
be observed (fig. 5), or arrangement in numerous
bizarre forms. Quite frequently small granules
EFFECT OF COLCHICINE ON TISSUES
could be seen lying at some distance from the
main mass. In the renal epithelium of case 1
(fig. 6), and in the tumor of case 3, were multinucleated cells which morphologically resembled
191
the cytoplasm of the "colchicine figures" tended
to be more oxyphilic than normal and in those
showing the more severe changes, the cell 'was
swollen by hydropic degeneration, the cell bounda-
Fic. 2. Later stage of colccihine arrest in liver. Cell undergoing disintegration. Case 2. X650
those described by Brues and Jackson, who
attributed them to changes produced in the
chromosomes of cells temporarily arrested by
colchicine, but in which division had resumed after
the colchicine inhibition had worn off. In general,
ries irregular, and the cytoplasm not infrequently
vacuolated. Occasionally colchicine figures were
found in the process of disintegration with rupture
of the cell membrane and escape of the chromosomal granules into the surrounding area.
192
VV. O. BROWN AND LINDON SEED
I t should be emphasized that from the morphologic appearance, colchicine does not appear to
produce specific changes characteristic of that
drug alone. In routine necropsy material with
•*£
numerous. In these instances the cells appear to
have started mitosis, but were arrested, and it
seems likely that changes in oxygen tension and
pH incident to the agonal period could be.re-
#' #
FIG. 3. Cells of stratum granulosum of epidermis showing colchicine effects. Note various chromosomal
patterns. Case 1. X650
FIG. 4. Crypt of Lieberkiihn of intestine. Two cells show colchicine arrest. Case 2. X650
no regard to the cause of death cellular changes
indistinguishable from those ascribed here to
colchicine are not infrequently found in the spleen
and other lymphoid structures, but are much less
sponsible for the mitotic arrest. Ludford2 arrived
at similar conclusions as regards colchicine, and
pointed out that totally unrelated physical and
chemical agents may produce the same changes.
193
EFFECT OF COLCHICINE ON TISSUES
He suggested that these were merely outward
manifestations of changes of the physical state of
the cell. What conclusions we have been able to
draw from necropsy material support this view.
capable of maturation.
were still present in the
Organs whose cells
spread mitotic arrest
These nuclear deformities
adult cell.
have shown rather wideapparently undergo not
FIG. S. Tumor cells showing various chromosomal patterns'in cholchicine arrest. Case 1. X975
&L
%
Fie. 6. Multinucleated giant cell in epithelium of renal tubule in Case 1. Note a second cell which is binucleated.
X650
Osgood6 observed that myeloblasts
myelocytes in tissue cultures which
treated with colchicine frequently
bizarre nuclear configurations, but that
and prohad been
contained
they were
infrequently a period of intense compensatory
proliferation as the inhibitory effects of colchicine
wear off. This was observed in the tumor in
case 3 and the bone marrow of case 2.
194
VV. 0. BROWN AND LINDON SEED
Although colchicine played no part in the death
of case 3, which was due to the cancer and its
secondary effects, in cases 1 and 2, colchicine was
the important causative factor, and nonfatal toxic
manifestations have been observed in several
other instances. Patients receiving a single dose
of colchicine frequently show a slight rise in
temperature which never reaches high levels and
which usually returns to normal in about 48 hours.
They also complain of pain and a sense-of heat at
the site of the malignancy, which before might
have been painless. Anorexia, nausea, and
vomiting, if severe, usually accompany toxicity.
General malaise, muscle aches, and pains may be
present in mild form from the beginning and may
be of little significance, but if severe, usually
indicate toxicity, and prostration is a terminal
affair. Probably the greatest single danger from
colchicine administration is agranulocytosis and
aplastic anemia,7 which was the chief cause of
death in cases 1 and 2. The hypostatic pneumonia
in case 2 is considered merely secondary to the
agranulocytosis. Less severe forms of this complication occurred during the treatment of other
cases in which the condition was recognized and
the drug stopped in time for the patient to effect a
recovery. The necessity for frequent and complete blood studies while the patient is under
colchicine treatment cannot be over-emphasized.
In blond individuals the drug may have a depilatory effect and may render the patient almost
bald, but this is readily appreciated in view of the
cellular changes in the skin and hair follicles.
This phenomenon was not observed in colored
patients whose skin and appendages do not appear
very sensitive to colchicine. A peripheral neuritis
as evidenced by myelin degeneration of the peripheral nerves occurred in case 1, but whether this
can be attributed to colchicine or not cannot be
stated. I t is our impression, however, that it can.
I t should be emphasized that the tumor in each
of the three cases cited was inoperable. I t was
also well known that the colchicine effect could
not be developed unless the dose of the drug was
large enough to approach toxic amounts.
SUMMARY
1. Colchicine exerts a toxic effect on living cells
which commonly results in the arrest of the process
of mitosis at an early stage, usually the metaphase,
with the production of bizarre and abnormal
nuclear configurations, and frequently leading to
cell death.
2. The effect of colchicine is general, and selective only in the sense that those tissues which
have the highest rates of cell division and metabolism are effected first, i.e. bone marrow, tumors,
skin, lymphoid structures, etc.
3. Colchicine produces no characteristic morphological changes which are specific for that drug
alone, and similar changes may be observed under
widely varying circumstances.
4. Colchicine is a dangerous drug and should be
used with extreme care. One of the greatest
dangers apparently lies in its depressant effects
on the bone marrow, and its administration should
be accompanied by frequent blood studies. A
finding that has not been mentioned before is the
occurrence of a peripheral neuritis in association
with colchicine administration.
REFERENCES
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(b)
(c)
(d)
(e)
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CLEARKIN, P. A.: Effect of colchicine on normal
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AMOROSO, E. C.: Colchicine and tumor growth.
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DUSTIN, A. P.: Effect of karyoklastic poisons
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E F F E C T OF COLCHICINE ON TISSUES
195
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