SYSTEMIC CRYPTOCOCCOSIS
A REPORT OP A CASE W I T H REVIEW OF THE LITERATURE*
JOEL R. COHEN, M.S., AND WILLIAM KAUFMANN, M.D.
Department of Pathology of The Springfield Hospital, Springfield, Massachusetts
Cryptococcosis (torulosis), as a clinical entity, was first described by von
Hansemann 20 in 1906; he attributed this disease to an infection caused by a
fungus that he believed to be a species of blastomyces. In 1916, Stoddard and
Cutler,18 in an extensive study of mycoses, established definite criteria for the
diagnosis and differentiation of cryptococcosis, blastomycosis and coccidioidomycosis. According to Levin 9 cryptococcosis was extremely rare; a total of
only 60 cases was reported until 1937, and all of these were diagnosed only at
autopsy. In the last 10 years, however, the disease has been reported more
frequently. Whether this is due to more accurate diagnostic procedures or to
an actual increase in the infection, is open to question.
A review of the available literature shows that the fungus Cryplococcus neoformans is capable of invading all the organs but has a marked predilection for
the brain and meninges. Because of the distribution of the organism throughout
the body and because of the protean symptoms produced, cryptococcosis is
often confused with a number of systemic diseases, including tuberculous
meningitis, encephalitis, carcinoma and Hodgkin's disease.13 Voyles and Beck21
reported a case of cryptococcosis in which a diagnosis of carcinoma of the prostate gland was first made, and another case in which the disease was masked by
a concurrent silicotuberculosis. Levin's 9 suggestion that the organism most
likely entered the body via the lungs is quite plausible; in his paper, however,
he reports one case in which at autopsy and on histologic examination organisms
were present in the brain and meninges, but nowhere else. Reeves, Butt and
Hammack17 have also reported 2 cases of meningeal and encephalic cryptococcosis that failed to show the organisms in any other organs examined, including bone marrow, lungs, spleen and kidneys.
Recently Carton and Mount 5 presented a report of 220 cases, including 30
new cases, of cryptococcosis collected from the literature. Of this total, 179
showed involvement of the central nervous system. Their review undoubtedly
included a few cases of superficial cryptococcosis of the skin.13 The 2 cases
reported by Cook6 may be added to those of Carton and Mount, which gives
us a total of 222 up to the date of the present writing.
Levin's 9 opinion is that cryptococcosis is a disease of adults, apparently
favoring men over women at the rate of 2 to 1. The disease is usuall}' a chronic
one, lasting approximately from 1 to 30 months. Levin, in his review of 1937,
cites 3 cases with a duration of 1 month or less, 10 cases with a duration of 2
months, 5 cases with a duration of 25 to 30 months and 1 case with a duration
of 6 years. Thus, the disease appears to be a serious one usually ending in
* Received for publication, June 21, 1952.
1069
1070
COHEN AND KAUFMANN
death. Nevertheless, there have been cases reported in which the organism
appears to have been vanquished by modern therapy. Marshall and Teed11 •12
followed a patient who was administered sulfadiazine and on whom a bilateral
mastoidectomy was performed. Nine years later the patient showed no signs
of the disease. O'Neill, Newcomb and Nielson15 described a case in which sulfadiazine and an autogenous vaccine were administered; there was some question as to whether Cryptococcus neoformans or some other cryptococcus species
was the etiologic agent. Reeves, Butt and Hammack17 have treated a patient
4 times, the first time with potassium iodide, after which she seemed to improve.
She had a remission, however, and therefore was treated with sulfapyridine.
Again, the disease recurred and she was put on sulfanilamide. Following apparent recovery she relapsed again and this time was treated with undenatured
cryptococcus antigen and potassium iodide. Subsequently the patient appeared
to be doing well. Binford's2 patient, apparently followed clinically for 1 year,
recovered spontaneously without any treatment. At the end of this period, a
guinea pig inoculated with her cerebrospinal fluid died of torulosis. One patient
treated by Toone19 for 2 months with potassium iodide survived for 18 months.
At the end of this time the patient had headaches, and her cerebrospinal fluid
contained C. neoformans. Another patient treated by Lewin and Roux10 with
sulfapyridine and penicillin (the latter administered intramuscularly and intrathecally) was still living 11 months after treatment. Finally, Voyles and Beck21
had a patient who during his first hospital stay was treated with sulfadiazine
and apparently did very well. However, symptoms soon recurred, and he was
treated with intramuscular and intrathecal injections of penicillin and with
potassium iodide. Clinical symptoms all disappeared but cultures of cerebrospinal fluid were still positive 2 years later. Interestingly enough, this patient
also had a history of syphilis, with a positive serologic test on the spinal fluid.
Therefore, out of 222 cases that we were able to collect only 7 appear to
have been arrested, and of these at least 4 2 - 1 0 - 1 5 - 1 9 are questionable.
The resistance of Cryptococcus neoformans to therapeutic agents, such as
those mentioned above, is well supported experimentally. Beck and Voyles1
produced cryptococcosis in dogs, rabbits, guinea pigs and mice, and then treated
one group of animals with iodides, a second group with sulfadiazine and a third
group with a combination of sulfadiazine and iodides. There was no evidence
of beneficial effect from any therapy in the animals.
A fairly rapidly progressive case of systemic cryptococcosis in a young man
who came to autopsy in our hospital, is reported in detail.
CASE HISTORY
C. W. R., Jr., a 37-year-old white man, was transferred from another hospital to this
hospital on February S, 1951.
The patient had become ill on January 14th with what was thought to be the grippe,
and 4 days later developed a rash resembling measles. At that time he also had a marked
photophobia. Two days later the patient complained of severe headache and dizziness.
A physician was called and made a diagnosis of measles. The patient was given oral penicillin, "stomache settlere" and pills for the headache. He had no fever or stiffness of the
neck. On January 25th, the patient was admitted to the first hospital.
CRYPTOCOCCOSIS
1071
On admission the man had a red throat. Babinski's sign was absent but there was marked
vertical and horizontal nystagmus (this condition was later shown to have been present
since the age of 7 and therefore was believed to be a congenital anomaly). During his stay
in the hospital, from January 25th to February 7th, the patient became progressively
stuporous and finally comatose. Laboratory examinations of urine and blood were essentially negative, except for persistent albumin in the urine. The blood and spinal fluid
Wassermann reactions were negative.
On January 25th the spinal fluid showed increased pressure, a positive Pandy test, a
total protein of 95 mg. per 100 ml., a cell count of 149 and a decreased sugar of 33 mg. per
100 ml. Cultures were negative. Measles encephalitis was still considered the most likely
diagnosis. On January 29th and February 1st, the patient's spinal fluid showed cell counts
of 114 and 135, respectively. At all times spinal fluid pressure was increased, and lumbar
puncture gave immediate relief of headache.
By February 7th, the patient had become stuporous to the point of near coma, although
he could still be aroused; his speech was dysarthric. When transferred to this hospital,
the diagnoses were: tuberculous meningitis; torulosis; and measles encephalitis. On February 8th a lumbar puncture showed a pressure of 550 mm. of H2O, a total protein of 175
mg., a chloride of 638 mg., a sugar of 13 mg. and a cell count of 90 lymphocytes, 7 polymorphonuclear neutrophils and 3 eosinophils; 51 unidentified cells were seen on direct
examination. On February 9th, a lumbar puncture showed initial pressure of 550 mm. of
H-0 and a total of 150 cells, all lymphocytes. The total protein was 1S5 and the chloride
667 mg. Cultures of the spinal fluids taken on February Sth and February 9th showed
growth of yeastlike organisms.
The organism was first noted while doing a spinal fluid count on February S, 1951. The
51 "unidentified" cells measured from 0.5 to 1.5 microns in diameter and closely resembled
red blood cells; however, they were smaller, and their budding appearance suggested
yeastlike organisms; special staining disclosed large gram-positive coccal forms of an
organism that showed single budding. After 48 hours' incubation on blood-agar plates,
under aerobic conditions, and on Mueller-Hinton medium, under 10 per cent CO* tension,
the spinal fluid showed a confluent growth of ovoid, white to light yellow, mucoid colonies,
which varied in size from 2 to 5 mm. in diameter. No hemolysis was present on the bloodagar plates. Microscopic examination of 10 per cent potassium hydroxide mounts revealed
a single budding, yeastlikc cell but no evidence of mycelia. The organism appeared to be
surrounded by a halo-like capsule; this was verified by an india-ink stain, which showed
the presence of capsules approximately twice the diameter of the .yeast cell. Growth at
37 C. on blood-agar plates seemed to bo more rapid than that obtained at 20 C. on Sabouraud's maltose agar. The organism did not ferment any of the common sugars, nor
did it liquefy gelatin. Thus, the organism was identified as Cryplococcus neoformans.
After prolonged incubation and a number of subcultures, the organism lost its mucoid
appearance on blood agar and on Sabouraud's maltose agar. The colonies became rough
in appearance and showed a faint concentrically ringed effect. Microscopic examination
of the organism now showed that the cells were still reproducing by single buds, but there
was some evidence of short, undeveloped germ tubes.
The patient was promptly treated with penicillin intramuscularly, 400,000 units daily
for 3 days; streptomycin, 1 Gm. every 12 hours for 3 days; and sodium sulfadiazine, 2.5
Gm. every 12 hours for 4 days, the first dose given intravenously. However, the disease
seemed to have progressed too far, and the patient died 7 days after coming to our hospital
and exactly 1 month after the onset of his initial symptoms.
At autopsy only the lungs and the brain showed marked gross changes. The right lung
weighed 520 grams; the left, 560 grams. Both lungs were heavier than normal, firm and
showed patchy consolidation, more marked in the left lower lobe than in the other portions. On section, the lung surfaces were quite moist and mottled, dark red to purple areas
alternating with gray-red foci. The dark areas were the moist ones and were firm. In the
large bronchi a fair amount of yellowish mucoid or mucopurulent material was present.
There was no fluid or any adhesion in the pleural cavities.
1072
COHEN AND KATJFMANN
T h e dura was adherent to the pia-arachnoid, especially in the frontal and basal areas
of the brain. T h e leptomeninges were generally thickened and injected. T h e entire base
of the brain, including the pons, medulla and cerebellum, showed thickening of the meninges and yellowish pink discoloration. A peculiar mottling of t h e frontal and temporal
lobes was present. In fact, the leptomeninges covering t h e vertex as well as t h e base of
t h e brain, the pons, t h e medulla and the cerebellum, showed rather marked thickening
and yellowish pink discoloration. Most striking, however, was the peculiar mottling of
the cortex of the frontal and the temporal lobes. Multiple coronal sections through the
brain revealed a marked mushiness of all areas of the brain, including the s t r i a t e bodies.
In several of the large cross sections, it was difficult to make out the architecture of the
s t r i a t e bodies, numerous minute cysts being present in them. T h e entire cortex of the
brain, u n d e r n e a t h t h e pia-arachnoid, had a mottled appearance, and innumerable minute
pinkish red dots were located within it. T h e ventricles did not appear t o be dilated, and
there were no gross lesions in the choroid plexus. In the cerebellum and in t h e pons, the
changes were similar to those observed in the brain, and around the fourth ventricle numerous foci of minute hemorrhage, or a t least reddish discoloration, were seen. T h e ependyma itself did not appear to be roughened grossly. In the cerebellum, foci of discoloration or minute cysts, such as described above, were also found.
Microscopic examination of all organs failed t o show anything significant, except for
t h e contents of the cranial cavity, t h e lungs and t h e prostate gland.
In the lungs, the changes were diffuse. There was patchy inflammation in some areas
and elsewhere a more confluent pneumonitis. T h e alveoli were markedly dilated and filled
either with blood, serum or a serofibrinous exudate (Figs. 2 and 3). In this intra-alveoli
exudate numerous single and budding yeastlike organisms were found, and the fungi were
located extracellular)}- or within macrophages and, frequently, within giant cells (Fig.
4). Macrophagic reaction was usually seen in t h e alveolar sacs, b u t wherever parenchyma
was destroyed, polymorphonuclear leukocytes and fibrin predominated. T h r o u g h o u t t h e
lungs there was a scattering of small, single and conglomerate granulomas, containing
occasional giant cells and many extracellular and intracellular cryptococci. Frequently
lesions were found in eroded and destroyed small and medium-sized bronchi, the lumens
of which also contained organisms.
In the prostate gland cryptococci were frequently found within the lumens of the acini
(Fig. 5). In these areas, only t h e slightest degree of inflammatory reaction occurred. However, after careful search throughout many sections cryptococci were also found in t h e
interstitial tissue and then a more active chronic inflammatory reaction was noticeable.
I t was striking, however, t h a t the giant cell and granulomatous response found elsewhere
seemed to be absent.
In the cranial cavity, t h e leptomeninges showed the most extensive inflammatory
reaction, and cryptococci were easily visible (Fig. 1). Granulomas with extracellular and
intracellular cryptococci, also in multinucleated giant cells, were frequent. In fact, it
appeared t h a t t h e organisms were most numerous in this location. W h a t were grossly
believed to be hemorrhagic areas and cysts in the brain, were now found to be areas of
actual necrosis, with hemorrhage as a result of cryptoeoceic infection. Organisms were
frequent in these small and large necrotic foci, and the lesions wore numerous around
F I G . 1 (left upper). Medium-power photomicrograph of leptomeningitis, showing intracellular and extracellular cryptococci.
F I G . 2 (right upper). Medium-power photomicrograph of section of lung showing the
cryptococci lying free in an alveolus, around which there is extensive hemorrhagic inflammation. Note the budding organisms slightly below the center.
F I G . 3 (left middle). Slightly higher power photomicrograph of lung showing organization of intra-alveolar exudate.
F I G . 4 (left lower). High-power photomicrograph of lung showing a multinucleated
giant cell containing intracellular cryptococci with halo-like capsules.
F I G . 5 (right lower). Medium-power photomicrograph of an acinus of prostate gland
showing intra-acinar cryptococci and slight peri-acinar chronic interstitial inflammation.
Si- "f V
^•Ti^ •«-5;«{- A#* « ? • •'-v* ili'^r
FIGS.
1073
1-5
1074
COHEN AND KAUFMANN
small blood vessels. All parts of the brain showed a destructive inflammatory process,
and there appeared to be no predilection for any portion of the central nervous system.
Frequently there was evidence of ruptured small granulomas in the cortex, with spilling
of material into the underlying leptomeninges. The meninges covering the cervical spinal
cord showed a reaction similar to that found in the brain, and granulomas with innumerable
cryptococci were present. The cortex of the cervical spinal cord revealed the same foci
of necrosis containing cryptococci that were found in the brain.
In the choroid plexus cryptococci were frequently seen, and there was a moderate degree of edema and chronic inflammatory reaction. Giant cells were extremely rare, and
organisms were found more frequently lying freely in the ^interstitial tissue and in the
vascular channels than within macrophages.
/
The final anatomic diagnosis was systemic Cryptococcosis, with involvement of the
brain, spinal cord, cerebellum, leptomeninges, lungs and prostate gland.
DISCUSSION
The case presented affords an opportunity to reiterate experience and observations made by others, namely, that Cryptococcus neoformans is a fungus
that produces extensive granulomatous changes in the tissues it invades and
that it appears very difficult for the body to dispose of the organism, even to
inactivate it. It appears that there is an attempt at phagocytosis, and the
formation of granulomas is sufficient evidence that the body is at least in a
position to build up one defense against the fungus. Obviously this one aspect
of defense is not enough to overcome the infection. Therapy with available
drugs and antibiotics offers only dubious promise, although there does not
seem to be any reason to discourage their use. Possibly the severity of the infection is of prime importance in the final outcome, with or without therapy.
It is well established that Cryptococcus neoformans is an ubiquitous organism,
much more widely spread over the world than the rate of human infection
would seem to indicate. Most cases of this infection have been reported from
the Uiii"tedJ3tates and only a few from Germany and England.
How the organism enters the body is still a matter of conjecture. There seems
to be a general belief that the fungus enters the body through the air passages
and that it has a predilection for the central nervous system. Nevertheless, as
brought out in this report, the literature reveals cases in which organisms were
frequently found only in the cerebrovascular system and the lungs were totally
negative. Moreover, the one case reported by Marshall and Teed, in which the
patient recovered after treatment with sulfadiazine and bilateral mastoidectomy,
would at least suggest that there is another portal of entry. .
In the man reported here both the central nervous system and the lungs
were involved. The finding of the organism in the prostate gland also seems to
be of importance to us, not so much because of its simple occurrence in the
prostate gland, but rather because it was found lying in the acini, multiplying
actively and producing little or no reaction. In both lungs and the central
nervous system, the histopathologic reaction was of the most severe form,
which to us would indicate rather severe virulence of the species. Why should
the reaction be less severe in the prostate gland if the spread of this organism
was of secondary hematogenous nature? Is it not more likely that the fungus
CRYPTOCOCCOSIS
1075
was located in the prostate gland primarily and then spread to the lungs, where
an extremely severe infection was set up that spread further to the brain with
fatal outcome?
The importance of making an early diagnosis and instituting prompt therapy
with purely empirical drugs seems established in spite of present experimental
evidence that the agents used so far have little benefit. It should not be forgotten, however, that the reaction in the body against the organism is of such
a nature as to indicate that natural forces in the body are always active to
localize and insulate the infection. Therefore, if a diagnosis can be established
early, and therapy instituted, chances for the reactive forces of the body to
localize the fungus may be enhanced. It would seem that examination of the
sputum should include search for fungi, and that discovery of unusual "cells"
in the spinal fluid calls for prompt identification, especially since Cryptococcus
neoformans presents neither morphologic or cultural difficulties for identification.
This is not the first case in which Cnjptococcus neoformans was discovered
in the prostate gland since Voyle and Beck found it, too. That systemic infection from primary foci in the prostate gland is within the realm of possibility,
both from an anatomic as well as an empirical point of view, does not seem to
need further discussion. Moreover, the roseola that occurred early in this disease,
before pulmonary or central nervous system symptoms occurred, seems to suggest the possibility of hematogenous spread.
SUMMARY
A case of systemic cryptococcosis with clinical, pathologic and mycologic
data, with the prostate gland as the possible primary focus, is reported in detail. The available literature is reviewed.
Acknowledgment. We wish to thimk D r . Joseph H a h n , Neurosurgeon-in-Chief of T h e
Springfield Hospital, for permission to use the clinical record in this case report.
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