THE DIAGNOSIS OF HISTOPLASMOSIS IN ULCERATIVE
DISEASE OF THE MOUTH AND PHARYNX*
LYLE A. WEED, M.D., AND EDITH M. PARKHILL, M.D.
From the Section on Bacteriology and the Section on Surgical Pathology, Mayo Clinic,
Rochester, Minnesota
Since the beginnings of pathology, emphasis has been placed on the relationship
of the morphologic changes to the pathologic process. In the course of time
certain patterns in tissue reactions have come to be associated with specific microorganisms and pathologists have been willing to assume the responsibility of
translating many of these changes into etiologic diagnoses. More comprehensive
and detailed studies, however, have shown that, in certain instances, different
organisms of widely varying biologic nature may incite similar histologic responses on the part of the host. Conversely, because infections vary with the
virulence and the number of invading organisms and with the natural resistance
of the host, a given type of infecting agent may, under different conditions, elicit
varying degrees and types of histologic reaction, even though pure cultures of
the organism may give rise to standard reactions in laboratory animals under
controlled experimental conditions. With the development of chemotherapeutic and antibiotic agents it is becoming more and more important that the
pathologist establish not only a histologic diagnosis but also the precise nature
of the invading organism and whether it is susceptible to the recognized therapeutic agents and to the new ones being developed. Such determinations are in
the best interests of the patient, the referring physician and the pathologist alike.
Careful studies at the Mayo Clinic of surgical and necropsy tissues in the past
have demonstrated certain limitations of histologic procedures when they are
not supplemented by adequate bacteriologic investigation. Histoplasmosis is a
disease which has been frequently misdiagnosed but which may readily be
recognized and proved with a minimal amount of equipment and trained personnel, using the newer technics that are generally available.
In 1906, while looking for mucocutaneous leishmaniasis, Darling18 found an
infection which he described as a new entity. In 1907 and 1908, he encountered
two additional similar infections and suggested the designation "Histoplasma
capsulata" for the organism.19 In 1926, Riley and Watson49 reported the disease
in a 52 year old woman who had not been outside of Minnesota for forty-two
years, thus indicating that the infection was not likely to be entirely tropical in
distribution. It is now recognized that the disease is essentially world-wide in
distribution, although most of the cases have been reported from the United
States.
In 1934, Hansmann and Schenken27 reported on a patient with skin lesions of
fifteen years' duration which, at autopsy, proved to be due to yeastlike organisms
and which are now recognized as having been those of histoplasmosis. In 1934,
* Presented at the Twenty-Sixth Annual Meeting of the American Society of Clinical
Pathologists, in Chicago, October 29, 1947. Received for publication, October 29,1947.
130
HISTOPLASMOSIS OF MOUTH AND PHARYNX
131
Dodd and Tompkins23 reported the first instance in which the diagnosis was
made before death. Since that time many cases have been reported in which the
diagnosis was made ante mortem. 8 .^,17,21,36,«,53,60 Increasing recognition of the
disease as a clinical entity which is associated with a specific etiologic agent has
become widespread, so that some of the cases recently reported in the literature
actually pertain to patients who had died of the disease several years previously.6
In the reported cases the patients have ranged in age from 2 months to 77
years. All tissues of the body have been involved, but the extent of involvement of the individual organs has varied greatly from case to case. In some
cases there has been general dissemination of the organism, but in others the
infection appears to have been limited to the adrenals, lymph nodes or local
ulcerated areas. With few exceptions the disease has been fatal in proved cases,
but there is epidemiologic evidence (obtained by skin tests) that many patients
recover and develop calcified pulmonary lesions simulating those of pulmonary
tuberculosis. Humphrey 30 has emphasized the involvement of the spleen, liver,
lymph nodes and bone marrow and has preferred to give the designation
"reticulo-endothelial cytomycosis". In more recent cases, however, it has been
shown that a generalized distribution of the organism in this system does not
always occur and that local lesions may develop, such as suppurative arthritis
and subcutaneous nodules or a wide variety of other local manifestations.
We have carefully reviewed the reports 1-65 of 73 cases of histoplasmosis, not
including 13 cited by Meleney39 in which the clinical aspects are not recorded in
detail. Several references in the literature have not been available to us and
others have not contained sufficient clinical data to warrant interpretation. In
the reports of 73 cases which we have reviewed, there have been such conditions
as skin ulcers (face, neck, trunk and penis), cutaneous abscesses, subcutaneous
nodules, generalized lymphadenopathy, purpura, perforated nasal septum, oral
lesions (ulceration or induration, or both), peritonsillar abscess, laryngeal ulcers,
mass in the epigastrium and ulcers of the rectum. The clinical signs and symptoms have included pain in the chest with productive cough, chills and fever,
weight loss, nausea, vomiting, weakness, enlarged abdomen, painful defecation
and diarrhea, with or without blood in the stool.
The clinical manifestations have been interpreted as syphilis (primary or tertiary), impetigo, breast abscesses, aleukemic leukemia, trench mouth, typhoid
fever, Addison's disease, splenic anemia, suppurative arthritis, gallbladder disease, gastric ulcer and carcinoma. In a few cases the condition has been recognized clinically as probable histoplasmosis. The pathologic diagnoses in these
cases, on biopsy, have been variously given as chronic adenitis, indeterminate
granuloma, blastomycosis, lymphoblastoma, Hodgkin's disease, leishmaniasis,
kala-azar, carcinoma, tuberculosis and histoplasmosis. In some of the cases
the disease was associated with tuberculosis,40 and in one case with cryptococcosis.42
Of the reports of 73 cases which we have reviewed, in 37 the patients were 40
years of age or over, a period of life which might be called the "cancer age".
Twenty-four of the 73 patients had oral lesions as part of the presenting complaint. Sixteen of these 24 patients with oral lesions (ulcers or induration) were
132
W E E D AND
PARKHILL
over 40 years of age. In the majority of reported cases the diagnosis has been
made on histologic grounds alone. Because of the varied clinical manifestations
and pathologic diagnoses coupled with our own experience, we should like to
report 4 cases of ulcers of the oral cavity which illustrate the difficulties and
uncertainties of the histologic diagnosis and emphasize the advisability of supplementing biopsy with bacteriologic study. For this purpose it is wise to arrange
to hold separately an adequate representative portion of each tissue specimen
from which reliable bacteriologic studies may be made if the histologic examination does not reveal a neoplastic process.
F I G . 1. (Case 1). Section from the left tonsillar pillar, a. Note the tendency
toward epithelial hyperplasia and the numerous large macrophages immediately
beneath the epithelium. T h e histologic interpretation is very easy with so many
organisms in the tissue. X 150. b . Macrophages shown adjacent to the epithelium
in Fig. l a . X 1200.
R E P O R T O F CASES
Case 1
T h e patient was a 77 year old retired railroad engineer. For two months he had complained of soreness of the left side of the lower jaw. His dentist cauterized the lesion and
filed down his plate, b u t the pain persisted. H e had lost 30 pounds (13.6 Kg.) during t h e
last four months. At the time of admission to t h e clinic there was an ulcerated area 1 cm.
in diameter with heaped-up edges on t h e left anterior tonsillar pillar, a similar area over the
mandible, one on t h e right tonsillar pillar and a smaller one on t h e epiglottis. Biopsy of
t h e left pillar showed organisms with t h e morphologic appearance of Histoplasma, and a
culture of t h e tissue removed for biopsy was positive for Histoplasma capsulatum.
A similar organism was cultured from t h e urine. T h e histoplasmin skin test was negative. T h e
HISTOPLASMOSIS OF MOUTH AND PHARYNX
133
patient died nine months after onset of oral symptoms. T h e embalmed body showed
persistence of the ulcer on the epiglottis and complete necrosis of both adrenals. H i s t o plasma was cultured from one of the adrenals.
Histologic examination.
Biopsy of tissue from the pharynx showed a granulomatous
lesion consisting chiefly of closely packed, large, pale, phagocytic endothelial cells associated with infiltration by leukocytes, chiefly neutrophils, and a few lymphocytes (Fig. l a ) .
T h e large endothelial cells were packed full of numerous intracytoplasmio organisms, 3 to
4 microns in diameter; these organisms were round or slightly ovoid, basophilic and had a
clear halo-like capsule, typical of Histoplasma (Fig. l b ) .
Case 2
T h e patient was a 37 year old merchant from Texas who had been well until 1940 when
F I G . 2. (Case 2). a. Section of tissue from mouth shows numerous macrophages
containing large numbers of organisms in the yeast form. X 155. b. Portion of the
tissue shown in Fig. 2a. X 1200. Culture was positive for Histoplasma
capsulatum.
he began losing weight and strength. In 1943, he was rejected by the draft board because
of a pulmonary lesion. In 1945, he was ill for six or seven weeks with chills and fever of
undetermined origin, for which he was treated with quinine. Recovery was gradual. In
September 1946, a sore mouth developed and a diagnosis of scurvy and trench mouth was
made. In December 1946, soreness of the mouth recurred, with an indeterminate lesion
for which he was treated with streptomycin, sulfonamides and vitamins. This lesion persisted until he was admitted to the clinic in J u n e 1947, with erosion of the corners of the
mouth and the lower lip. T h e tip of the tongue contained several punched-out areas and
the tongue could not be protruded because of pain. Biopsy of the tongue showed organisms
the morphology of which was compatible with Histoplasma on direct examination.
Cultures from the lesion and from the sputum were positive for H. capsulalum.
Histologic examination.
Biopsy of tissue from the mouth showed an ulcerating, granulomatous lesion with ill-defined masses of large endothelial cells which were not arranged in
134
WEED AND PARKHILL
the form of "tubercles". Between and adjacent to these cells there was moderate infiltration with inflammatory cells, which in some areas consisted chiefly of polymorphonuclear
leukocytes, in other areas chiefly of plasma cells. There was also an occasional multinucleated foreign body giant cell. Many of the large endothelial cells and the giant cells
were packed with small, round or oval organisms with a dark central mass enclosed by a
clear capsule (Fig. 2); these small organisms averaged about 4 microns in diameter, and
had the morphologic appearance of H. capsulaium.
Case 8
The patient was a 48 year old man from Texas who had lived in Mexico from 1912 to 1915.
He entered the clinic on June 12, 1940, with the complaint of weight loss and sore throat of
two and one-half years' duration. In May 1938, he had become nervous, weak and subject
to dizzy spells. In June 193S, all of his lower teeth had been removed. This procedure was
followed by a severe sore throat for several weeks, which was treated with silver nitrate
locally. He had begun losing weight and had run an afternoon fever but had had no cough,
dyspnea, expectoration or hemoptysis. It had been customary for him to have an annual
roentgenologic examination and the results had been negative for the past three years.
The sore throat continued until April 1939, when a physician diagnosed a malignant disease
and treated him with roentgen rays with some temporary relief. In August 1939, a recurrence of the ulcers of the mouth prompted re-examination and three biopsies were made;
in each instance a nonspecific granuloma was reported. He experienced hoarseness, with
difficulty in swallowing, and severe diarrhea which was associated with ulcers of the colon.
Cultures made from the ulcers of the colon and from the lesions in the mouth showed
"Monilia". He was treated with iodides until he became intolerant of them, and with this
treatment did not improve. He was then treated with Monilia vaccine, which made his
condition very much worse. The results of repeated tests for tubercle bacilli were negative.
During the period of one and one-half years prior to admission to the clinic his weight fell
from 217 to 109 pounds (98.4 to 49.4 Kg.) and he developed extreme weakness. One month
before admission to the clinic he had had blood in the stools three times.
At the time of admission to the clinic the patient had enlarged submaxillary lymph
nodes, the entire soft palate was gray, and the uvula was long and irregular and its mucosa
contained many red nodules. There were numerous, gray, irregular nodules on the false
vocal cords. Proctoscopic examination showed irregularly distributed superficial ulcers
of the rectum and the sigmoid. Grossly, the ulcers were not typical of any specific infection. The examining physician believed they were too superficial for tuberculosis, too
deep for bacillary dysentery and too large for amebic dysentery. Impression smears made
from tissue removed for biopsy showed organisms which were interpreted as Leishmania
braziliensis. On histologic examination the tissue from the rectum was interpreted as
inflammatory. Tissue from the pharynx was interpreted as that of a granulomatous lesion,
with intracellular organisms which probably were Leishmania tropica. The results of five
separate examinations for acid-fast bacilli were negative. Impression smears from the
lesion in the mouth, treated with Giemsa's stain, showed organisms which were interpreted
as L. braziliensis. The results of cultures from the floor of the mouth were positive for H.
capsulatum.
Histologic examination. Biopsy showed a diffuse distribution of numerous large foreign
body giant cells, associated with small, poorly defined collections of large phagocytic cells
(Fig. 3a) which were surrounded by a dense infiltration by leukocytes, consisting of few
neutrophils, eosinophils and lymphocytes and large numbers of plasma cells, which extended
through the tissue up to the covering epithelium. The epithelium was hyperplastic,
showed proliferations which extended into the underlying tissues and, in places, simulated
squamous cell carcinoma. On examination under high power, the cytoplasm of the giant
cells and of many of the large phagocytic cells contained small, round or ovoid, darkstaining organisms having a clear capsule, and appearing morphologically typical of H.
cwpsulatvm (Fig. 3b).
HISTOPLASMOSIS OF MOUTH AND PHARYNX
135
>4
F I G . 3. (Case 3). a. Section of pharyngeal ulcer. Note the scarcity of macrophages containing Histoplasma as contrasted with the more recent lesion in the
bowel shown in Figs. 3c and 3d. X 375. b. Giant cell shown in Fig. 3a. X 1360.
c. Section of biopsy specimen of a recent rectal ulcer showing enormous numbers of
organisms in the macrophages. X 375. d. Parasite-laden macrophages adjacent
to the glandular epithelium. X 680.
136
-
WEED AND PARKHILL
Biopsy of tissue from t h e rectum showed chiefly large .numbers of macrophages, associated with occasional giant cells, packed in t h e stroma between t h e mucosal glands (Fig.
3c). These cells were packed with enormous numbers of organisms (Fig. 3d) which were
similar to those seen in t h e pharyngeal lesion.
Case 4
The, patient was a 23 year old man who entered the clinic complaining of weakness,
chronic fatigue, weight loss, low-grade fever and stomatitis of two and one-half y e a r s '
duration. I n May 1940, he had begun to lose weight and by September had lost 50 pounds
(22.7 K g . ) . During this time he was resting a t home. In November, he began to have a
F I G . 4. (Case 4). a. Section of ulcer in t h e floor of the m o u t h showing granulomatous n a t u r e with giant cell formation. X 50. b. Note absence of phagocytes
containing organisms. No organisms suggestive of Histoplasma capsulatum could
be found in the histologic sections. Cultures were positive for t h e organism. X 250.
fever, up to 101 F . and profuse night sweats. By May 1941, he had improved and was able
to return t o work for a few days, b u t the weakness recurred and work had to be discontinued. In June 1941, he developed ulcers in t h e pharynx, bleeding from t h e gums and
fever. T h e disease was diagnosed as trench m o u t h and he was treated for this condition,
b u t t h e ulcers persisted. Roentgenograms showed clouding in t h e central portions of both
lungs. H e was sent to a sanatorium where his fever varied between 99 and 100 F . H e was
discharged in August 1941, because tubercle bacilli could not be demonstrated in his s p u t u m .
During t h e next year t h e p a t i e n t did no work. He rested and had plenty of food and
fresh air, but he still felt fatigued, weak and short of breath on exertion and had occasional
edema of t h e ankles. I n August 1942, a blood test by his physician showed "spirochetal
infection" for which he was given weekly intravenous injections for four months without
improvement. During t h e rest of 1942 he had aching in t h e left hip and elbow j o i n t s ,
walked with a broad base and, at times, had a tendency to fall to t h e right side. Upon
HISTOPLASMOSIS OF MOUTH AND PHARYNX
137
admission to the clinic in January 1943, he was emaciated, had a sallow complexion, a pulse
rate of 104 and a temperature of 99.8 F. There were granulomatous lesions on the soft
palate near its posterior border, one on the hard palate, one in the left buccal fold opposite
the bicuspid and a large ulcer involving almost the entire floor of the mouth. A fifth ulcerative lesion involved the tip of the epiglottis. Clinical impressions included blood dyscrasia, brucellosis, sarcoidosis, sarcoma, Hodgkin's disease, coccidioidomycosis or aspergillosis. On the basis of previous experience, one physician considered the lesions to
be probably due to Histoplasma. A biopsy of the lesion from the floor of the mouth led
to a diagnosis of tuberculosis. The results of guinea pig inoculation were negative for
tuberculosis. Cultures of the material from the floor of the mouth were positive for H.
capsulatum. Histoplasma were found in direct smears. The patient died in July 1944.
Permission for autopsy was refused.
Histologic examination. Biopsy of a lesion of the mouth showed an inflammatory reaction. There were several nests of endothelial cells organized into well-formed "tubercles",
with an occasional multinucleated giant cell, sometimes at the center, sometimes near the
periphery of the tubercle (Fig. 4). At the base of an adjacent ulcerated area were unorganized masses of endothelial cells. Lymphocytic infiltration was almost absent; there was
moderate infiltration with polymorphonuclear leukocytes, chiefly neutrophils, and near
the ulcerated area there was, in addition, a rather diffuse infiltration with plasma cells.
COMMENT
In Case 1 the organisms were easily demonstrated by histologic examination
and were interpreted as probably being H. capsulatum. In Cases 2 and 3 the
original interpretations were more difficult because the clinical findings were
much more confusing. The organisms, on biopsy, were visible, but were not
properly interpreted until the diagnosis was established by culture. In Case 4,
no organisms were visible on histologic examination so that the diagnosis had to
be made entirely on the basis of culture alone.
The ulcers in Cases 1 and 2 were of relatively recent development and contained
many organisms. In Case 3, the lesions in the oral cavity were of long duration
and contained few visible organisms, but the rectal lesions were of short duration
and contained many organisms which were easily recognized in the histologic
sections. In Case 1 many organisms were in the oral lesions at the time of diagnosis. The ulcer on the epiglottis, however, which was not subjected to biopsy
but which was presumed to have the same etiology as the pharyngeal ulcers,
showed no recognizable organisms in the tissue sections at the time of autopsy.
In this case the adrenals showed necrosis and no organisms were visible in the
histologic preparations, but the cultures were positive for H. capsulatum even
though the body had been embalmed six to eight hours. These findings may be
interpreted as evidence that in some cases the organisms either tend to disappear
from a lesion or become changed into some form which is not recognizable at the
present time. The case of Parsons and Zarafonetis,45 in which there were ulcers
of the tongue that had remained healed for five years and the patient had remained apparently well, together with the epidemiologic evidence obtained by
skin testing, supports the view that histoplasmosis may eventually be shown to
be, like coccidioidomycosis, a common disease in which there is a fatal termination
in only a small percentage of cases. This, however, is entirely speculative at
present.
138
WEED AND PARKHILL
CONCLUSIONS
. 1. The clinical manifestations of histoplasmosis vary extensively and may
appear as ulcerated or indurated lesions in the oral cavity simulating those of
tuberculosis, malignant disease and leishmaniasis.
2. On biopsy the organisms may be present in the tissue in sufficient numbers
to warrant a histologic diagnosis or the organisms may be so scarce as to render
an etiologic evaluation impossible.
3. The organism, Histoplasma capsulatum, when present in tissue removed
for biopsy may be easily isolated by inoculating the emulsified tissue onto blood
agar containing 50 units each of penicillin and streptomycin per cubic centimeter
of medium to inhibit bacterial growth. This is a suitable medium for other
mycotic agents such as Blastomyces dermatitidis, Coccidioides immitis, Cryptococcus hominis and others.
4. Tissue for biopsy should be so handled that adequate material may be kept
separately for suitable bacteriologic investigation if the histologic examination
does not reveal a neoplastic process.
REFERENCES
1. A G R B S S , H A R R T , AND G R A Y , S. H . : Histoplasmosis a n d reticuloendothelial h y p e r p l a s i a .
Am. J . D i s . Child., 57: 573-589, 1939.
2. AMOLSCH, A. L . , AND W A X , J . H . : Histoplasmosis in infancy: report of a case.
P a t h . , 15: 477-482,1939.
Am. J .
3 . A N D E R S O N , W. A. D . , M I C H E L S O N , I . D . , AND D U N N , T . M . : H i s t o p l a s m o s i s in i n f a n c y ;
r e p o r t of case.
Am. J . Clin. P a t h . , 11: 344-355, 1941.
4. B E A M E R , P . R . , R E I N H A R D , E . H . , AND GOODOF, 1 . 1 . : Vegetative endocarditis caused
by higher bacteria and fungi.
Am. H e a r t J . , 29:99-112,1945.
5. B E A M E R , P . R . , S M I T H , E . B . , AND B A R N E T T , H . L . : H i s t o p l a s m o s i s — r e p o r t of a case i n
a n infant a n d experimental observations. J . P e d i a t . , 24:270-280,1944.
6. B O L T J E S , B E N : Histoplasmosis; report of a case with brief review of t h e l i t e r a t u r e .
J . Kansas M . S o c , 44: 226-229, 1943.
7. B R O D E R S , A. C . D O C H A T , G. R . , H E R R E L L , W. E . , AND V A U G H N , L . D . : An u n u s u a l case
of histoplasmosis.
P r o c . Staff Meet., M a y o Clin., 19: 123-128, 1944.
8. B R O W N , A. E . , H A V E N S , F . Z., AND M A G A T H , T . B . : Histoplasmosis: r e p o r t of case.
P r o c . Staff Meet., M a y o Clin., 15: 812-816, 1940.
9. B U I E , R . M . , J R . : Histoplasmosis of D a r l i n g ; first reported case in N o r t h Carolina.
J . Bowman G r a y School Med., 1:112-116,1943.
10. C L E M E N S , H . H . , AND B A R N E S , M . L . : Histoplasmosis of D a r l i n g : report of a case.
South. M . J . , 33: 11-15, 1940.
11. Clinical-Pathological Conference: Histoplasmosis. Clin. P r o c . Child. H o s p . , Washington, D . C , 1: 168-172, 1945.
12. Clinical-Pathological Conference: Presentation of case. California M e d . , 6 5 : 29-31,
1946.
13. C O L V I N , S. H . , J R . , G O R E , I . , AND P E T E R S , M . : Case of histoplasmosis (Darling) w i t h
a u t o p s y . Am. J . M . S c , 207:378-385,1944.
14. C O N L I N , F . M . , AND H A N K I N S , C. R . : Histoplasmosis. Case r ep o r t . N e b r a s k a M . J . ,
32:101-103,1947.
15. C R U M R I N E , R . M . , AND K E S S E L , J . F . : Histoplasmosis (Darling) w i t h o u t splenomegaly.
Am. J . T r o p . M e d . , 11: 435-449, 1931.
16. C U R T I S , A. C , AND CAWLEY, E . P . : Genital histoplasmosis. J . Urol., 57: 781-787,1947.
17. C U R T I S , A. C , AND G B E K I N , J . N . : Histoplasmosis: a review of cutaneous a n d adjacent
mucous membrane manifestations with a report of three cases. J . A. M . A., 134:
1217-1224, 1947.
18. D A R L I N G , S. T . : A protozoon general infection producing pseudotubercles in t h e lungs
and focal necroses in t h e liver, spleen a n d lymph nodes. J . A. M . A., 46: 1283-1285,
1906.
19. D A R L I N G , S. T . : Histoplasmosis: a fatal infectious disease resembling kala-azar found
among natives of tropical America. Arch. I n t . Med., 2 : 107-123, 1908.
20. D A V I S , H . V., AND N E F P , F . C : Histoplasmosis in infancy. Am. J . D i s . Child., 7 1 :
171-177, 1946.
HISTOPLASMOSIS OF MOUTH AND PHARYNX
21. D E A N , L . W., J R . : Histoplasmosis of larynx.
22. D E R B Y , D . C. L . , C A R D , W. I
D a r l i n g : report of a case.
139
Arch. Otolaryng., 36: 390-392,1942.
W I L S O N , R I C H A R D , AND D U N C A N , J . T . : Histoplasmosis of
L a n c e t , 1: 224-227, 1942.
23. D O D D , K A T H A R I N E , AND T O M P K I N S , E D N A H . : A case of histoplasmosis of D a r l i n g in a n
infant. Am. J . T r o p . M e d . , 14: 127-137, 1934.
24. GALVIS, A. G.: Histoplasmosis en Colombia. Soc. de biol. de Bogota, 2 : 203-207,1947.
25. G E R M A N , W. M . , A S H M U N , S T E R L I N G , AND D I L L E , C. E . : Histoplasmosis—case r e p o r t .
Am. J . Clin. P a t h . , 13: 12-14, 1943.
26. G U N T E R , W. A., AND LAFFERTY, C. R . : Histoplasmosis of D a r l i n g ; report of a case.
J . M . A. Alabama, 9 : 337-339, 1940.
27. HANSMANN, G. H . , AND SCHENKEN, J . R . : A unique infection in m a n caused b y a new
yeast-like organism, a pathologic member of t h e genus Sepedonium. Am. J . P a t h . ,
10: 731-738,1934.
28. H E N D E R S O N , R . G., P I N K E R T O N , H E N R Y , AND M O O R E , L . T . : H i s t o p l a s m a c a p s u l a t u m
as a cause of chronic ulcerative enteritis. J . A. M . A., 118:885-889,1942.
29. H I L D , J . R . : Histoplasmosis in infancy. Am. J . D i s . Child., 63:131-139,1942.
30. H U M P H R E Y , A. A.: Reticuloendothelial cytomycosis (histoplasmosis of Darling).
Arch. I n t . Med., 65: 902-918, 1940.
31. I A M S , A. M . , T E N E N , M . M . , AND FLANAGAN, H . F . : Histoplasmosis in children; review
of literature with report of case. A m . J . D i s . Child., 70:229-240,1945.
32. K E M P E R , J . W., AND BLOOM, H . J . : Histoplasmosis: report of a case. J . Oral Surg.,
2: 167-172, 1944.
33. K E Y , J . A., AND L A R G E , A. M . : Histoplasmosis of t h e knee. J . Bone a n d J o i n t Sure.,
40: 281-290, 1942.
34. KTJZMA, J . F . , AND SCHUSTER, M . : Histoplasmosis; r e t i c u l o e n d o t h e l i a l cytomycosis.
Wisconsin M . J . , 45: 591-595,1946.
35. L A M , F . K . , AND P R I C E , S.: Histoplasmosis in m a n . Hawaii M . J . , 6:313-315,1947.
36. L E V Y , B . M . : Oral manifestations of histoplasmosis. J . Am. D e n t . A., 32:215-220,1945.
37. M C L E O D , J . H . , E M M O N S , C . W., R O S S , S I D N E Y , AND B U R K E , F . G . : H i s t o p l a s m o s i s :
report of 4 cases, 2 in siblings.
J . P e d i a t . , 2 8 : 275-295, 1946.
Histoplasmin test a n d other diagnostic procedures.
38. M A R T I N , W. P . , AND S I L B E R , B E R N A R D : Histoplasmosis of D a r l i n g ( r e t i c u l o e n d o t h e l i a l
cytomycosis); case report. Am. J . Clin. P a t h . , 14:119-124,1944.
39. M E L E N E Y , H . E . : Histoplasmosis (reticuloendothelial cytomycosis): a review with
mention of thirteen unpublished cases. Am. J . T r o p . Med., 20:603-616,1940.
40. M E L E N E Y , H . E . : Pulmonary histoplasmosis; report of 2 cases. Am. R e v . T u b e r c , 44:
240-247,1941.
41. M E L E N E Y , H . E . : Toxoplasmosis mistaken for histoplasmosis in a c a t . Am. J . T r o p .
Med., 25:163,1945.
42. M I D E R , G. B . , SMITH, F . D . , AND B R A Y , W. E . : Systemic infection with Cryptococcus
neoformans (Torula histolytica) a n d Histoplasma capsulatum in t h e same p a t i e n t .
Arch. P a t h . , 43: 102-110, 1947.
43. M O O R E , M O R R I S , AND JORSTAD, L . H . : Histoplasmosis a n d i t s i m p o r t a n c e t o otorhino-
laryngologists; a review with report of a new case.
52: 779-815, 1943.
Ann. Otol., R h i n . a n d Laryng..
44. P A L M E R , A L I C E E . , AMOLSCH, A. L . , AND S H A F F E R , L . W . : Histoplasmosis w i t h m u c o -
cutaneous manifestations. Arch. D e r m a t . a n d Syph., 45: 912-916, 1942.
45. PARSONS, R. J . , AND ZARAFONETIS, C. J . D . : Histoplasmosis in m a n ; report of 7 cases
and review of 71 cases. Arch. I n t . Med., 75:1-23,1945.
46. R A M S E Y , T . L . , AND APPLEBAUM, A. A . : Histoplasmosis " D a r l i n g " . Am. J . Clin. P a t h . ,
12:85-94,1942.
47. R E I D , J . D . , S C H E R E R , J . H . , H E R B U T , P . A., AND I R V I N G , H . : Systemic histoplasmosis
diagnosed before death a n d produced experimentally in guinea pigs.
Clin. Med., 27:419-434,1942.
J . Lab. and
48. R H O D E S , P . H . , CONANT, N . F . , AND G L E S N E , L . R . B . : Histoplasmosis; r e p o r t of a case
in an infant of 3 m o n th s of age. J . Pediat., 18: 235-241,1941.
49. R I L E Y , W. A., AND WATSON, C . J . : Histoplasmosis of D a r l i n g : with report of a case
originating in Minnesota. Am. J . T r o p . Med., 6: 271-282, 1926.
50. SAGLAM, T E V F I K : Histoplasmosis. Schweiz. m e d . Wchnschr., 76: 1153-1156, 1946.
51. SCHLUMBERGER, H . G., AND SERVICE, A. C : A case of histoplasmosis in an infant with
autopsy. Am. J . M . S c , 207:230-239,1944.
52. S C O T T , E . P . : Histoplasmosis; report of a case in a n infant 15monthsof age. J . P e d i a t . ,
19:668-671,1941.
53. SEABURY, J . H . , AND D R Y G A S , H . H . : Penicillin in t h e t r e a t m e n t of histoplasmosis: t w o
case reports. Ann. I n t . Med., 25: 340-346,1946.
54. S H A F F E R , F . J . , S H A U L , J . F . , AND M I T C H E L L , R . H . : Histoplasmosis of D a r l i n g ; fourth
case to be reported in t h e United S t a t e s .
J . A. M . A., 113:484-488,1939.
140
WEED AND PARKHILL
55. SIMSON, F . W., AND BARNETSON, J.: Histoplasmosis: report of a case. J. Path, and
Bact., 64: 299-305,1942.
56. SWAN, L. L., AND FINNEGAN, J. V.: Histoplasmosis; report of a case with autopsy.
Wisconsin M. J., 45: 763-765,1946.
57. THOMAS, W. C , AND MITCHELL, J. H.: Histoplasmosis; report of diagnosis from biopsy
of cutaneous nodules. Am. J. Med., 2: 538, 1947.
58. THOMAS, W. C , AND MOOREHEAD, R. P . : Histoplasmosis; report of a case in North
Carolina. North Carolina M. J., 4: 378-382, 1943.
59. TOMLINSON, W. J., AND GROCOTT, R. G.: Canine histoplasmosis. Am. J. Clin. Path.,
15: 501-507, 1945.
60. VAN PERNIS, P. A., BENSON, M. E., AND HOLINGEB, P.: Specific cutaneous reactions
with histoplasmosis. J. A. M. A., 117: 436-437, 1941.
61. VAN PERNIS, P. A., BENSON, M. E., AND HOLINGEB, P. H.: Laryngeal and systemic
histoplasmosis (Darling). Ann. Int. Med., 18: 384-393, 1943.
62. WILLIAMS, R. H., AND CROMARTIE, W. J.: Histoplasmosis: report of a case. Ann. Int.
|W Med., 13: 2166-2171,1940.
63. WOOD, W. B., AND MOORE, R. A.: Case reports of Barnes Hospital. Clinical and postmortem records used in weekly clinicopathologic conferences at Barnes Hospital,
St. Louis. Case 22. J. Missouri M. A., 40: 251-254,1943.
64. WORQAN, D. K.: Histoplasmosis: a summary of the known facts about the disease;
report of a case. Bull. School Med. Univ. Maryl and, 30: 69-79,1945.
65. WRIGHT, R. B., ANDHACHTEL,F. W.: Histoplasmosis of Darling; report of a case. Ann.
Int. Med., 16:309-319,1941.