2016, Volume 32, Number 2, Page(s) 105-111
Adrenal Histoplasmosis in Immunocompetent Patients Presenting as Adrenal Insufficiency
Smeeta GAJENDRA, Rashi SHARMA, Shalini GOEL, Ruchika GOEL, Lipika LIPI, Hemanti SARIN, Mridula GULERIA, Ritesh SACHDEV
Department of Pathology & Laboratory Medicine, Medanta the Medicity, GURGAON, INDIA
Keywords: Histoplasmosis, Immunocompetence, Adrenal insufficiency, PAS reaction, Grocott methenamine silver
Histoplasmosis is an infectious disease caused by the dimorphic fungus Histoplasma capsulatum, endemic in central and eastern states
of United States, South America and Africa. India is considered to be non-endemic area for histoplasmosis. Disseminated histoplasmosis may
affect almost all systems. Disseminated histoplasmosis with asymptomatic adrenal involvement has been described in immunocompromised
patients; whereas isolated adrenal involvement with adrenal insufficiency as the presenting manifestation of the disease is rare.
Material and Method: Twelve patients from a non-endemic area with adrenal histoplasmosis, who were immunocompetent and diagnosed as
adrenal histoplasmosis by cytology/histopathology between January 2012 to December 2014 were studied. 18F-FDG PET/CT (fluorodeoxyglucose
positron emission tomography/computed tomography) was used to assess the extent of involvement.
Results: There were a total of 12 immunocompetent males (mean age: 56.9 years). Ten patients had bilateral adrenal involvement and two had a
unilateral left adrenal mass. All the patients had histopathologically/cytologically proven adrenal histoplasmosis. Two patients had simultaneous
histoplasmosis of other sites, one in the epiglottis and the other in the alveolus. 18F-FDG PET/CT was performed in 10 patients showing high
FDG uptake in the adrenals. All these patients received Amphotericin B and/or Itraconazole treatment that led to symptomatic improvement.
Conclusion: A diagnosis of invasive fungal infection requires a high index of suspicion, especially in immunocompetent patients who present
with nonspecific symptoms, clinical signs, laboratory and radiological features that can resemble adrenal neoplasms. Clinical specimens must be
sent for cytopathology/histopathology together with fungal culture for a definite diagnosis and appropriate management.
Histoplasmosis is a granulomatous infectious disease
caused by the dimorphic fungus Histoplasma capsulatum,
endemic in central and eastern states of United States, South
America and Africa. India is considered to be a non-endemic
area for histoplasmosis. The spectrum of this illness varies
from asymptomatic infection to widespread disseminated
disease, more prevalent in immunocompromised patients.
Histoplasmosis occurs in 0.65% of cases among non-AIDS
patients who develop systemic mycosis1
. It is primarily
a pulmonary disease; however, disseminated infection may
affect almost all systems including the reticuloendothelial
system, gastrointestinal tract, renal tract, central nervous
system, bone marrow and adrenal glands2
adrenal gland involvement is rare, usually involving
bilateral adrenals. It is more common in males. We
describe 12 immunocompetent patients who had adrenal
histoplasmosis presenting as adrenal insufficiency.
This was a retrospective analysis of 12 cases of histoplasmosis
involving the adrenals in immunocompetent
males admitted to a tertiary care hospital of North India
from January 2012 to December 2014. All of them had
cytological/histopathological evidence of histoplasmosis.
Fungal morphology was delineated using the Gomori-
Grocott methenamine silver (GMS), and Periodic Acid
Schiff (PAS) stains. 18F-FDG PET/CT (fluorodeoxyglucose
positron emission tomography/computed tomography)
was performed to assess the extent of involvement.
The patients were male with a mean age of presentation
of 56.9 years (range: 44-72 years). All patients were
immunocompetent, presented with nonspecific symptoms
and clinical signs, and underwent adrenocortical function
testing, which revealed adrenal insufficiency. Ten out of 12
cases (83.4%) had bilateral adrenal masses and two had a unilateral left adrenal mass. Two patients had simultaneous
histoplasmosis of other sites such as the epiglottis and lung.
On CT scan, adrenal masses were 1.5 to 6.6 cm in diameter.
18F-FDG PET/CT was done in 10 patients showing high
FDG uptake in the adrenals (Figure 1
). Four cases showed
mediastinal/abdominal lymphadenopathy. Five cases were
diagnosed by endoscopic ultrasound guided fine needle
aspiration, 5 cases by histopathological examination of
the adrenal and one case by bone marrow examination.
In one case (Case 5), both histopathology of epiglottis and
endoscopic ultrasound guided fine needle aspiration of the
left adrenal were performed. Endoscopic ultra-sound (EUS)
guided fine needle aspiration cytology (FNAC) smears
showed scattered stripped epithelial cells of adrenal gland
origin in a dense amorphous background with scattered
lipid globules, debris, areas of dense necrosis and mixed
population of numerous inflammatory cells. Ziehl-Neelsen stain showed no acid-fast bacilli. On PAS and GMS,
numerous capsulated yeast-like fungal organisms with
uneven budding were evident, morphologically resembling
Histoplasma species (Figure 2A,B
). Histopathology of
the adrenal gland revealed extensive areas of necrosis
surrounded by palisades of histiocytic cells (Figure 3A
with focal areas showing epithelioid morphology with giant
cell granuloma (Figure 3B
). Many of the histiocytic cells
showed yeast forms of 2-4 micron in size with a perinuclear
halo confirming closely to the morphology of Histoplasma
). PAS (Figure 3E
) and GMS (Figure 3F
stain highlighted the fungal structures, further confirming
the diagnosis of Histoplasmosis. The antifungal drugs
itraconazole, and/or amphotericin B were administered
in all cases. These patients showed clinical improvement
and were followed up for 0.5 to 2 years. The cases are
summarized in Table I
Click Here to Zoom
|Figure 1: 18F-FDG PET/CT scan
showing high FDG uptake in bilateral
Click Here to Zoom
|Figure 2: Cytology
smear. A) Multiple
in histiocytic cells
B) Histoplasma yeasts
with GMS positivity
Click Here to Zoom
|Figure 3: A) Histopathology showing extensive areas of necrosis surrounded by palisades of histiocytic cells (H&E; x10). B) Focal areas
showing granuloma (H&E; x20). C-D) Many of the histiocytic cells showing Histoplasma (H&E; x100 and x400). E) Histoplasma yeasts
with PAS positivity (PAS; x200). F) Histoplasma yeasts with GMS positivity (GMS; x200).
Adrenal infection is most frequently caused by hematological
dissemination. The adrenal glands are also a frequent site
of metastasis. Mycobacterium tuberculosis (TB) is the
most common pathogen causing adrenal infection. Fungal
infection of the adrenal gland is rare, but occurs commonly
in immunocompromised patients such as AIDS patients,
transplant recipients, those with hematologic malignancies
and patients on corticosteroids. Histoplasma species are
the commonest fungi involving the adrenals. The range
of adrenal involvement by histoplasmosis is varied as:
(a) mildest form characterized by isolated cortical foci of
parasitized macrophages, (b) extensive caseative necrosis
with enlargement of bilateral adrenals, (c) extensive
infarction, (d) granulomatous replacement of adrenals,
and (e) calcified mass lesion that may mimic tubercular or
In histoplasmosis, the spectrum of illness ranges from
chronic course of disease to acute fatal infection. Most
patients have nonspecific symptoms and clinical signs. It
usually presents as a self-limiting pulmonary infection,
which is usually asymptomatic or can be associated
with mild influenza-like symptoms. The progressive
disseminated form of the disease is rare and occurs mainly in
immunocompromised patients. The disseminated form may
affect almost all systems, including the reticuloendothelial
system, lungs, gastrointestinal tract, renal tract, central
nervous system, bone marrow and adrenal glands.
Adrenal involvement by histoplasmosis may occur during
the active course of dissemination or may evolve many
years after the disease become inactive. Histoplasmosis presenting as asymptomatic bilateral adrenal enlargement
has been described previously5-7 but unilateral adrenal
involvement is rare. In our study, a unilateral adrenal
mass was seen in two cases at the time of presentation.
Adrenal histoplasmosis has a wide spectrum of clinical
manifestations including chronic fatigue, weight loss,
anorexia and fever. It may lead to adrenal insufficiency by
progressive destruction of bilateral adrenal glands. Primary
adrenal insufficiency/Addison's disease occurs in 5-71% of
adrenal histoplasmosis cases and is the commonest cause of
death3. These patients exhibit fever, malaise, orthostatic
hypotension, nausea and vomiting with hyperkalemia and
hyponatremia7. Tuberculosis and fungal infections (such
as histoplasmosis, coccidiodomycosis, blastomycosis) are
two broad categories that are important as causes of adrenal
insufficiency and tuberculosis is the most common cause.
Physical examination may reveal hepatosplenomegaly or
lymphadenopathies. In our study on 12 cases, organomegaly
and lymphadenopathies were revealed in 2 and 4 cases,
In disseminated histoplasmosis, abdominal imaging
usually reveals mild to moderate hepatomegaly with or
without splenomegaly. Abdominal lymphadenopathy
and focal hypodense lesions in the spleen have also been
described. The patients with adrenal histoplasmosis reveal
unilateral or bilateral adrenal masses of varied imaging
features. On ultrasonography, the lesions may show a
uniformly hypoechoic to heterogenous echopattern with
preservation of normal adrenal gland outlines. The range
of CT findings include minimal enlargement with faint
flecks of calcium, moderate enlargement with focal low
attenuation nodules, and massive enlargement with large areas of necrosis or dense calcification8. However, the
typical CT findings of adrenal histoplasmosis are bilateral
symmetrical adrenal enlargement with low-density areas
of necrosis and hemorrhage. Other infectious causes
such as paracoccidioidomycosis are indistinguishable
from histoplasmosis on imaging, and metastasis may
mimic infection as central necrosis is common in both
conditions. In our cases, all adrenal masses were hypodense
on CT, and homogeneous in eight but heterogeneous
in four. Heterogeneous enhancement was seen in four,
homogeneous enhancement in four and no enhancement
in four patients.
Diagnosis involves performing enzyme immunoassay
on urine, serum cerebrospinal fluid and bronchoalveolar
lavage fluid. Diagnosis of disseminated disease can also
be done on bone marrow examination, as in one of our
cases (case 8). Diagnostic accuracy has improved greatly
with the use other laboratory tests such as serology,
complement fixation, a precipitation test, latex particle
agglutination test, agar-gel double immune-diffusion
test, radioimmunoassay, polymerase chain reaction and
microscopy9. However, the gold standard for diagnosis
of histoplasmosis is tissue culture10. On fine needle
aspiration cytology, Histoplasma is commonly seen
within the cytoplasm of the macrophages on a necrotic
background and exhibits narrow based budding or can
also be seen extra-cellularly as the fragile cytoplasm of the
macrophages may get disrupted at the time of preparing
smears11. Characteristic histopathology of adrenal
histoplasmosis includes demonstrating fungal elements
in the glands. There may be localized mononuclear cells
infiltrating developing granulomata with multinucleated
giant cells. Often yeasts are detected in areas of caseating
necrosis. Yeasts show uninucleate hyaline spherules or
ovules 2 to 4 μm size. Yeasts have a single bud attached
by a narrow base and are often seen in clusters. By using
PAS and GMS stain, yeasts can be seen in necrotic areas.
Our six cases were diagnosed on cytology; five cases were
diagnosed on histopathological examination of the adrenal
and one case on bone marrow examination.
The differential diagnoses of bilateral adrenomegaly are
metastasis, lymphoma, adrenal haemorrhage, sarcoidosis
and infections that include histoplasmosis, tuberculosis,
cryptococcosis, coccidioidomycosis and blastomycosis12. Bilateral involvement with adrenal enlargement
is common in malignancy, but adrenal insufficiency is
very uncommon, accounting to <1% of cases of adrenal malignancy. In three of our cases, there was suspicion
of malignancy due to the presence of significantly bulky
bilateral adrenal glands forming a conglomerate soft tissue
density mass with heterogeneous enhancement and central
necrosis on CT abdomen. On imaging, histoplasmosis
may mimic malignancy because central necrosis can be
seen in both conditions. However, central hypodensity
and peripheral rim enhancement of the adrenals is more
common in tuberculosis and histoplasmosis. Adrenal
FNAC along with histopathology, culture, polymerase
chain reaction, and urine antigen can confirm the diagnosis
of histoplasmosis and can differentiate it from other
The majority of individuals who are asymptomatic with
histoplasmosis recover spontaneously and do not require
any specific treatment. Chronic and acute severe cases
require treatment4. Correct preoperative diagnosis
of adrenal histoplasmosis may obviate the need for
surgery while early treatment with antifungal therapy
may restore adrenal reserve. In patients with adrenal
insufficiency, treatment with corticosteroids may be
promptly started without a complete laboratory diagnosis
of adrenal insufficiency from blood cortisol level and
low ACTH-stimulated cortisol responses13. Among
patients with adrenal insufficiency, a large proportion
requires replacement therapy, although reversal of adrenal
dysfunction has been described after prolonged antifungal
treatment. The recommended anti-fungal treatment is
amphotericin B for critically ill hospitalized patients.
This had to be replaced by itraconazole later on because
of nephrotoxicity. Itraconazole is well tolerated and has
excellent central nervous system penetration. Ketoconazole
may be used in milder presentations. Recurrence has been
described as long as nine years after cessation of treatment,
and therefore treatment duration of one to two years
reduces the risk of relapse.
In conclusion, adrenal histoplasmosis does occur in
immunocompetent patients and has to be considered in
the differential diagnosis of bilateral/unilateral adrenal
masses presenting with adrenal insufficiency. A diagnosis
of invasive fungal infection is critical and requires a high
index of suspicion, especially in immunocompetent
patients who have presented with nonspecific symptoms,
clinical signs, and laboratory and radiological features
resembling adrenal neoplasms. Clinical specimens must
be sent for histopathology and fungal culture for a definite
diagnosis and an appropriate management.
1) Larbcharoensub N, Srisuma S, Ngernprasertsri T, Aroonroch
R, Chongtrakool P, Santanirand P, Chirachariyavej T,
Sirikulchayanonta V. Invasive fungal infection in Ramathibodi
Hospital: A ten-year autopsy review. J Med Assoc Thai.
2) Wheat LJ. Histoplasmosis: A review for clinicians from nonendemic
areas. Mycoses. 42006;9:274-82.
3) Koene RJ, Catanese J, Sarosi GA. Adrenal hypofunction from
histoplasmosis: A literature review from 1971 to 2012. Infection.
4) Larbcharoensub N, Boonsakan P, Aroonroch R, Rochanawutanon
M, Nitiyanant P, Phongkitkarun S, Poonvutikul S,
Watcharananan SP, Ngarmukos C. Adrenal histoplasmosis: A
case series and review of the literature. Southeast Asian J Trop
Med Public Health. 2011;42:920-5.
5) Bhansali A, Das S, Dutta P, Walia R, Nahar U, Singh SK,
Vellayutham P, Gopal S. Adrenal histoplasmosis: Unusual
presentations. J Assoc Physicians India. 2012;60:54-8.
6) Kumar N, Singh S, Govil S. Adrenal histoplasmosis: Clinical
presentation and imaging features in nine cases. Abdom Imaging.
7) Kauffman CA. Histoplasmosis: A clinical and laboratory update.
Clin Microbiol Rev. 2007;20:115-32.
8) Wilson DA, Muchmore HG, Tisdal RG, Fahmy A, Pitha JV.
Histoplasmosis of the adrenal glands studied by CT. Radiology.
9) Grover SB, Midha N, Gupta M, Sharma U, Talib VH. Imaging
spectrum in disseminated histoplasmosis: Case report and brief
review. Australas Radiol. 2005;49:175-8.
10) Hage CA, Wheat LJ. Histoplasmosis. In: FaucivAS, Braunwald E,
Kasper DL, editors. Harrison's principles of internal medicine.
Vol 1. 17th ed. New York: McGraw-Hill; 2008: 1244-7.
11) Eloubeidi MA, Luz LP, Crowe DR, Snowden C, Morgan DE,
Arnoletti PJ. Bilateral adrenal gland enlargement secondary
to histoplasmosis mimicking adrenal metastases: Diagnosis
with EUS-guided FNA. Diagn Cytopathol. 2010;38:357-9. doi:10.1002/dc.21210.
12) Vyas S, Kalra N, Das P J, Lal A, Radhika S, Bhansali A, Khandelwal
N. Adrenal histoplasmosis: An unusual cause of adrenomegaly.
Indian J Nephrol. 2011;21:283-5.
13) Chedid MF, Chedid AD, Geyer GR, Chedid MB, Severo
LC. Histoplasmosis presenting as addisonian crisis in an
immunocompetent host. Rev Soc Bras Med Trop. 2004;37:60-2.