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Progressive Disseminated Histoplasmosis
Mimicking as Anal Carcinoma – Look at the
Mountain, Not at Stone: A Case Report
Mahaveer Singh 1
Abhishek Sharma 2
Kalpana Sankhala 3
Hemant Bareth 4
Supriya Suman 4
1
Department of Endocrinology, National
Institute of Medical Sciences and
Research Hospital, Nims University
Rajasthan, Jaipur, India; 2Department of
General Medicine, National Institute of
Medical Sciences and Research Hospital,
Nims University Rajasthan, Jaipur, India;
3
Department of Pathology, National
Institute of Medical Sciences and
Research Hospital, Nims University
Rajasthan, Jaipur, India; 4Department of
Pharmacy Practice, Nims Institute of
Pharmacy, Nims University Rajasthan,
Jaipur, India
Correspondence: Mahaveer Singh
Department of Endocrinology, National
Institute of Medical Sciences and Research
Hospital, Nims University, Rajasthan,
Jaipur, 303121, India
Tel +918949836075
Email drms.mamcmed@gmail.com
Abstract: Disseminated histoplasmosis is a systemic disease caused by the dimorphic
fungus Histoplasma capsulatum. Here, we are presenting a case of shock who was diagnosed
to have primary adrenal insufficiency. This 68-year-old man had bilateral adrenal mass and
later presented with chronic fever and ulcerated anal mass in the oncology clinic. The
oncologist made a provisional diagnosis of anal carcinoma with adrenal metastasis. He
was suspected of having an adrenal crisis and was admitted to the intensive care unit. He
also had granulomatous hepatitis and acute kidney injury. The working diagnosis was
changed to systemic inflammatory/infective pathology. The biopsy of the anal tissue done
to look for the aetiology showed Histoplasma. He was started on oral itraconazole therapy.
He improved symptomatically (resolution of fever, improvement in pain) when assessed after
seven days. His anal ulcer healed after 21 days of itraconazole therapy.
Keywords: adrenal metastasis, anal carcinoma, Histoplasma, ulcerated anal mass
Background
Disseminated histoplasmosis is a systemic disease caused by the dimorphic fungus
Histoplasma capsulatum.1 Histoplasmosis is endemic in the Ohio and Mississippi
river valleys, large parts of Latin America and South Asia.2 Histoplasmosis is
acquired through the inhalation of infectious conidia found in moist, acidic, and
nitrogen-rich soil. The clinical severity of histoplasmosis depends on many factors
like inhaled quanta, fungal virulence, and host immune response.
In the autopsy series of progressive disseminated histoplasmosis, gastrointestinal symptoms were found in 10% to 12% with a higher prevalence of involvement
in autopsy series (20% to 30%).3 The symptoms of gastrointestinal involvement are
oral ulceration, dysphagia, odynophagia, diarrhoea, abdominal pain, and weight
loss. In progressive disseminated histoplasmosis, anal involvement is infrequent
and found in only 2–3% of patients.3 Progressive disseminated histoplasmosis
mimicking anal carcinoma is very rare. We are reporting a case of progressive
disseminated histoplasmosis, who presented with ulcerated anal mass.
Case Presentation
Sixty-eight-year-old farmer, case of chronic obstructive pulmonary disease, presented
to our outpatient department with fatigue, dizziness, pigmentation, and low blood
pressure. He had these symptoms for three months. Suspecting adrenal insufficiency,
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Received: 18 June 2021
Accepted: 20 August 2021
Published: 1 October 2021
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Singh et al
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we sent concordant random serum cortisol and plasma adrenocorticotrophic hormone. Low random serum cortisol (3
ug/dl) and elevated plasma ACTH (120 pg/mL) confirmed
the diagnosis of primary adrenal insufficiency. As suspicion
of adrenal crisis was there, we admitted him to the intensive
care unit. He also had acute kidney injury (serum creatinine
2.3 mg/dl, estimated glomerular filtration rate-30 mL/min)
with metabolic acidosis (pH-7.1, with bicarbonate 11 meq/l)
and hyperkalemia (Serum potassium-6 meq/l). He was given
a saline bolus to correct the dehydration. Hydrocortisone
infusion was given to cover the glucocorticoid replacement.
His blood pressure improved along with the recovery of
kidney functions. Computed tomography was done after
stabilization showed bilateral adrenomegaly (Figure 1),
with the size of the right and left adrenals, 3×2 cm ad
4×3 cm, respectively. Subsequently, the patient had been
discharged on 15 mg/m2 hydrocortisone equivalent and
100 microgram fludrocortisones. We planned for the CT
guided adrenal biopsy in the follow-up after ruling out
pheochromocytoma.
Two months later, he came to the oncology outpatient
clinic with a complaint of pain during defecation and an anal
mass with ulceration. Before coming to the oncology clinic,
he was evaluated by a surgeon and, suspecting anal carcinoma, was referred back to our institute. The oncologist
made a diagnosis of metastatic carcinoma anus with paraneoplastic fever. We were called in to have a look. When we
saw him, he looked cachectic and more pigmented than the
previous admission. His blood pressure was 90/60 mmHg in
supine position right arm, with severe orthostasis on standing up from bed. His pulse rate was 110/min, and the axillary
temperature was 101-degree Fahrenheit. He stopped treatment in between and stopped five days back.
He had a linear ulcer of 4.0×1.5 cm on the upper
anterior gingiva (Figure 2). He had firm hepatomegaly
(8 cm below the right subcostal margin). The spleen was
enlarged by 6 cm towards the umbilicus. Chest examination revealed rhonchi and inspiratory crepitations throughout the lung fields.
He had an ulcer on the anal verge, covering 240 degrees
on the verge (Figure 3). The ulcer had overhanging edges.
Suspecting adrenal crisis due to treatment noncompliance, he was admitted to the medical intensive care unit. He
was given normal saline and hydrocortisone infusion. On
investigations, the patient had elevated liver enzymes along
with elevated serum alkaline phosphatase. He also had nonoliguric acute kidney injury (Table 1). The ultrasonographic
examination revealed hepatosplenomegaly with no focal
lesions. Chest X-ray showed prominent broncho-vascular
markings. The working diagnosis was changed from the
carcinoma anus to a systemic infection/inflammation with
granulomatous hepatitis and renal injury.
The differential diagnosis of a patient with an anal ulcer,
oral ulcer, primary adrenal insufficiency, granulomatous
Figure 1 CECT abdomen shows bilateral adrenal enlargement with the right (3 x 2 cm) and left (4 x 3 cm). Both the adrenals were heterogeneous, had irregular margins and
calcifications.
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Figure 2 4 cm x 1.5 cm ulcer on the upper gum line, with a whitish coating over
the ulcer.
macrophages with budding oval yeast forms surrounded by
a halo suggesting the diagnosis of Histoplasma capsulatum.
The Histoplasma capsulatum was confirmed by PAS positivity (Figure 4). As the diagnosis was established on the
anal biopsy and clinically fit into the progressive disseminated histoplasmosis, we kept the adrenal biopsy as
a salvage procedure. The nephrologist was in the opinion
of wait and watch for the kidney injury as it may improve
with the treatment of underlying disease.
The patient was started on oral itraconazole therapy
(800 mg a day for three days followed by 200 mg twice
a day). He was discharged on 15 mg/m2 of hydrocortisone
as a steroid replacement, itraconazole (200 mg twice a day
with milk) as an antifungal treatment. The patient was
advised to monitor the temperature every six hours and
come if any adverse effects. We planned weekly follow-up
in the first month to assess the clinical response (resolution
of the fever, healing of the ulcers, improvement in kidney
injury), steroid replacement (under or over replacement)
and treatment side effects (gastritis, hepatitis). The imaging of the adrenals and cortisol reserve will be tested after
six months of therapy.
At seven days follow-up, the patient’s appetite
improved, and he became afebrile.
His renal function and liver function improved when
assessed on day seven compared with the status at discharge. The comparison is shown in Table 1. His pain
during defecation also decreased.
His fatigue improved, and he gained 2 kg of weight
after two weeks. The anal ulcer healed after three weeks of
antifungal therapy.
Patient’s Perspective
Figure 3 Anal region showing a 2.0×2.0-cm area of induration at the left lateral
anus.
hepatitis, and kidney injury are disseminated tuberculosis,
disseminated fungal infection (histoplasmosis), disseminated
CMV infection and syphilis.
The patient was stabilized on the hydrocortisone infusion
with a plan to biopsy the anal ulcer. The adrenal biopsy
would have been the subsequent investigation if the diagnosis was not confirmed on the anal biopsy. Anal biopsy
revealed focally ulcerated squamous mucosa. Underlying
stroma showed neutrophils, lymphocytes, plasma cells and
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I was terrified when the suspicion of anal carcinoma was
made and discussed with me. I had fever and anorexia for
a long time, causing a severe dent in my quality of life. My
doctor told me that it could be a systemic disease in the
background of the bilateral adrenal enlargement and primary adrenal insufficiency, with granulomatous hepatitis
and acute kidney injury. I was advised for a biopsy from
the anal ulcer. I got relieved when I heard that it is not
cancer and is a fungal infection. The happiness increased
further when during treatment discussions, I was informed
that it is curable.
Discussion
Histoplasma is a fungus of the eumycete’s family.
Histoplasmosis capsulatum var capsulatum is the most
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Table 1 Lab Investigations at Admission, at Discharge (*Day Eight After Admission and Three Days After Itraconazole Therapy) and
Follow Up at Day 7 in the Endocrine OPD
Investigation
At Admission
At Discharge*
At First, Follow
Normal Range
Up, Seven Days
After Discharge
Hematology Analysis Report
Hb (g/dl)
10.1
11
13–18
Total leucocyte count (ths/ul)
Blood neutrophils (%)
7.8
72
7000
70
4.5–12.5
45–75
Blood lymphocytes (%)
Blood monocytes (%)
22
04
24
4
25–45
2–8
Blood eosinophils (%)
02
2
1–6
Platelet Count (x103/uL)
121
150
150–450
Renal Function Tests
Serum Urea (mg/dl)
69
51
71
15–45
Serum Creatinine (mg/dl)
2.51
1.90
1.3
0.6–1.6
Serum Calcium (mg/dl)
Serum phosphorus-Inorg (mg/dl)
7.1
3.6
7.5
3.5
8.5–10.5
2.5–5
Serum sodium (mmol/L)
139
136
136
135–145
Serum potassium (mmol/L)
Urine spot potassium (meq/l)
2.9
3.0
3.95
3.5–5.5
25–125
40 meq/l
Liver function tests
Serum SGOT (IU/L)
119
59
37
10–50
Serum SGPT (IU/L)
Serum albumin (g/dl)
99
3.0
64
2.4
93
2.6
14–63
3.5–5.2
Serum globulin (g/dl)
3.3
4.0
4.1
2.3–3.6
Serum alkaline phosphatase (iu/l)
Serum bilirubin (T/D) mg/dl
1174
482
314
45–145
0.0–1.2/0.0–0.25
0.6/0.3
prevalent species of Histoplasma. Histoplasmosis is also
called “Darling’s disease”, “Spelunker’s disease”, or
“caves disease”.4,5 In India, histoplasmosis is endemic in
the Gangetic belt of the UP and West Bengal.6
Histoplasma resides in its microfoci (droppings, bird’s
feathers, soil of old buildings, old bushes, and trees).
Disruption of these microfoci causes the spread of microconidia in the air and inhalation into the lung. Dissemination is
not very common and occurs in 0.1% to 1% of patients.
Some of these patients with dissemination develop progressive disseminated histoplasmosis.7
Gastrointestinal involvement was found in 20% to 30%
of cases of progressive disseminated histoplasmosis.8 In
a review of the 77 reported cases of gastrointestinal histoplasmosis, the small intestine was the most commonly
involved site. Ileal ulceration was the most common symptom of gastrointestinal histoplasmosis (Table 2). In histopathology analysis of gastrointestinal lesions, Lamps et al
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0.6/0.3
0.5/0.2
evaluated 56 specimens from 52 patients evaluated with
hematoxylin and eosin and silver stain and found that in
gross gastrointestinal features, ulcers (49% of patients)
were the most common clinical manifestation of gastrointestinal histoplasmosis, followed by nodules (21%), haemorrhage (13%), obstructive masses (6%). Lymphohistiocytic
infiltration (83%) was the most common finding on microscopic examination.
The first description of anorectal histoplasmosis was done
by Weiss et al in 1952.9 They described a 62-year-old man
who had dysphagia, weight loss, fever, and pain during defecation. Proctoscopy of the patient showed polyp in the rectum
and anal canal. Biopsy of the anal polyp showed Histoplasma.
In another case report, similar to our case, Matthew
Wheel wright reported a 66-year-old male patient who
presented with an anal ulcer with suspicion of the carcinoma on imaging.10 Core biopsy of anal mass showed
intracellular yeast suggestive of Histoplasma.
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Figure 4 Histologic features of perianal biopsy: (A) High power (1000×) of H&E-stained section demonstrates yeast of Histoplasma capsulatum; (B) High power (1000×) of
PAS-stained section demonstrates a mononuclear inflammatory infiltrate composed of histiocytes, lymphocytes, and plasma cells along with Histoplasma capsulatum; (C) Low
power (400×) of PAS-stained section shows histiocytes with intracytoplasmic fungal yeast forms (2–5 µm) with a characteristic halo.
Anorectal histoplasmosis can present with lower intestinal
bleeding. Mullick et al reported a case in which a 69-year-old
man presented with lower gastrointestinal bleeding.11 The
colonoscopy showed an anal mass mimicking squamous cell
carcinoma on appearance. Biopsy of this mass showed
Histoplasma on the periodic acid Schiff and Gomori methenamine silver stains.
Antifungal agent itraconazole or amphotericin B can be
used for the treatment of adrenal histoplasmosis. The clinical
phenotype of the adrenal histoplasmosis determines the treatment protocol. Moderate to severe gastrointestinal histoplasmosis requires the amphotericin B treatment for initial 2 to 4
weeks, followed by itraconazole for 1 to 2 years. Mild
gastrointestinal progressive disseminated histoplasmosis
can be treated by oral itraconazole therapy for 1 to 2
years.12 Mortality in disseminated histoplasmosis is 80% to
100% without treatment and 25% with treatment.13 Relapse
has been found in 10% to 20% of immunocompetent patients
after nine years of follow-up. In AIDS, the relapse rate is very
high, approaching 80% if the patient’s CD4 count is persistently below 100/ul.1,14
Conclusion
The exophytic reactive ulcerative growth of the anal canal
can mimic carcinoma anus. In our case, systemic symptoms
like fever, anorexia, and multiorgan dysfunction point
towards infective causes like progressive disseminated histoplasmosis. Our case illustrates that the bull’s eye
Table 2 Clinicopathologic Manifestations of Gastrointestinal Histoplasmosis
Site
Small Intestine
Frequency of Involvement
56–79% (ileum most common)
Clinicopathologic Manifestation
Frequency
Ulceration (ileum most common)
30–49%
Large Intestine
55–65%
Mucosal nodules
21%
Stomach
14–17%
Stricture or mass
18%
Esophagus
8–18%
Lymphoid hyperplasia
15%
Rectum
13%
Hemorrhage or petechiae
13%
Pancreas
6%
Mass
6%
Gallbladder
6%
Perforation
5.2%
Anus
2%
Ulceration
Appendix
2–2.5%
–
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approach, used by today’s specialist era, can miss the whole
clinical picture. This patient also reminds us of the title “By
looking at stone, a mountain can be missed”.
Abbreviations
CMV, cytomegalovirus; ACTH, adrenocorticotropic hormone; CT, computed tomography; AmB, amphotericin B;
CD4, cluster of differentiation; PAS, periodic acid-Schiff.
Data Sharing Statement
All data generated during this study are available from the
corresponding author on reasonable request.
Patient Consent
Patient provided written informed consent for the case details
and accompanying images to be published. No institutional
approval was required to publish this case report.
Author Contributions
All authors made a significant contribution to the work
reported, whether that is in the conception, study design,
execution, acquisition of data, analysis and interpretation,
or in all these areas; took part in drafting, revising or
critically reviewing the article; gave final approval of the
version to be published; have agreed on the journal to
which the article has been submitted; and agree to be
accountable for all aspects of the work.
Funding
No funding was received for this case report.
Disclosure
The authors report no conflicts of interest.
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