Histoplasmosis of the Head and Neck Region Mimicking Malignancy: A Clinic-Pathological Predicament
Neha MITTAL1,2, Asawari PATIL1,2, Priyamvada SINGHAL3, Munita Meenu BAL1,2, Swapnil Ulhas RANE1,2, Shivakumar THIAGARAJAN2,4
1Department of Pathology, Tata Memorial Center, MUMBAI, INDIA
2Homi Bhabha National Institute, MUMBAI, INDIA
3Department of Pathology, Subharti Medical College, UTTAR PRADESH, INDIA
4Department of Head and Neck Surgical Oncology, Tata Memorial Center, MUMBAI, INDIA
Keywords: Head and neck, Histoplasmosis, Granuloma, Histopathology, Pseudoepitheliomatous hyperplasia
Histoplasmosis is a systemic, deep mycotic infection caused by Histoplasma capsulatum. Disseminated histoplasmosis (DH) is synonymous with HIV seropositive immunocompromised individuals; however, isolated histoplasmosis involving the head and neck mucosal sites mimicking malignancy is a clinical predicament. The result, in a superficial biopsy with marked pseudoepitheliomatous hyperplasia (PEH), in a tertiary care cancer center where the number of squamous carcinomas far outnumber the infectious diseases, could be catastrophic.
Material and Method: The archives of a tertiary care cancer hospital were searched (2010-2019) for cases of histoplasmosis involving the head and neck mucosal sites in HIV non-reactive patients.
Results: Six cases of isolated head and neck histoplasmosis were seen in biopsies from 4 men and 2 women, with an age range of 46-72 years. Three of these patients suffered from chronic illnesses. The most common site involved was the larynx (vocal cords) in three cases, two cases were involving lips, and one involving the tongue. The biopsies were reviewed in-house with a clinical diagnoses of malignancy in all and an outside biopsy diagnosis of “squamous cell carcinoma” in 2 cases. The important histological findings in the biopsy were PEH (3 cases), granulomas (2 cases), lymphoplasmacytic inflammation (all cases). Eosinophils were conspicuous by their absence. Intracellular histoplasma was seen in all cases, albeit to varying density, which was confirmed with GMS stain.
Conclusion: A high index of suspicion, meticulous history taking by oncologists, and appropriate distinction of PEH from neoplastic squamous proliferation by pathologists in superficial biopsies and an apropos deeper wedge biopsy are essential to clinch the correct diagnosis.
Histoplasmosis, also known as “Darling’s disease”1,
and “Ohio valley disease”3,
a systemic fungal infection caused by the thermally
dimorphic fungus Histoplasma capsulatum. This fungus
exists as hyphae in the soil environment at a temperature
below 35°C and yeast forms in host tissue at 35-37°C 3,
a typical climate of fertile river valleys. The usual route of
transmission is through inhalation of spores in bird or bat
droppings found in moist and acidic and nitrogen-rich soil
. Construction-related or even recreational activities
which involve disturbing the top 20 cm layer of the soil
can lead to the release of the infectious conidia in the air,
which can be inhaled 4
. These yeast forms then replicate
within the reticuloendothelial system and disseminate
in the absence of a good immune status 4
histoplasmosis can occur in three forms:  primary acute
onset pulmonary form,  chronic pulmonary form,
and  disseminated form 5,6
. The disseminated form
of histoplasmosis is practically synonymous with HIV infection and has been an AIDS-defining infection since
. Histoplasmosis infection is often classified as being
present in an HIV positive or HIV negative individual,
as there are differences in presentation and response
to therapy 6,7
. However, isolated mucocutaneous or
mucosal presentation in HIV non-reactive patients, which
may clinically and histologically simulate malignancy, is
rare and often less reported. The commonly involved sites
in the head and neck are tongue, larynx, hard and soft
palate, buccal mucosa, gingiva, and lips 8-11
we report a series of six cases of isolated histoplasmosis of
head and neck mucosal sites which presented to a tertiary
care cancer center in view of their clinical resemblance
to malignancy. Notably, two of these had a histological
diagnosis of malignancy from outside laboratories.
The study has been conducted in compliance with the
Declaration of Helsinki, and complies with the institutional
medical ethical standards. The study was approved by the
Institutional review board (project no. 900886). We retrieved cases of histoplasmosis involving the head
and neck region where histopathological material was
available for evaluation from the archives of the surgical
pathology department of a tertiary care referral cancer
center. A total of 8 cases of head and neck histoplasmosis
were retrieved over a nine-year period (2010-2018). Of
these, in 2 cases, head and neck mucosal involvement was
seen as a part of disseminated systemic histoplasmosis
(DH) in HIV-positive patients; hence these cases
were excluded. Only cases of isolated head and neck
involvement in non-HIV reactive patients were included
in this study. The relevant clinical details of patients were
taken from hospital electronic medical records, including
demographic details, history of co-morbidities including
diabetes, other chronic illnesses, general and local clinical
examination details. In all the cases, only biopsies were
received for histopathological examination. The biopsies
were reviewed by 2 head and neck pathologists for detailed
histomorphological findings, including the site of biopsy,
presence of pseudoepitheliomatous hyperplasia (PEH),
type (lymphoplasmacytic, neutrophilic or eosinophilrich),
and degree of inflammation, type of tissue reaction
(granulomatous or not), presence, location (intra- or
extra-cellular) and a semi-quantitative estimation of the density of organisms. The density of fungal organisms
was evaluated on H & E stained slide and labeled as ‘low’
when only scattered organisms were seen in a 40x field;
and ‘high’ when an entire 40x field was full of intracellular
A total of six cases of histoplasmosis involving head
and neck region in HIV non-reactive individuals were
found. Out of six, four were males and two females. The
demographic features, site involved, associated medical
illness, treatment, and outcome of these cases are described
in Table I
. The median age of the patients was 59 years, with
a range of 46-72 years. The most common site involved was
the larynx (vocal cords) in three cases, along with two cases
involving the lip and one involving the tongue (Figure 1
All the patients were seronegative for HIV; however, covert
immunosuppression was found on detailed history taking
in all three cases in which clinical information was available.
Of these three patients, one had alcoholic liver disease
(Case 3, Policeman by occupation), one patient suffered
from chronic renal failure and was on dialysis (Case 5,
Grocery shop owner), and one had uncontrolled diabetes
mellitus, type II (Case 6, Homemaker). All these cases were clinically diagnosed as ‘cancer’. Also, two patients were
diagnosed with “squamous cell carcinoma” on biopsies that
were done and reported at an outside center.
Click Here to Zoom
|Figure 1: Clinical picture of Case 5. Ulcerated and indurated
lesion on the left lateral border of tongue mimicking a malignant
lesion on clinical examination.
The histopathological features of these cases were given in
Table II and Figures 2 and 3. To summarize, in the biopsy,
the overlying mucosa showed PEH in four cases (Case
1, 2, 5 and 6). Submucosal dense inflammation rich in
histiocytes was seen in all cases, albeit to varying degrees.
The histiocytic response seen was of two types; one type
comprising foamy histiocytes distended with numerous
yeast forms of intracellular fungal organisms (Case 3, 4,
5 and 6) and the second showing epithelioid to spindled histiocytes with very few intracellular microorganisms.
Granulomas were seen in two cases. Eosinophils, which
usually are a useful pointer towards fungal infection, were
conspicuous by their absence. Gomori’s Methenamine
Silver (GMS) and Periodic acid-Schiff (PAS) stains were
done in all the cases and highlighted the morphology of
Histoplasma capsulatum in the form of predominantly
intracellular, 2-4 micron organisms with a pseudocapsule.
Biopsy diagnosis was possible in all the cases. In two cases,
biopsies were done outside and reported as malignancy
(squamous cell carcinoma) and were sent to our center for
a second opinion. The correct diagnosis was rendered upon
review in our institute. Follow-up is available in only two
cases (Case 5 and 6), and both of these patients responded
to 4 weeks of antifungal therapy (Itraconazole) with
complete resolution of the lesions. However, both these
patients succumbed to their chronic underlying illness
(Chronic renal failure and Diabetes mellitus) and died 18
months and 10 months post-treatment for histoplasmosis.
The rest of the patients were referral cases.
Click Here to Zoom
|Figure 2: Histopathological findings of histoplasmosis (usual, non-granulomatous type). A case of oral histoplasmosis (Case 5) with
prominent pseudoepitheliomatous hyperplasia. A) Prominent pseudoepitheliomatous hyperplasia of the squamous mucosa with small
groups and tongues of squamous epithelium appear to infiltrate into the underlying submucosa, which closely resembles squamous cell
carcinoma on low power (x100). B,C) Many foamy macrophages scattered in between the squamous islands (B) and in the submucosa
(C), which are teeming with intracellular organisms of 2-4 microns (x200). These organisms are strongly positive for GMS (D) and PAS
(E, conforming to the morphology of Histoplasma).
Click Here to Zoom
|Figure 3: Histopathological findings of histoplasmosis with a granulomatous host response. A case of the less common type of
histoplasmosis with a granulomatous host response (Case 2) and only a few yeast forms; a potential pitfall. A) Low power view to show
relatively less prominent pseudoepitheliomatous hyperplasia with only mildly hyperplastic squamous mucosa(x100). B) Submucosal
region showing an ill-formed epithelioid cell granuloma with giant cells, and epithelioid histiocytes (x200). C) Another area in the
same biopsy with an admixture of epithelioid and foamy histiocytes; the foamy histiocytes show few intracellular organisms, which are
highlighted by GMS (D, x200).
Histoplasma capsulatum is a dimorphic fungus with damp
soil (commonly near river beds) as its environmental
reservoir. Pulmonary infection and disease as the most
common presentation in humans. Though well-known
now, these facts took decades to prove 10
. This clinical
disease was first described by Samuel Darling in 1905 while
performing an autopsy on a patient in Panama (Central
. The organism is unencapsulated; however,
it produces a characteristic halo/clear zone in tissues,
which was misinterpreted by Darling as a capsule and
hence the name 1
. Oral manifestation of histoplasmosis was first reported by Hansmann and Schenken in 1934
. In India, histoplasmosis is rare and is endemic only
in small regions of West Bengal and Maharashtra 6,9
Panja and Sen described the first case of histoplasmosis
involving the skin and viscera from Kolkata 12
of the patients have been reported from Northern or
North-eastern states with endemic areas around the three
main rivers, namely Brahmaputra, Ganga, and Yamun a
. Cases from Western and Southern India have been
in the form of few case reports and short series 11-14
However, an increasing number of cases of Disseminated
Histoplasmosis are being reported from all over India in the
last decade 14
. Increasing awareness among physicians,
marked urbanization with construction-related activities
disturbing the layers of soil, and the increasing number of HIV-positive patients may all be deemed responsible 14
However, isolated mucosal involvement is still a rare and
most plausibly under-reported occurrence.
Fewer than 5% of patients exposed to the infection contract an
asymptomatic and self-limiting pulmonary disease known
as “Asymptomatic Pulmonary Histoplasmosis”, following
which the infection passes onto the reticuloendothelial
system and skin 5. This is responsible for the disseminated
forms of the disease, especially in HIV-positive patients 8.
The involvement of the head and neck region may occur as a
part of disseminated disease 15,16 (25-45% disseminated
cases have oral cavity involvement) or rarely as isolated,
sporadic involvement of the head and neck region which
may or may not be associated with immunosuppression. In one of the reported series from Brazil, 9 out of 11 patients
showed oral histoplasmosis as the first manifestation
of disseminated histoplasmosis, with five having HIV
seropositivity 17. However, occurrence in non-HIV
infected hosts is worth reporting as fungal infections, in
these patients, may be overlooked and misdiagnosed.
The clinical resemblance of mucosal histoplasmosis
and mucosal cancers adds to the conundrum, especially
in dedicated oncology centers where the numbers of
malignancies far exceed the cases with a benign /infectious
etiology 15. Availability of clinical information regarding
HIV seropositivity forewarns clinicians and pathologists
to suspect unusual causes of infection. However, hidden
chronic immunosuppressive conditions such as extremes
of age, diabetes, alcoholism, and toxic therapies for malignancies may not be considered as harbingers of the
same. Many of the patients do not have any identifiable risk
factors for Histoplasmosis, particularly in a non-endemic
area 15. Even though all our cases were seronegative for
HIV, one case each had alcoholic liver disease (case 3),
chronic renal failure (Case 5) or diabetes (Case 6), which
are well-known causes of immunosuppression. In three
cases, as they were only referral cases, history suggestive of
immunosuppression could not be elucidated.
Clinically, mucosal histoplasmotic lesions are seen as
firm, painful ulcers with verrucous, necrotic and polypoid
proliferations which may be accompanied by regional
lymphadenopathy, strongly simulating squamous cell
carcinoma 17-20. This was true for all our cases as well,
wherein all the cases presented with ulcerated lesions and were clinically suspected to be malignant lesions of their
respective sites. Histologic findings of histoplasmosis are
equally perplexing. Pseudoepitheliomatous hyperplasia
(PEH) of the overlying mucosal epithelium is a common
feature that may potentially mislead an unwary pathologist.
The distinction of PEH from squamous cell carcinoma in
a superficial biopsy with overwhelming inflammation,
which is not uncommon in ulcerated mucosal squamous
carcinomas, often presents diagnostic challenges to even
the most experienced pathologists. Pseudoepitheliomatous
hyperplasia is a benign condition characterized by
hyperplasia of the epidermis seen in response to a wide
variety of conditions, including infections, neoplasia,
inflammation, and trauma, and it closely mimics
squamous cell carcinoma 21. PEH of varying degrees
was seen in 67% (4 out of 6 cases) of our cases and was
particularly worrisome in 2 cases (cases 5 and 6). While
the squamous epithelium of PEH can appear infiltrative
and atypical; however, careful evaluation of histological
features is usually sufficient to differentiate PEH from
a squamous carcinoma. It is a known fact that atypical
mitoses, lymphovascular invasion, and perineural invasion
are never seen in PEH, and dyskeratosis is an exceedingly
rare phenomenon in PEH. Two of these features, i.e.,
Atypical mitoses and dyskeratosis, are of value even on
small biopsies 21-23. Nonetheless, exceptional difficulty
may be encountered in differentiating the above two in
small biopsies, and immunohistochemistry for p53, Matrix
metalloproteinase 1, and E-cadherin have been found to be
useful 24. In one of the case series from the same institute
(2007), five cases of histoplasmosis were reported, which
had clinically presented as carcinoma involving the oral
cavity (3 cases), hypopharynx (1case), and larynx (1 case).
Out of the five cases, three were mistaken for squamous cell
carcinoma due to florid PEH of the overlying epithelium
on a superficial biopsy. Two of these patients underwent
radical treatment in the form of partial alveolectomy and
hemiglossectomy with node dissection, respectively. This
study concluded that a deep wedge biopsy is recommended
to demonstrate the organisms in the subepithelial tissue,
especially those with overt or hidden immunosuppression
18. The policy of deeper wedge biopsies was adopted
since then, and all the cases in our study were diagnosed to
have histoplasmosis on biopsies, and none of the patients
underwent unnecessary radical surgery.
Goodwin et al. described three types of tissue reactions
in histoplasmosis: diffuse histiocytosis, focal histiocytosis,
and tuberculoid granulomas. Diffuse histiocytosis is one
of the characteristics of disseminated histoplasmosis;
focal histiocytosis occurs in moderate to severe degrees
of infection, clinically presenting as oropharyngeal ulcers
with an area of central necrosis. Tuberculoid granulomas
are seen when the number of microorganisms in tissue
macrophages is too small, indicating near normal tissue
response and nearly normal immunocompetence 25. Four
of our cases (cases 1, 3, 5 and 6) showed focal histiocytosis
(Figure 2), and the rest of the two cases (cases 2 and 4)
showed tuberculoid granulomas (Figure 3). One of these
patients had the lowest density of fungal organisms amongst
all. All our cases typically showed diffuse lymphohistiocytic
infiltrate with fungal elements about 2-4 μm in size detected
within the cytoplasm of histiocytes which were highlighted
on GMS stain. A classic “halo” appearance caused by the
cytoplasm retracting from the thick cell wall is helpful in
identifying the fungi 4. Special stains like GMS stain and
PAS stain highlight the fungi as the capsule of yeast is a
polysaccharide and stains poorly with H and E stain 5,6.
All our cases showed intracellular fungi on GMS stain.
To summarize, if suspected, the diagnosis of head and neck
histoplasmosis is achievable with the basic tools available
in many histopathology laboratories. Thus, it is advisable
that pathologists should refrain from over-diagnosis of
malignancy on small-sized biopsies, superficial biopsies
with improper orientation, and dense inflammatory
changes. Such situations necessitate the request for deeper
sections or repeat deeper biopsies. Fulfillment of stringent
malignant features should always remain the cornerstone
for the diagnosis of cancer.
The cases in this series hold a very important “back to basics”
lesson for the clinicians as well as the pathologists. The
importance of a meticulous history and thorough physical
examination, even for obvious localized diseases, should
not be underscored by clinicians, including oncologists.
The fundamentals of neoplasia and its distinction from
inflammation-related atypia on histology are indelible
lessons for pathologists to prevent any unnecessary
treatment to the patients.
We wish to acknowledge the untiring efforts of the technical staff of
our department. We also wish to thank the patients and their families
for their support and trust.
Conflict of Interest
The authors declare no conflict of interest.
Concept: NM, AP, Design: NM, AP, PS, Data collection or processing:
NM, AP, PS, MB, SR, ST, Analysis or Interpretation: NM, AP, PS,
MB, SR, ST, Literature search: NM, AP, PS, Writing: NM, PS, AP,
Approval: NM, AP, PS, MB, SR, ST.
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