Article Text
PDF
Abstract
Laryngeal histoplasmosis is a very rare cause of laryngitis which is encountered usually in the immunosuppressed states but can also occur in immunologically intact status. We report a rare case of laryngeal histoplasmosis in a man in his 60s, a chronic smoker who presented with a history of progressive hoarseness for 3 months. The glottic growth was biopsied. The rarity of diagnosis was aided by histopathological examination of the tissue, which revealed histoplasmosis. Management was done with intravenous liposomal amphotericin B and oral itraconazole with complete resolution of symptoms.
- Infections
- Head and neck cancer
- Ear, nose and throat
- Ear, nose and throat/otolaryngology
Statistics from Altmetric.com
Background
The most common cause of a proliferative lesion in the vocal cords in the elderly smokers is squamous cell carcinoma of glottis. Very rarely, chronic laryngitis presents with similar signs and symptoms. Laryngeal histoplasmosis is a very rare aetiology of chronic laryngitis masquerading malignancy. This is also known as Cave’s disease and is caused by the dimorphic fungus Histoplasma capsulatum. To our best knowledge, isolated laryngeal histoplasmosis is reported in only a few hundred cases. The diagnosis of histoplasmosis require a high degree of clinical suspicion, and the gold standard for it is culture of the organism. The rarity of the disease needs the accountability of every case encountered to know about the endemicity and varied presentations of the disease.
Case presentation
A male patient in his 60s belonging to the state of Haryana, North India, presented with a history of progressive hoarseness for 3 months without dysphagia, dyspnoea and foreign body sensation. The patient had a known case of pelvic inflammatory disease, benign prostate hypertrophy, chronic obstructive pulmonary disease and type 2 diabetes mellitus for 1 year on medication. The patient was a cigarette and bidi (thin hand-rolled cigarette which contains tobacco wrapped in tendu leaf and secured with colourful string at one or both ends) smoker with >20 pack-per-year history and also had a history of alcohol misuse for 15 years. There was no history of trauma, exposure to radiation or any surgery. His family history was otherwise unremarkable.
Examination of the oral cavity and oropharynx revealed no abnormalities. Fibre optic laryngoscopy (figure 1) revealed a proliferative lesion on the anterior and middle one-third of the left true vocal cord. Both vocal cords were mobile and airway was adequate. There was no palpable cervical lymphadenopathy. The rest of the otorhinolaryngology examination was normal. Depending on the clinical examination, clinical differential diagnoses were squamous cell carcinoma, granulomatous disease and mycotic laryngitis.
Preoperative fibre optic laryngoscopy image showing irregular asymmetrical thickening of the left true vocal cord (blue arrow). L, left; R, right.
Investigations
The patient was advised to undergo a contrast-enhanced CT (CECT) scan of the neck to look for the extent of the disease. CECT (figure 2) scan revealed a poorly enhancing (precontrast Hounsfield unit (HU) of ~22 and postcontrast HU of~45) irregular and asymmetrical thickening of the left vocal cord with maximum thickness of 7 mm (figure 2). There was no significant cervical lymphadenopathy. The rest, otherwise, was normal. All routine blood and urine examination results were normal except for plasma glucose fasting (116 mg/dL) and plasma glucose postprandial (217 mg/dL). HbA1c (8%) was suggestive of poorly controlled blood sugar. Erythrocyte sedimentation rate (ESR) (50 mm) fell in the first hour. Depending on the imaging, which revealed irregular asymmetrical thickening of the left true vocal cord, it was suspected to be neoplasm. So, the patient was scheduled for microlaryngoscopy and biopsy of the lesion.
Contrast-enhanced CT image of the neck showing poorly enhancing irregular asymmetrical thickening of the left true vocal cord (yellow arrow).
Differential diagnosis
Depending on the clinical examination and CECT scan of neck as mentioned earlier, the most suspicious clinical diagnosis was neoplasm of the vocal cord. The other differential diagnoses were granulomatous disease and mycotic laryngitis. So, the patient was scheduled to be taken up for microlaryngoscopy and biopsy of the lesion under anaesthesia (total intravenous anaesthesia (TIVA)) for histopathological examination.
Treatment
The patient was informed about his condition. After preanaesthetic check-up and after informed consent was obtained from the patient, he was taken up for surgery. The patient underwent microlaryngoscopy and biopsy of the lesion under TIVA. The specimen was sent for histopathological examination, which was suggestive of histoplasmosis. He underwent microlaryngoscopy and excision biopsy of the lesion (figure 3) with cold steel instrument under TIVA. The specimen was sent for histopathological examination, KOH mount, fungal culture and sensitivity, acid fast bacilli stain (AFB), Gram stain, bacterial culture and sensitivity, GeneXpert for tuberculosis, mycobacterial culture. Haemostasis was achieved. Immediate postoperative phase was uneventful. There was no postoperative complication.
Intraoperative image showing biopsy of the lesion from the left true vocal cord. L, left; R, right.
KOH mount showed budding yeast cell. On Ziehl-Neelsen stain, the AFB was negative and Gram stain showed budding yeast cell. On urine culture, no growth was seen after 72 hours of incubation at 37°C. On histopathological examination, the gross examination showed grey brown tissue bit measuring 0.5×0.4 cm. Microscopic examination (figure 4) showed tissue bit lined by stratified squamous epithelium. The subepithelium showed dense mixed inflammatory infiltrate composed of lymphocytes, plasma cells and histiocytes. Many 2–5 micron sized yeast forms were seen within the macrophages with crescent-shaped nuclei and perinuclear halo (highlighted on periodic acid–Schiff (PAS) and Grocott’s stain) conforming to morphology of Histoplasma. Focal areas of necrosis were noted. No epithelioid granulomas were seen. No dysplasia or evidence of malignancy was noted. PAS stain highlighted the yeast form of Histoplasma. On fungal culture, mycelial form growth was seen after 8 weeks of incubation.
Photomicrographs of histopathological findings of left vocal cord growth biopsy. (A) Photomicrograph shows fragment lined by stratified squamous epithelium with extensive ulceration (H&E stain, ×4). (B) Ulcerated areas show dense mixed inflammatory infiltrate (H&E stain, ×10). (C) Photomicrograph showing 2–5 µm yeast form of Histoplasma within the macrophages with crescent-shaped nuclei and perinuclear halo (black arrows) (H&E stain, ×40). (D) PAS stain highlights yeast form of Histoplasma within the macrophages (PAS stain, ×40). PAS, periodic acid–Schiff.
Postoperatively, the patient was put on medical treatment with intravenous liposomal amphotericin B and oral itraconazole and is under follow-up.
Outcome and follow-up
On the first follow up done at 1 week after the postoperative day, no evidence of disease was seen on the left true vocal cord on fibre optic laryngoscopy (figure 5). On voice analysis, reduction in the fundamental frequency was found, but it was not significant. A clear and significant improvement was visible in the values of jitter, shimmer and maximum phonation times (table 1).
Postoperative fibre optic laryngoscopy image showing the left true vocal cord cleared of the disease (violet arrow). L, left; R, right.
Comparison of preprocedure and postprocedure voice parameters
Discussion
Histoplasmosis is also known as Darling’s disease, Ohio Valley disease, reticuloendotheliosis, Spelunker’s lung and cave disease,1 and was first described by Samuel Taylor Darling in a worker during construction of the Panama Canal in 1906.2
Histoplasmosis is caused by dimorphic fungus H. capsulatum member of the family Ascomycetes. Broadly, three varieties of Histoplasma are known: H. capsulatum var. capsulatum, H. capsulatum var. duboisii and H. capsulatum var. farciminosum. Histoplasma can exist in mycelial form or the yeast form. It is the microconidia of the mycelial form that are effectively inhaled and can travel as far as host alveoli and are then transformed to the pathogenic yeast form with an optimal growth rate at 37°C.3 Yeast form finds its niche in the macrophages after evading the innate body response and continues to replicate in the host cell and eventually induces host cell apoptosis in order to disseminate and infect other cells.4 However, the ability to cause infection involves a dynamic interaction between the host defence mechanisms and the pathogen’s evasive responses.5
Predisposing factors for fungal laryngitis include the factors that alter the immune response: diabetes mellitus, immunosuppressive medication, for example, chemotherapy and systemic corticosteroids, AIDS, chronic lymphocytic leukaemia, nutritional deficiencies and factors that alter the mucosal barrier like previous radiotherapy, inhaled corticosteroids, gastro-oesophageal reflux, trauma (eg, intubation) and smoking.6 This disease is an occupational hazard among farmers,7 construction workers8 and cave explorers.9 The patient had more than one risk factor that predisposed him to contracting the infection, namely, the smoking habit, occupation as farmer, place of residence, which falls in the endemic zone of histoplasmosis, and associated comorbidity, type 2 diabetes mellitus.
Laryngeal histoplasmosis commonly involves glottic and supraglottic areas followed by subglottis.10 The most common sites are false vocal cord11 and aryepiglottic fold. The other sites that are commonly involved are true vocal cords, epiglottis,11 12 pharyngoepiglottic fold, postcricoid region13 and vallecula. The symptoms of laryngeal histoplasmosis can range from globus,14 cough, sore throat, hoarseness15 to dysphagia, odynophagia and rarely stridor.12 16–18 Due to its varied wide spectrum of presentation, histoplasmosis is also known as the syphilis of the fungal world.18 The differential diagnoses of histoplasmosis include carcinoma, lupus, papillomatosis, lymphoma, Wegener’s disease, and granulomatous diseases like tuberculosis, syphilis and leishmaniasis.19
Histoplasmosis is a disease of the middle-aged male population. In the Indian subcontinent, it is mainly reported in the rural population, engaged in agriculture or activities leading to high exposure to dust and soil, such as excavation.20 21 The histoplasmosis cases identified in the Indian subcontinent were found to be 623 from the year 1954–2020, with the increasing trend of diagnosis in the last 2 years probably due to the increasing awareness among clinicians about the disease.22 The endemic pockets for histoplasmosis exist along the Ganga river basins like those in Uttar Pradesh and West Bengal and along the plains of the rivers, Yamuna and Brahmaputra.20 Other regions with cases of histoplasmosis identified are Delhi, Rajasthan, Maharashtra, Haryana, Bihar and Chandigarh.23 The reporting of this rare disease has seen an increasing trend post 2004 likely due to increasing awareness, available testing set-up and achievable treating regimens.
Reaching the diagnosis of histoplasmosis is complex as the symptoms and appearance of the disease mimics other diseases. The gold standard for diagnosis is culture, but obtaining adequate tissue and fluid samples can be difficult.5 Culture of H. capsulatum is difficult and requires appropriate medium at 25°C–30°C, which promotes the growth of mycelial forms in 2–3 weeks but may take up to 8 weeks. Cytopathological examination of tissue aspirates and fluids show ovoid yeast cells predominantly found phagocytosed within macrophages and histiocytes in cluster forms, but may sometimes be seen in extracellular spaces. Specific histochemical stains like gomori methenamine silver and PAS stains can be used to differentiate H. capsulatum from other pathogens.24 25 Other methods of detection include antigen testing in body fluids, most commonly in urine, and serological tests including immunodiffusion, complement fixation enzyme immunoassay and radioimmunoassay.5 Detection of Histoplasma using molecular methods may mark the next era of Histoplasma diagnostics, but the current assays have not yet been approved by the Food and Drug Administration.
Laryngeal histoplasmosis has traditionally been treated with various antifungal agents (local and/or systemic). Excision of the lesion with application of gentian violet has also been reported to be successful.26 Systemic therapy with liposomal amphotericin B in intravenous dose of 3 mg/kg body weight per day up to total maximum dose of 2–4 g has been found to be effective and is recommended for 1–2 weeks, followed by oral itraconazole (200 mg three times per day for 3 days and then 200 mg two times per day for a total of at least 12 months).27 28 Ketoconazole is also effective but is less well tolerated than itraconazole.29 Mucosal lesions usually respond within 6–8 weeks, but relapse may occur.27 30 Treatment should include not only relieving the symptoms but also the elimination of the predisposing factors like smoking cessation, management of the gastro-oesophageal reflux disease, ample management of immunosuppressed and nutrition deprivation states, institution of vocal hygiene measures,6 usage of protective measures like use of wetting agents to decrease dust generation and exclusion of birds/bats from high-risk sites.
Patient’s perspective
I am a farmer by occupation and spend most of my time in the fields and with my grandchildren. Talking is essential for me to teach and help my grandchildren in their school homework. I had hoarseness and it was difficult for me to talk to my grandchildren. I am thankful to my doctor for taking care of it and bringing my life back to normal at the earliest.
Learning points
Laryngeal histoplasmosis is a rare entity and the diagnosis is usually missed as the disease and the organism per se mimic other diseases and other pathogens. Diagnosis of histoplasmosis requires a high degree of clinical suspicion.
Hoarseness is the most common presenting symptom and a laryngeal growth is the most common finding on laryngeal examination.
The endemic subsites are not yet identified, but the detection of cases is on a rise in both immunocompetent and immunocompromised patients.
The treatment of histoplasmosis is mostly medical, but excision of lesion to debulk it can aid in early recovery and decreased dissemination of the disease.
Clinicians need to consider the diagnosis of histoplasmosis in ‘at-risk’ populations with symptoms and findings collaborating to it, as the prognosis of the disease is usually fair with the correct on-time treatment with only a few fatal cases.
Ethics statements
Patient consent for publication
References
Footnotes
Twitter @DKGupta40940519
Contributors DKG: planning of treatment, conducting the surgery, idea of publication in BMJ and proofreading. DT: writing of the manuscript, obtaining consent from the patient. BP: collection of data including picture and review of literature. VS: principal pathologist.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.