Pyogenic Granuloma of the Lower Airway- A Systematic Review

1. Assistant Professor, Department of ENT, Pondicherry Institute of Medical Sciences, Puducherry, India. 2. Associate Professor, Department of ENT, Pondicherry Institute of Medical Sciences, Puducherry, India. 3. Associate Professor, Department of ENT, Pondicherry Institute of Medical Sciences, Puducherry, India. 4. Postgraduate Resident, Department of ENT, Pondicherry Institute of Medical Sciences, Puducherry, India. 5. Senior Resident, Department of ENT, Pondicherry Institute of Medical Sciences, Puducherry, India. 6. Professor and Head, Department of ENT, Pondicherry Institute of Medical Sciences, Puducherry, India.

Abstract

Introduction: Pyogenic granulomas (PGs) are benign lesions that are very common in the upper aerodigestive tract. These lesions occur due to hormonal imbalance or due to a predisposing traumatic factor. They are relatively rare in the lower respiratory tract. There are few published papers of PG involving the lower airway in the past 30 years.

Aim: A case of pyogenic granuloma of larynx mimicking malignancy has been presented along with the systematic review on methods of diagnosis, successful management, and prevention of pyogenic granuloma recurrence in the lower respiratory tract.

Materials and Methods: This systematic review of literature included reports from 1981 till date, where complete details of the records were available. These reports were collected from the search engines “PubMed” and “Google Scholar” using the MeSH terms “pyogenic granuloma” OR “lobular capillary haemangioma” AND “lower respiratory tract”. The results were reviewed by three different authors independently with a main focus on methods of diagnosis and successful management and prevention of recurrence.

Results: A 59-year-old male patient presented to ENT Department with hoarseness of voice for the past six months. On examination with video laryngoscope, a pale pinkish polypoidal mass originating from the anterior commissure and extending into the subglottic wedge with normal vocal cord mobility was noted. Neck examination showed splaying of thyroid cartilage with tenderness and there were no palpable lymph nodes. Computed Tomography (CT) examination suggested a neoplastic etiology of thyroid cartilage erosion. The patient was managed by microlaryngeal excision of the mass and histopathological analysis revealed pyogenic granuloma with no evidence of malignancy. From the 25 papers reviewed, a predisposing trauma like a history of intubation/lower airway procedures like bronchoscopy or laryngoscopy is not a prerequisite for the occurrence of PG of the lower airway. The lesions can be excised via microlaryngoscopy or using the bronchoscope depending on the site of lesion. The various surgical modalities used for excision are cold steel dissection, laser excision and cryotherapy.

Conclusion: Meticulous dissection and removal of the lesion with postoperative measures to prevent additional trauma like antireflux measures and appropriate antibiotic therapy seems to be helpful in preventing recurrence. Role of steroids in the management of pyogenic granuloma has not been supported by adequate literature. Further studies are required to comment on the adequacy of duration of follow-up.

Larynx, Lobular capillary haemangioma, Tracheobronchial tree

Pyogenic granulomas or Lobular Capillary Haemangiomas (LCH) are common benign vascular lesions with rapid growth pattern. They are usually seen in the skin and upper aerodigestive tract. Pyogenic granulomas have a multifactorial etiology which include viral infections, chronic irritation, sudden hormonal variations, pre-existing arteriovenous malformations, and trauma (1),(2). Pyogenic granuloma of the larynx and the tracheobronchial tree is an exceedingly rare occurrence (3),(4). They are usually bound to recur and have been effectively managed by surgical excision, intralesional corticosteroids and laser therapy (5),(6),(7). This article focuses on one such case and a systematic review of the current literature on the varying manifestations, diagnostic and treatment modalities, focussing on the incidence of recurrence and the role of steroids to prevent it.

Material and Methods

A systematic review of literature was conducted according to PRISMA guidelines 2020 (8), with all published records available till date. Specific MeSh terms were used to search case reports/series those involving the lower airway from the larynx till the tracheobronchial tree. The search engines “PubMed” and “Google Scholar” were searched to retrieve the published reports.

Search strategy: To search for relevant articles, MeSH terms with a combination of Boolean operators were used. The terms used were “pyogenic granuloma” OR “lobular capillary haemangioma” AND “lower respiratory tract”.

Selection process: All articles published from the year 1980 till date were retrieved. Articles in English language with full text available were included. Those which were published in other language or those where full text was unavailable were excluded. Total 25 studies/case reports were included (Table/Fig 6).

Data collection process: The authors screened each of the retrieved record independently. All data available from each of these records were tabulated and analysed.

Data items: Any data that went missing or any unclear information were noted as such. The data from the relevant articles like the varying manifestations of symptoms, details on the exact site of presentation of the lesion, treatment modalities, duration of follow-up, incidence of recurrence and morbidity were tabulated. The following calculations were performed with the available data: average and range of age of the patients, geographic distribution, relative frequency of the most common sites of occurrence of the lesion, presenting features, management options employed, complications, rate of recurrence.

Study risk of bias or certainty assessment: Two reviewers independently screened the complete published records of each article. Disagreements were resolved by consensus or by a third reviewer.

The tools proposed by Murad MH et al., Munn Z et al., and the JBI tool was used for quality assessment (9),(10),(11). The JBI tool domains and their leading explanatory questions are:

Selection: 1. Does the patient(s) represent(s) the whole experience of the investigator (centre) or is the selection method unclear to the extent that other patients with similar presentation may not have been reported?

Ascertainment: 2. Was the exposure adequately ascertained?

3. Was the outcome adequately ascertained?

Causality: 4. Were other alternative causes that may explain the observation ruled out?

5. Was there a challenge/rechallenge phenomenon?

6. Was there a dose-response effect?

7. Was follow-up long enough for outcomes to occur?

Reporting: 8. Is the case(s) described with sufficient details to allow other investigators to replicate the research or to allow practitioners make inferences related to their own practice?

Questions 4, 5 and 6 are mostly relevant to cases of adverse drug events)

Effect measures/Synthesis methods: These are not applicable as most of the records were case reports. Hence no sensitivity analysis was conducted.

Ethical concerns: An informed written consent was obtained from the patient to publish his details. There are no other ethical concerns involved in this paper.

Case Report

A 59-year-old male patient, farmer from Tamil Nadu, presented to ENT Department with persistent progressive hoarseness of voice for the past six months. There was no pain or difficulty in breathing or swallowing. He had no history of diabetes, hypertension, tuberculosis, or bronchial asthma, COPD. He did not give any history of consumption of alcohol or tobacco in any form. He denied any history of previous illness requiring hospital admission. A detailed ENT examination including video laryngoscopy (Table/Fig 1) showed a pale pinkish fleshy polypoidal mass arising from the anterior commissure and extending into the anterior subglottic wedge with normal vocal cord mobility. Airway was adequate posterior to the lesion and other areas of larynx appeared normal. Neck examination revealed splaying of thyroid cartilage with tenderness although there were no palpable lymph nodes. With the above history and clinical presentation, a provisional diagnosis of malignancy of the larynx was made and hence a CT (Table/Fig 2) was requested; which was also suggestive of a neoplastic aetiology with radiologic evidence of thyroid cartilage erosion. Hence, the patient underwent for a microlaryngeal excision of the mass and biopsy (Table/Fig 3) under general anaesthesia. The histopathological analysis of the specimen (Table/Fig 4)a-c showed polypoidal lesion with ulceration of overlying epithelium. The angiomatous tissue had numerous proliferations of thin-walled blood vessels arranged in lobules. There was a background of stroma with fibroblastic proliferation and mixed inflammatory infiltrates. This was reported to be polypoidal capillary haemangioma (pyogenic granuloma) with no evidence of malignancy.

Patient was started on antibiotics (amoxicillin and potassium clavulanate 625 mg, twice a day), anti reflux measures and was kept on close follow-up. In the 6^th postoperative week (Table/Fig 5), he again began to have hoarseness of voice and was found to have a recurrence at the same site. He was taken up for microlaryngeal excision and biopsy under general anaesthesia, once again. Histopathological evaluation revealed features of pyogenic granuloma. Adjuvant measures like adequate voice rest, speech therapy and breathing exercises along with the anti-reflux measures were started. He was also given a short course of oral steroids at a dose of 1 mg/kg body weight, under antibiotic cover, which was then gradually tapered and stopped. He was found to be asymptomatic till six months postoperatively. Hence, a complete management of laryngeal pyogenic granuloma with meticulous excision, along with antireflux measures and oral steroid therapy under antibiotic- amoxicillin and potassium clavulanate 625 mg, twice a day cover helped in preventing recurrence of the lesion in this patient.

Results

There were 25 studies with complete data from the year 1981.There were three case studies/reports, one with four neonates by Walner DL et al., and the other being a retrospective study by Fechner RE et al., comprising of the records of 46 patients (3),(4). There was also a retrospective study on receptors presented in these lesions with 22 patients (12). The rest were all case reports. Most of the reports were from the USA followed by Turkey (Table/Fig 7) (1),(2),(3),(4),(5),(6),(7),(12),(13),(14),(15),(16),(17),(18),(19),(20),(21),(22),(23),(24),(25),(26),(27),(28),(29). There was a total of 94 cases reported from all the available articles other than the present case. Although PGs are more common in pregnancy due to hormonal imbalance (9), these studies showed males and females to have been equally affected. They appear to present in varied age groups (4). History of airway manipulation like an intubation were present in 75% of the study population. Tobacco and alcohol did not seem to have an additional influence according to this literature (5),(13),(15). Hoarseness of voice, cough, and haemoptysis were the predominant presenting complaints. Patients with laryngeal PG manifested with voice change whereas those with tracheal or bronchial lesions manifested with cough and haemoptysis. Although laryngeal PG were more than the tracheal PG (10/94 cases), lesions in the trachea bronchial tree were more difficult as it was difficult to secure the airway prior to the surgery or for administration of anesthesia (14). All these lesions were surgically removed using microlaryngoscopy with cold steel dissection or laser. Cryotherapy and brachytherapy were used in a few cases in an attempt to prevent recurrence (1),(27). There was one report (19), where botulinum toxin was given for a successful management and to prevent recurrence. All these lesions were confirmed histopathologically as PG. According to the data available, steroids where used in a total of five cases- both in adults as well as in children (3),(5). Topical application was done intraoperatively in neonates and multiple intralesional steroid injections were given in a young adolescent boy for recurrence (5). Out of 94 patients that were reported, 11 cases showed recurrence. Presence of a laryngeal trauma like an intubation is not a primary entity determining the occurrence of pyogenic granulomas. Meticulous dissection and removal along with antireflux measures seem to be the important factors determining recurrence in these cases, however there are reports in which the cause of recurrence is unknown (20),(21),(22). Administration of steroids may be helpful but is not proved to be the modality of choice to prevent recurrence.

Quality appraisal of the case reports and case series reviewed: The original articles which were three in number were methodologically analysed using the format used by Munn Z et al., and Murad MH et al., (9),(10). Each article was appraised for quality as tabulated in (Table/Fig 8) (1),(2),(3),(4),(5),(6),(7),(12),(13),(14),(15),(16),(17),(18),(20),(21),(22),(23),(24),(25),(26),(27),(28),(29). The validity was the average of subjective opinion of the three authors.

Discussion

Pyogenic granulomas are most often seen in children and young adults. About 70% of PGs are seen in the head and neck region. They occur predominantly in the nasal cavity, oral cavity and oropharynx (1),(2),(3). These benign tumors are known for recurrence as they have a rapid regrowth period of 18 months to 3 years. LCH or PG are pinkish friable masses that can be pedunculated or sessile, often arising from the upper aerodigestive tract (4),(5). The exact cause for PG is unknown but are often thought to be predisposed by prior insult to the local tissue in the form of trauma or instrumentation as they are often surrounded by inflammatory changes. This inference is supported by the few reports with a positive history of laryngeal manipulation prior to the occurrence of this lesion in present literature review (12),(15). Other factors seem to be hormonal shifts such as in pregnancy, effect of certain drugs, cytogenetic clonal deletion, production of angiogenetic caused by local irritation etc, VEGF, decorin, transcription factors pATF2 and pSTAT3, signal transduction pathways MPAK are factors overexpressed in PG. These are stimulated by local trauma. Their exact mechanism and roles in LCH or PGs remain unclear. In the lower airway, laryngopharyngeal reflux is an additional traumatic factor that can predispose to PGs (1),(6).

According to Fechner RE et al., there are no pyogenic granulomas in the larynx or trachea (4), but according to current review of literature, these rare laryngo- tracheo-bronchial lesions generally present with hoarseness of voice, aphonia, decrease in voice quality, dyspnoea, wheezing, sensitivity in the throat, dry cough, haemoptysis, stridor, and dysphagia. Most patients do not complain of pain. In a laryngeal PG, the subglottis is the most common subsite to be involved. (7),(12),(14). Tracheal and bronchial lesions are fewer in number and are diagnosed with fibreoptic bronchoscopy and high-resolution computer tomography (24),(25),(26),(27),(28),(29).

Pyogenic granulomas were earlier used synonymous with granulomas that occur due to a pre-existing traumatic experience like intubation granuloma that occur in the arytenoids. According to Fechner RE et al., LCH have diagnostic lobular arrangement of capillaries that clearly distinguish them from granulomas (4). They also claim that, LCH occurred spontaneously whereas granulomas occurred due to pre-existing trauma and that, they should not be used as pathological misnomers for each other (4),(5),(6),(7).

The histopathology is the gold standard of diagnosis. Microscopically, although they are similar to granulation tissue in early stages, there is a background of mixed inflammatory infiltrates with oedematous stroma. The prominent finding is supposed to be numerous capillaries and venules arranged in a radial lobular pattern. As the lesion matures, the stroma becomes more fibromyxoid and there is less inflammatory infiltrate. There are surroundings of acute and chronic inflammatory cells forming granulomas. Surface erosion or ulceration which may occur initially may re-epithiliase. The differential diagnosis for these lesions includes granulation tissue, lipoma, papilloma, angiofibroma, histiocytoma, haemangiopericytoma, angioendothelioma, angiosarcoma, tuften haemangioma, intravascular angiomatosis granulomatous infections, hyperplasia, and varicosities (11),(12),(13),(14),(15).

Treatment options include surgical excision using cold steel dissection, laser photocoagulation, electrocautery snare, liquid nitrogen freezing, micro irradiation, brachytherapy, intralesional injection of ethanol or corticosteroids and sodium tetradecyl sulphate sclerotherapy. All modalities of treatment seem to give satisfying results although, recurrences have been observed in a few cases (19),(20),(21),(22),(23),(24),(25),(26),(27),(28). Although there is one report with usage of botulinum toxin to prevent recurrence, there is no strong evidence to support this finding (19). There is dearth of studies in this literature comparing the treatment modalities to prove the superiority of any single technique and chances of reducing recurrences. Adequate long term follow-up for atleast three years is required according to the current data. Many studies have been reported without following-up the patient and hence the status of recurrence cannot be commented upon. There are number of studies that had less than three months or no follow-up of the patients (2),(6),(12),(16),(22). Whilst there are reports where the lesion was successfully managed without recurrence with a follow-up of at least one year (1),(13),(20). There were two studies in which patients had multiple recurrence which was treated using multiple injections of steroids and brachytherapy respectively (5), (28). An additional therapy with anti reflux measures is proven to be beneficial. Proton pump inhibitors and H2 blockers given for a period of 12 weeks postoperatively reduces laryngopharyngeal reflux and aids in preventing recurrence as seen in the present case (6).

Limitation(s)

There are several limitations in this study. Since most studies are case reports, a publication bias is possible. The results in this study depend on the quality of literature search. Completeness of the search was maximised by having two reviewers perform this task independently. Some articles were not able to be retrieved in full text and in English language and thus were not included in the study.

Conclusion

Pyogenic granulomas or lobular capillary haemangiomas occur very rarely in the lower airway. Prior trauma is not a prerequisite for these lesions. These lesions present with progressive voice change and breathing difficulty. They can be successfully managed by thorough surgical excision, intralesional or postoperative steroid therapy along with long term anti reflux measures to prevent recurrence. Although there is not adequate literature to optimise the duration for follow-up in these cases, a period of one to three years following the procedure seem to be the usual teething period for recurrence, based on this systematic review. Hence, a close follow-up one year and a yearly visit till three years postoperatively is suggested.

Acknowledgement

The authors would like to acknowledge Dr. Anand M and the entire Department of Pathology of our institution for providing us with the histopathological images and for participating actively in ruling out other probable differentials.

DOI and Others

DOI: 10.7860/JCDR/2022/53755.16496

Date of Submission: Jan 06, 2022
Date of Peer Review: Feb 07, 2022
Date of Acceptance: May 20, 2022
Date of Publishing: Jun 01, 2022

AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was Ethics Committee Approval obtained for this study? No
• Was informed consent obtained from the subjects involved in the study? No
• For any images presented appropriate consent has been obtained from the subjects. NA

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