Granulomatous Conditions of the Nose

Granuloma

Granuloma is a central area of necrosis surrounded by inflammatory cells. These cells can be epithelioid, giant, neutrophils, and macrophages. Granuloma can occur in conditions of infection, inflammation, and autoimmune disease; some neoplasms rarely have granuloma.

Granulomatous Conditions Affecting the Nose & Paranasal Sinuses

There are three types of conditions: infective, inflammatory, and neoplastic. Infective conditions are further divided into bacteria, fungi, and protozoa. Rhinosporidiosis is now considered a protozoal infection.

Sarcoidosis

It is a systemic disease of unknown cause characterized by non-caseating granuloma in many tissues and organs.

Pathophysiology and Immunopathogenesis of Sarcoidosis

The etiology of sarcoidosis is unknown. Theories suggest it is an immunological response to an unidentified antigen in genetically predisposed individuals. The antigen may be infectious or environmental, including mycobacteria, fungi, chemicals such as beryllium and zirconium, pine pollen, and peanut dust. These are abnormalities of both cell-mediated and humoral immune systems. When an individual is exposed to an antigen, there must be an antigen-presenting cell. An alveolar macrophage is an antigen-presenting cell. 

It will cause IL-1 and IL-2 T lymphocyte proliferation. This will attract monocytes from the blood because of the release of monocyte chemotactic factors. Another factor called macrophage migration inhibiting factor will inhibit the dispersal of monocytes. Monocyte aggregation will occur, due to which calcitriol will be released, causing a fusion with the epithelioid cells and leading to granuloma.

Histology of Sarcoidosis

• There will be non-caseating necrosis.
• It is characterized by epithelioid cells surrounded by lymphocytes and fibroblasts but devoid of caseation. 
• There are two typical cells: an asteroid body and a Schaumann body.
• The asteroid body is a stellate inclusion in the giant cells, while Schaumann’s body is a concretion of calcium and protein.

Progression of Sarcoidosis

When there is an antigenic stimulus, Antigen-presenting cells will stimulate the T cells.  Inflammatory mediators like interleukins, TNF, and prostaglandins are released. Either the phase of the disease may go towards resolution with the secretion of IL-10, or the patient may progress to fibrosis if there is a release of tumor necrosis factor.

Clinical Features of Sarcoidosis

• The most common presentation is bilateral hilar lymphadenopathy or lung involvement, which is visible on chest radiographs in 90% of cases.
• Eye and skin lesions occur next in frequency.
• It affects young adults between the 3rd and 5^th decades.
• The prevalence is 2 times higher in women than men but varies widely in different countries and populations. 
• Cutaneous features - erythema nodosum, dermal papules, and lupus pernio.
• Ocular manifestations - keratoconjunctivitis and anterior/ posterior uveitis.
• Respiratory symptoms - Sinusitis, paratracheal/ hilar adenopathy, interstitial pneumonitis, necrotizing, and sarcoid granulomatosis.  
• Cardiac - Pericarditis and myocarditis.
• Neurological - peripheral neuropathy, cranial neuropathy, leptomenigitis, spinal myelopathy, and perivascular grey/white lesion.
• Liver and GI: granulomatous hepatitis, granulomatous arthritis
• Renal: Interstitial cystitis
• Musculoskeletal: Acute periarthritis, chronic, granulomatous synovitis, dactylitis, granulomatous myositis, osteolytic lesions.
• Crusting is seen majorly in rhinoscleroma and atrophic rhinitis.

Diagnosis of Sarcoidosis

• Diagnosis usually relies on histology, imaging, hematology, and clinical acumen.
• A biopsy is taken from the areas of the nose, such as the septum and turbinate.
• Serum levels of angiotensin-converting enzyme (ACE) can be helpful in diagnosing sarcoidosis. However, the test has low sensitivity and specificity.
• Kveim test
  • It is an intra-dermal test. 
  • Take an intradermal injection of splenic tissue from a patient with a known sarcoidosis case and give it to the patient in whom sarcoidosis is suspected.
  • If a skin nodule develops after the injection, send the nodule for further histopathological examination. 
  • The appearance of non-caseating granuloma with central epithelioid cells surrounded by lymphocytes and fibroblasts confirms sarcoidosis.
• Chest X-ray

• Stage 0 – Normal X-ray
• Stage 1- Bilateral hilar adenopathy, often with right paratracheal involvement.
• Stage 2- Combination of adenopathy plus infiltrates.
• Stage 3- Infiltrates alone
• Stage 4- Fibrosis
• The plane X-ray will show splaying of the nasal bones and soft tissue mass across the septum.

• CT-chest is done to understand pathology further.

• Perfusion studies are conducted to understand the involvement of the lung.
• Bronchoalveolar lavage is taken to understand the cytology of the bronchoalveolar fluid.
• Gallium 67 scanning also plays a role in diagnosing sarcoidosis.

Treatment of Sarcoidosis

• Most cases of stage I sarcoidosis undergo spontaneous remission within 2 years without specific treatment.
• The mainstay of treatment is systemic corticosteroids.
  • Oral prednisone is administered in doses of 10 to 40 mg daily.
• Local treatment with intra-nasal steroids may be used to reduce the oral dosage.
  • It is given if there are additional nasal symptoms. 

Granulomatosis with Polyangiitis/Wegener's granulomatosis

It is characterized by granulomatous vasculitis of the upper and lower respiratory tracts and renal involvement/glomerulonephritis. Hallmark: Involvement of the upper airway (nose, paranasal sinuses), the lower airway (lung), and renal involvement. In this condition, there is vasculitis with granuloma. It is an Uncommon disease. The male-to-female ratio is 1:1.

The disease can be seen at any age.

• 15% of patients are <19 years of age.
• However, it rarely occurs before adolescence. 
• The mean age of onset is 40 years.

The histopathologic hallmark is necrotizing vasculitis of small arteries and veins with granulation formation, which may be intravascular or extravascular. 

Clinical Features of Wegener's Granulomatosis

It can be divided into three categories.

• Type 1
  • It is a limited form of the disease.
  • Characterized by upper airway symptoms and few systemic findings.
  • They typically present with several weeks of symptoms that are similar to those of an upper respiratory tract infection but are unresponsive to antibodies.
  • Nasal pain is often associated with serosanguineous rhinorrhea and crusting.
• Type 2
  • Patients present with systemic features that are not as severe as those with type 3 disease. 
  • It is characterized by a prolonged upper respiratory tract infection with continued nasal discharge that progresses to nasal pain, tenderness, serosanguineous discharge, ulceration, and crusting.
  • Pulmonary involvement is often present and is associated with a cough, hemoptysis, and cavitary lesions on chest radiography.
• Type 3
  • It is a widely disseminated form of systemic disease.
  • It commonly consists of the upper and lower airways, cutaneous lesions, and progressive renal involvement.
• Typically, saddle nose deformity and septal perforation are seen.

Diagnosis of Wegener's Granulomatosis

In active disease, cANCA is positive. ANCA is of 2 types

• cANCA (c- cytoplasmic)
• pANCA (p-proteinase)

In cases of localized disease of the respiratory tract, cANCA, abnormal kidney function tests, and urinalysis are performed in patients with renal involvement and rheumatoid factor. Rheumatoid factor is positive in a low titer in two-thirds of patients. 

In addition, ESR, CRP, SACE (Serum angiotensin-converting enzyme), chest X-ray, and other respiratory functions should be conducted. ESR, CRP, and SACE - Elevated

Nasal biopsy should be taken from the septum and turbinate.

The main histological features are not pathognomic but are as follows: 

• Vasculitis is mandatory, and fibrinoid vascular necrosis is a common finding.
• There has to be granuloma of epithelial cells, the type being large, irregular, and lined with histocytes.
  • They may show fibrinoid necrosis but can also be non-necrotic.
• Multi-nuclear giant cells are often present, and eosinophils are numerous.

Treatment of Wegener's Granulomatosis

Daily cyclophosphamide, combined with glucocorticoids, has been repeatedly proven to induce remission and prolong survival effectively in patients with severe disease.

Induction of remission

• At the initiation of therapy, glucocorticoids are usually given as prednisone, 1 mg/kg per day for the first month, followed by gradual tapering on an alternate day or daily schedule with discontinuation for 6-9 months.
• Cyclophosphamide is given orally at 2mg/kg per day.
•  Since it is renally eliminated, the dosage should be reduced in patients with renal insufficiency.
• Newer drugs: Rituximab and TMP-SMX can be given.

Surgical

• Surgical reconstruction is done for saddle nose deformity and to repair septal perforation.
• Functional endoscopic sinus surgery may benefit patients with chronic nasal crusting.
• Saline irrigations—with or without antibiotics—are essential for management. However, nasal debridement, along with mucosa-sparing techniques and frequent postoperative care, may be helpful to minimize scar formation.

Eosinophilic Granuloma

Clonal proliferation of Langerhans cells is associated with a heterogeneous inflammatory infiltrate of eosinophils, histiocytes, lymphocytes, plasma cells, and neutrophils.

Clinical Features of Eosinophilic Granuloma

• It predominantly occurs in bones.
• The skull, especially the temporal, frontal, and parietal bones, is a common site of involvement.
• Males are affected twice as frequently as females.
• The usual presentation is a painful swelling of the involved bone, often for many months, associated with cervical lymphadenopathy.
• Mandible lesions produce toothache, gum ulceration, and loose teeth, whereas the involvement of the temporal bone may stimulate acute mastoiditis. 

Radiological Evaluation of Eosinophilic Granuloma

• Punched out bony lesions in the skull and the jaw’s radiolucent areas around the teeth.
• Lesions in the skull often show beveled margins due to angulated destruction of the cortical bone.

Treatment of Eosinophilic Granuloma

• Unilocal disease: Combination of curettage/excision and radiotherapy
• Generalized disease:
  • Rapid course with a poor prognosis
  • Depending on the response additional chemotherapy with etoposide and steroids is given for ≥ 12 months, depending upon the response.
  • Alpha interferon and bone marrow transplantation have also been used successfully.

Giant Cell Granuloma

It is a benign granuloma where there is an aggregate of giant cells in a fibrovascular stroma.

Clinical features of Giant cell granuloma

• Pain and swelling over the affected bone.
• Frontal headache, diplopia, hearing loss, vertigo, and tinnitus.
• Most patients are under 20 years old.
• Female to male preponderance of 2:1.
• Maxilla and mandible are commonly affected, followed by sphenoid and temporal bones.

Imaging in Giant cell granuloma

The lesions are expansile and lytic with a soap bubble center and well-demarcated edges.

Histology of Giant Cell Granuloma

Cellular fibroblastic stroma containing an aggregate of giant cells.

Differential Diagnosis of Giant cell Granuloma

• Solid variant of aneurysmal bone cyst.
• Brown tumor of hyperparathyroidism. 

Treatment of Giant Cell Granuloma

Curettage alone is associated with recurrence; excision should be undertaken where possible.

Granulomatous Neoplasia

Granulomatous neoplasia is an extranodal NK/T cell lymphoma. It is an aggressive non-Hodgkin lymphoma primarily affecting the nasal cavity, nasopharynx, and sinuses. It was previously known as midline malignant reticulosis or polymorphic reticulosis.

It is responsible for the classical destruction of the midface. The long-term remission rate is low in patients with this disease, and 50% die from distant extra nodal spread or from relapses outside the treatment field. The association of disease with Epstein-Barr virus (EBV) and nasal T-cell lymphoma has been frequently reported. Various studies report the detection of EBV DNA and RNA in tumor cells associated with high titers of EBV antibodies in patients with T-cell lymphoma. The causative role of EBV in the pathogenesis of T-cell lymphoma has been strongly suggested but remains to be definitively determined.

Clinical features of Granulomatous Neoplasia

• Prodromal phase
  • Lasts for several years.
  • Complaining of persistent nasal destruction and rhinorrhea
• Period of activity
  • Areas of necrosis develop on and around the nasal cavity
  • Purulent discharge crusting and tissue loss.
  • Progressive destruction of the nasal framework, palate, upper lip extending into the pharynx and orbit, and skull base is often associated with pyrexia secondary to infection.
• Terminal stage
  • Hemorrhage, associated with gross facial mutilation and exhaustion, can eventually lead to death. 
  • This might take several years and is associated with systemic metastases.
• As symptoms progress, usually unilateral mucosal ulceration with extension into the palate, maxillary sinus, and upper lip helps distinguish lymphoma from WG, associated with diffuse nasal mucosal ulceration.

Treatment of Granulomatous Neoplasia

• Radical full-course radiotherapy of 55 Gy or more and wide field coverage, including the nose, sinuses, and palate.
• Advanced chemotherapy for high-grade lesions
• Surgical management is limited to reconstructing bony and soft tissue defects after treatment, particularly in cases of hard palate or orbital floor obstruction.

Frequently Asked Questions:

Q: Which granulomatous disease is the kveim test done for?

Answer: Sarcoidosis

Q: What is the mainstay of treatment for sarcoidosis?

Answer: Systemic corticosteroids

Q: Punched-out bony lesions in the skull are seen in which disease?

Answer: Eosinophilic Granuloma

Also Read: Nasal Tip Surgery and Its Deformities

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