Conditions Simulating Neoplasia and Granulomatous Disorders : Part II
Sinonasal Tuberculosis
Definition and Etiology
Infection of the nose and sinuses by Mycobacterium tuberculosis.
Incidence
Apart from lupus vulgaris, tuberculosis (TB) within the nose and sinuses is rather uncommon. We have seen two cases in the past 30 years. However, there is a resurgence in association with HIV and social deprivation. Thirty-five cases have been reported in the English-language literature over the past 95 years.1
Site
The nose and sinuses can be the primary site or secondary to more widespread infection. The nasal cavity is more common than the sinuses, but cases have been described in the frontal and sphenoid.2–4
Diagnostic Features
Clinical
The symptoms are chronic nasal obstruction, rhinorrhea, and epistaxis together with crusting and ulceration. Any part of the nasal cavity and nasopharynx is affected and the ulceration can lead to palatal and septal fenestration.5–7 There is generalized ulceration and sloughing, which may suggest other chronic granulomatous conditions such as Wegener′s granulomatosis and sarcoid. Cervical lymphadenopathy may be present, due either to TB or a secondary inflammation.
Our patients, both women (42 and 65 years old), were otherwise fit and well and no other site of infection was determined. In both there was extensive involvement of the nasal vestibule, cavity, and nasopharynx and both had palatal ulceration. A predominance in middle-aged women is typical.
Imaging
Nonspecific inflammatory changes with some degree of cartilage and bone destruction are seen on CT scanning. Imaging of the chest should obviously be undertaken.
Histological Features and Differential Diagnosis
Representative biopsy will reveal caseating granulomas with Langerhans giant cells, and staining and culture for acid-fast bacilli will be positive.
Other granulomatous conditions must be excluded and the pseudoepitheliomatous reaction that can occur must be differentiated from squamous cell carcinoma.8
Treatment and Outcome
Once the condition is diagnosed, the assistance of infectious disease physicians will be invaluable in the evaluation of the patient and the choice and duration of antibiotic regime.
References
1. Butt AA. Nasal tuberculosis in the 20th century. Am J Med Sci 1997;313(6):332–335 2. Mohasseb G, Nasr B, Lahoud S, Halaby G. Hypophyseal tuberculosis. A case report. [Article in French] Neurochirurgie 1983;29(2):167–170 3. Shah GV, Desai SB, Malde HM, Naik G. Tuberculosis of sphenoidal sinus: CT findings. AJR Am J Roentgenol 1993;161(3):681–682 4. Sierra C, Fortún J, Barros C, et al. Extra-laryngeal head and neck tuberculosis. Clin Microbiol Infect 2000; 6(12):644–648 5. Waldman SR, Levine HL, Sebek BA, Parker W, Tucker HM. Nasal tuberculosis: a forgotten entity. Laryngoscope 1981;91(1):11–16 6. Waldron J, Van Hasselt CA, Skinner DW, Arnold M. Tuberculosis of the nasopharynx: clinicopathological features. Clin Otolaryngol Allied Sci 1992;17(1):57–59 7. Kim YM, Kim AY, Park YH, Kim DH, Rha KS. Eight cases of nasal tuberculosis. Otolaryngol Head Neck Surg 2007;137(3):500–504 8. Sim DW, Crowther JA. Primary nasal tuberculosis masquerading as a malignant tumour. J Laryngol Otol 1988;102(12):1150–1152Wegener′s Granulomatosis or Granulomatosis with Polyangiitis
Definition
An idiopathic chronic inflammatory disease characterized by necrotizing granulomatous lesions and systemic vasculitis strongly associated with antineutrophil cytoplasmic antibodies (C-ANCA).
Etiology
The cause is unknown but this is probably an autoimmune disease. Several recent studies, both in vitro and in vivo, are now indicating that ANCA induce the systemic vasculitis1 by binding to and activating neutrophils, which causes the release of oxygen radicals, lytic enzymes, and inflammatory cytokines. ANCA may also induce immune complex formation and may directly adhere to and kill endothelial cells, thereby causing vasculitis.2 While PR3-ANCA (proteinase-3) is highly specific for Wegener′s granulomatosis, the initial trigger may be infection or other environmental factors, possibly combined with a genetic susceptibility. Exposure to silica is one possibility. However, Staphylococcus aureus colonization of the nose, which is found more frequently in Wegener′s granulomatosis, has been strongly implicated as a causative agent, especially in relapses.3,4 A strong association with HLADPB1*0401 has also been described.5
Synonyms
First described by Klinger in 1932, this condition was ascribed to Wegener after his publication in 1936.6,7 In recent times it has been referred to as C-ANCA positive granulomatosis and most recently the nomenclature has been changed to granulomatosis with polyangiitis (GPA).8
Incidence
The true incidence of Wegener′s granulomatosis (WG) has been underestimated in the past. Even with the advent of the ANCA test, many localized forms of the disease may go unrecognized. In Europe a prevalence of 23.7 per million has been reported; in the United States, 30 per million.9
The overall incidence ranges from 2.9 to 12 per million per year depending on the geographic region.
Site
Classically WG affected the nose, lungs, and kidneys. However, it can present in any system and limited forms of the disease are now well recognized, having been first described by Carrington and Liebow in 1966.10 In addition to the nose, the audiovestibular system, larynx, and cranial nerves may be affected. Any organ can be affected, including the eye, skin, heart, gastrointestinal tract, and nervous systems.
Diagnostic Features
Clinical Features
The peak incidence is in the fourth to fifth decades but the condition can occur at any age (range 13 to 78 years). The average age at diagnosis was 50 years in a study we performed on a cohort of 199 patients.11 It seems to be more aggressive in younger people. Men and women appear equally affected and the vast majority are white (93%).12–15 However, there is some evidence that males are more likely to have “severe” disease and females the more “limited” phenotype.13
Two-thirds of patients initially present with an ENT-related symptom, of which 41% were rhinological, 16% otological, and 6% laryngopharyngeal in our study (Fig. 18.16).11 Nasal symptoms were commoner in those diagnosed at <40 years (55%) than in those >60 years (27%). Typically the patient presents with nasal symptoms of crusting (75%), discharge (70%), nasal stuffiness (65%), bleeding (59%), reduced sense of smell (52%), and facial pain (33%). The hyposmia may be simply a result of mechanical obstruction of the olfactory region or specific cranial nerve involvement. Deep-seated facial pain is quite a distressing symptom and may be secondary to sinus changes, but may also be due to an osteitis of midfacial bone, indicative of disease activity (Fig. 18.17). When all sinonasal symptoms are ranked, crusting and epistaxis are first and second in importance.14
The external appearances of the nose may change in ~25% of patients, with a characteristic supratip collapse that is somewhat different from that seen after nasal septal trauma and only seen in WG and relapsing polychondritis (Fig. 18.18). The nose folds inwards and looks as though it could be pulled out. This may or may not be associated with septal perforation. Sometimes the entire internal structure of the nose disappears, creating a large featureless cavity. On endoscopic examination the nasal mucosa is often very friable, granular, and covered with old blood and crust (Fig. 18.19). Adhesions may be present and the condition should be suspected in patients who develop significant adhesions after minor nasal surgery. As the condition progresses, there can be bone erosion of the skull base and patients may occasionally develop meningitis.
The ears can also be involved in a variety of ways. Patients may develop a chronic serous otitis media, and if grommets are inserted a persistent discharge that should be a clue to the presence of WG. Hearing loss can be conductive due to this, sensorineural due to cranial nerve involvement, or mixed. Scarring in the nose and eustachian region will often lead to persistent middle ear problems. Patients may also present with balance problems or a facial nerve palsy. In our study on 199 patients, 50% had aural fullness and 42% experienced dizziness. Otalgia was also complained of by one-third.11
In the mouth there may be gingivitis, ulceration, and oroantral fistulas, although midline palatal necrosis is rare in contrast to the situation with cocaine abuse (see below) (Fig. 18.20).
An area that is frequently overlooked is the larynx, and in particular the subglottis where stenosis may occur.16 This can be a presenting problem but may be overshadowed or confused with lower respiratory tract symptoms. This condition should be considered in any patients with dyspnea, hoarseness, or inspiratory stridor and is estimated to occur in ~16% of WG patients.17 It is commoner when WG starts in childhood.18 In addition, the vocal fold mobility may be affected by cranial neuropathy.
Although WG can present in a myriad of ways, in many patients relatively minor upper respiratory symptoms are associated with disproportionate unwellness, fatigue, weight loss, and night sweats, heralding generalized WG, the systemic symptoms and signs of which are legion (Table 18.9). In the lungs, the necrotizing vasculitis leads to hemoptysis and cough, and pleuritic pain with gradual dyspnea as lung function is lost. The necrotic cavities may heal by fibrosis or form encapsulated abscesses. It is important to distinguish this from the effects of subglottic stenosis, which may be overlooked.
Renal involvement can occur in 75% of patients and eventually leads to renal failure.
In the orbit, granulomatous infiltration and vasculitis can result in proptosis (~2%) and corneal exposure, pain, and visual loss (~8%).17 Patients may also have epiphora and dacrocystoadenitis. They may present with a “red eye” due to episcleritis or keratitis, which is seen in 15% of early-stage WG.18 About half of patients have some ocular problems during the course of their disease.19
There can be arthralgia; skin lesions such as purpura, subcutaneous nodules, ulcers, vesicles, and papules; pericardial effusions; and neuropathies; as a result patients may be seen by a wide range of specialists (Table 18.9).
Not surprisingly the quality of life in these patients is significantly affected. In our study of 199 patients with WG using two validated quality of life (QoL) instruments—general (SF-36) and rhinosinusitis-specific quality of life (Sinonasal Outcome Test-SNOT-22)—a significant effect of sinonasal involvement on the general QoL was demonstrated.14 This also showed that Wegener′s-related sino-nasal morbidity is at least as significant as that in the general rhinosinusitis population, which may in part explain the delay in diagnosis of this disease.
Diagnosis
Prior to the advent of the ANCA test, diagnosis relied on clinical signs and symptoms supported by raised ESR (erythrocyte sedimentation rate), CRP (C-reactive protein), altered renal function on blood and urine testing, and chest radiography, which might show evidence of granulations, infiltration, necrotic cavitation, and fibrosis. Urine testing can still be helpful if it shows proteinuria, microscopic hematuria, and red cell casts.
However, the ANCA test was first described in 1985 by Van Der Woude and colleagues and has significantly helped in the diagnosis of WG and other vasculitides.20 It is 99% specific with a sensitivity of 73% using combined immunofluorescence and enzyme-linked immunosorbent assay (ELISA) techniques.
Bodily system | Manifestation |
Ear, nose, throat | Nasal obstruction, crusting, bleeding, sinusitis |
Otalgia, otorrhea, deafness | |
Oral lesions, laryngitis | |
Upper respiratory tract | Stridor, cord palsy/fixation |
Tracheal stenosis | |
Lower respiratory tract | Pulmonary infiltrates, nodules or hemorrhage |
Ophthalmic | Scleritis, episcleritis, retinitis, retro-orbital granuloma |
Cardiac | Arrhythmias, effusion, infarction, myocarditis |
Renal | Nephritis, renal impairment, renal failure |
Gastrointestinal | Diarrhea, bleeding |
Peripheral nervous system | Sensory or motor polyneuropathy, mononeuritis |
Central nervous system | CNS lesions, meningeal vasculitis |
Skin | Purpura, nonhealing ulceration |
Musculoskeletal | Arthralgia, myalgia |
Up to 95% of patients with active systemic disease are ANCA positive and in most patients the ANC antibodies are directed against proteinase 3 (PR3). In vitro and animal models suggest that the interaction of ANCA with cytokine-primed neutrophils results in premature activation, respiratory burst, and degranulation of neutrophil granulocytes, with subsequent endothelial cell damage and necrotizing vasculitis. Altered T cell responses with predominant TH1-type cytokine release might facilitate autoantigen recognition in WG.1
Sequential monitoring of the c-ANCA is a very useful tool in management and as early as 1989 a 4-fold increase in titer was shown to indicate a relapse,21 but it is recognized that not all patients show the classical pattern of fluctuation with disease activity.22 The c-ANCA was only positive in 68% of relapses.15 In addition, unfortunately, the c-ANCA lacks sensitivity in the limited forms of the disease (dropping to 50%) and/or following therapy with corticosteroids, so a negative ANCA does not exclude WG. Interestingly, a few patients (~5%) have a positive MPO-ANCA.
The American College of Rheumatology proposed a clinical classification in 1990 to distinguish WG from other vasculitides (Table 18.10) and a range of validated indices have been developed to semiquantify disease activity (e.g., Birmingham vasculitis activity score), extent, and damage.
Cocaine Abuse
It is now well-recognized that cocaine abuse in the form of “snorting” can induce midline destruction of the nose and palate.23 This may be preceded by progressive nasal obstruction, epistaxis, and crusting, which closely resemble the sinonasal symptoms of WG. Ulceration of the mucosa is followed by septal perforation and serious destruction of the midface can ensue (Fig. 18.21). Furthermore, the c-ANCA and PR-3 can be positive, making differentiation between the conditions extremely difficult.23,24 However, on further investigation, there are some subtle differences in the ANCA between the two groups25 and it seems that massive apoptosis with abundant caspase-3 and -9 expression is found in the cocaine users but not in WG patients.26 ANCA react with human neutrophil elastase in the cocaine group but not in autoimmune vasculitis,27 so this may help with the differential diagnosis.
Imaging
Imaging of the sinuses can be helpful as there are characteristic features on CT and MRI. In a patient without a history of previous sinonasal surgery, a combination of bone destruction and new bone formation on CT is virtually diagnostic of WG, especially when accompanied on MRI by a fat signal from the sclerotic sinus wall (“tramlines”) giving a high signal on T1W sequences. In a series of 28 patients, 86% showed nonspecific mucosal thickening in the nose or paranasal sinuses, 75% showed evidence of bone destruction, and 50% evidence of new bone formation in the walls of the sinuses.28 These changes were present in both localized and systemic forms of WG. Progressive midfacial loss can be observed and can mimic that seen in NK/T-cell lymphoma. Concomitant bone destruction in the skull base can also be seen in some individuals (Figs. 18.22, 18.23, 18.24, 18.25).
When scans are done in this area it is always worth asking for an additional series with bone widths, which optimally show the orbits as these are involved in at least a third of cases where sinus changes are present and may occur independently. Appearances on CT are of an ill-defined soft tissue mass completely obscuring the optic nerve and extraocular muscles, often starting in the retro-orbit, with associated local bony destruction. The process can advance so that the entire orbital is overwhelmed by the process. On MRI, low to intermediate signal granulomas on T1W and T2W imaging may be distinguished from surrounding fat and ocular muscles.29 With time, the granulomatous tissue may be replaced by fibrosis, altering the tissue signals.
Furthermore, any patients with dyspnea, hoarseness, stridor, or other airway problems should be considered for imaging of the larynx to show subglottic stenosis.
Imaging of the lungs can reveal diffuse infiltration, multiple pulmonary nodules (2–4 cm in diameter) or large necrotic cavitating granulomatous masses (10 cm diameter or larger), some with fluid levels, which may compress or discharge into adjacent bronchi. On CT there may be ground-glass shadowing around the nodules, probably due to hemorrhage.29 Progressive consolidation and scarring occur with time. Pleural effusions and hilar lymphadenopathy are less common than in other granulomatoses.
Histological Features and Differential Diagnosis
WG is characterized by three key findings:
Granulomatous inflammation
Necrosis
Vasculitis
The granulomas are composed of CD4+ and CD8+ T cells, CD28− T cells, histiocytes, CD20+ B lymphocytes, neutrophil granulocytes, macrophages, and multinucleated giant cells surrounding an area of central necrosis. Occasional eosinophils may confuse the diagnosis with Churg-Strauss syndrome.
The vasculitis predominantly affects small to mediumsized vessels (capillaries, venules, arterioles, and arteries) and again is associated with necrosis. In the kidneys a rapidly progressive glomerulonephritis can occur and diagnosis can be confirmed by renal or lung biopsy. However, it can be very difficult for the diagnosis to be made on the histological findings alone, which are usually reported as “consistent with” rather than definitive. Many nasal biopsies are taken, particularly from the edge of incidental septal perforations, more in hope than expectation as they are rarely diagnostic of WG even when the condition is present.30,31 Abnormal tissue from the sinuses is likely to provide a better yield.32
The differential diagnosis is from any of the other granulomatous conditions (Table 18.1) including sarcoid, T-cell lymphoma, and a range of infectious conditions such as tuberculosis, and fungal conditions, particularly rhinosporidiosis and rhinoscleroma.
Natural History
Prior to the advent of systemic cytotoxic therapy, WG was a serious disease that generally had a fatal outcome within 2 years, usually due to renal failure. Before 1970, only 50% of patients survived 5 months from diagnosis and 82% were dead within 1 year.33 Even the advent of corticosteroids only improved mean survival to 12.5 months.34 Fortunately, that situation improved enormously with the combination of corticosteroids and cyclophosphamide, a regimen introduced by Fauci and colleagues, but remission was often followed by relapses and treatment-related toxicity was substantial.35 Modern regimens aim to rapidly induce remission to limit organ damage and maintain this while minimizing side effects of the medications.
However, WG should still be regarded as potentially life-threatening, particularly as there is often delay in diagnosis. Some patients are overwhelmingly ill within a couple of days; in others the condition takes months to be recognized by the patient and their doctor. A survey conducted on over 700 patients in the United States36 revealed that a third of patients waited 6 months or longer before their diagnosis was made. In a study of 199 British patients, the delay was even longer with 43% waiting over 6 months and 23% undiagnosed after 12 months from their initial presentation.11 Furthermore, there did not seem to be any improvement over the years in this delay to diagnosis. The delay was greatest when patients presented with eye symptoms (>14 months) but ENT symptoms were associated with the second longest delay (of >8 months). This is particularly disappointing as over half the patients (56%) saw an ENT surgeon prior to their diagnosis.
As ENT surgeons we see manifestations of either limited or systemic forms of the disease. The European Vasculitis Study Group (EUVAS) distinguishes “localized” (i.e., WG restricted to the respiratory tract) and “early systemic” WG (i.e., nonimminent WG without renal organ involvement) from “generalized” WG (Table 18.11).37 The majority of patients ultimately develop systemic disease within a few months or several years, but whether all localized forms go on to systemic disease, and if so what determines progression and the speed with which it happens, is unknown. This clearly has important implications for treatment as the medications are not without their potential side effects nor is it known whether treatment of limited disease prevents dissemination.
The condition also has a fluctuating course that is different from individual to individual and the disease is a classic example of “snakes and ladders” in which, as medication is reduced to minimize adverse effects or other events such as infection occur, patients may experience recrudescences of disease activity. These can also be triggered by many events from an episode of influenza to pregnancy.
If the patient survives these relapses (and their treatment), in many individuals the disease does eventually burn out.
Treatment
To obtain rapid remission, steroids are usually used in combination with cyclophosphamide in the severe systemic forms. Both may be used parenterally or orally. Cyclophosphamide is often given in pulsed form together with bolus doses of methylprednisolone in the acute situation and then orally for maintenance (EUVAS).37 The typical daily dose of cyclophosphamide is 2 mg/kg and generally should not exceed 200 mg/day, with lower doses in the elderly or those with renal problems. However, the long-term side effects of both drugs are an issue and not all patients are steroid responsive. Cyclophosphamide can cause significant leukopenia, alopecia, and hemorrhagic cystitis and is associated with a significantly increased risk of certain malignancies. There is an 11-fold increase in the chances of lymphoma or leukemia in the longer term17 and a 33-fold increase in the chances of bladder cancer. In addition, fertility is affected, with 60% of women of child-bearing age developing ovarian failure.
Methylprednisolone is used up to 1 g/day intravenously in severe cases, tapering down to oral prednisolone from a maximum of ~ 80 mg/day. The aim is to reduce the prednisolone within the first 6 to 9 months if patients do well in order to minimize the side effects, either to stopping the drug altogether or to a low maintenance dose of 5 to 7.5 mg/day.38 The long-term multisystem side effects of corticosteroids include osteoporosis, diabetes, hypertension, changes in skin and muscle, and classic “steroid facies” to name but a few.
For longer-term maintenance, in addition to prednisolone, azathioprine and more recently mycophenolate mofetil, an inhibitor of purine synthesis, are being used. These may be “steroid-sparing,” thus reducing the requisite dose of prednisolone or be monotherapy for longer-term maintenance, and are less often associated with significant side effects.37,39 In the United Kingdom, among 199 patients, 71% were on oral steroids and 41% on azathioprine for maintenance.11 A prospective randomized study by Jayne et al showed that substituting azathioprine for cyclophosphamide once a patient was in remission did not increase the rate of relapse.38
Plasmapheresis is used in those with severe renal involvement. Immunoglobulin replacement and other cytotoxic agents such as methotrexate are sometimes used. Methotrexate is given once a week (typically 15–20 mg/week), usually in combination with oral steroids, and patients should receive supplemental folic acid. Again this drug must be given with caution if there is renal damage. It is probably best used for longer-term maintenance rather than for the initial induction of remission.40
Most recently monoclonal antibodies, in particular the anti-CD20 antibody rituximab, have been used with some success,32 and the RAVE (Rituximab for ANCA-associated Vasculitis) study41 on 197 patients showed intermittent infusion of rituximab to be equivalent to daily cyclophosphamide for induction of remission and possibly superior in relapsing disease. TNF-α inhibitors such as infliximab and etanercept have been less convincing versus placebo.42
Patients require frequent monitoring so that the treatments can be titrated against the activity of the condition and also for the side effects of the drugs. Thus, regular ANCA tests as well as full blood counts, ESR, CRP, and renal function tests are needed.
Bone densitometry and prophylaxis against osteoporosis should be considered, although the routine use of bisphosphonate treatment has been questioned as an association with osteonecrosis of the jaws has been reported, albeit mainly in patients taking the drug for malignancy.43 Calcium and vitamin D supplements, and hormone replacement therapy in postmenopausal women, can all be considered.
Once the disease has burnt out, some individuals will continue to require a small dose of prednisolone (e.g., 5 mg/day) to provide baseline replacement of their corticosteroid requirement.
The possible role of an infectious agent such as Staphylococcus aureus led to the use of long-term oral co-trimoxazole (trimethoprim-sulfamethoxazole) and topical antistaphylococcal creams in the nose. There is some evidence that co-trimoxazole reduces relapses in the respiratory tract,44 and can also reduce the chance of Pneumocystis pneumonia infection.
ENT Treatment
Nose
Topical medications such as some form of douching, a topical intranasal corticosteroid, and/or nasal lubricant such as glucose and glycerin drops or an aqueous gel can be helpful. Surgery has a limited role, but it is sometimes worthwhile endoscopically exploring the sinuses if only to confirm that the opacification is granulation/fibrosis rather than infection. The skull base may need reinforcement in selected patients who develop meningitis secondary to bone erosion, which again can be effected endoscopically using established on-lay techniques.
Repair of the septal perforation is unlikely to be successful, but many younger patients now request “cosmetic” improvement of the external nasal deformity. As long as the disease has been quiescent for a reasonable period of time (e.g., 1 year), this can be undertaken with success.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
