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Q1: What is the main differential diagnosis of this patient's pulmonary nodules?
Multiple pulmonary nodules may have varied causes (box 1), however, they strongly suggest metastatic tumour and this diagnosis, together with fungal or tuberculous granulomas, accounts for well over 95% of the cases.1 Many types of tumours may disseminate causing pulmonary nodules but some of the more frequently encountered include breast, urogenital, testicular, and thyroid cancers as well as choriocarcinoma, melanoma, and osteosarcoma. Considerably less common in this presentation are primary pulmonary lymphoma, bronchoalveolar carcinoma, and Kaposi's sarcoma. However, the absence of a detectable primary tumour on clinical evaluation1 decreases the likelihood ratio of this diagnosis. The adrenal mass is unlikely to be a primary cancer since these tumours are rare (only 4% of all single adrenal masses) and usually large in size (only 4/130 adrenal cancers were <3 cm). The characteristics of the pulmonary nodules (large, variable in size, and non-calcified) all indicate that this is not a granulomatous disease, and moreover the patient is not immunocompromised and has no history of being in an endemic area. The patient's systemic symptoms and acute phase response are consistent with both diagnostic possibilities as well as with less common alternatives of septic pulmonary emboli or vasculitis. The first could be due to right sided infective endocarditis on the tricuspid valve, although the patient (who used drugs 17 years before) vehemently denied current intravenous drug abuse. Pulmonary vasculitis could perhaps be linked to the
Box 1: Multiple pulmonary nodules*: main differential diagnosis
Malignancy, mostly metastatic.
Granulomatous disease (histoplasmosis, cryptococcosis, etc, tuberculosis, sarcoidosis).
Pulmonary infarcts (especially septic) or abscesses.
Rare causes such as pulmonary amyloidosis, arteriovenous malformations, etc. *Cavitation may occur in most nodules mainly indicating an active disease process.
Box 2: Drenching night sweats: main differential diagnosis
Protracted viral infection (for example herpesvirus, HIV).
Granulomatous disease (for example tuberculosis, sarcoidosis, brucellosis, fungal infection).
Malignancy, especially haematological (for example lymphoproliferative disease, leukaemia, myelodysplastic syndrome; also metastatic carcinoma or sarcoma).
Vasculitis (for example temporal arteritis, polyarteritis).
Box 3: Palpable purpura*: main differential diagnosis
Infection associated (for example upper respiratory tract infection).
Drug associated (for example antibiotics).
Malignancy associated, mostly haematological.
Autoimmunity associated in the context of known rheumatoid arthritis, systemic lupus erythematosus, etc and in the context of active systemic vasculitis.
*Some cases of septicaemia, endocarditis, cholesterol, or myxoma emboli and the antiphospholipid antibody syndrome may mimic palpable purpura and should be considered and excluded.
Q2: How does the appearance of the skin signs affect the diagnosis?
Splinter haemorrhages are commonly due to minor trauma to the nails and are often considered clinically unhelpful.2This is not the case when a patient with undiagnosed systemic illness develops new splinter haemorrhages. Although omitted from many textbooks, such an appearance suggests an association with several systemic conditions occluding small arteriolar vessels such as the primary antiphospholipid antibody syndrome, systemic vasculitis, and cholesterol crystal emboli. They can also occur in about 1:6 patients with infective endocarditis. However, the absence of a murmur or a predisposing condition, the negative blood cultures, and the normal echocardiography make infective endocarditis unlikely in this patient, as does the near normal temperature. Cancer and granulomatous disease do not cause splinter haemorrhages. Thus, their appearance places a systemic vasculitis at the top of the differential diagnosis. The development of palpable purpura confirms this diagnosis and even narrows it further. Palpable purpura is caused by skin infiltration by small vessel vasculitis. Once the probability of an infection is lessened by the negative evaluation and cryoglobulinaemia is excluded by the normal rheumatoid factor and complement, the lack of drug exposure or previous autoimmune disease leaves vasculitis of malignancy or systemic vasculitis as the main differential diagnosis (box 3). Malignancy associated cutaneous vasculitis is not only uncommon (less than 10% of all cases), but almost always limited to haematological malignancies, which are not likely here.3Thus, again, cutaneous vasculitis as part of a systemic vasculitis syndrome is suggested. This is encountered mainly in polyarteritis and overlap syndromes (up to 33% on presentation) which do not cause pulmonary nodules, and in Wegener's granulomatosis (up to 10% on presentation).
Q3: How would you proceed with the diagnosis?
To confirm a postulated diagnosis of Wegener's granulomatosis and rule out diagnostic alternatives, an urgent testing of the patient's serum for antineutrophil cytoplasmic antibodies (ANCA) is indicated, as well as a percutaneous computed tomography guided biopsy of a pulmonary nodule.
Within 24 hours of the appearance of splinter haemorrhages and palpable purpura, the patient had undergone a computed tomography guided biopsy of a large superficial pulmonary nodule and the results of a test for ANCA were obtained. The latter was positive for c-ANCA by indirect immunofluorescence assay (+ 4) and anti-PR-3 by enzyme linked immunosorbent assay (ELISA; over 10 times the cut off point in normals). The biopsy demonstrated small vessel necrotising vasculitis with prominent giant cells, granulomas, and eosinophils. Skin biopsy showed leucocytoplastic vasculitis. Upper respiratory tract involvement was confirmed by the appearance of aphthous ulcers in the soft palate and tonsillar exudate. Sinus examination and computed tomography were normal. The patient was immediately started on intravenous hydrocortisone, which was later switched to oral prednisone at 1 mg/kg with the addition of methotrexate 15 mg/week. Oral bisphosphonates, calcium, vitamin D, and folic acid were prescribed to decrease adverse drug reactions due to the corticosteroids and methotrexate, respectively. The patient, who by that time was bedridden and severely ill, responded dramatically. He became ambulatory and felt much better within 48 hours and could be discharged soon after. His chestx ray was much improved on last follow up.
Wegener's granulomatosis is an uncommon necrotising vasculitis distinguished by its predilection to affect small vessels of the upper respiratory tract, pulmonary parenchyma, and kidneys. Our patient exhibits two distinct histopathological patterns of Wegener's granulomatosis: microvasculitis or capillaritis is the infiltration and destruction of capillaries, venules, and arterioles by neutrophils. This is seen in the patient's skin involvement but did not occur in the kidney, which is affected in only about 20% of patients at presentation. The second pattern, granulomatous vasculitis, involving small/medium sized arteries and veins with prominent multinucleated giant cells, was revealed in the lung biopsy. Pulmonary involvement on presentation was reported in almost 50% of the patients and may be asymptomatic in 1:3. Multiple or solitary nodules with or without cavitation, are the most frequent manifestations.4 Nasal, sinus, tracheal, or ear symptoms are present on diagnosis in about 75% of the patients but are often considered trivial at first, as in our patient who had a blocked nose, mild epistaxis, pain upon swallowing and ear pain attributed to upper respiratory infection. However, these complaints are often accompanied by systemic symptoms such as fatigue, arthralgia/myalgia (67%), fever (23%), and weight loss (15%) which should alert the clinician to their true meaning. On retrospect, our patient's eye involvement (15% on presentation) was also a clue, but the appearance of striking skin signs (13% initially) was almost diagnostic in this context. Palpable purpura (most commonly), but also skin ulcers, vesicles, papules, and subcutaneous nodules have all been seen in Wegener's granulomatosis.4 ,5 However, we have not encountered a previous mention of splinter haemorrhages in this disease. ANCA is a sensitive and highly specific test for active Wegener's granulomatosis (91% and 98%, respectively). The likelihood ratio of a positive test result was 33 and of a negative test result was 0.3.6 As in our patient, the antigenic specificity of ANCA in most patients with Wegener's granulomatosis is antiproteinase 3, whereas most patients with other forms of small vessel vasculitis such as microscopic polyangiitis or Churg-Strauss syndrome, have perinuclear ANCA antimyeloperoxidase. Combined corticosteroids and low dose daily cyclophosphamide treatment have dramatically improved the survival of patients with Wegener's granulomatosis whose mean survival is otherwise five months. Extended follow up of patients treated with this regimen indicate, however, that relapses are common and that treatment related adverse drug reactions, in particular an increase in malignancies, is also a significant problem.4 Thus, in patients like ours, who do not have a life threatening disease, substituting cyclophosphamide for methotrexate and later adding co-trimoxazole for the prevention of relapses, might prove worthwhile.7 ,8