Case report of osteolytic lesions in a patient with multisystem granulomatous disease

Background

Sarcoidosis is a multisystem disease characterised by non-caseating granulomas. Although lungs and lymph nodes are most commonly affected, the disease can involve any organ system.1 Sinonasal sarcoidosis is relatively rare and the incidence appears to be between 0.7% and 6%.2

However, as the symptoms of patients with sinonasal sarcoidosis resemble the symptoms of chronic rhinitis and chronic inflammatory rhinosinusitis, sinonasal sarcoidosis might be an overlooked disease manifestation.3

Bone involvement is reported in 3%–13% of patients with sarcoidosis.4 Older data suggest that the hands and feet are most commonly affected, with spinal involvement rarely reported.5 However, axial bone involvement may be more common than previously documented, since earlier studies relied mostly on plain X-rays, which may be less sensitive for axial bone lesions.5 Osseous sarcoidosis also appears to be more common in white women and bone involvement is usually diagnosed in middle-aged or elderly patients.5 6

Bone lesions are commonly asymptomatic and patients who have bone involvement may have higher incidences of multiorgan involvement.5 Although osseous sarcoidosis appears to be mainly osteolytic in nature,7 lesions may also appear sclerotic or permeative.5 The radiographic appearance may be indistinguishable from other osteolytic lesions and therefore a biopsy is usually required to confirm the diagnosis.5 8

Skull sarcoidosis is extremely rare, and a recent systematic review yielded only 22 documented cases.5 8 9

No general consensus exists for the treatment of bone or sinonasal sarcoidosis, but corticosteroids are the most commonly prescribed first-line drugs.3 10 Various second-line agents including methotrexate and hydroxychloroquine have been reported useful as steroid sparing agents.3 11 12

Cryptococcus neoformans is a yeast found in soil and pigeon droppings. Inhalation of these organisms may result in pulmonary cryptococcosis and the infection may undergo haematogenous spread to any organ system, including the central nervous system, bones and skin, although this is rare in immunocompetent hosts.13 Cryptococcal lesions of the skeletal system occur in less than 10% of patients with disseminated disease and radiography typically demonstrates osteolytic lesions.14 Although the optimal treatment of cryptococcal pneumonia is uncertain, treatment generally consists of 6–12 months of oral fluconazole.15

This case report raises awareness that although osseous sarcoidosis is uncommon, it can affect any bone, and bone involvement is frequently asymptomatic. Furthermore, it may serve as a reminder that bone involvement is more common in white female patients. Importantly, most patients with bone sarcoidosis have a good response to corticosteroids used in combination with methotrexate.

Case presentation

We present a case of a 70-year-old white woman with multisystem granulomatous disease involving her lungs, bones and lymph nodes. The patient had a background of chronic rhinosinusitis that was treated with intranasal corticosteroids. She had no other relevant medical or family history. She presented initially at another centre with a lump in the left side of her neck and further imaging revealed extensive supraclavicular, mediastinal, hilar and intra-abdominal lymphadenopathy. A supraclavicular lymph node biopsy confirmed non-suppurative, non-caseating granulomatous lymphadenitis. At that time comprehensive lung function testing was normal: FEV1 (forced expiratory volume in 1 s) 2.54 L (98% predicted), FVC (forced vital capacity) 3.01 L (89% predicted), TLC (total lung capacity) 4.79 L (92% predicted) and DLCO (diffusing capacity for carbon monoxide) of 24.03 mL/min/mm Hg (110% predicted). Consideration was given towards tuberculosis, but due to the lack of culture positivity and in the absence of systemic symptomatology, sarcoidosis was thought to be more likely. However, as the patient was clinically well she was not started on any therapy.

Subsequently, over the next 5 years, she developed progressive breathlessness and productive cough with discoloured sputum prompting referral to our centre. CT chest showed progression of pulmonary parenchymal infiltrates as well as the longstanding lymphadenopathy. Lung function testing now showed a mixed obstructive and restrictive defect. The functional and clinical deterioration was consistent with the progressive parenchymal appearances on CT imaging. Endobronchial lung biopsy revealed non-necrotising granulomatous inflammation while a BAL specimen showed scanty growth of Cryptococcus neoformans and moderate growth of Staphylococcus aureus. The patient received intravenous ceftriaxone and had a good initial response to treatment with resolution of cough and sputum production. She also completed 3 months of oral fluconazole for suspected cryptococcal infection. Although a diagnosis of sarcoidosis was considered most likely, the patient was not initiated on systemic corticosteroids at the time. This decision was made because of the clinical response to antibiotics and due to concerns about the cryptococcal and staphylococcal growth.

Subsequent outpatient review confirmed that the initial clinical response to antibiotic therapy was not maintained with further deterioration in her exercise tolerance and increased breathlessness. The productive cough had improved and there was no neck-stiffness, headaches, or subjective fevers.

On examination, she was hemodynamically stable and afebrile. She had good air entry bilaterally, a clear chest with no crackles or wheezes and her saturation was 98% on room air. There were no extrapulmonary signs of sarcoidosis on physical examination. The patient also had no skin lesions, cellulitis, arthritis, ocular abnormalities or abdominal pain indicative of disseminated cryptococcosis. Nonetheless, a craniofacial CT was ordered to exclude disseminated cryptococcosis before initiating immunosuppression. This revealed multiple lytic lesions, with involvement of the calvarium, the clivus and the paranasal sinuses. A clival lesion was biopsied as it appeared representative and readily accessible and histopathology revealed granulomas without vasculitis but with bone resorption. This was considered somewhat atypical for sarcoidosis and therefore the patient underwent further investigations to exclude an underlying infection and other granulomatous diseases. However, no conclusive evidence was found that her presentation was due to widespread infection or another granulomatous condition. Therefore, the patient was treated with oral prednisolone and methotrexate, which led to significant clinical and radiological improvement (for overview of clinical course, see figure 1).

Investigations

When first reviewed at our centre, lung function tests revealed a mixed obstructive and restrictive picture: FEV1 1.43 L (64% predicted), FVC 2.15 L (74% predicted), TLC 4.52 L (88% predicted) and DLCO of 16.42 mL/mm Hg/min (83% predicted). High-resolution CT chest confirmed a perilymphatic nodular pattern and diffuse symmetric mediastinal and hilar adenopathy (figure 2A). The parenchymal progression on CT imaging was consistent with the patient’s functional and clinical deterioration.

During the course of her illness, the patient was extensively investigated for other granulomatous diseases.

Full blood count, urea and electrolytes, liver function tests, parathyroid hormone and C reactive protein were within normal ranges on admission. Her urine microscopy revealed no haematuria, proteinuria or casts. Serum protein electrophoresis revealed no significant abnormalities. A repeat antinuclear antigen, extranuclear antigen, tuberculosis interferon gamma release assay and serum cryptococcal antigen were all persistently negative. Although the patient previously had a negative antineutrophil cytoplasmic autoantibody (ANCA), immunofluorescence staining and ELISA assays were repeated, due to the extensive upper airway involvement on CT. Cytoplasmic ANCA (C-ANCA) was negative, but her perinuclear ANCA (P-ANCA) was positive on immunofluorescence staining. ELISA assays for both myeloperoxidase (MPO) and proteinase 3 (PR3) were negative and titres were unrecordably low. Lumbar puncture confirmed normal opening pressure, no cells and a negative cerebrospinal fluid (CSF) cryptococcal antigen.

A craniofacial CT revealed multiple lytic lesions involving the calvarium, the clivus (figure 2B) and the paranasal sinuses (left frontal sinus, bilateral ethmoid sinuses and left maxillary sinus). Subsequently, a brain MRI confirmed focal, circumscribed enhancing lesions involving the calvarium, clivus and visualised upper cervical spine (figure 2C).

Frontal sinus and clivus biopsy revealed well-formed, non-necrotising, destructive granulomas, without vasculitis (figure 2D). Fungal stain and culture, and acid-fast bacilli were all negative but there was a light growth of Staphylococcus epidermidis on a frontal sinus swab and clivus tissue sample.

Differential diagnosis

Disseminated cryptococcal infection was considered due to the scanty growth of Cryptococcus neoformans on the recently performed bronchoalveolar lavage (BAL), as well as the extensive bony involvement. Ultimately, this appeared highly unlikely due to the well-formed granulomas on histopathology, negative cryptococcal antigens on serum and CSF, negative fungal growth and stain on biopsies and swabs, and the overall appearance of our patient with no systemic signs and symptoms of widespread fungal sepsis.

Due to the extensive sinus involvement on CT and positive P-ANCA, granulomatosis with polyangiitis was also entertained. The well-formed, non-necrotising granulomas on histopathology, the negative MPO and PR3 ELISA assays and the slow progression of the disease made this unlikely. Importantly, two types of ANCA assays are in wide use and this includes the indirect immunofluorescence assay (P-ANCA and C-ANCA) and ELISA (MPO and PR3). Of these two techniques, the immunofluorescence is more sensitive, and the ELISA is more specific. The optimal approach to clinical testing for ANCA is therefore to perform both immunofluorescence and ELISA to detect antibodies against the vasculitis specific target antigens.16 17

Furthermore, a positive P-ANCA immunofluorescence staining pattern may also be detected in a wide variety of inflammatory illnesses, including sarcoidosis, and has a low specificity for vasculitis.18 The clinical significance of this non-specific finding in these disorders remains unclear.19 A positive immunofluorescence assay should therefore always prompt testing by ELISA to determine the specific antibody (or antibodies) responsible for the pattern.19

Although cryptococcal infection and granulomatosis with polyangiitis were the two main differential diagnoses, the patient was extensively investigated to exclude other conditions that could cause multiple osteolytic lesions.

Multiple myeloma was excluded with a normal serum protein electrophoresis and immunofixation, tuberculosis was deemed highly unlikely due to the negative tuberculosis interferon gamma release assay, negative acid-fast bacilli and negative TB culture. A normal parathyroid hormone level excluded hyperparathyroidism and multiple brown tumours.

Finally, the sinus and clivus biopsies excluded other causes of osteolytic lesions including metastatic bone disease, primary non-Hodgkin's lymphoma of bone and Langerhans cell histiocytosis.

Therefore, widespread sarcoidosis with bone involvement was considered to be the most probable diagnosis.

Treatment

The patient was initiated on oral prednisolone 30 mg daily as well as oral methotrexate 10 mg weekly.

This decision was made in accordance with the literature that shows that corticosteroids remain the most common first-line therapy for bone and sinus sarcoidosis.3 10 In addition to being the most commonly prescribed steroid-sparing agent in sarcoidosis, methotrexate appears especially useful in cases of bone and sinonasal sarcoidosis.3 11 12

The patient was also reinitiated on oral fluconazole for the Cryptococcus neoformans. She was previously treated for 3 months and although the optimal treatment of cryptococcal pneumonia is uncertain, treatment generally consists of 6–12 months of oral fluconazole.15 While we were unable to undoubtedly confirm whether the Cryptococcus neoformans was truly pathological, we believed that the benefits of treatment outweighed the risks, especially given the ongoing immunosuppression.

Immunosuppression is a risk factor for early death in skull base osteomyelitis and conditions altering the vascularity of bone appears to be a risk factor for superimposed osteomyelitis.20 21 The patient also had sinus involvement and sinusitis can be a predisposing factor for frontal bone and maxillary osteomyelitis.21 Although it was difficult to establish whether the Staphylococcus epidermidis, cultured from a frontal sinus swab and clivus tissue sample, was a contaminant, or whether the destructed bone was secondarily infected, we decided to treat the patient with intravenous vancomycin for 2 weeks followed by an oral course of clindamycin for 3 months.

Due to the extensive bone involvement, an orthopaedic consultation was obtained to assess the risk of pathologic fractures and spinal cord compression. This was felt to be extremely unlikely and no surgical intervention was indicated.

Outcome and follow-up

After the initiation of prednisolone and methotrexate, the patient reported dramatic improvement in breathlessness and she also had significant radiological improvement on follow-up imaging. An outpatient F18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scan, 3 months after the initiation of immunosuppressants, revealed marked improvement with no definite evidence for residual FDG-avid disease (figure 3). The previously demonstrated intense FDG-uptake within the lymph nodes above and below the diaphragm, within multiple skeletal lesions and within lesions involving the lungs, liver and spleen all resolved (figure 4A and B). The CT scan also showed interval improvement of the peribronchovascular and perifissural nodules bilaterally. Furthermore, the patient also had significantly improved lung function tests with normalisation of ventilatory capacity, transfer factor and lung volumes. After previously demonstrating a mixed obstructive and restrictive picture, she now had normal comprehensive lung function: FEV1 1.97 L (88% predicted), FVC 2.84 L (99% predicted), TLC 4.93 L (96% predicted) and DLCO 19.5 mL/mm Hg/min (98% predicted). The patient also reported significant improvement in her chronic sinusitis symptoms. Due to the patient’s clinical improvement, the prednisolone was gradually tapered and the methotrexate was steadily increased. The patient was very compliant with her treatment and the main tolerability issue was weight gain due to the prednisolone. This subsequently improved after the dose was reduced.

The marked clinical and radiological response to prednisolone and methotrexate provided further reassurance for the diagnosis of widespread sarcoidosis with bone involvement.