Unusual presentation of sarcoidosis, requiring a positron emission tomography/CT (PET/CT) for diagnosis

Abstract

A 43-year-old man presented to hospital after routine laboratory tests showed an acute kidney injury and hypercalcaemia. He had no relevant medical history and normal physical examination, other than a 6-week history of lower back pain for which he had been taking naproxen. Low parathyroid hormone (PTH) levels indicated a PTH-independent hypercalcaemia. Investigations including CT of thorax, abdomen and pelvis and subsequent bone biopsy and renal biopsy were unremarkable. Positron emission tomography/CT (PET/CT) scan was ultimately considered as a diagnostic test and showed abnormalities in the right subpectoral and portacaval region with intense fluorodeoxyglucose F 18 uptake in local lymph nodes. A biopsy of the right subpectoral node showed granulomatous change consistent with sarcoidosis. PET/CT scanning can play an important role in the investigation of suspected malignancy, infection and inflammatory disease and in this case, was required to diagnose an atypical presentation of sarcoidosis.

Background

Sarcoidosis is a multisystem disorder of unknown aetiology characterised by granulomatous inflammation. Pulmonary presentation is the most common, although any organ can be affected. Hypercalcaemia occurs in 11% of patients, and 40% of patients have hypercalciuria.¹ Intrarenal calcium deposition can lead to renal failure. In sarcoidosis calcium metabolism is altered as sarcoidal macrophages possess 25-hydroxyvitamin D–1α-hydroxylase, converting an inactive vitamin D metabolite to a more active form, 1,25 dihydroxyvitamin D.¹ The diagnosis is established by clinical and radiological findings and histological evidence of noncaseating epithelioid cell granulomas.²

In this case, we report on an atypical presentation of sarcoidosis, in which the patient presented with an acute kidney injury and hypercalcaemia. Ultimately, this case required a positron emission tomography/CT (PET/CT) to find an area of lymphadenopathy which we were able to biopsy and prove the diagnosis of sarcoidosis histologically.

Case presentation

A 43-year-old man was referred to hospital by his general practitioner (GP) with a 6-week history of lower back pain treated with naproxen combined with esomeprazole. He had no respiratory symptoms, weight loss, night sweats or signs of an acute infection. He had no relevant medical history, worked as a fitter, was an ex-smoker with a 10 pack-year history and drank alcohol socially. He reported no recent international travel and had no family history of note. His drug history comprised a recent prescription for naproxen and esomeprazole only. Physical examination showed blood pressure of 145/100 mm Hg but was otherwise normal. Routine blood tests by his GP had shown corrected calcium 2.9 mmol/L (range 2.2–2.6), creatinine 153μmol/L (range 50-120μmol/L) with an eGFR (estimated Glomerular Filtration Rate) of 46 mL/min/1.73 m² (range >90 mL/min/1.73 m²).

Investigations

Full blood count and electrolytes were normal, erythrocyte sedimentation rate was 16 mm/hour (range 1–10 mm/hour). Chest X-ray was normal. Urinalysis was clear. Parathyroid hormone (PTH) was low at 7 pg/mL (range 10–65 pg/mL). Serum albumin was 40 g/L (range 35–40 g/L) with a serum calcium 2.92 mmol/L (range 2.2–2.6 mmol/L). Phosphate levels were normal at 0.95 mmol/L (range 0.74–1.4 mmol/L). Other routine blood tests were normal including alkaline phosphatase. Serum protein electrophoresis demonstrated no paraproteins. Vitamin D (25 dihydroxyvitamin D) levels were 61 nmol/L, within normal limits (adequate range 50–75 noml/L). Urine albumin/creatinine ratio was normal. A 24-hour urinary calcium collection showed elevated calcium excretion at 24.3 mmol/24 hours (range 15–20 mmol/24 hours). ACE levels were elevated at 85 U/L (range 8–52 U/L) but this result did not become available for several weeks. 1,25 dihydroxyvitamin D was not taken during initial workup. A CT thorax/abdomen/pelvis showed mildly enlarged peritoneal and left external iliac nodes, which were of uncertain significance. The patient had previously undergone an MRI lumbar spine, which showed widespread lumbar disc degeneration, foraminal stenosis at L4-5, L5-S1 and disc protrusion at L5-S1 effacing both S1 roots. Ultrasound of neck found no thyroid or parathyroid abnormalities. Nuclear medicine bone scan was normal except for an area of right frontal sinus uptake, which correlated with sinusitis on CT brain.

This case was discussed with other specialists. His imaging was discussed at a radiology multidisciplinary meeting. Blood film and bone marrow biopsy by haematology were normal. Nephrology advised vasculitic and autoimmune screening which were negative. A subsequent renal biopsy showed tubular calcification, but no evidence of acute tubular necrosis and normal immunofluorescence. A subsequent PET/CT scan showed an area of intense uptake in relation to an enlarged right subpectoral node with an standardised uptake value (SUV) of 4.5 (levels>2.5 are considered abnormal) (figure 1), and an intensely fluorodeoxyglucose F 18 (FDG) positive portacaval node with an SUV of 8.14 measuring 11 mm in diameter (figure 2). Subtle activity within the mediastinal and hilar lymph nodes and diffusely within bone marrow suggested a lymphoproliferative disorder with a differential diagnosis of sarcoidosis. Subsequent biopsy of the subpectoral lymph node showed necrotising granulomatous lymphadenitis, with focal calcifications. Dense aggregates of non-caseating granuloma which is made up of epithelioid histiocytes and lymphocytes can be seen on the biopsy micrograph provided (figure 3).

Figure 1.

FDG PET/CT showing an area of intense FDG uptake in a right subpectoral node. FDG, fluorodeoxyglucose F 18; PET/CT, positron emission tomography/CT.

Figure 2.

Another focus of avid FDG uptake in the portacaval nodes. FDG, fluorodeoxyglucose F 18; PET, positron emission tomography.

Figure 3.

Dense aggregates of non-caseating granuloma which is made up of epithelioid histiocytes and lymphocytes (arrow).

Differential diagnosis

Hypercalcaemia associated with acute kidney injury has a wide differential diagnosis including non-steroidal anti-inflammatory drug (NSAID) induced nephropathy, multiple myeloma and other lymphoproliferative disorders, primary hyperparathyroidism, hyperthyroidism, renal disorders such as glomerulonephritis, acute tubular necrosis and acute interstitial nephritis, occult malignancy and sarcoidosis. Based on our initial investigations and we were able to quickly rule out hyperparathyroidism, multiple myeloma and an underlying vasculitis or renal disorder.

PET/CT narrowed our differential to two possible diagnoses. These included sarcoidosis or lymphoproliferative disease. The PET/CT identified an area for targeted lymph node biopsy which showed necrotising granulomas with calcifications. Based on this finding, together with elevated serum ACE and the overall clinical picture, a diagnosis of sarcoidosis was made allowing for appropriate treatment and follow-up.

Treatment

NSAID therapy was discontinued and switched to alternative non nephrotoxic analgesic agents. Intravenous fluids were given initially with intravenous zoledronic acid later to reduce serum calcium. Electrolytes and renal function were regularly monitored and showed improvement. He was discharged without a diagnosis, for early nephrology review. Laboratory tests 3 weeks after discharge showed a deterioration of renal function and recurrence of hypercalcaemia. The patient was thus readmitted for further investigation. When the diagnosis of sarcoidosis was made, oral prednisolone 40 mg daily was commenced and subsequently tapered. This patients calcium level responded very quickly to steroids, normalising to a corrected calcium level of 2.53 mmol/L (range 2.2–2.6 mmol/L) 3 days after starting prednisolone.

Outcome and follow-up

The patient is currently on maintenance prednisolone 10 mg daily, once-weekly alendronic acid/cholecalciferol 70 mg/5600units, pantoprazole 20 mg once daily and calcium carbonate 500 mg two times per day. Bisphosphonate, vitamin D and calcium supplementation were prescribed on discharge to prevent steroid induced osteoporosis. This will be readdressed as steroid dose is tapered.

He has maintained normal renal function with no recurrence of hypercalcaemia. His most recent creatinine was 83 μmol/L (range 50–120 μmol/L), with eGFR of 87 mL/min/1.73 m² (range >90 mL/min/1.73 m²). His corrected calcium has normalised to 2.41 mmol/L (range 2.2–2.6 mmol/L), with a PTH level of 32 pg/mL (range 8–52 U/L). This patient’s sarcoidosis was diagnosed in October 2019. He is currently under active follow-up, allowing his oral steroid dose to be titrated downwards.

Discussion

FDG is a PET tracer which accumulates in tissue which has increased glucose metabolism.³ In contrast to CT and MRI modalities, PET scanning provides both metabolic and anatomical detail and is primarily of use in the diagnosis and management of cancers, allowing for treatment planning and the monitoring of therapeutic response to chemotherapy and radiotherapy.⁴ CD4+ and activated macrophages in sarcoid granulomas rely on GLUT/SLC2A glucose transporter membrane proteins and as FDG is analogous to glucose, these cells are visible on PET/CT, indicating leucocyte-mediated disease, as in sarcoidosis.⁵ In the present case, our patient was a 43-year-old Irish man who was fit and active. Diagnosis was difficult due to an atypical presentation with absence of findings on routine imaging. PET scanning has been shown to be very sensitive in the assessment of inflammatory and metabolic reactions associated with sarcoidosis and has proven to be of benefit in locating occult sarcoid tissue.^{6 7} A positive PET scan can also indicate malignancy or infection and therefore should not be used as a screening tool for sarcoidosis.⁶ Youssef et al performed a systematic review, evaluating the accuracy of FGD PET/CT in the diagnosis of cardiac sarcoidosis. In this meta-analysis, seven studies were included, representing 164 patients, found that PET/CT had a pooled sensitivity of 89% and specificity of 79% in identifying cardiac sarcoidosis.⁸ PET/CT has been shown to be of benefit in diagnosing complex and atypical presentations of sarcoidosis, as in the present case, facilitating effective treatment.⁵ Using PET/CT imaging in sarcoidosis may have prognostic importance and be useful in assessment of treatment response.^{9 10} There is no evidence to support PET/CT as a screening tool for suspected sarcoidosis and investigation should start with clinical assessment, routine blood tests, chest X-ray and CT scanning. In those patients with possible cardiac, central nervous system, and musculoskeletal involvement by sarcoidosis, PET/CT is an imaging option that should be considered.³ In the present case, in which the differential diagnosis included sarcoidosis but without evidence of active disease on routine imaging, PET/CT proved vital in making the diagnosis.

Patient’s perspective.

On Friday 2^nd August I was admitted to hospital thinking as I was feeling fine, fit and well that this was a quick check and we would be flying off on holidays as planned on Monday 5^th August. I was slightly wrong there as it was nearly the October bank holiday weekend before I was fully home again.

I had felt fine. I was tired, but no more tired than anyone else. I was working as a fitter and framer at home, and I felt fully well in myself to keep it all going. I loved being busy, and apart from lower back pain, I believed I was a healthy man.

It was a shock to learn that all was not as well as I thought. The low kidney function came back a surprise as again I was feeling fine. High calcium meant very little to me only that I wasn't a good thing in the eyes of the doctors. Life was good, and work was busy, I was feeling fine and looking forward to the holiday. I was what you call a happy man.

During my stay in the hospital, I was also very comfortable and very well looked after. At every stage, the tests were always clearly explained. And I always knew what was going to happen. Under the care of the doctors and nurses, I had no worries as I always felt I was in very safe hands. All the staff were wonderful, kind and caring.

My diagnosis came as a shock as of all the things I thought I had never heard of sarcoidosis. Even my wife, who likes to think she is Dr Google had not heard of this, and that quietened her, for once!

Yes, I was worried that I seemed to be an unusual case in that I had none of the usual symptoms. The blood test in early July was random really and only because of my back pain. My wife made me go to the doctor as she thought that me complaining of back pain would ruin her holiday!

Anyway, I am happy that of all the things I thought I had the least bad options. I really thought it was cancer hidden away somewhere, I still don't really understand it all, and I don't need to, but I’m happy that it is under control.

We as a family are so grateful. A few times, we imagined the worst. When doctors said, all options were being considered. We were than hypercalcaemia associated with acute kidney injury has kful to the doctors for being open about it and that it wasn't kept hidden. My son was a teenager at the time, and no matter what we felt, it was better than my wife, and I knew about all possible outcomes. We were thankful that I was under the care of such brilliant minds, who left no stone unturned in getting to the root of the problem. We are grateful to the staff for making what was a worrying and comfortable time by being so kind and caring.

Sometimes I thought I would never get home. Life is back to normal now. The medications are fine, really. I have regular check-ups, and it is very comforting to know that any slight increase will be detected quickly.

Learning points.

• The diagnosis of sarcoidosis can prove to be elusive, given the varying organ involvement and presentations.

• Sarcoidosis should be considered in patients with hypercalcaemia and low parathyroid hormone levels.

• Intrarenal calcium deposition can ultimately result in renal failure.

• Positron emission tomography/CT (PET/CT) provides both anatomical and metabolic detail allowing clinicians to locate areas of abnormal cell turnover.

• PET/CT is an imaging option in cases of sarcoidosis, in which the diagnosis cannot be made by other imaging and diagnostic techniques.