Isolated splenic sarcoidosis: a rare cause of hypercalcaemia in a patient with type 1 diabetes

Abstract

A 30-year-old man was admitted to Intensive Therapy Unit (ITU) with status epilepticus secondary to severe hypoglycaemia on a background of type 1 diabetes. CT of the brain showed generalised cerebral oedema. He was successfully stepped down to a medical ward after 2 weeks. He was noted to have persistently high calcium, which required multiple doses of pamidronate. Parathyroid hormone level was appropriately low. CT of the thorax, abdomen and pelvis showed mild hepatosplenomegaly with small pathological lymph nodes throughout the abdomen. Bone marrow biopsy was unremarkable. Lymph node biopsy was difficult to achieve, and therefore a positron emission tomography scan was arranged. This showed an enlarged and hypermetabolic spleen. Differential diagnoses at this point included lymphoma and sarcoidosis. He underwent diagnostic splenectomy, and the diagnosis of sarcoidosis was confirmed histologically. Calcium level remained normal 17 months after splenectomy.

Background

Sarcoidosis is an idiopathic multisystem disorder most commonly involving the lungs. Isolated extrapulmonary sarcoidosis is uncommon and occurs only in <10% of cases. Sarcoidosis involving only the spleen is very rare and only 20 cases have been described in the literature until 2021. We describe a rare case of isolated splenic sarcoidosis causing significant hypercalcaemia, which was diagnosed and treated with open splenectomy. It was challenging to establish the diagnosis due to difficulty in accessing appropriate lymph nodes, but positron emission tomography (PET)-CT was very useful in identifying the spleen as the only major affected organ, which guided us to do a diagnostic splenectomy.

We aim to review the literature to look into the available data of all case reports of isolated splenic sarcoidosis to create awareness of this condition.

Case presentation

A 30-year-old man was noted to have seizures on the ward, for which he was admitted a few days ago. His capillary glucose was unrecordably low. In total, 200 units of Novorapid insulin pen was found empty on his bedside. It remained unclear whether this was an intentional or unintentional overdose.

He had a medical history of type 1 diabetes (T1DM), chronic kidney disease stage 4 and peripheral vascular disease requiring below-knee amputation. He had poor glycaemic control with hypoglycaemia unawareness and previous admissions for diabetic ketoacidosis.

Due to difficulty in controlling his seizures, he was intubated and transferred to Intensive Therapy Unit (ITU). CT of the head showed generalised cerebral oedema. He required four antiepileptics to control his seizures despite achieving normoglycaemia. An electroencephalogram, at the time, was not suggestive of non-convulsive status. An MRI of the brain performed a few days later showed resolution of cerebral oedema but no other organic pathology. His corrected calcium was normal. He had a couple of episodes of hypercalcaemia a few months before this admission in the context of acute kidney injury but resulted in complete normalisation after rehydration.

He was eventually successfully extubated and stepped down to our medical ward. This was complicated by hospital-acquired pneumonia, erratic blood glucose requiring intravenous insulin, urinary tract infection, acute kidney injury and swallowing issues requiring nasogastric feed.

Investigations

During this time, he was noted to have high calcium of 3.01 mmol/L, which was treated with multiple doses of pamidronate with partial response. Parathyroid hormone (PTH) level was appropriately low at 0.7 pmol/L (normal range: 1.6–7.2 pmol/L), which was suggestive of PTH as the independent cause of hypercalcaemia. A subsequent CT of the thorax, abdomen and pelvis showed mild hepatosplenomegaly along with small but numerous pathological lymph nodes throughout the upper abdomen and retroperitoneum, suspicious of haematological malignancy. The lung parenchyma was normal with no hilar lymphadenopathy. Upper abdominal and retroperitoneal lymph nodes were too small for percutaneous biopsy. Ultrasound of the groin showed normal-looking lymph nodes with no radiological evidence of infiltration, so was not biopsied. He was also noted to have hyperglobulinaemia but with no abnormal bands.

A bone marrow trephine biopsy showed normal appearances with no obvious infiltration. The haematology multidisciplinary team (MDT) felt that haematological malignancy was unlikely but needed a tissue biopsy to prove. Sarcoidosis was also suspected strongly, given moderately raised serum ACE of 140 U/L (normal range: 8–52 U/L) and inappropriately normal 1,25 (OH)₂ vitamin D of 78 pmol/L (normal range: 55–139 pmol/L). Twnety-four-hour urinary calcium was at the upper end of the normal range at 6.37 mmol/24 hours (normal range: 2.50–7.50 mmol/24 hours)

During this time, he also had a renal biopsy performed by renal physicians, which showed advanced diffuse and nodular diabetic glomerulosclerosis but no evidence of sarcoidosis.

After discussion with the radiology department, a PET scan was arranged due to diagnostic uncertainty and to find a target for tissue biopsy. This revealed an enlarged hypermetabolic spleen (figure 1) measuring 13.5 cm craniocaudal and maximum standardised uptake value (SUV_max) of 10.2. Mildly increased uptake (SUV <5) was present symmetrically in mediastinal and pulmonary hilar nodes without enlargement, which was thought to be non-specific.

Figure 1.

Selected image from Fluorodeoxyglucose positron emission tomography-CT, coronal reformats, fused image and frontal maximum intensity projection, standardised uptake value scale of 0–6. The scan appears postprandial, having been given normal insulin on the ward in error. The spleen is enlarged and shows a marked increase in FDG uptake throughout. Mild uptake in thoracic nodes, which are not enlarged, is also present, but this is a common and non-specific pattern.

Differential diagnosis

The main differential diagnosis included lymphoma and sarcoidosis.

Treatment

After MDT discussion, he underwent open splenectomy for diagnostic clarity, and the histology revealed innumerable epithelioid granulomas, with up to 50% of the volume of the spleen replaced by epithelioid granulomas in places but no evidence of a lymphoproliferative process (figure 2A–C). Stains for infective causes were negative. This was consistent with a diagnosis of sarcoidosis The whole spleen weighed 400 g and measured 15×9.5×6 cm.

Figure 2.

(A) Low-power picture showing how the spleen is involved by numerous epithelioid granulomas. (B) Medium power of a cluster of epithelioid granulomas, showing giant cells and one with an asteroid body. (C) High-power picture of slide B focusing on the asteroid body (yellow arrow).

Outcome and follow-up

He is now 17 months post-splenectomy with normal corrected calcium and no evidence of relapse of sarcoidosis. He is having regular follow-ups with diabetes and renal teams.

Discussion

Sarcoidosis is a chronic, infiltrative, multisystem disease characterised histologically by the formation of non-caseating epithelioid granulomas. The exact aetiology is unknown, but there is evidence that it results from the body’s immune system responding to unknown antigen or antigens. Potential culprits include occupational and environmental exposures, and infectious agents, for example, components of mycobacteria, Kveim-Siltzbach reagent and vimentin. The occurrence of sarcoidosis in more than one member of families suggests the possibility of genetic predisposition.

Sarcoidosis was first described by Jonathan Hutchinson in 1877 at King’s College Hospital London as cutaneous nodules,¹ but Caesar Boeck used the term sarkoid (sarcoid) for the first time in 1899 when he assumed that these lesions were similar to sarcoma but benign.² Since then, the multisystem involvement of this condition is well appreciated.

It typically involves the pulmonary system in about 90% of cases,³ with only 10% of cases with isolated extrathoracic sarcoidosis.⁴ In all, 5%–10% of patients with sarcoidosis present with Lofgren’s syndrome, which is a clinical triad of hilar adenopathy, acute arthritis and erythema nodosum. It is usually a self-limiting disease and in the presence of all features has 95% specificity for sarcoidosis.

Heerfordt-Waldenström syndrome is another rare subacute form of sarcoidosis consisting of facial nerve palsy, parotid gland enlargement and anterior uveitis and fever.

Isolated splenic sarcoidosis (ISS) is extremely rare, and to the best of our knowledge, only 20 cases have been reported in the English literature until now^5–24; therefore, it is not well established how best to manage this condition. Diagnosis is challenging due to its rarity and other splenic conditions in the differentials. A splenic biopsy is risky due to the high risk of bleeding and seeding, so diagnostic splenectomy is usually the gold standard. These case reports have been summarised in table 1.

Table 1.

Previous case reports of isolated splenic sarcoidosis including our case report

Author/year	Age/ sex	Presentation	Ca+	Calcitriol	CT/MRI	PET	Treatment
Present study	31 /M	High Ca+	High	Normal	Splenomegaly No nodularity	High uptake in spleen	OS
Kobayashi et al (2021)5	76 /F	Hypoechoic splenic lesions on surveillance CT	–	–	Multiple hypoechoic splenic lesions	High splenic uptake	LS
Thomas et al (2020)6	67 /F	Fever, night sweats, weight loss	High	–	Enlarged spleen with multiple wedge infarcts	High splenic uptake	–
Stoelting et al (2020)7	58 /F	Hypersplenism, severe epistaxis	–	–	Massive splenomegaly, no splenic lesions	Not done	OS
Mikamori et al (2019)8	59 /F	Splenic nodules on routine USS	N	–	Multiple hypoechoic splenic lesions	Increased uptake in spleen	LS
Jhaveri et al (2018)9	40 /F	Fever, night sweats, fatigue	N	–	Splenomegaly with multiple hypoechoic splenic lesions	Increased uptake in splenic nodules	LS
Gaudemer et al (2018)10	42 /F	Chronic abdominal pain	–	–	Multiple hypoechoic splenic lesions	Increased uptake in spleen	–
Tu et al (2016)11	44 /F	Epigastric pain	–	–	Accessory spleen in the greater omentum	Not done	AS
Ruiz-Serrato et al (2015)12	50 /F	Weight loss, anorexia	N	–	Multiple hypoechoic splenic lesions	Not done	OS
Souto et al (2014)13	29 /F	Nausea, vomiting, epigastric pain	NA	–	Multiple hypoechoic splenic lesions	No uptake in spleen	LS
Dennis et al (2014)14	65 /M	Headache, weight loss	High	Raised	No nodularity of spleen	Intense uptake in spleen	LS
Sreelesh et al (2014)15	50 /F	Weight loss, anorexia	N	–	Splenomegaly with multiple hypoechoic splenic lesions	Not done	OS
Bauones et al (2014)16	37 /F	Chronic abdominal pain	–	–	Multiple hypoechoic splenic lesions	Not done	LS
Palade et al (2012)17	66 /F	Anaemia	–	–	Multiple hypoechoic splenic lesions	Not done	LS
Hsu et al (2011)18	74 /F	Weight loss	High	Normal	Splenomegaly with multiple hypoechoic splenic lesions	Not done	LS
Cuilliere-Dartigues et al (2010)19	18 /M	Night sweats, severe neutropenia	N	–	Splenomegaly with multiple hypoechoic splenic lesions	Increased uptake in spleen	LS
Ogiwara et al (2010)20	71 /F	Hypoglycaemia due to ectopic IGF	–	–	Splenic mass with central contrast enhancement	Not done	OS
Joglekar et al (2009)21	46 /F	Nausea, vomiting, weight loss	High	–	Splenomegaly with multiple hypoechoic splenic lesions	Not done	OS
Giovinale et al (2009)22	53 /F	Chronic epigastric pain	N	–	Single splenic nodule	Not done	OS
Chen et al (2007)23	50 /M	Thrombocytopenia	–	–	Multiple hypoechoic splenic lesions	Not done	LS
Zia et al (2005)24	47 /F	Nausea, vomiting, epigastric pain	–	–	Multiple hypoechoic splenic lesions	Not done	LS

–, not available; AS, accessory splenectomy; Ca+, calcium; calcitriol, active vitamin D; F, female; IGF, insulin-like growth factor; LS, laparoscopic splenectomy; M, male; N, normal; OS, open splenectomy; PET, positron emission tomography.

A total of 20 cases of ISS were identified using PubMed. The majority of the patients were females (17 out of 21, 81%) unlike our male patient, with age between 18 and 76 years. The most common presenting complaints were constitutional (fever, epigastric pain, weight loss and night sweats); however, four patients presented with haematological abnormalities related to hypersplenism. Corrected calcium was normal in six cases (30%) and raised in five cases (25%). No data were available for the rest of the cases.

Active vitamin D (1,25(OH)₂D) was only mentioned in three case reports. Of these, it was inappropriately normal in two cases in the presence of hypercalcaemia and only one patient had a high active vitamin D.

CT/MRI showed multiple hypoechoic splenic lesions in the majority of case reports (14 of 20), a single splenic lesion in 2 cases and an accessory spleen with sarcoid involvement in 1 case. Only 3 of 20 case reports described splenomegaly with no nodularity similar to our patient.

PET imaging was performed in only eight patients, all of which showed increased splenic uptake, except in one case, where there was no uptake in the spleen.

All patients had a splenectomy (either laparoscopic or open); however, operative data were not available in two cases.

Post-splenectomy data, where available, showed resolution of symptoms and hypercalcaemia in all cases.

Our case was interesting for the following reasons compared with previous case reports:

1. Male gender (ISS is more common in females).

2. Young age—sarcoidosis typically affects people in the fourth–fifth decade of life.

3. Hypercalcaemia with unsuppressed active vitamin D (only 10%–40% has hypercalcaemia).

4. The spleen was homogeneously enlarged with no nodules (majority had splenic lesions).

5. Our patient was the only one with T1DM.

In conclusion, our case of ISS is a unique and rare form of sarcoidosis. Only 20 cases have been reported in the English literature until now. To our knowledge, this is the first reported case of isolated splenic sarcoidosis in a patient with T1DM. ISS should be included in the differential diagnoses of unexplained hypercalcaemia. PET scan modality can be useful in challenging cases to provide tissue targets for histological diagnosis and appropriate treatment.

Learning points.

• Isolated splenic sarcoidosis (ISS) is rare but can potentially cause life-threatening hypercalcaemia.

• Hypercalcaemia with unsuppressed or elevated active vitamin D and raised ACE levels, if present, are important clues for the diagnosis.

• Positron emission tomography scan can identify the organs involved, the extent of the disease and potential targets for tissue biopsy but does not differentiate from malignancy.

• All patients should be evaluated for the systemic disease at diagnosis and follow-up.

• Splenectomy can provide a cure for ISS, but long-term follow-up is mandatory for other organ involvement.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s)