Malignancy-associated hypercalcaemia is mediated via three mechanisms: tumour secretion of PTHrP, metastatic disease to bone and over-production of 1,25(OH)2D [1]. Whilst PTHrP and bony metastases account for the majority of cases of malignancy-associated hypercalcaemia, in GISTs, the most common mechanism appears to be over-production of 1,25(OH)2D.

We found 11 case reports of GIST-associated hypercalcaemia in the literature with 6 cases documenting an elevation of 1,25(OH)2D [2,3,4,5,6,7]. High 1,25(OH)2D can arise from direct ectopic tumour secretion or from tumour production of 1-α hydroxylase, leading to the catalytic conversion of 25-hydroxyvitamin D (25(OH)D) to 1,25(OH)2D. The subsequent hyperabsorption of dietary calcium and increased renal tubular calcium reabsorption leads to hypercalcaemia.

Of the 11 case reports, elevated levels of PTHrP were observed in 2 cases [8, 9]. PTHrP functions similarly to PTH, increasing the synthesis of receptor activator of nuclear factor kappa (RANK) ligand and activating osteoclasts resulting in bone resorption and calcium release [1]. The true prevalence of PTHrP-mediated mechanisms for hypercalcaemia in GIST may be underreported owing to the variable availability of PTHrP testing at different sites, including ours. The remaining 3 case reports do not document a specific cause for hypercalcaemia [10,11,12].

GIST-associated metastatic bone disease occurs rarely and there are no case reports of this as the cause for hypercalcaemia [13]. Metastatic disease, however, is common; 9 out of 11 case reports we found reported metastatic disease at presentation, predominantly intraperitoneal, contrasting with the localized disease seen in our patient.

Sarcoidosis is a multi-organ, granulomatous disease that commonly manifests as hypercalcemia and acute kidney injury, as in our case with presence of mediastinal lymphadenopathy and non-caseating granulomas on liver biopsy. It is a diagnosis of exclusion, and although interestingly this patient subsequently developed a mycobacterial infection whilst on high dose corticosteroids, mycobacterial, parasitic infection and malignancy were excluded initially by histopathology. Occupational exposures and drug-induced reactions were excluded on basis of history. Similar to malignancy-associated hypercalcaemia, mononuclear cells in granulomas express 1-α hydroxylase, catalysing the conversion of 25(OH)D into 1,25(OH)2D and leading to hypercalcaemia as previously described [14].

There is a clear association between sarcoidosis and malignancy; a meta-analysis by Bonifazi et al. of over 25,000 patients showed sarcoidosis to be associated with an increased risk of skin, haematopoietic, upper gastrointestinal, kidney, liver and colorectal cancers [15]. The pathophysiological link between the conditions, however, is less clear. Tumour-associated granulomas have been described in malignancies, whereby tumoral antigens derived from mutated peptides may induce immune activation and formation of granulomas through a T-cell medicated host response resulting in a sarcoid-like reaction [16]. Sarcoid-like reactions are histologically identical to that of sarcoidosis with non-caseating granulomas, and often occur in close proximity to the tumour or metastases [17]. In our case, although the liver biopsy showed non-caseating granulomas directly adjacent to GIST, the presence of concurrent mediastinal lymphadenopathy and hypercalcaemia which persisted after resection of the GIST, was consistent with systemic sarcoidosis.

The association between sarcoidosis and GISTs however, is less clear, with the current evidence limited to case series and case reports. Espejo et al., between 2007 and 2016, identified 8 patients with dual diagnoses of sarcoidosis and sarcomas in Florida (5 of the 8 cases being GISTs). The authors postulated that if the two conditions were independent, then these 8 cases represented a higher-than-expected rate of dual diagnoses, suggesting a non-random association [18]. Others have described individual case reports of dual diagnoses of GIST and sarcoidosis [19,20,21].

Our understanding of the potential pathophysiological relationship between the two conditions may also be hindered by the chronological variability in their detection. Of the cases we reviewed, sarcoidosis was detected simultaneously with GIST, after GIST and before GIST in approximately equal proportion (3 cases, 3 cases and 2 cases respectively) [18,19,20,21]. It is interesting to note that in Espejo et al.’s case series, in the cases where sarcoidosis was diagnosed after GIST, the sarcoidosis was diagnosed at the time of a GIST relapse [18]. Furthermore, owing to both conditions’ potential for insidious and often asymptomatic presentations, the time between the diagnoses of these conditions varied from 4 months up to 2.5 years, further clouding the ability to establish a clear chronological relationship.

Despite unclear pathophysiological pathways, the growing number of case reports poses an interesting clinical question. When detected together, can definitive management of GIST assist in reducing the burden of corticosteroid therapy in the sarcoidosis? Although far from definitive, we found it notable that our patient’s corticosteroid therapy was rapidly truncated to 4 months due to the development of a mycobacterial infection and to date has not had a relapse of sarcoidosis.

We also wonder whether sarcoidosis could have concurrently been present in the previous case studies of GIST presenting with hypercalcaemia due to elevated 1,25(OH)2D levels. Without histopathology samples demonstrating granulomas, the biochemical features of sarcoidosis and non-sarcoidosis related hypercalcaemia in GIST may be difficult to distinguish and of note, at least 5 of the 6 studies with high 1,25(OH)2D levels also reported treatment of their patients with corticosteroids [2,3,4, 6, 7].