Hepatic Involvement in Advanced Systemic Mastocytosis: Clinical and Histopathological Correlates and Future Implications
Authors: Farmer Isabel , Green Anna C , Sriskandarajah Priya , Schwaab Juliana , Rets Anton , Moulton Deborah , Hussein Hayder KA , Asirvatham Susan , George Tracy I. , Reiter Andreas , Radia Deepti H. 
Published: December 2024

Background

Systemic mastocytosis (SM) is a rare haematological disorder associated with the KIT D816V mutation in &gt;95% of cases. In addition to bone marrow (BM), advanced SM (AdvSM) is characterised by accumulation of neoplastic mast cells (MC) and, in cases of an associated haematological neoplasm (SM-AHN), other KIT D816V+ lineages, in the liver, spleen and gastrointestinal tract with organ dysfunction.

The frequently observed significant elevation of alkaline phosphatase (ALP) is accepted as evidence of hepatic infiltration. However, few patients (pts) undergo liver biopsy (LB), hence the hepatic MC infiltrate is likely underestimated. Additionally, while MCs are known to cause liver fibrosis alternative causes for these histopathological findings may be overlooked.

Methods

We undertook a retrospective review of 14 AdvSM and 2 Smouldering SM (SSM) pts who had undergone LB. Clinical, laboratory, radiological and endoscopic data were collected. We assessed MC infiltration in LB as well as background fibrosis and the presence of an AHN. Contemporaneous BM biopsy was reviewed. The original LB was reviewed in 8/16 cases; the report in the remaining 8, and data collated based on the Rossignol et al (2024) study.

Results

Pt median age was 69 (range 27-79) years with a slight male predominance (9/16; 56%). SM-AHN accounted for 11/16 (69%) cases with chronic myelomonocytic leukaemia (CMML) in 9/11; 3/16 had aggressive SM and 2/16 had SSM. All cases were C-KIT D816V+ and 13/16 (81%) pts had ascites. Median tryptase was 173µg/l (range 9-1540).

ALP was elevated in all pts (median 225U/L; range 101-1400), with higher levels observed in SM-AHN (median ALP 341 U/L). Gamma-glutamyl transferase was also raised (median 151 IU/L; range 69-320), while other typical liver enzymes were within normal range. Coagulation parameters, reflective of liver synthetic function, were normal. Eight of 16 (50%) pts had additional screens including hepatitis and autoantibodies and in only 1 case was an abnormality detected (alpha-1 antitrypsin deficiency).

Liver volume quantification by magnetic resonance imaging in 7/16 showed variable size (mean 1848cm3; range 1278.5-3127; normal mean +/- standard deviation 1505 ± 385). Descriptive wording included “irregular, shrunken and lobulated”. Splenomegaly was universal (mean 1001 cm3; range 409.1-1612.4; normal mean volume 236.89 ± 77.58) but the median haemoglobin (111g/L) and platelet counts (173 x 109 /L) were normal.

Fibroscan showed significant fibrosis (F3/4) in 5/6 (83%) pts. Upper gastrointestinal endoscopy showed 10/11 (91%) with abnormalities including oesophageal varices and portal hypertensive gastropathy.

LBs were undertaken in known (11/1; 69%) and unknown (5/16; 31%) SM cases. Indications included liver function test abnormalities, recurrent ascites or possible drug related toxicity. No bleeds were sustained through transjugular or conventional routes. Two of 4 pts who were on a tyrosine kinase inhibitor (TKI) were known to have BM complete remission.

The MC infiltrate on LB was very dense (&gt;80 MCs/high power field (hpf)) in 6/9 LBs with no obvious correlation with BM MC burden/ALP. Morphologically, liver MCs (LMC) were predominantly round/ovoid and exceeded spindle shaped forms in 8/11.MC morphology was comparable to the BM in 5/9 cases, and discrepant in 4/9 cases with LMCs being round/ovoid vs spindle-shaped in the BM.

Immunophenotypically, CD117 and tryptase were universally expressed (13/13) and LB/BMT expression was comparable. CD25 was positive in 13/15 LMCs and discrepant with the BMT in only 1 (negative in liver). CD30 was positive in only 2/7, (weak). 1 case was CD30 negative in the liver and positive in the bone marrow. All LBs with a MC infiltrate &gt;5/hpf showed fibrosis. The presence of EMH +/- AHN was variable with EMH reported in 3 cases.

Conclusions

Overall, our study demonstrated high MC burden on LB in the majority of AdvSM and SSM pts, with associated fibrosis. The LMC infiltrate did not always correlate with BM burden or ALP levels. The discrepancies between morphology and immunophenotype of MCs in liver and BM suggest further work is warranted to improve our understanding of the role of MCs on liver function, especially in the era of novel TKIs. Collaboration with hepatologists to devise a pathway inclusive of LB/non-invasive monitoring by fibroscan to infer MC clearance, is invaluable, particularly in transplant-eligible patients.