Diagnostic assessment

A subsequent nuclear medicine whole body bone single-photon emission CT (SPECT)/CT scan demonstrated the neck-tie sign of the sternum (Fig. 1) and diffuse crisp radiotracer uptake throughout the rest of the skeleton consistent with a superscan pattern, an image appearance representing intense osteoblastic activity (Fig. 1) [5]. The neck-tie sign is thought to represent expansion of the manubrium and sternal marrow without concurrent expansion of the manubriosternal joint, with increased tracer uptake on bone scintigraphy giving an appearance of a neck-tie [6].

Figure 1: Panel A: neck-tie sign on bone scintigraphy. Panel B-D: diffuse crisp radiotracer uptake throughout the spine on a nuclear medicine whole body bone single-photon emission CT (SPECT)/CT scan.

A bone mineral density (BMD) scan revealed a significantly elevated Z-score of 2.9 of the left total hip. At the lumbar spine and left femoral neck, the BMD Z-scores were 1.7 and 1.8, respectively. A bone formation marker (procollagen type 1 N-terminal propeptide 95 μg/L [reference range, 15-70 μg/L]) was elevated, while a bone resorption marker (C-terminal telopeptide 480 ng/L [reference range, 150-800 ng/L]) was normal.

Investigations for causes of diffuse osteosclerosis ruled out malignancy (normal electrophoresis, flow cytometry on peripheral blood, and mammography). Urine fluoride was not elevated at 1.2 mg/L (SI: 63 μmol/L) (reference range, <2.0 mg/L [SI: <105 μmol/L]). Other investigations included a normal corrected serum calcium 9.9 mg/dL (SI: 2.46 mmol/L) (reference range, 8.6-10.3 mg/dL [SI: 2.15-2.65 mmol/L]) paired with a normal parathyroid hormone (PTH) of 55.6 pg/mL (SI: 5.9 pmol/L), (reference range, 18.8-81.1 pg/mL [SI: 2.0-8.5 pmol/L]), and vitamin D was 20.43 ng/mL (SI: 51 nmol/L) (reference range, >20 ng/mL; SI >50 nmol/L). Hepatitis C serology was negative in addition to a lower CRP 21 mg/L (SI: 200 nmol/L) and neutrophil count had normalized (8.7 × 103/μL [SI: 8.7 × 109/L]). Thyroid function tests demonstrated subclinical hypothyroidism not requiring treatment (thyroid-stimulating hormone 8.29 mIU/L, [SI: 8.29 μIU/mL] (reference range, 0.4-4.2 mIU/L; SI: 0.4-4.2 μIU/mL), with free thyroxine (T4) 0.88 ng/dL (SI 11.3 pmol/L) (reference range, 0.8-1.8 ng/dL; SI: 10.0-23.0 pmol/L).

Further investigation revealed an elevated tryptase level of 126 ng/mL (SI: 126 μg/L) (reference range <11.4 ng/mL, SI: <11.4 μg/L). Bone marrow biopsy yielded a “dry tap” aspirate with trephine demonstrating abnormal aggregates of spindle-shaped mast cells >15 in a group, with positive staining for tryptase and CD25 (Fig. 2). No other hematological malignancy was identified. Peripheral blood c-KIT D816 V testing and all-heme next-generation sequencing (to identify other somatic mutations which may signify a poor prognosis) yielded no somatic variants.

Figure 2: Trephine sample demonstrating spindle-shaped mast cells, with positive staining for tryptase. Microscope magnification 100×.

A diagnosis of diffuse osteosclerosis secondary to SM was made. In the absence of “B and C” findings, her disease was classified as indolent SM (Table 1).

Major criterion
Multifocal dense infiltrates of mast cells (≥15 mast cells in aggregates) in bone marrow biopsies and/or in sections of other extracutaneous organ(s)
Minor criteria
≥25% of all mast cells are atypical cells (type I or type II) on bone marrow smears or are spindle-shaped in mast cell infiltrates detected in sections of bone marrow or other extracutaneous organs
KIT-activating KIT point mutation(s) at codon 816 or in other critical regions of KIT in bone marrow or another extracutaneous organ
Mast cells in bone marrow, blood, or another extracutaneous organ express one or more of: CD2 and/or CD25 and/or CD30
Baseline serum tryptase concentration > 20 ng/mL (in the case of an unrelated myeloid neoplasm, an elevated tryptase does not count as an SM criterion. In the case of a known HαT, the tryptase level should be adjusted
The diagnosis is SM if at least 1 major and 1 minor or 3 minor criteria are fulfilled