Systemic Mastocytosis: A Rare and Unusual Cause of Pancytopenia

Introduction

Mast cells are tissue-bound immune cells that have a pivotal role in allergic and inflammatory responses. They originate from haematopoietic progenitors and mature at specific sites, where their functions vary. Systemic mastocytosis (SM) represents a spectrum of clonal mast cells.^[1] The 2016 classification by the World Health Organization (WHO) categorised SM as a subset of myeloproliferative neoplasms. This framework distinguishes the condition by its clinical presentation, primarily separating it into skin-focused forms and more complex systemic variants.^[2] SM is defined by the systemic proliferation of aberrant mast cells across the bone marrow and extra-skeletal organ systems.^[3,4]

SM is a rare disorder with an estimated prevalence of around 10 cases per 1 lakh population.^[4] Cutaneous mastocytosis classically presents with symptoms ranging from localised urticaria to angioedema, while SM may present with multi-system features include flushing, abdominal pain, tachycardia, diarrhoea, hypotension, musculoskeletal pain and neuropsychiatric symptoms.^[1]

Case Details

A 68-year-old lady presented to the emergency department with frequent episodes of loss of consciousness for the past 1 month. Each episode was associated with hypotension, palpitation and fatigue. The course of the episode was delineated by the patient as a sense of fatigue and dizziness, which was followed by an episode of sudden blackout. The patient usually gained consciousness around 5–10 minutes later; however, palpitations, fatigue and nausea persisted after the episode for several minutes.

None of the bystanders reported any abnormal body movement or any involuntary stool and urine passage during the episode. The patient did not report any focal neurological deficits or sensory phenomena during or after the event. The patient denied fever, headache, aural fullness, or any hearing disability. The episodic complaints occurred without diarrhoea or chest discomfort. Additionally, she did not report any skin rash, pruritus, or poor oral intake. Her previous medical history was insignificant.

On examination, she was found to be hypotensive with a blood pressure of 86/52 mmHg, tachycardia (pulse:114/minute), SpO2 of 95%, and random blood sugar levels of 127 mg/dL. With an intravenous fluid bolus, hemodynamic stability was achieved within a span of one hour. Lung and cardiac examination did not reveal any murmur or bilateral bibasilar crepitation. A chest X-ray was normal. Electrocardiogram was suggestive of sinus tachycardia and the transthoracic echocardiography showed normal function of heart. Holter monitoring did not reveal any significant arrhythmia.

Baseline laboratory investigations revealed pancytopenia with a hypo-proliferative marrow with haemoglobin of 2.9gm%, total leukocyte count of 2.19 × 109/L (59% neutrophils, 32.9% lymphocytes, 6.8% monocytes) and platelet count of 7,000 × 109/L with corrected reticulocyte count of 1.1%. Peripheral blood smear revealed lymphocytosis. Notably, her routine nutritional workup was within normal limits. Baseline laboratory evaluations—including metabolic, renal, hepatic, and thyroid panels—were unremarkable. Her urinary and serum metanephrine and 5- Hydroxy indoleacetic acid (5-HIAA) were negative. Ultrasonography revealed a normal liver and mild splenomegaly up to 12 cm in oblique dimension.

Bone marrow biopsy and aspiration revealed hypocellular marrow with dense spindle-shaped mast cells infiltrate (16%) [Figure 1]. Immunohistochemistry with CD117 marker and toluidine blue staining confirmed mast cell proliferation [Figure 2]. Additionally, total serum tryptase level was elevated at 42 ng/mL. Based on the above clinical findings, she was diagnosed as a case of aggressive SM with features due to mast cell degranulation and bone marrow infiltration leading to evident cytopenia. She was managed with low-dose glucocorticoids and packed cell transfusion, along with other supportive treatment. Histamine antagonists were not prescribed, and she was discharged after counselling and educating her about other related signs and symptoms, including anaphylaxis. She has been on our routine outpatient follow-up and has currently shown significant improvement.

OPEN IN VIEWER Figure 1.

Bone marrow biopsy and aspiration of the patient showing pancytopenia and hypo-proliferative marrow with dense infiltrates of spindle -shaped mast cells^[4]

OPEN IN VIEWER Figure 2.

Immunohistochemistry with CD17 marker and toluidine blue staining confirming the presence of mast cells in the bone marrow^[4]

Discussion

SM is the clonal expansion of mast cells triggered by constitutive activation of the KIT receptor tyrosine kinase. This is predominantly attributed to the c-KIT D816V point mutation (80% of cases), which confers ligand-independent signalling.^[1,2] Upon activation, the proto-oncogene encodes KIT (CD117), a transmembrane tyrosine kinase receptor. KIT expression is characteristic of early haematopoietic progenitor cells, though it is also maintained in specific terminally differentiated populations, most notably the interstitial cells of Cajal in the gut, respiratory epithelium, skin, etc.^[1] These neoplastic cells may also express CD2 and/or CD25 in addition.^[2]

Mast cells contain various mediators such as histamine, tryptase and cytokines responsible for diverse systemic manifestations. Triggers include immunologic stimuli, drugs, venoms, physical stress and neuropeptides.^[1] The WHO classification distinguishes between cutaneous and systemic disease, with diagnostic criteria based on tissue histology, immunophenotyping and molecular testing [Table 1].

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Table 1.

Criteria to diagnose systemic mastocytosis^[4]

Major	Minor
Presence of multifocal, dense mast cell infiltrates—defined as aggregates of ≥15 cells— identified in extracutaneous biopsies (primarily bone marrow) and visualised via tryptase or CD117 (KIT) immunohistochemistry (IHC)	Morphological atypia: In histological sections, more than 25% of mast cells within the infiltrate exhibit atypical (spindled) morphology; alternatively, more than 25% of mast cells in bone marrow aspirate smears are identified as immature or atypical. Aberrant immunophenotype: Mast cells demonstrate the co-expression of CD117 with CD2 and/or CD25 as determined by flow cytometry or immunohistochemistry. Molecular profile: Identification of a KIT activating point mutation, most commonly at codon 816 (e.g., KIT D816V), in the bone marrow or other extracutaneous tissues. Serological markers: A persistent elevation of total serum tryptase levels exceeding 20 ng/mL (in the absence of an associated myeloid neoplasm).
Diagnosis: 1 major + 1 minor or 3 minor criteria

SM is further stratified into distinct subtypes based upon B-findings and C-findings.

B-findings include:

A bone marrow biopsy demonstrating >30% mast cell infiltration and/or a basal serum tryptase level exceeding 200 ng/mL.

C-findings are characterised by:

Bone marrow failure manifesting as one or more cytopenias: an absolute neutrophil count (ANC) < 1.0 × 109/L, haemoglobin (Hb) < 100 g/L or a platelet count < 100 × 109/L.

Various subtypes of SM have been described further based on B and C-findings [Table 2].

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Table 2.

Subtypes of systemic mastocytosis^[4]

Subtype	Definition
Indolent SM	Negative for ‘C’ findings. No diagnostic evidence of a related blood cancer
Smouldering SM	Negative for ‘C’ findings. Two or more B-findings in the absence of an associated haematologic neoplasm (AHN)
SM with AHN	SM with a concurrent non-mast cell clonal haematologic disorder
Aggressive SM	≥1 ‘C’ findings. Negative for mast cell leukaemia (MCL)
MCL	Bone marrow (biopsy/aspirate ≥20% mast cells) Peripheral blood ≥20% mast cells Aleukemic MCL variant (<10% circulating mast cells)

Identifying SM often requires a high degree of suspicion. The patient can present with a wide range of clinical symptoms, including syncope, light-headedness, abdominal pain, diarrhoea, nausea, vomiting, generalised body aches, osteoporosis, wheezing, shortness of breath, nasal congestion, generalised fatigue, various neuropsychiatric symptoms, etc. Many patients cycle through multiple specialists and facilities without finding the answers or relief they need.^[5,6]

Treatment of SM in resource-constrained settings is mainly supportive, focusing on trigger avoidance, use of antihistamines, and oral cromolyn for gastrointestinal manifestations. Supplementary treatments like leukotriene antagonists or H2/PPI blockers may be used as needed. For specific clinical profiles, specialised options including omalizumab, corticosteroids, cytoreductive agents, or tyrosine kinase inhibitors can be evaluated.^[7]

Conclusion

With this wide array of symptomatology, often the delayed presentation of the patient to a physician contributes towards the disease being either misdiagnosed or easily missed at the primary care point. A high degree of clinical suspicion is essential for recognising patients with diverse, non-specific symptoms. Careful history examination and a comprehensive laboratory evaluation are required to reach the final diagnosis, which could drastically improve the quality of life of the patient as treatment is so simple and very effective.