1. Advanced Systemic Mastocytosis with Associated Hematologic Non-Mast Cell Lineage Disease
in a patient with advanced liver disease: a case report
Lindsay Elizabeth Cox*1, Maria Jesusa Gracia DeGuzman, MD2, Raj R. Gupta2,3, MD, Olga Fundyler, MD4
Author affiliations: 1-Philadelphia College of Osteopathic Medicine; 2- Oconee Regional Medical Center; 3-Georgia Cancer Specialists; 4-Southern Pathology Associates
Case presentation
A 60-year-old man presented in mild distress with complaints of weakness, nausea, and
bloody diarrhea. He denied having a fever, chills, vomiting, shortness of breath,
palpitations, leg swelling, or a recent infection. Further history eventually revealed the
diarrhea to be long-standing for almost 1 year, with associated unintentional fifty-pound
weight loss despite progressive abdominal distension.
Social history was significant for alcohol abuse, both beer (half a case) and hard liquor.
He denied using tobacco products or illicit substances. His past medical history was
significant for advanced liver disease attributed to alcohol. Home medications included
diuretics. He denied taking any other over-the-counter drugs or herbal supplements.
Physical exam revealed a positive fluid wave and tenderness on exam but no rigidity,
with a blood pressure of 79/40 mmHg, and heart rate of 113 beats per minute. Initial labs
revealed a creatinine of 3.07, platelets of 137,000/mcL, hemoglobin of 7.7, and a white
blood cell count of 42,500 WBC/mcL. His clinical picture appeared consistent with sepsis
and septic shock in the setting of a suspected Spontaneous Bacterial Peritonitis (SBP), and
he was subsequently treated in the intensive care unit. The patient completed a 12-day
hospital course, during which time he underwent a diagnostic paracentesis of ascitic fluid,
which showed no evidence of SBP. Septic workup, including gallbladder studies and stool
for Clostridium difficile toxin, was eventually negative, and there was no prior steroid
therapy. Hepatitis serology and autoantibody panels were also negative. The patient
underwent EGD which showed varices, and a colonoscopy with an unremarkable biopsy.
His persistent lymphocytosis, repeated episodes of hypotension, and refractory anemia/
thrombocytopenia despite multiple transfusion attempts eventually warranted a bone
marrow biopsy. The biopsy revealed markedly hypercellular bone marrow with left shifted
myelopoiesis, clustered mast cells exhibiting spindle-cell morphology, and other histologic
findings consistent with the diagnosis of SM-AHNMD, including an aberrant CD25 surface
marker, which was virtually diagnostic. (see Pictures 1-6 from core biopsy)
After initial hospitalization, the patient was later readmitted in multi-organ failure, awith
hepatorenal syndrome for which he received dialysis, but his family eventually decided on
palliative care with hospice. He expired 34 days after primary presentation.
Picture 1: H&E. 4X. Hypercellular bone marrow Picture 2: Tryptase immunohistochemistry. 20X.
Clustered and focally spindled mast cells
Picture 3: Tryptase immunohistochemistry. 40X. Clustered mast cells Picture 4: CD25 immunohistochemistry. 20X.
Aberrant CD25 expression among mast cells
Picture 5: Reticulin. 20X. Increased fibrosis in association with
mast cell proliferation
Picture 6: H&E. 100X. Atypical mast cell proliferation.
Introduction
Systemic Mastocytosis (SM) is a primary mast cell disorder in which there is a clonal
expansion of mast cells in extra-medullary sites. [1] Sites of proliferation may involve any
vascularized organ, although the typical sites involved include the liver, gastrointestinal
(stomach and duodenum), and lymphoid tissues (spleen). Hepatic, splenic, and bone
marrow fibrosis occur as a result of these cell-mediated processes. Gastrointestinal
involvement results in malabsorption and subsequent symptoms of diarrhea, weight
loss, anemia, and abdominal pain. [2] Degranulation of mast cells can result in symptoms
of severe allergy and anaphylaxis, and the clinical course can range from indolent to
rapidly progressing, and invariably fatal. The prognostic course is determined by subtype
present; the Indolent subtype (ISM), which includes the Smouldering type (SSM),
generally carries a good prognosis. The other more malevolent classifications may be
described as the Advanced Systemic Mastocytoses and include Systemic Mastocytosis
with Associated Hematologic Non-mast Cell Disease (SM-AHNMD), Aggressive Systemic
Mastocytosis (ASM), and Mast Cell Leukemia (MCL) (see Table 1). The Advanced Systemic
Mastocytoses carry a poor prognosis, and mortality is often secondary to mast cell
degranulation in target organs with resultant anaphylactic shock or from organ failure
following the invasion of mast cells into tissues (see Table 2). [3,4]
Table 1: Subtypes of Systemic Mastocytosis
Per the World Health Organization, the presence of the sole major criterion and one
minor criterion OR three or more minor criteria confer a diagnosis of Systemic
Mastocytosis. [5]
SM-AHNMD meets criteria for both Systemic Mastocytosis and for an Associated
Clonal Hematologic Non-Mast cell lineage Disorder (AHNMD). In approximately 20-50%
of all cases of SM, there is an associated hematologic malignancy present [2, 6, 7]. The SM
component in SM-AHNMD often presents as ASM and less frequently as MCL. [2]
The Advanced Systemic Mastocytoses group carry a poor prognosis. No curative therapy
has been defined [7] and cytotoxic agents have demonstrated only partial efficacy [8]. With
no cure and only symptomatic management available, a diagnosis of SM-AHNMD, ASM,
and MCL confer inevitable mortality. [9]
Subtype Distinguishing features
Indolent SM. No B or C findings; no AHNMD
 Smouldering SM + 2 or more B findings, no C.
SM-AHNMD SM + AHNMD
Aggressive SM + One or more C finding. BM aspirate <20% MC
Mast cell Leukemia SM + One or more C finding. BM aspirate >20% MC
Site of involvement Symptoms
Cutaneous Flushing, itchiness, telangectasias, bullae
Gastrointestinal Malabsorption, steatorrhea, ulcers
Hepatic Abnormal LFTs, portal hypertension, ascites
Cardiovascular Vasodilation, tachycardia, hypotension, collapse
Lymphatic Splenomegaly with hypersplenism
Marrow Anemia, thrombocytopenia, fibrosis, myelodysplasia/
myeloproliferative findings
Other systemic Fatigue, cachexia
Mast cell mediator Symptoms
Histamine Pruritis, urticaria, gastric hypersecretion, bronchoconstriction,
systemic hypotension, increased vasopermeability
Cytokines (TNF-alpha, TGF-beta, nerve growth factor) and
growth factors (IL-3, IL-5, IL-6)
Activation of vascular endothelial cells, cachexia, and fibrosis,
Mast cell and eosinophil proliferation, B cell proliferation with
polyclonal increase in immunoglobulins and paraproteins
Proteases (tryptase, chymase) Fibrinogen degradation, stimulation of fibroblast proliferation,
activation of procollagenase and tissue remodeling (degrade
fibronectin)
Heparin Local anticoagulation, osteopenia, and osteoporosis
Cysteinyl leukotrienes (LTC4, LTD4, LTE4) Increased vasopermeability, vasodilation, bronchoconstriction
Prostaglandins Vasodilation, bronchoconstriction, flushing
Platelet Activating Factor Increased vasopermeability, vasodilation
Discussion
The case as it relates to Alcoholic Liver Disease (ALD)
The patient had many features of ALD, including ascites, esophageal
varices, gynecomastia, hepatosplenomegaly, palmar erythema, and spider
angiomas. The patient clearly had liver cirrhosis, however it is not
unreasonable to suspect that the mastocytosis had contributed in some
degree to this injury, as the fibrotic changes that occur with mast cell
infiltration makes mastocytosis a known contributor to liver injury. [1]
In both ALD and SM, thrombocytopenia may result from primary bone
marrow hypoplasia, or splenic sequestration. The hypoplastic bone marrow
also leads to a transient leukopenia and patients are at increased risk of
infection. [10] Moderate leukocytosis (<20,000/mcL) is known to occur in
moderate to severe cases of alcoholic hepatitis. [10] In contrast, this patient
developed massive leukocytosis, peaking at 118,000 cells/dL. Of note, a
leukemoid reaction may also be seen, albeit rarely, in the setting of alcoholic
hepatitis, with white counts exceeding 100,000. It is associated with very high
mortality rates.[11]
Classifying the Systemic Mastocytosis
Transformation of the Mastocytosis into the ASM variant (independent of
the AHNMD) is possible. [12] By definition, ASM is characterized by the
presence of one or more “C” findings, and may or may not express the D816V
c-kit mutation [13]. C findings include: hepatomegaly with organ dysfunction,
splenomegaly with hypersplenism, malabsorbption due to mast cell infiltrates,
pathologic fractures of bone and/or large osteolytic lesions, and marrow
dysfunction in the form of a cytopenia (Hgb <10 g/dL, platelets <100 x109/L),
not caused by an AHNMD. [14]
The evidence for hepatomegaly with impairment of liver function,
splenomegaly with hypersplenism, and malabsorption fulfills three C findings
but cannot be attributed solely to the mastocytosis because of the
compounding clinical picture of alcohol abuse. If one biopsy had positively
identified a distinct mast cell infiltrate of the liver, spleen, or gut mucosa,
transformation into a more aggressive variant, ASM-AHNMD would have been
more established. [4] Nevertheless, it is reasonable to suspect that
transformation ASM-AHNMD may have occurred, as this best explains the
patient’s rapid deterioration and sudden mortality.
The case as it relates to AHNMD
The most commonly associated hematologic disorders in SM-AHNMD are
myeloproliferative or myelodysplastic diseases, [15] though lymphoproliferative
diseases, such as myeloma and lymphomas and secondary acute leukemias
have been reported. [16] The bone marrow specimen was negative for the
highly specific bcr-abl fusion gene, essentially disqualifying CML from the
differential diagnosis. The mutated JAK2 V617F was also not identified on the
pathological specimen. While the somatic mutation in Janus Kinase 2 is a
diagnostic marker for myeloproliferative neoplasms, a negative value does not
rule out MPNs. [17]
Several features of PMF were present in the patient’s clinical picture,
including severe fatigue, weight loss, hepatosplenomegaly with progressive
anemia requiring frequent red blood cell transfusions, portal hypertension
with the development of varices, and ascites. Again, these features are also
seen as C findings in ASM, and also in ALD, which may further obfuscate the
presence of malignancy in a known alcoholic.
Acknowledgments
The authors thank all medical staff involved in the care of this patient, most especially the hospitalists,
and Dr. Elenora Savitchi, laboratory director at Oconee Regional Medical Center, for her role in diagnosing
this case and her invaluable assistance in obtaining histologic pictures used in this poster. We thank
graphic designer Andrea Gutierrez for her professional services in the layout of this poster.
Conclusion
This patient presented with long-standing diarrhea and episodic
hypotension, symptoms commonly encountered by an internist.
Systemic Mastocytosis is known to present with these symptoms,
and contribute to liver injury. This case highlights that a diagnosis of SM
can be delayed or obfuscated behind alcoholic liver disease and the
stigmata of cirrhosis. It also underscores the need to consider bone
marrow biopsy early, in a patient with persistent leukocytosis, if prior
workup is unable to offer a clear cause.
Though rare, it is hoped that the information presented will
encourage consideration of this disease entity, as a potential cause of
systemic findings in a patient presenting with a similar clinical picture.
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Table 3: Symptoms resulting from specific mast cell mediators
Table 2: Symptoms resulting from mast cell degranulation in target tissue. Systemic Mastocytosis is known to cause episodic
hypotension, anaphylaxis, and contribute to liver injury.
Major criterion:
• Multifocal, dense infiltrates of mast cells (≥15 mast cells in aggregates) detected on sections of bone
marrow and/or biopsy specimens from other extra-cutaneous organ(s).
Minor criterion:
• In biopsy sections of bone marrow or other extra-cutaneous organs, >25 percent of the mast cells in the
infiltrate are spindle-shaped or have atypical morphology, OR of all mast cells in bone marrow aspirate
smears, >25 percent are immature or atypical.
• Detection of an activating point mutation at codon 816 of KIT in bone marrow, blood or another
extracutaneous organ (CD 117+ D816V).
• Mast cells in bone marrow, blood, or other extra-cutaneous organs must express CD2 (LFA-2) and/or CD25
(interleukin-2) in addition to usual mast cell markers.
• Total serum tryptase must persistently exceed 20 ng/mL (unless there is an associated clonal myeloid
disorder, in which case this parameter is not valid).
Prognosis
Poor prognostic factors in SM include: older age at diagnosis, weight loss,
thrombocytopenia, hypoalbuminemia, low hemoglobin, elevated lactate
dehydrogenase, elevated alkaline phosphatase, hepatosplenomegaly, ascites,
excess bone marrow blasts, and qualitative changes in RBC and/or WBC
morphology-- most of which were present in this patient. [18, 19]
Treatment
The Advanced Systemic Mastocytoses are incurable, and therefore
treatment should be directed at preventing and controlling the associated
mast-cell mediator derived symptoms [3, 7], and utilizes H2-blockers, anti-
histamines and an Epipen. Additionally, management of the associated
hematologic malignancy should be approached with the conventional gold-
standard medical therapy targeted to the specific associated leukemia or
myelodysplastic syndrome, i.e. with hydroxyurea. [19, 20]