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, awithhepatorenal 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 Mastocytosiswith 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

DiscussionThe 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 MastocytosisTransformation 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 AHNMDThe 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 leukemiashave 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.

[1] Harrison’s principles of internal medicine—17th ed. / editors, Anthony S. Fauci et al. 2008 McGraw-Hill Companies, Inc. ch. 311 p 2067,8[2] Elizabeth H. Nora, MD, PhD; Kirsten L. Hamacher, MD; Clive S. Zent, MD; Amit K. Ghosh, MD. Indolent Systemic Mastocytosis as the Cause of a Long History of Unexplained Hypotensive Episodes. Southern Medical Journal2006;99(8):876-879[3] Peter Valent, Wolfgang R. Sperr, and Cem Akin. How I treat patients with advanced systemic mastocytosis December 23, 2010; Blood: 116 (26)[4] Parker R.I. Hematologic aspects of mastocytosis: I: Bone marrow pathology in adult and pediatric systemic mast cell disease. J Invest Dermatol. 1991;96(3):47S.[5] Horny HP, Metcalfe DD, Bennet JM, et al. Mastocytosis. In: WHO classification of tumours of haematopoietic and lymphoid tissues, 4th ed, Swerdlow SH, Camp E, Harris NL, et al (Eds), IARC, Lyon 2008

6] Horny H. Sotlar K, Valent P, Institute of Pathology. Mastocytosis: State of the Art. Pathobiology 2007;74:121–132[7] Hennessy B, Giles F, Cortes J, O'brien S, Ferrajoli A, Ossa G, Garcia-Manero G, Faderl S, Kantarjian H, Verstovsek S. Management of patients with systemic mastocytosis: review of M. D. Anderson Cancer Center experience. Am J Hematol.2004;77(3):209. [8] Ayalew Tefferi, Srdan Verstovsek, Animesh Pardanani. How We Diagnose And Treat Who-Defined Systemic MastocytosisIn Adults. Haematologica January 2008 93: 6-9[9] Worobec AS, Kirshenbaum AS, Schwartz LB, Metcalfe DD. Treatment of three patients with systemic mastocytosis with interferon alpha-2b. Leuk Lymphoma. 1996;22(5-6):501.[10] Savage D, Lindenbaum J. Anemia in alcoholics. Medicine (Baltimore). 1986;65(5):322.[11] Mitchell RG, Michael M 3rd, Sandidge D. High mortality among patients with the leukemoid reaction and alcoholic hepatitis. South Med J. 1991 Feb;84(2):281-2.

[12] Valent P, Akin C, Sperr WR, Horny HP, Metcalfe DD. Smouldering mastocytosis: a novel subtype of systemic mastocytosis with slow progression. Int Arch Allergy Immunol 2002;127(2):137-139[13] Floman Y, Amir G. Systemic mastocytosis presenting with severe spinal osteopenia and multiple compression fractures. J Spinal Disord. 1991;4(3):369.[14] Valent P, Horny HP, Escribano L, et al. Diagnostic criteria and classification of mastocytosis: a consensus proposal. LeukRes 2001;25:603-625.[15] Yavuz AS, Lipsky PE, Yavuz S, Metcalfe DD, Akin C. Evidence for the involvement of a hematopoietic progenitor cell in systemic mastocytosis from single-cell analysis of mutations in the c-kit gene. Blood. 2002;100(2):661.[16] Tzankov A1, Sotlar K, Muhlematter D, et al. Systemic mastocytosis with associated myeloproliferative disease and precursor B lymphoblastic leukaemia with t(13;13)(q12;q22) involving FLT3. J Clin Pathol. 2008 Aug;61(8):958-61.

[17] Baxter EJ, Scott LM, Campbell PJ , et al. Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet. 2005;365(9464):1054.[18] Lim KH, Tefferi A, Lasho TL, Finke C, Patnaik M, Butterfield JH, McClure RF, Li CY, Pardanani A. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009;113(23):5727.[19] Lawrence JB, Friedman BS, Travis WD, Chinchilli VM, Metcalfe DD, Gralnick HR. Hematologic manifestations of systemic mast cell disease: a prospective study of laboratory and morphologic features and their relation to prognosis. Am J Med. 1991;91(6):612.[20] Lim KH, Pardanani A, Butterfield JH, Li CY, Tefferi A. Cytoreductive therapy in 108 adults with systemic mastocytosis: Outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine. Am J Hematol. 2009;84(12):790.

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).

PrognosisPoor 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]

TreatmentThe 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]