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Mast Cell Leukemia

Mast cell leukemia (MCL) is a very rare form of systemic mastocytosis. Patients typically present with symptoms of mast cell activation, involvement of liver, spleen and lymph nodes. Diagnostic criteria have been published by the World Health Organization and comprise those for systemic mastocytosis and the presence of at least 20% of mast cells in a bone marrow aspirate smear. Due to the rarity of the disease, therapeutic guidelines have not yet been established. Patients are usually treated with tyrosine kinase inhibitors, cytoreductive therapy, or allogeneic stem cell transplantation. Despite all efforts, mortality remains high and survival times are short.


Presentation

Upon activation, mast cells release a wide variety of mediators, such as tryptase and histamine [1]. MCL patients often present with symptoms of mast cell activation, i.e., with symptoms resulting from the effects of mast cell mediators on distinct tissues and organs. In this regard, fever, asthenia, malaise, headache, flushing, tachycardia and diarrhea are commonly reported. Furthermore, MCL patients tend to lose their appetite and may consequently lose weight. The latter may be due to gastroduodenal ulcers, or because of hepatomegaly and splenomegaly, which are common findings in those suffering from MCL. An involvement of liver and spleen is observed in about two thirds of all patients [2]. Some also suffer from ascites. Less frequently, lymph node involvement can be demonstrated. MCL patients may occasionally present with urticaria pigmentosa, but skin changes are not characteristic of the disease [3] [4]. While other organ systems, namely the cardiovascular system, the respiratory and genitourinary tracts may be involved in MCL, such findings a rare. Organ involvement may be assessed by means of diagnostic imaging and histological examinations of tissue samples [5].

It is important to remember that MCL may occasionally be associated with diseases like chronic myelomonocytic leukemia, chronic eosinophilic leukemia and other myeloproliferative neoplasms as well as myelodysplastic syndromes [6] [7]. It cannot be ruled out that such comorbidities may affect clinical and laboratory findings.

Anemia
  • We are reporting the case of a 79-year-old woman, without any hematological particular history consulting for hyperthermia, repeated malaise and subacute anemia. Her clinical examination was normal.[ncbi.nlm.nih.gov]
  • , Refractory anemia with excess of blasts, Chromosome 5q deletion syndrome, Sideroblastic anemia, Paroxysmal nocturnal hemoglobinuria, Refractory cytopenia with multilineage dysplasia ) CFU-Mast Mastocytoma ( Mast cell leukemia, Mast cell sarcoma, Systemic[wikidoc.org]
  • In addition, mild anemia was detected. The disease was characterized by a massive increase in well-granulated, mature, and often spindle-shaped MCs (80 %) in BM smears. The serum tryptase level amounted to 332 ng/mL.[ncbi.nlm.nih.gov]
Fishing
  • As the disease progressed, we observed serial morphologic changes from immature mast cells with myeloblasts to only metachromatic blasts and atypical mast cells as mast cell leukemia; FISH analysis showed that the neoplastic mast cells originated from[ncbi.nlm.nih.gov]
  • […] in this situation : Flow cytometry of bone marrow aspirate for mast cells and other abnormalities Cytogenetic karyotype on bone marrow aspirate (typically abnormal when an associated hematologic neoplasm is present) Fluorescent in situ hybridization (FISH[arupconsult.com]
Death in Childhood
  • […] in childhood 37 ( KIT gene sequencing was not available at that time).[dx.doi.org]
Hepatosplenomegaly
  • […] leukemia is characterized by a substantial increase in atypical mast cells in the peripheral blood, diffuse infiltration with atypical mast cells in the bone marrow, a strong association with peptic ulcer disease, prominent constitutional symptoms, and hepatosplenomegaly[ncbi.nlm.nih.gov]
  • This case presented a relatively fulminant clinical course with acute mast cell leukemia and "C" findings (cytopenia, hepatosplenomegaly, and weight loss), mast cell sarcoma, and severe basophilia.[ncbi.nlm.nih.gov]
  • Findings on CT scan of the abdomen suggestive of mast cell leukemia include: Ascites Hepatosplenomegaly Upper abdominal lymphadenopathy CT of the abdomen demonstrates ascites, hepatosplenomegaly, and upper abdominal lymphadenopathy.[wikidoc.org]
  • Chemotherapy with cytosine arabinoside and idarubicin was ineffective and the patient died of multi-organ failure with rapidly progressing hepatosplenomegaly and large-volume ascites 3 months after admission.[ncbi.nlm.nih.gov]
  • Enlargement of the liver and spleen, or hepatosplenomegaly is characteristic. The mast cells release also many anticoagulants like heparin which can lead to serious bleeding. Liver and splenic dysfunction also contributes to hemorrhage.[checkorphan.org]

Workup

MCL is a rare form of systemic mastocytosis. Consequently, the diagnosis of MCL can be made when general criteria required for systemic mastocytosis and specific criteria for MCL are met [8]. With regards to the former, systemic mastocytosis may be diagnosed in patients who present with multifocal, dense infiltrates of mast cells in sections of bone marrow and/or other extracutaneous organs, and one of the following signs and symptoms:

  • More than 25% of the mast cells in bone marrow biopsy specimens are spindle-shaped or of atypical morphology, or more than 25% of the mast cells in bone marrow aspirate specimens are immature or atypical.
  • An activating KIT D816 mutation is detected by means of genetic analyses of bone marrow or blood samples or specimens derived from other extracutaneous organs.
  • Besides physiological mast cell markers, mast cells in bone marrow, blood or other extracutaneous organs express CD2 and/or CD25.
  • Total tryptase levels in serum persistently exceed 20 ng/ml, unless the patient suffers from an associated clonal myeloid disorder, in which case this criterion doesn't apply.

Of note, infiltrates are considered dense if there are at least 15 mast cells in aggregates. Furthermore, systemic mastocytosis may be diagnosed if the major criterion of multifocal mast cell infiltrates isn't met but three out of four minor criteria are.

In MCL, the histological examination of bone marrow biopsy samples also reveals a diffuse infiltration by immature, atypical mast cells. Accordingly, the proportion of normal hematopoietic precursors and fat is reduced. Common features of atypical mast cells are hypogranular cytoplasm and irregularly shaped nuclei. In bone marrow aspirate smears, more than 20% of all nucleated cells are mast cells. It is highly recommended to realize cytological analyses of bone marrow aspirates and to not rely on estimates regarding the proportion of mast cells derived from biopsy sample examinations. In case of typical MCL, mast cells account for more than 10% of peripheral white blood cells. This is not to be expected in case of atypical, aleukemic MCL. Contrary to what may be assumed, this atypical form of MCL may account for the majority of cases [2]. Aleukemic MCL may progress to leukemic MCL [9].

Treatment

There is no standard therapy for MCL. Due to the rarity of the disease, there is limited experience with distinct therapeutic regimens, the patients' response and survival. Several strategies have been followed:

  • Some authors consider the application of tyrosine kinase inhibitors the mainstay of treatment, since it counteracts the effects of the causal KIT mutation [10]. It is important to take into account the results of genetic analyses when deciding for a determined agent, since some sequence anomalies may render the disease resistant to certain drugs. For instance, Bcr-Abl tyrosine kinase inhibitors like imatinib are ineffective in patients with KIT mutation D816V. By contrast, multi-target protein kinase inhibitors like midostaurin can be applied irrespective of the underlying mutation [11]. Promising results have been obtained in vitro using dasatinib and nilotinib, but it remains to be seen whether they can be reproduced in vivo [12]. Other agents are currently tested in clinical studies, too.
  • Cytoreductive chemotherapy is a less specific approach to therapy. Generally, treatment regimens similar to those recommended for are followed to reduce high burdens of neoplastic cells.
  • On the other hand, allogeneic stem cell transplantation may be considered to treat MCL patients. Unfortunately, retrospective studies show low response rates in individuals who received such treatment [13].

Prognosis

The overall risk of transformation of systemic mastocytosis to MCL has been estimated to 6%. Those individuals suffering from systemic mastocytosis with associated clonal hematological non–mast cell-lineage disease or aggressive systemic mastocytosis are at higher risks of developing MCL than those diagnosed with other forms of mastocytosis [14]. In any case, it should be noted that MCL may develop de novo, irrespective of previously diagnosed mast cell disorders. Unfortunately, MCL is usually refractory to therapy. Mean survival times have been calculated repeatedly, to about six months [2] [4] or two years [15] - all authors coincide in that MCL is associated with a poor prognosis, though.

Etiology

MCL is associated with acquired, gain-of-function mutations of the gene encoding for the receptor tyrosine kinase c-Kit [10]. The KIT gene is located on chromosome 4 and is considered a proto-oncogene. c-Kit locates to the membrane of hematopoietic stem cells and functions as a receptor for the cytokine mast cell growth factor. The latter is also known as stem cell factor and is involved in cell cycle regulation, proliferation and differentiation. In case of activating mutations, mast cell survival and proliferation are enhanced. Additionally, the threshold for the activation of mast cells by other stimuli is lowered.

While mutation D816V is most frequently detected in patients suffering from MCL, other mutations of the same codon or mutations of other codons may also account for the disease. Additional mutations affecting genes like SRSF2, TET2, ASXL1, N/KRAS, CBL, IDH1/2, and RUNX1 may be identified in the majority of MCL patients if comprehensive analyses are carried out. It has been postulated that such additional mutations are acquired prior to KIT mutations, but a causal relation has not yet been established between both events [10].

Of note, activating KIT mutations play major roles in the pathogenesis of other diseases, too. Besides other hematopoietic neoplasms, non-hematopoietic tumors like gastrointestinal stromal tumors and melanomas have also been related to such mutations.

Epidemiology

The incidence of mastocytosis has been estimated to less than 10 per 1,000,000 inhabitants. Both European and North American studies concluded that the prevalence of mastocytosis is about 1 in 60,000 persons [9]. Presumably, less than 1% of all these cases correspond to MCL [2].

MCL is most commonly diagnosed in patients in their fifth to seventh decade of life, but isolated case reports of MCL in children and young adults are available in literature [2] [16] [17]. Females seem to be affected more frequently than males [2] [4].

Sex distribution
Age distribution

Pathophysiology

According to current knowledge, the main pathophysiological event leading to systemic mastocytosis and MCL is the acquisition of a gain-of-function mutation of KIT. Under physiological conditions, tyrosine kinase c-Kit is activated only upon binding of its ligand, mast cell growth factor or stem cell factor. Subsequently, autophosphorylation and dimerization of c-Kit take place. Activated c-Kit then intervenes in several signaling cascades involved in the regulation of cell cycle, proliferation and differentiation. Signaling pathways affected comprise phosphoinositide 3-kinase signaling, JAK/STAT and mitogen-activated protein kinase cascades. As a consequence of activating KIT mutations, c-Kit remains constitutively active. Its regulating effect on mast cell proliferation and survival is no longer exerted. These cells start to proliferate in an uncontrolled manner, while at the same time, their rate of apoptosis is reduced [12].

Little is known about the events determining if an individual carrying activating KIT mutations develops MCL or other forms of mastocytosis. It may be speculated that additional mutations of other genes play major roles in this regard, but evidence cannot currently provided.

Prevention

No recommendations can be given to prevent MCL.

Summary

MCL is a very rare form of systemic mastocytosis and accounts for less than 0.5% of all cases of mastocytosis. MCL may develop secondary to other forms of mastocytosis or appear de novo. Despite its designation as leukemia, it rather resembles systemic mastocytosis with regards to clinical features [2]. The clinical picture is characterized by symptoms of mast cell activation, particularly by those related to increased levels of histamine. Liver, spleen, and lymph nodes are usually involved in the disease, while skin changes are less frequently observed.

The diagnosis of MCL relies on clear-cut criteria defined by experts of the World Health Organization. Since MCL is a form of systemic mastocytosis, the diagnosis of MCL first of all requires that criteria for systemic mastocytosis are met. Additionally, mast cells have to account for more than 20% of all nucleated cells observed in bone marrow aspirate smears. Depending on the subtype of MCL - a typical, leukemic subtype is distinguished from an atypical, aleukemic one - the proportion of mast cells in circulating white blood cells may or may not exceed 10%.

Therapeutic guidelines have not yet been established. Due to the low prevalence of the disease, it is difficult to conduct conclusive clinical studies to assess the efficacy of determined treatment regimens. To date, the application of tyrosine kinase inhibitors or cytostatic drugs as well as the transplantation of stem cells all represent possible therapeutic measures. Unfortunately though, neither has yielded satisfactory results and survival times remain short. Most MCL patients die within a year after diagnosis.

Patient Information

Mast cells are white blood cells and part of the immune system. They fulfill a variety of functions and in order to do so, they secrete mediators like tryptase and histamine. Mast cells develop in the bone marrow, are eventually released into the peripheral blood and infiltrate distinct organs. Under physiological conditions, proliferation and differentiation of mast cell precursors are tightly regulated and the numbers of mast cells in bone marrow and blood are low. However, DNA sequence anomalies may be acquired that interfere with the aforementioned processes and that facilitate the proliferation of mast cells. Such events may trigger neoplastic mast cell disorders like systemic mastocytosis, a disease that may follow a benign or an aggressive course. Mast cell leukemia (MCL) is a form of aggressive systemic mastocytosis.

In patients suffering from systemic mastocytosis, mast cells accumulate within the bone marrow or other organs, but rarely within the skin. Liver, spleen, and lymph nodes are most commonly involved in case of MCL. Contrary to less aggressive forms of the disease, MCL also involves an increase of circulating mast cells. This is why it is called "leukemia" instead of "mastocytosis". Abundant mast cells release abundant mediators and these will have negative effects on several organ systems. Consequently, MCL patients suffer from fever, malaise, headaches, flushing, tachycardia and diarrhea. They are prone to develop peptic ulcers and tend to lose their appetite and weight.

Unfortunately, treatment options are limited. Most patients are given tyrosine kinase inhibitors, drugs that may limit the uncontrolled proliferation of mast cells. Chemotherapeutic regimens that have been proven effective in other types of leukemia may also be followed. Finally, MCL patients may be considered for stem cell transplantation. Despite all efforts, most individuals diagnosed with MCL die within a year after receiving the diagnosis.

References

Article

  1. Castells M. Mast cell mediators in allergic inflammation and mastocytosis. Immunol Allergy Clin North Am. 2006; 26(3):465-485.
  2. Georgin-Lavialle S, Lhermitte L, Dubreuil P, Chandesris MO, Hermine O, Damaj G. Mast cell leukemia. Blood. 2013; 121(8):1285-1295.
  3. Valent P, Berger J, Cerny-Reiterer S, et al. Chronic mast cell leukemia (MCL) with KIT S476I: a rare entity defined by leukemic expansion of mature mast cells and absence of organ damage. Ann Hematol. 2015; 94(2):223-231.
  4. Valentini CG, Rondoni M, Pogliani EM, et al. Mast cell leukemia: a report of ten cases. Ann Hematol. 2008; 87(6):505-508.
  5. Fu Z, Zhang J, Liu M, Li Z, Li Q. Extramedullary Involvement of Mast Cell Leukemia Detected by 18F-FDG PET/CT. Clin Nucl Med. 2016; 41(7):578-579.
  6. Cehreli C, Alacacioglu I, Piskin O, et al. Mast cell leukemia associated with undefined morphology and chronic basophilic leukemia. BMC Hematol. 2014; 14(1):17.
  7. Hu Z, Konoplev S. Aleukemic mast cell leukemia associated with chronic myelomonocytic leukemia and chronic lymphocytic leukemia. Blood. 2017; 130(19):2150.
  8. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4 ed. Lyon, France: IARC Press; 2013.
  9. Magliacane D, Parente R, Triggiani M. Current concepts on diagnosis and treatment of mastocytosis. Transl Med UniSa. 2014; 8:65-74.
  10. Jawhar M, Schwaab J, Meggendorfer M, et al. The clinical and molecular diversity of mast cell leukemia with or without associated hematologic neoplasm. Haematologica. 2017; 102(6):1035-1043.
  11. Youk J, Koh Y, Kim JW, et al. A scientific treatment approach for acute mast cell leukemia: using a strategy based on next-generation sequencing data. Blood Res. 2016; 51(1):17-22.
  12. Verstovsek S. Advanced systemic mastocytosis: the impact of KIT mutations in diagnosis, treatment, and progression. Eur J Haematol. 2013; 90(2):89-98.
  13. Ustun C, Reiter A, Scott BL, et al. Hematopoietic stem-cell transplantation for advanced systemic mastocytosis. J Clin Oncol. 2014; 32(29):3264-3274.
  14. Lim KH, Tefferi A, Lasho TL, et al. Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood. 2009; 113(23):5727-5736.
  15. Jain P, Wang S, Patel KP, et al. Mast cell leukemia (MCL): Clinico-pathologic and molecular features and survival outcome. Leuk Res. 2017; 59:105-109.
  16. Chantorn R, Shwayder T. Death from mast cell leukemia: a young patient with longstanding cutaneous mastocytosis evolving into fatal mast cell leukemia. Pediatr Dermatol. 2012; 29(5):605-609.
  17. Sugita K, Kaneko T, Sekine Y, Taguchi N, Miyauchi J. [Mast cell leukemia evolved from RAEB-T (5q-syndrome) in a 12 year-old girl]. Rinsho Ketsueki. 1996; 37(5):430-436.

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Last updated: 2018-06-22 06:17