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Home , Leukemia, Mast cell leukemia, Solitary mastocytoma

CASE REPORTS

Pediatric Dermatology Vol. 29 No. 5 605–609, 2012

Death from : A Young Patient with Longstanding Cutaneous Evolving into Fatal

Rattanavalai Chantorn, M.D.,*, and Tor Shwayder, M.D.

*Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand, Department of Pediatric Dermatology, Henry Ford Hospital, Detroit, Michigan

Abstract: Mastocytosis is a broad term used for a group of disorders characterized by accumulation of mast cells in the skin with or without extracutaneous involvement. The clinical spectrum of the disease varies from only cutaneous lesions to highly aggressive systemic involvement such as mast cell leukemia. Mastocytosis can present from birth to adult- hood. In children, mastocytosis is usually benign, and there is a good chance of spontaneous regression at puberty, unlike adult-onset disease, which is generally systemic and more severe. Moreover, individuals with systemic mastocytosis may be at risk of developing hematologic . We describe a girl who presented to us with a solitary at age 5 and later developed maculopapular cutaneous mastocytosis. At age 23, after an episode of anaphylactic shock, a marrow examination revealed mast cell leukemia. She ultimately died despite aggressive and transplantation.

Mastocytosis is characterized by the abnormal common forms of CM in childhood. The excoriation growth and infiltration of mast cells (MC) in various of lesions causes hives and perilesional erythema, tissues and is classified into two broad categories: which characterizes Darier’s sign (Fig. 3). SM is cutaneous mastocytosis (CM) and systemic mastocy- characterized by multifocal MC infiltrates with or tosis (SM) (1). The course of mastocytosis is variable without skin involvement and is markedly more and is dependent on the subtype and age of onset common in adults than in children. Mast cell (2–4). Mast cell disease in children is usually only leukemia is a rare variant of SM, with few cutaneous and not associatedwithsystemicor cases reported in the literature and usually associated malignant disorders. In adults, MC disease can with grave (6–12). The purpose of this be systemic and progressive (4). Mastocytosis affects article is to report a case of longstanding childhood infants and children twice as frequently as adults (5). CM evolving to fatal MC leukemia during young Mastocytoma and (UP) are adulthood.

Address correspondence to Tor Shwayder, M.D., Director, Pediatric Dermatology, Henry Ford Hospital, Detroit, MI 48202, or e-mail: [email protected].

DOI: 10.1111/j.1525-1470.2011.01650.x

2012 Wiley Periodicals, Inc. 605 606 Pediatric Dermatology Vol. 29 No. 5 September ⁄ October 2012

CASE REPORT that were positive for Darier’s sign (Fig. 3). Otherwise, review of systems was normal. She denied any symptom A girl had been diagnosed with of release, including flushing, palpitation, since 5 years of age (Fig. 1). Her first presentation was a , , , and . red-brown thumb print–sized plaque in front of the left Because her underlying cutaneous disease was gradually ear that had history of bullous formation after blunt spreading, she was carefully examined. General physical trauma (Fig. 2). Skin confirmed the diagnosis of examination, pressure, pulse, and respiration were cutaneous MC disease at age 5 (outside punch biopsy) all normal. , function test, and age 19, when this lesion was removed completely. renal function test, and urinalysis were normal. The She was regularly followed by a pediatrician and a preauricular solitary mastocytoma was sensitive and pediatric dermatologist and had had normal develop- ‘‘annoying’’ to the patient. She was treated using ment. intralesional steroids several times and topical cortico- At the age of 10, more spots had slowly appeared on steroids as needed. Eventually, at age 19, she requested the neck, the V of the neck, the shoulders, and the back removal. Histopathology showed nodular infiltration of MC with prominent infiltrate of extending throughout the thickness of the dermis and subcutaneous fibroadipose tissue (Figs 4 and 5). Histochemical stains for Giemsa, Leder, and Alcian blue confirmed MC (Fig. 6). At age 23, she was given acetaminophen with codeine and aspirin for neck and low back pain. This precipitated anaphylactic shock, requiring intubation and hospital- ization. Diagnosis of systemic mastocytosis was made based on results as follows: 8.1 g ⁄dL, white count 7,200 cell ⁄mL ( 86%, lym- phocytes 6.9%, 8.3%), 267,000 ⁄mL, and a serum tryptase was >200 ng ⁄mL, and urine his- Figure 1. Preauricular mastocytoma: similar clinical picture tamine greater than two times normal limits. Bone to first presentation.

Figure 2. Sister kicked her in this area, resulting in prompt Figure 3. Urticaria pigmentosa macules gradually increas- large bullae. ing in number over upper back. Note positive Darier’s sign. Chantorn and Shwayder: Death from Mast Cell Leukemia 607

Figure 6. Low-power view of preauricular biopsy Giemsa stain showing multiple mast cells.

attacks per day consisting of tachycardia, flushing, mild shortness of breath, chest pressure, mild , and low back pain, lasting approximately 20 to 30 minutes Figure 4. Low-power view of preauricular area excision. Mast cell infiltrate throughout thickness of biopsy. each, and resolving without complications. She was admitted to the hospital for further examination and monitoring. Laboratory tests demonstrated hemoglobin of 13.3 g ⁄dL, count 26,200 cell ⁄mL (neutrophils 58.5%, 9%, monocytes 2.5%, 28.7%), absolute count 15,327 cell ⁄mL, absolute eosinophil count 7,519 cell ⁄mL, and platelet count 122,000 ⁄mL. Repeat bone marrow aspi- rate smear showed that 79% of MC had atypical spindle- shaped morphology and confirmed the diagnosis of MC leukemia with rapid progression. Abdominal ultra- sonography revealed mild . Induction chemotherapy with and ida- rubicin was started and induced some response. She subsequently underwent HLA identical sibling allo- genic peripheral blood stem cell transplantation, with fludarabine and as a conditioning regimen. Twelve days later, she started to engraft. Unfortu- Figure 5. High-power view of preauricular biopsy with dense nately, she continued to have episodes of histamine mast cell infiltrate. Note rare atypical multinucleated mast cells. release symptoms. Repeat bone marrow biopsy was done and demonstrated 70% of MC with sheets of atypical MC. Flow cytometric analysis revealed an marrow aspiration and biopsy showed that multiple atypical population of cells that expressed CD117, small aggregates of MC occupied 5% of the bone mar- CD25, CD58, CD63, and CD33, but were negative for row medullary space and stained strongly positive for CD2. Cytogenic studies were positive for a BCR-ADL tryptase.Rarespindle-shapedMCwerealsoseeninthis rearrangement. C- analysis was not per- bone marrow study. Long bone survey was unremark- formed. These findings were consistent with persistent able. Computed tomography of the chest, abdomen, and MC leukemia. In addition, she had developed skin pelvis were normal except for an ectopic right pelvic rash, with a diagnosis of graft versus host disease, kidney. She was treated using systemic and was treated with high-dose systemic steroids and and H1 and H2 antihistamine. oral tacrolimus. During the 4 months after being diagnosed with sys- Her last admission was because of progressive temic mastocytosis, she had one or two mastocytosis and refractory edema. Upon hospitalization, she had 608 Pediatric Dermatology Vol. 29 No. 5 September ⁄ October 2012 developed with no evidence of any signs or symp- SM is characterized by multifocal infiltration of MC toms of . Cultures from blood and urine were in various organs, including bone marrow, gastrointes- examined and were negative. She received broad-spec- tinal tract, lymph nodes, liver, and . The bone trum antibiotics, antiviral agents, and antifungal drugs, marrow is the most common documented site of MC but she continued to have fever and developed shock, accumulation outside of the skin (17). Mast cell leukemia requiring intubation and resuscitation, complicated by is a rare disorder, accounting for 1% of SM cases in one disseminated intravascular coagulopathy and metabolic review of 342 patients of SM from the Mayo Clinic (7). acidosis. She was unresponsive to treatment and died The clinical manifestation of SM results from 5 months after she was diagnosed with MC leukemia at MC-derived chemical mediators or infiltration of various the age of 23 years and 10 months. organs by neoplastic cells (4,18). Individuals with SM are Because of her death, we reviewed the earlier pathol- at certain risk of developing secondary hematologic ogy from her preauricular lesion. There were rare mul- malignancies, especially in (19). Indi- tinucleated MC within infiltrate (Fig. 5). Several of our viduals with MC leukemia usually have significant dermatopathologists and the National Institutes of organopathy but often present without cutaneous Health (NIH) reviewed this slide and thought that it was eruptions (9,18). consistent with cutaneous MC disease. At no time was Investigations are not generally indicated in pediatric the specter of raised during the time this mastocytosis, although in cases of extensive cutaneous was present, from before grade school until it was involvement, a complete blood count and serum tryptase removed at age 19. should be performed to evaluate for systemic disease, and repeated as needed depending on the clinical setting. More extensive evaluations such as extensive laboratory, DISCUSSION imaging, or bone marrow studies, are recommended only Mastocytosis is defined by an excessive accumulation of in symptomatic pediatric cases with suspected hemato- MCs in one or more organ systems. The somatic muta- logic or systemic disease (20). The first important step is tion in KIT has reinforced the clonal nature of the dis- evaluation of serum tryptase. From one study, 35 of 42 ease. The most common activating point mutation of individuals with SM diagnosed according to bone mar- KIT is a substitution of valine for aspartic acid at codon row biopsy had levels of total tryptase >20 ng ⁄mL (21). 816 (Asp 816 Val.) (13). Recently, another gene muta- Tryptase levels correlate with tumor burden of MC in tion, a TET2 mutation, was discovered to be involved in bone marrow, although persistently high serum tryptase the pathogenesis of systemic mastocytosis (14). Mast cell levels are not specific for SM and do not predict the may be restricted to the skin (CM) but may severity of disease (21). Blood was found in also involve in extracutaneous sites (SM). approximately 20% of individuals with SM (22). A bone Pediatric mastocytosis most commonly presents in marrow examination is useful in the diagnosis examina- the cutaneous form, especially in urticaria pigmentosa, tion and for staging the disease. Immunohistochemical mastocytoma, and occasionally diffuse cutaneous stains for MC tryptase or CD117 (KIT) and immuno- mastocytosis. Bullous or vesicular formation may be phenotyping for CD25 or CD2 of bone marrow aspirate found. Mastocytosis in children usually develops within cells may be more sensitive for the detection of early the first year of life but may be congenital. The course of stages of bone marrow involvement in individuals with disease tends to resolve gradually and spontaneously SM (23). Akin et al reported the correlation between before puberty. Cutaneous symptoms result from re- levels of plasma soluble KIT (sKIT) and soluble inter- lease of mediators from MC, including , leukin-2 receptor a chain (also known as sCD25) and tryptase, interleukins, tumor necrosis factor alpha. clinical symptoms severity, severity of the bone marrow These mediators cause flushing, pruritus, and blistering. pathology, and the ability to detect a kit mutation in Mastocytosis syndrome with headache, flushing, pruri- blood: KIT D816V (24). Demonstration of the mutation tus, diarrhea, vascular instability, hypotension, and of c-kit proto- is helpful in the diagnosis of SM. shockrarelypresentsinchildrenevenincasesof Moreover, there have been c-kit associated extensive cutaneous involvement. Individuals with with more-aggressive disease and disease responsive to extensive cutaneous involvement in adult-onset disease tyrosine inhibitors. experience more systemic symptoms than in pediatric There is no cure for mastocytosis. Treatment is mastocytosis (15). In children, the diffuse type of cuta- focused on providing symptomatic relief. Patients and neous mastocytosis has rare associations with hemato- parents should be counseled on avoidance of the triggers logic disorders and rare infiltration of organs other than of MC degranulation. H1 and H2 histamine receptor the skin (16). blockers and cromolyn sodium have variable effects on Chantorn and Shwayder: Death from Mast Cell Leukemia 609 the cutaneous and gastrointestinal symptoms of disease. 7. Pardanani A, Tofferi A. Systemic mastocytosis in adults: a Patients with a propensity toward vasodilatory shock review on prognosis and treatment based on 342 Mayo should carry an Epi-pen self injector for self adminis- clinic patients and current literature. Curr Opin Hematol 2010;17:125–132. tration of subcutaneous epinephrine. Cytoreductive 8. Waters WJ, Lacson PS. Mast cell leukemia presenting as chemotherapy and allogenic bone marrow transplanta- urticaria pigmentosa: report of a case. Pediatrics 1957;19: tion are therapeutic options for patients with MC 1033–1042. leukemia. Recently, several investigational drugs, 9. Travis WD, Li CY, Hoagland HC et al. Mast cell including mesylate, , and midostaurin leukemia: repot a case and review of the literature. Mayo Clin Proc 1986;61:957–966. (PKC412), have shown in vitro anti-KIT activity (7), but 10. Torrey E, Simpson K, Wilbur S et al. Malignant masto- the results of treatment hava not been successful. Prog- cytosis with circulating mast cells. Am J Hematol 1990;34: nosis of MC leukemia is poor, with median survival of 283–286. 2 months (7). 11. Abraham EK, Augustine J, Amma S et al. Malignant This report illustrates a person with solitary masto- systemic mastocytosis. Indian J 1992;29:192–197. 12. Baghestanian M, Bankl H, Sillaber C et al. A case of cytoma who had been diagnosed since 5 years of age. She malignant mastocytosis with circulating mast cell precur- developed maculopapular cutaneous mastocytosis after sors: biologic and phenotypic characterization of the puberty that we thought might be natural progression of malignant . Leukemia 1996;10:159–166. the disease. Finally, she developed SM and died from 13. Nagata H, Worobec AS, Oh CK et al. Identification of a MC leukemia. Mutation of c-kit or another proto- point mutation in the catalytic domain of the protoonc- ogene c-kit in peripheral blood mononuclear cells of oncogene is considered to play an important role in patients who have mastocytosis with an associated the pathogenesis of mastocytosis (test not done on our hematologic disorder. Proc Natl Acad Sci USA 1995;92: patient). Unlike MC leukemia, which from the literature 10560–10564. review, usually presents with or 14. Tefferi A, Levine RL, Lim KH et al. Frequent TET2 lymphadenopathy without cutaneous manifestation, our mutations in systemic mastocytosis: clinical, KITD816V and FIP1L1-PDGFRA correlates. Leukemia 2009;23: case strongly warns us to carefully follow patients in 900–904. whom skin lesions are persistent or present as new rec- 15. Brockow K, Akin C, Huber M et al. Assessment of the ognizable eruptions. Marked eosinophilia and extremely extent of cutaneous involvement in children and adults high longstanding elevation of serum tryptase may be a with mastocytosis: relationship to symptomatology, tryp- clue to the probability of bone marrow involvement with tase levels, and bone marrow pathology. J Am Acad Dermatol 2003;48:508–516. neoplastic cells. History and physical examination 16. Hannaford R, Rogers M. Presentation of cutaneous should be thoroughly evaluated in the case of masto- mastocytosis in 173 children. Australas J Dermatol 2001; cytosis in adults. 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