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Burning Mouth Syndrome and Mast Cell Activation Disorder Lawrence B

Burning Mouth Syndrome and Mast Cell Activation Disorder Lawrence B

Burning mouth syndrome and mast cell activation disorder Lawrence B. Afrin, MD, Charleston, South Carolina DIVISION OF HEMATOLOGY/ONCOLOGY, MEDICAL UNIVERSITY OF SOUTH CAROLINA

Burning mouth syndrome (BMS), a chronic diffuse oral syndrome affecting ϳ1% of the general population, is diagnosed when explanatory oral pathology and other identifiable causes are absent. BMS has been recognized for decades, but its etiology remains unknown and has not previously been attributed to mast cell . Three cases of BMS are reported in which evidence of an underlying mast cell activation disorder (MCAD) was found; all 3 patients’ oral pain responded well to MCAD-directed therapy. Mediators released from mast cells have a wide range of local and remote effects and potentially may cause the neuropathic changes and/or inflammation thought to lead to the symptoms of BMS. Mast cell disease either in oral tissue or at sites remote from the mouth should be considered in the of BMS. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2011;111: 465-472)

Burning Mouth Syndrome (BMS), also termed Burning Studies have shown trigeminal-facial sensory anom- Mouth Disorder,1 is a distinct pain disorder classically alies, increased pain thresholds, and mucosal neurovas- consisting of chronic diffuse oral mucosal pain (often cular microcirculatory system disturbances in BMS relieved by eating or drinking), , and xerosto- patients.4 Presently it is thought that changes in the mia in the absence of lesions or other detectable peripheral and/or central may cause the changes in the which can explain the pain, symptoms in BMS, but the specific natures of these though oligosymptomatic presentations (i.e., pain with changes and their true etiologies remain elusive. The most or without dysgeusia or ) are more com- specific pathway to BMS symptoms yet suggested has monly seen. Epidemiologic studies in the Americas, identified, via positron-emission tomographic scanning, Europe, and South Africa suggest that BMS affects nigrostriatal dopaminergic inhibition putatively affecting 0.7%-15% of the general population, much more often trigeminal nociception through loss of sensory inhibition, women (7:1 vs. men) in their middle and later years. but evidence remains inconclusive.4 There is no definitive Spontaneous remission is rare, although one-half to cure for BMS. A large variety of treatments have been two-thirds of patients may experience improvement proposed, but overall response to therapy is generally within 6-7 years of onset. BMS typically significantly poor. , , , alpha-lipoic adversely affects quality of life, and BMS patients acid, pyridostigmine, and cognitive/behavioral therapy, commonly are chronic high consumers of health care among other agents and therapies, have benefited some resources. Many conditions have been noted to cause patients, but responses have not been predictable or reli- BMS symptoms, such as , allergic reactions, able.2-5 As such, identification of a specific underlying , dental treatment, nutritional deficiencies, cause, presumably permitting specific therapy (more , oral , Sjögren syndrome, and other likely than empiric therapy) to yield symptom relief, is the endogenous and iatrogenic salivary gland dysfunction. imperative in each BMS patient. Associations of variable strength between BMS and BMS has not previously been attributed to mast cell many other conditions (e.g., , diabetes) have disease (MCD). Of hematopoietic origin but largely been noted as well. The term BMS is often applied confined (in sparse distributions) to solid tissues in all initially to patients presenting with symptoms and with- systems throughout the body, MCs normally react to out immediately identifiable oral lesions to which the local chemical and physical stimuli by producing and pain can be reasonably attributed. However, chronic releasing a wealth of potent mediators which help diagnosis of BMS is typically reserved for cases which 6 remain idiopathic after thorough evaluation.2-5 maintain homeostasis in both local and remote tissues. More than 200 MC mediators7 directly and indirectly affect processes in virtually all cells with resulting tissue/organ and clinical consequences. Specific conse- Received for publication Aug 15, 2010; returned for revision Nov 23, quences in the individual patient with aberrantly func- 2010; accepted for publication Nov 29, 2010. tioning MCs depend on the specific pattern of mediator 1079-2104/$ - see front matter © 2011 Mosby, Inc. All rights reserved. release, which can differ substantially from one patient doi:10.1016/j.tripleo.2010.11.030 to the next, making clinical recognition of any variant

465 OOOOE 466 Afrin April 2011 of MCD challenging. Given the range of molecular and refractory to multiple antibiotics before resolving spontane- cellular effects of MC mediators, symptoms and find- ously 3 months later. Initial extensive investigations by spe- ings in MCD span the gamut of human symptomatol- cialists in internal medicine, , endocrinology, ogy and clinicopathology.8 Aberrant MC function has rheumatology, infectious disease, dentistry, otolaryngology, been found to underlie a growing spectrum of previ- oral surgery, gastroenterology, and pain management were ously idiopathic (and often inflammatory) illnesses,9,10 unrevealing, including normal oral examinations and oral biopsies and consistently normal routine blood counts and including some neuropathic conditions, raising the pos- serum chemistries. She was thought by her oral physicians sibility of a link with BMS. and pain management specialists to have BMS, but her en- Historically, MCD has been thought to be rare and docrinologist thought a neuroendocrine disorder or systemic largely has been divided between childhood dermato- mastocytosis was more likely. Serum serotonin was found logic presentations of urticaria pigmentosa (UP) and mildly elevated at 272 ng/mL (normal range 50-220 ng/mL). even rarer adult presentations of systemic mastocytosis Plasma free catecholamines showed elevated norepinephrine (SM), whose most striking symptom is unprovoked (738 pg/mL, normal range 80-520 pg/mL) and (32 anaphylaxis. Although specific genetic anomalies have pg/mL, normal range 0-20 pg/mL). Urinary metanephrines, only rarely been found in UP, it has become clear that vanillylmandelic acid (VMA), homovanillic acid (HVA), and SM (as defined by World Health Organization consen- 5-hydroxyindoleacetic acid (5-HIAA) were repeatedly nor- sus diagnostic criteria11) is primarily a disease whose mal. Other biochemical and radiographic searches for thyroid cellular and clinical behaviors result specifically from dysfunction, pheochromocytoma, carcinoid, other adrenal tu- the D816V mutation of the MC transmembrane KIT mors, and medullary thyroid carcinoma were unrevealing. stem cell factor receptor. KIT is expressed more heavily Serum tryptase and 24-hour urinary N-methylhistamine (uNMH) and prostaglandin D (uPGD ) were tested to also by far on the membrane of the MC than on any other 2 2 cell and directly or indirectly governs the majority of evaluate for systemic mastocytosis, but results were normal. Upper and lower endoscopies with an extensive set of random MC functions.12 More recently, though, there has been mucosal biopsies looking for major gastrointestinal tract in- developing recognition of a much larger spectrum of flammatory disorders showed only mild chronic gastritis and MC with extremely heterogeneous presenta- reflux esophagitis. In mid-2005, serum chromogranin A was tions which often overlap little with classic SM. These found by a gastroenterologist (looking for a gastrointestinal diseases, collectively called systemic mast cell activa- neuroendocrine disorder) to be mildly elevated at 91 ng/mL 13,14 tion syndrome or disorder (MCAD), appear to be (normal range 0-50 ng/mL). Repeated testing 4 months later attributable to a wide variety of non-D816V mutations found a level of 8,617 ng/mL (without use at either time of in KIT (or, occasionally, in other mast cell regulatory proton pump inhibitors or any finding of renal or cardiac proteins)15,16 which cause affected MCs to aberrantly failure). release mutation-specific sets of mediators yielding She was suspected of having a neuroendocrine malignancy clinical, laboratory, and pathologic presentations dis- and was referred for oncologic evaluation. Her oral symptoms tinct from SM. remained her worst symptoms by far. Physical examination Presented here are 3 patients who presented with remained essentially unremarkable; only mild dermatographism BMS, were found to harbor MCAD, and experienced was seen. An extensive search for neuroendocrine malignancy good relief of BMS symptoms with MCAD-directed (urinary 5-HIAA/metanephrines/VMA/HVA, computerized to- mography (CT), magnetic resonance imaging, positron-emis- therapy. sion tomography/CT scanning, octreotide scanning, and CASE 1 methyliodobenzguanine scanning) was unrevealing; serial se- A 58-year-old woman with a past medical history (PMH) rum chromogranin A determinations showed continued of hypertension, osteoporosis, and diverticulosis presented marked fluctuations (93-1,100 ng/mL). Bone marrow aspira- acutely in mid-2004 with mild fatigue and severe, disabling, tion and biopsy (looking for metastatic neuroendocrine ma- burning pain, dysgeusia, and xerostomia throughout the oral lignancy or systemic mastocytosis) were normal. Symptoms mucosa (pain was consistently 10 on a 0-10 scale). Vague continued, and repeated upper and lower endoscopies with mild discomfort was also present throughout the entire re- biopsies in mid-2006 (again looking for a focus of neuroen- mainder of the gastrointestinal tract, but she denied any sense docrine malignancy as the putative source of the elevated of acid reflux. She reported anorexia due to her oral symp- chromogranin and, presumably, the symptoms) again showed toms but was not losing weight. She also reported coincident chronic gastritis and reflux esophagitis. onset of episodes of other varying symptoms at varying times, Repeated esophagogastroduodenoscopy in mid-2007 was including flushing, , , irritated eyes, mild again grossly normal; a set of random mucosal biopsies now proximal dysphagia, nonbloody diarrhea, and migratory showed increased eosinophils in a gastric polyp and eosino- . She endorsed subtle dyspnea but denied wheezing or philic esophagitis in the gastroesophageal junction, of uncer- . By early 2005, episodic flushing had largely tain clinical significance at the time. Repeated upper and abated, but a migratory abdominal wall developed. lower endoscopies with biopsies in mid-2008 found reflux No infectant could be found, and the cellulitis proved to be esophagitis and chronic duodenitis but not increased eosino- OOOOE Volume 111, Number 4 Afrin 467 phils. Repeated bone marrow aspiration and biopsy were again normal. Throughout these investigations, symptoms proved to be refractory to multiple empiric therapies, including assorted narcotics, benzodiazepines, antidepressants, , pilo- carpine, proton pump inhibitors, antibiotics, and and multivitamin supplementation. In early 2009, owing to in- creasing suspicion of MCD as the only possible unifying diagnosis for her full assortment of problems, immunohisto- chemical reexamination of the mid-2008 duodenal biopsy found gross overexpression of CD117 (55 cells per high power field; Fig. 1) and CD2 (145 cells per high power field), but not CD25. KIT D816V mutation analysis was negative. Plasma histamine was found to be mildly elevated (9 nmol/L, normal range 0-6 nmol/L). Repeated serum tryptase and uNMH were normal. MCAD was diagnosed. Initiation of (loratadine 10 mg, famotidine 40 mg) and nonsteroidal antiinflammatory drugs (celecoxib 200 mg), all twice daily, immediately decreased her oral and other gastrointestinal pain to 1/10. Other symptoms moder- ately improved, too. Examination showed resolution of mal- aise. Improvement had been sustained 20 months so far at the time of writing, although during a 4-month period of loss to follow-up in which she also stopped celecoxib and loratadine, burning mouth pain flared to 5/10, immediately returning to 1/10 upon starting aspirin 650 mg twice daily.

CASE 2 A 60-year-old woman with a PMH of well controlled mild diabetes mellitus type 2 and mild hypercholesterolemia de- veloped buccal ulcers with white pseudomembranes and se- vere diffuse burning mouth and throat pain (persistently 10 on a 0-10 scale). was clinically diagnosed, but multiple treatments proved to be unhelpful. All of the oral lesions grossly resolved spontaneously after 6 months, but 10/10 pain persisted. After another 6 months, a random oral mucosa biopsy by her oral surgeon (while the oral mucosa continued to grossly appear normal) revealed superficial li- chenoid changes and a perivascular lymphocytic infiltrate in the deeper connective tissue. A specific cause for her severe symptoms and the clinical significance of the histologic find- ings were uncertain. Evaluations by her internist and another oral surgeon also were unrevealing for a specific cause. Rou- tine blood counts and serum chemistries were normal. No potentially causative of her symptoms (e.g., an- giotensin-converting enzyme inhibitors) had been prescribed. Fig. 1. Photomicrographs of patient 1’s endoscopic duodenal Her pain was refractory to multiple empiric therapies, includ- biopsy interpreted as chronic duodenitis on hematoxylin and ing assorted narcotics, benzodiazepines, antidepressants, pro- eosin (H&E) staining and reinterpreted on CD117 immuno- ton pump inhibitors, antibiotics, and multivitamin supplemen- histochemical staining as showing increased MCs compared tation. She was diagnosed with BMS by all of her physicians with established norms,46 although clusters of Ն15 cells as in at the time. systemic mastocytosis11 are not seen. A, B, Chronic duode- Three years after symptom onset, further evaluation dis- nitis on H&E staining (magnifications ϫ20 and ϫ40, respec- covered additional chronic symptoms, including migraine tively) without apparent increase in MCs. C, Representative , , osteoarthritis, episodic field of the biopsy with CD117 staining (ϫ40) showing migratory pruritus, and unpredictable flushing. Physical ex- increased MCs (55 per ϫ40 field in the full microscope image amination showed a tired woman but was otherwise unre- [normal up to 20], 37 in the subfield captured by the camera markable, including in the oral cavity. No dermatographism and shown in this panel). Images acquired via Olympus DP21 was noted. Laboratory studies, however, showed mildly ele- camera at 1,600 ϫ 1,200 resolution. vated plasma histamine (8 nmol/L) and highly elevated OOOOE 468 Afrin April 2011

uPGD2 (733 ng/24 h, normal range 100-280 ng/24 h). Serum She experienced no improvement after 2 weeks of twice- tryptase, serum chromogranin A, and uNMH were normal. daily loratadine 10 mg and famotidine 40 mg, but within 2 The prior biopsy was not available for further analysis, and days of starting twice-daily aspirin, she began realizing sig- the patient refused further biopsies (oral or otherwise). nificant improvement in all symptoms, improving further as Initiation of twice-daily loratadine 10 mg and famotidine the dose was increased. At an aspirin dose of 650 mg twice 40 mg immediately improved all symptoms, including reduc- daily, her oral pain was “tremendously” improved at 6/10, ing her mouth and throat pain to 4/10. One month later, and at 975 mg twice daily it was 3/10. She appeared energetic addition of celecoxib 100 mg once daily immediately resulted and happy. Cognitive dysfunction appeared resolved, and she in complete or nearly complete resolution of all of her resid- no longer placed her hands to her mouth. Dermatographism ual symptoms, including reducing her mouth and throat pain persisted unchanged. Improvement had been sustained 5 to 1/10. Examination showed resolution of malaise. Improve- months so far at the time of writing, except for a 4-day period ment had been sustained 14 months so far at the time of of abstention from aspirin before a procedure, during which writing. time her burning oral pain returned within 2 days to 9/10 but remitted again to 3/10 shortly after resuming aspirin. CASE 3 A 64-year-old woman acutely developed persistent 10/10 burning mouth pain, xerostomia, and dysgeusia. No cause DISCUSSION 4,5,17-23 was immediately evident. PMH included frequent upper re- The etiology of BMS has long been unclear. spiratory infections in childhood, episodes of at ages Known causes of diffuse oral mucosal pain include 35 and 63 years, and stage II breast cancer at age 59 years (most commonly candidal), erosive oral in- treated only with surgery and 5 years of tamoxifen. She flammatory disorders, , allergy, Sjögren dis- appeared depressed. Oral examination was repeatedly normal. ease, and side effects. However, the essence Evaluations by 2 internists, a dentist, 2 otolaryngologists, of primary/idiopathic BMS is chronic oral mucosal pain infectious disease and rheumatology specialists, and 2 oral with no clear provocation and no detectable explana- surgeons were unrevealing, including routine hematologic and chemistry laboratory evaluation, 2 oral mucosa biopsies, tory oral pathology. Although the true nature of their and a minor salivary gland biopsy. All of her oral physicians relationship to BMS remains unclear, many comorbidi- thought that she met criteria for BMS, and her other physi- ties and abnormalities have been recognized in BMS cians had no other suggestions. Her pain and other symptoms patients, including , fatigue, psychiatric illness were refractory to multiple empiric medical therapies, includ- (especially and ), inflammatory syn- ing propoxyphene/acetaminophen, venlafaxine, and multiple dromes, nutritional deficiencies, , dys- courses of antibiotics. functional uterine bleeding, menopause, pruritus, tinni- Further evaluation 8 months after symptom onset found tus, contact or systemic allergy, , , coincident development of anorexia (but no weight loss), cold and central and peripheral neural dysfunction. Given intolerance, night sweats, throat irritation, mild proximal dys- phagia, palpitations, nausea, treatment-refractory culture-neg- the etiologic uncertainty and associative menagerie in ative urethritis, migratory edema, fluctuating cognitive dys- BMS, treatment unsurprisingly remains unsatisfactory. function, and presyncope 2-3 times per week. Other than her Symptoms persist for most BMS patients, engendering oral pain and dysgeusia, she denied neuropathy; she also much consultation and testing, often to little avail. denied episodes of marked hypertension, wheezing, or diar- The mast cell and associated disease were first rec- rhea. There were no suspect medications; she reported an ognized more than a century ago.24 In 1869, Nettleship allergy to hydrocodone. On examination, marked malaise, and Tay described a rare urticarial skin disease, a mild word-finding and memory dysfunction, and moderate symmetric distribution of pigmented maculopapular le- dermatographism were additionally noted. Although oral ex- sions later termed UP. In 1877, Ehrlich described a amination remained unremarkable, she frequently placed her fingertips to her face about her mouth as if trying to massage granule-laden connective tissue cell with unique meta- away the pain. MCAD was thought to be the best explanation chromatic staining properties, which he termed a mas- for her full assortment of symptoms. Serum tryptase and tzelle, or well nourished cell. In 1887, Unna associated chromogranin A, plasma histamine, and 24-hour urinary MCs with UP, and in 1949 Ellis associated MCs with

NMH and PGD2 were normal. However, plasma factor VIII internal disease, initially defining SM. In 1987, level was markedly elevated (287%, normal range 50%- Schwartz identified tryptase as a marker of SM, and in 150%) and plasma free catecholamines showed elevated nor- 1995 Furitsu et al. identified the D816V activating epinephrine (690 pg/mL, normal range 80-520 pg/mL) and mutation of the KIT transmembrane receptor tyrosine dopamine (28 pg/mL, normal range 0-20 pg/mL). Blind bi- kinase (CD117), which later was proved to be present opsies were taken throughout the gastrointestinal tract on bidirectional endoscopy but were normal on hematoxylin and in most adult SM. In 1998, Escribano et al. showed eosin (H&E) staining and CD117 immunohistochemical some SM MCs, unlike any known normal cells, coex- staining. Flow cytometry was not available, and the patient press CD117/CD25 or CD117/CD2. Many features of declined to undergo marrow examination. SM, such as mast cell aggregation, spindle morphol- OOOOE Volume 111, Number 4 Afrin 469 ogy, and CD25 expression, are now understood to be been documented to cause pure red cell aplasia in the specifically driven by the KIT D816V mutation.16 bone marrow.30 Therefore, elaboration of different sets MCs are of hematopoietic origin but circulate only of mediators in different MCAD patients results in briefly early in their development and complete matu- different symptoms (in multiple body systems, syn- ration in a wide distribution of tissues. Although overall chronously or dissynchronously, and often subtle or much more sparsely distributed than most other types slow to develop) and different objective findings and of cells, MCs are relatively abundant beneath environ- secondary illnesses. The symptoms in MCAD often are mentally exposed epithelial surfaces and adjacent to traceable to childhood or adolescence and typically are blood and lymphatic vessels, permitting sentinel func- intermittent and/or fluctuant over years to decades. Fre- tion.25 MC recruitment, development, and survival are quent health provider consultations (often to little avail) governed principally by interactions between KIT and and substantially delayed diagnosis are the norm. Be- its ligand (stem cell factor). Although other rare forms fore diagnosis, MCAD patients typically are seen as exist, the spectrum of MCD is principally divided into inexplicably chronically ill and learn to live with their cutaneous mastocytosis (CM), SM, and MCAD. Both symptoms, many of which come to be attributed by CM (usually diagnosed in childhood) and the 10-fold default to aging or circumstantial events. Contrary to less prevalent SM (most common in middle-aged the typical paradigm in which specific symptom A ϩ adults) are rare proliferative diseases of equal gender specific examination finding B ϩ specific laboratory distribution. Prevalence estimates for SM and CM are result C leads to suspicion of diagnosis D, an underly- in the range of 0.001% to 0.01%.6,8,14,26-28 The various ing MCAD can be reasonably suspected in the patient forms of CM (UP is most common) are limited to skin who suffers any assortment of chronic idiopathic ail- involvement. SM usually involves the skin, too, but ments potentially explicable by aberrant MC mediator extracutaneous involvement is additionally present. SM release, as well as in the patient in whom a definitively is generally subdivided (per current World Health Or- diagnosed major illness is insufficient to explain some ganization diagnostic criteria11) into indolent SM (by aspects of the presentation (e.g., frequent syncope in an far the most common form), SM with associated clonal early-stage patient). hematologic non-MC lineage disorder, aggressive SM Although some of the laboratory and pathologic con- (involving organ dysfunction due to MC infiltration), sequences specifically resulting from the KIT D816V and the very rare MC leukemia. mutation in SM are now known,16 research to identify In contrast to SM and CM, MCAD is a more recently the specific consequences of the other mutations found recognized entity8 and appears to be relatively nonpro- in MCAD is just beginning. The causes of the muta- liferative and significantly more prevalent, although tions in MCD are unknown; hypotheses include genetic epidemiologic investigations have not been performed or epigenetic inheritance and infections by DNA-trans- and would be inherently challenging owing to the dis- forming . The mutagenic capacity of some vi- order’s marked genetic and thus clinical heterogeneity. ruses has been well established, and the ability of some A European consensus in 200714 proposed diagnostic viruses to infect MCs has also been established,31 criteria for MCAD consisting of clinical and laboratory though no MC-infecting mutagenic has yet been evidence of aberrant MC mediator release and, ideally, identified. pathologic demonstration of abnormal MCs, all in the MCs elaborate scores of mediators, but few (e.g., absence of meeting formal criteria for proliferative tryptase, histamine, PGD2) are relatively specific to mastocytosis and in the absence of any other definable MCs,32-34 increasing the importance of clinical assess- illness accounting more fully for the complete clinical ment in diagnosis of MCAD. In SM, tryptase (compris- presentation. More recently, other groups13,29 have of- ing ϳ25% of the MC’s total protein load35)iscom- fered similar proposals for diagnostic systems for monly elevated in the serum and reflects the extent of MCAD. the proliferating MC population. In contrast, in MCAD Much of the challenge in diagnosing MCAD stems serum tryptase is usually normal16 and one or more from the substantial clinical heterogeneity to which MC surveys of other MC mediators (e.g., histamine, PGD2, biology gives rise. Although MCs in different tissues heparin, carboxypeptidase A,9 serotonin,36 chromo- produce different sets of mediators as needed to help granin A,36 catecholamines,37 factor VIII,38 etc.) may maintain local homeostasis, MCs in toto synthesize and be required to identify, or at least suggest, aberrant MC release more than 200 mediators,7 each causing a activity. No standard screen has been defined based on unique array of direct and indirect local effects plus evidence, but in practice an assessment of serum tryp- possibly remote effects depending on various factors, tase, plasma histamine and PGD2, and uNMH and including circulation and neural activation. For exam- uPGD2 (preferably while off NSAIDs) constitutes a ple, MCAD situated in the gastrointestinal tract has reasonable initial screen, possibly repeated (and/or fol- OOOOE 470 Afrin April 2011 lowed by assessment of other mediators, such as noted blockers, leukotriene inhibitors), and/or stabilizing ac- above) if the initial screen is negative but clinical tivated mast cells (e.g., cromolyn, pentosan, interferon, suspicion persists. Although the mediators aberrantly or tyrosine kinase inhibitors, such as imatinib). Stan- expressed in any given variant of MCAD may be most dard dosing of any of these agents for the purpose of increased when the patient is most symptomatic, in- controlling MC disease is not established. In practice, creases above normal nevertheless can usually be found selection and optimal dosing of these agents remain in one or more mediators (even between, or without, largely empiric and vary substantially among patients. frank “attacks”) and may warrant subsequent search for For example, celecoxib was prescribed as 200 mg twice histologic evidence. Identifying elevated MC mediators daily in case 1 versus 100 mg once daily in case 2 is challenging for many reasons, including unpredict- because patient 1’s pain objectively appeared much able durations and periodicities of mediator release, worse than patient 2’s. Financial issues sometimes af- brief half-lives, and heat lability. Twenty-four-hour fect treatment selection and dosing as well. An effec- chilled urine samples can be difficult to collect and tive regimen is identifiable in most patients, but pa- transport properly but provide a better understanding of tience often is required while progressing through average mediator levels unless spot urine or blood multiple therapeutic trials. Cytotoxic samples can be collected within a few hours of a frank typically provides little benefit, and cellular therapy anaphylactic episode. (i.e., allogeneic stem cell transplantation, usually per- Detection of aberrant MCs is desirable (but not re- formed for refractory hematologic malignancies which quired) as diagnostic confirmation before treatment. In develop secondarily to MCD) almost never eradicates SM, MC aggregates are commonly found in marrow, MCD. nodes, gastrointestinal and respiratory tracts, and skin. Although criteria for SM were not met in the present However, in MCAD, aggregates of MCs are rarely 3 cases, MCAD was supported by consistent clinical found and quantitative and/or qualitative MC aberrancy histories and investigations as well as by responses to is usually shown via molecular techniques, such as MCAD-directed therapy. Although the therapeutic re- immunohistochemistry and multicolor flow cytom- sponses of BMS symptoms to MCAD-directed therapy etry.39 The sparse and patchy distributions of MCs in suggest that MC mediators may have directly or indi- MCAD also may inhibit detection of their increased rectly caused these symptoms, the identities of the numbers via random biopsies (as in the present case 3), specific mediator(s) and pathway(s) responsible for and KIT mutation analysis is constrained by lack of BMS symptoms remain unknown. Therefore, the rela- commercial assays for most of the non-D816V muta- tionship of MCAD to BMS remains one of association, tions found to date in MCAD.15,16 Diagnosis is further not causation. The differential findings of mediator complicated by the pleomorphism of MCs, which can expression in the patients reported here suggest that yet masquerade as lymphocytes (as in the present case 1), other mediators not examined may have been the cul- plasma cells, macrophages, histiocytes, or spindle prits either in activating oral tissue nociceptors or more cells.40,41 Therefore, even when H&E staining of biop- proximal neural pathways or in otherwise causing neu- sies shows no increase in MCs of classic appearance, rotoxicity in the oral nociceptive pathways. advanced pathologic analysis for MCD (e.g., tryptase, Of note, the mélange of clinical problems often giemsa, toluidine blue, and/or CD117 stains; flow cy- found in association with BMS mirrors the marked tometry for coexpression of CD117/CD25 or CD117/ clinical heterogeneity of MCAD. Thus, one potential CD2, etc.) is warranted when clinical findings are sug- unifying explanation for the wealth of diseases, syn- gestive of MCD. The cases here and in other dromes, and findings inexplicably associated with idio- reports15,16,30 suggest that a gastrointestinal tract sur- pathic BMS is that assorted variants of MCAD may vey with random biopsies evaluated specifically for underlie at least some portion of the heterogeneity of MCD may be more productive in an evaluation for associated findings in some BMS patients. Given that MCAD than marrow examination, but this point has not many MC mediators have inflammatory and neuropsy- been specifically studied. chiatric effects,9,10,42 this hypothesis is not inconsistent Treatment of MCAD is almost as challenging as with current thinking regarding a neuropathic origin to diagnosis. Standard therapy remains undefined, and it is BMS. MCAD perhaps can even explain some of the not presently possible to predict which one or more of oddest associations with BMS, such as the rare idio- the several therapies available will prove to be optimal pathic Cronkhite-Canada Syndrome (CCS)43 involving for the individual patient. Therapeutic approaches in- nonadenomatous gastrointestinal tract polyps and, in clude inhibiting mediator production (e.g., NSAIDs, different CCS subtypes, varying incidences of burning such as aspirin, often requiring high doses8), blocking mouth,44 dysgeusia, xerostomia, diarrhea, abdominal released mediators (e.g., histamine H1 and H2 receptor discomfort, alopecia, , and dys- OOOOE Volume 111, Number 4 Afrin 471 trophy. Gastrointestinal histologic observations and cribano L, Valent P. Mastocytosis. In: Swerdlow SH, Campo E, therapeutic response similar to those found in case 1 Harris NL, et al., editors. WHO classification of tumors of have also been described in a CCS patient.45 hematopoietic and lymphoid tissues. 4th ed. Lyon: International Agency for Research on Cancer; 2008. p. 54-63. Although the true nature of the relationship between 12. Akin C, Metcalfe DD. The biology of Kit in disease and the MCAD and BMS remains unclear, the findings in the application of pharmacogenetics. J Allergy Clin Immunol present report suggest that MCAD should be consid- 2004;114:13-9. ered in the differential diagnosis of primary/idiopathic 13. Akin C, Valent P, Metcalfe DD. Mast cell activation syndrome: BMS in patients who also have other findings (e.g., proposed diagnostic criteria. J Allergy Clin Immunol e-pub ahead of print;2010 [10.1016/j.jaci.2010.08.035]. episodic presyncope) for which the complex (but not 14. Valent P, Akin C, Escribano L, Födinger M, Hartmann K, especially enigmatic) biologic behavior of MCAD pro- Brockow K, et al. Standards and standardization in mastocytosis: vides a potentially unifying explanation. Evaluation for consensus statements on diagnostics, treatment recommenda- MCAD may even be warranted in carefully assessed tions and response criteria. Eur J Clin Invest 2007;37:435-53. patients whose sole symptoms are BMS symptoms but 15. Molderings GJ, Kolck UW, Scheurlen C, Brüss M, Homann J, who are not found to harbor any of the other diseases Von Kügelgen I. Multiple novel alterations in Kit tyrosine kinase in patients with gastrointestinally pronounced systemic mast cell traditionally associated with BMS. Comprehensive his- activation disorder Scand J Gastroenterol 2007;42:1045-53. tory and physical examination remain the clinician’s 16. Molderings GJ, Meis K, Kolck UW, Homann J, Frieling T. best tool for initially directing the evaluation of BMS Comparative analysis of mutation of tyrosine kinase Kit in mast symptoms. 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