Page 1330 - Hematology_ Basic Principles and Practice ( PDFDrive )

1176 Part VII Hematologic Malignancies

TABLE Criteria for the Diagnosis of Mast Cell Activation an SM patient with 100 ng/mL baseline tryptase, an anaphylactic
72.7 response to a bee sting is followed by an increase to 150 ng/mL, the
reaction is called MCA (100 + 20 + 3 = 123; this means any value
A. Typical symptoms (see below) above 123 qualifies as a MCAS criterion). It is important to know
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B. Increase in serum total tryptase by at least 20% above baseline that after such an anaphylactic reaction, it takes at least 24–48 h (after
plus 2 ng/mL during or within 4 h after a symptomatic period complete resolution of symptoms) until the baseline of tryptase is
C. Response of clinical symptoms to histamine receptor blockers or again reached.
MC-targeting agents, e.g., cromolyn In patients with IgE-mediated hymenoptera venom anaphylaxis,
Typical Symptoms particularly individuals with an elevated baseline tryptase level (sepa-
Flushing rate from the acute rise after a sting), the suspicion for an underlying
Pruritis clonal MC disorder is increased. The differential diagnosis for MCAS
Urticaria includes less severe allergic or toxic reactions, endocrinologic disor-
Angioedema ders, cardiac diseases or severe infectious diseases (septicemia) leading
Nasal congestion to shock.
Nasal pruritis
Wheezing
Throat swelling Diagnostic Evaluation of Mastocytosis
Headache
Hypotension Tissue biopsy in conjunction with clinical and pathology expertise
Diarrhea are critical in establishing the diagnosis of SM. BM MC burden is
MC, Mast cell. best quantified by morphologic analysis and immunohistochemical
Modified from Valent P, Akin C, Arock M, et al: Definitions, criteria and global stains such as tryptase, CD117 (KIT), and CD25 on the core biopsy.
classification of mast cell disorders with special reference to mast cell activation Multiparameter flow cytometric analysis of BM aspirates can also be
syndromes: a consensus protocol. Int Arch Allergy Immunol 157:215, 2015. used to quantify the percentage of MCs, and generally correlates with
SM burden defined by morphologic/immunohistochemical evalua-
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tion. Morphologic evaluation of the BM aspirate is additionally
important for evaluating dysplasia and excess myeloblasts, and most
TABLE Classification of Mast Cell Activation Syndromes relevant to MCL, the number of atypical MCs. Based on this evalu-
72.8 ation, the presence of MCL can be excluded or can be confirmed
Category and Variants Proposed Criteria during the diagnostic work-up.
The most important morphologic feature of mastocytosis, in
Primary MCAS = (mono) MCA criteria fulfilled and MC (mono) particular its systemic variants, is the presence of compact infiltrates
+
clonal MCAS clonality proven (CD25 MC and/or KIT consisting of densely packed atypical MCs. Compact MC infiltrates
Mastocytosis D816V) a are almost never detected in reactive states, even in those with
Primary MCAS without marked MC hyperplasia. Accordingly, compact MC infiltrates can
evidence of mastocytosis
be regarded as the only major criterion for diagnosis of mastocytosis,
Secondary MCAS MCA criteria fulfilled and criteria for the which also underlines the important role of the hematopathologist
Allergy diagnosis of allergy or other diseases in making these diagnoses. Investigation of an adequate BM biopsy
Other underlying disorder b that can produce MCA fulfilled as well trephine specimen is crucial to assess or exclude a diagnosis of SM.
Idiopathic MCAS c MCA criteria fulfilled, but no disease In most patients a few compact infiltrates can be identified even
that could lead to MCA diagnosed by using conventional stains like Giemsa-Wright or toluidine blue,
a CD25 MCs plus KIT D816V detectable, or KIT D816V detectable, but MCs which both facilitate detection of the pathognomonic metachromatic
+
cannot be demonstrated to express CD25. granules. The MCs are round or spindle shaped, and often exhibit
b Disorders associated with MCA include autoimmune diseases, certain bacterial at least some hypogranulation. The nuclei are round or elongated
infections, and some adverse drug reactions. depending on the shape of the cell. Prominent nucleoli are not
c Idiopathic MCAS is a final diagnosis but needs an extensive workup in order to seen. Almost always such compact infiltrates also contain mature
exclude all potential underlying conditions. Idiopathic and secondary MCA
episodes may occur at different time points in the same patient. eosinophils, histiocytes, and sometimes large follicle-like aggregates
MC, Mast cell; MCA, mast cell activation; MCAS, mast cell activation syndrome. of lymphocytes that are polyclonal in nature. Reticulin fiber density is
From Valent P, Akin C, Arock M, et al. Definitions, criteria and global always increased with the exception of a few very small but diagnostic
classification of mast cell disorders with special reference to mast cell activation infiltrates. Larger compact and mixed infiltrates often show patchy
syndromes: a consensus protocol. Int Arch Allergy Immunol 157:215, 2012.
collagen fibrosis. The degree of reticulin fibrosis in most cases of
MCL is low, which can be used as a criterion that allows one to
distinguish MCL from aggressive SM, which usually exhibits marked
SM criteria are typically present. However, at the time of diagnosis, reticulin or even collagen fibrosis (Fig. 72.2). Immunohistochem-
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a diagnosis of an underlying MC disease cannot be established. In istry should be performed in all cases in order to enumerate the
both instances, the diagnosis is primary (clonal) MCAS. Because of numbers of loosely scattered MCs and to detect small but diagnostic
the very low numbers of MCs, techniques to enrich for MCs and/or compact infiltrates. The degree of MC infiltration should always be
use of sensitive techniques to detect KIT D816V (e.g., allele-specific documented by the hematopathologist: it is recommended to refer
PCR) may be necessary to detect neoplastic MCs in these patients. to the section area and to the overall cellularity in this respect. This
Currently, there is no evidence that these two entities are “prodromal” enables monitoring of the disease during and after therapy. MCs
SM conditions with a defined rate of progression to systemic MC almost always coexpress tryptase and CD117; in most SM cases, MCs
disease. If neither an underlying allergy or another underlying reactive also aberrantly express CD25, whereas aberrant expression of other
process nor a clonal population of MCs can be detected in an MCAS antigens such as CD2 is more rarely encountered and therefore
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patient, the final diagnosis is idiopathic MCAS. Criteria for MCAS of minor diagnostic importance (Fig. 72.3). Interestingly, it could
include an event-related increase in serum tryptase, typical clinical be shown that MCs may lose immunohistochemically detectable
symptoms, and response of these symptoms to drugs targeting MC tryptase expression during or after therapy with TK inhibitors such
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activation, MC-derived mediators, or their specific receptors. All as midostaurin, and MCs in cases of intestinal involvement by
three MCAS criteria must be fulfilled to characterize the condition SM may lack tryptase expression at diagnosis (e.g., incomplete
as MCAS. The minimal increase in tryptase is defined by the follow- immunophenotype). However, it can be stated definitively that a
ing formula: 20% of baseline plus absolute 2 ng/mL. Example: if in cell lacking expression of CD117 (KIT) cannot be a MC. Although