Page 1332 - Hematology_ Basic Principles and Practice ( PDFDrive )

1178 Part VII Hematologic Malignancies

level >20 ng/mL is suggestive of the presence of SM. Conversely,
patients with CM usually exhibit a serum tryptase level <20 ng/mL,
or it may be within normal range. Other medical conditions besides
SM and anaphylaxis that can produce an elevated tryptase level
include renal failure, chronic helminth infections (MC hyperplasia),
SCF treatment, and myeloid neoplasms, including MDS, MPN,
AML, and CEL—notably patients with the FIP1L1-PDGFRA
fusion gene.
Although there is a close correlation between high tryptase levels
and advanced SM, serum tryptase levels do not necessarily reflect
the aggressiveness of the disease. Likewise, SSM is partially defined
by a very high serum tryptase level exceeding 200 ng/mL, and in
many of these cases, progression dose not occur for many years.
Contrasting the smoldering state, most patients with typical ISM
have lower serum tryptase levels, although enzyme levels can vary
widely among patients according to the MC burden. Patients with
ASM and MCL may exhibit serum tryptase levels in the several-
hundred range to over 1000 ng/mL. In many of these patients,
serum basal tryptase levels increase rapidly over time (in contrast to
ISM and SSM). Although discordances can exist between the serum
Fig. 72.5 WELL-DIFFERENTIATED SYSTEMIC MASTOCYTOSIS. tryptase level and the degree of MC infiltration of the marrow and
Core biopsy, Giemsa stain. Bone marrow shows aggregates of exclusively other organs, it is the most useful and widely available biomarker
round mast cells with an abundance of metachromatic granules. This is the that can be used to assess changes in the MC burden in response to
typical phenotypical appearance of a well-differentiated systemic mastocyto- cytoreductive therapy.
sis. The disease was otherwise subtyped as indolent systemic mastocytosis
with skin involvement but missing KIT D816V mutation and also lack of
CD25 expression by the mast cells (not depicted). Clinical Manifestations

Organomegaly
MCL. Well-differentiated SM usually lacks aberrant expression of
CD25 and does also not show the typical activating point mutations Splenomegaly and hepatomegaly, without associated organ damage,
at codon 816 of KIT (Fig. 72.5). have traditionally been referred to as “B” findings and are one of the
CD30 (Ki-1) is a cytoplasmic and membrane-bound antigen defining features of SSM. Similarly, SM-related substantial (palpable,
expressed by neoplastic cells in Hodgkin lymphoma and anaplastic >2 cm) lymphadenopathy has been included in the category of “B”
large-cell lymphoma. Recently, however, CD30 has also been shown findings. Organomegaly by itself does not indicate inexorable pro-
17
to be expressed by neoplastic MCs in SM. Although the antigen gression to advanced SM or organ damage. However, even in the
was originally reported as an immunohistochemical marker that is absence of organ damage, symptomatic splenomegaly may warrant
primarily expressed in the cytoplasm of MCs in more advanced forms therapeutic intervention similar to patients with myelofibrosis or
of SM, other studies have detected CD30 by immunohistochemistry other hematologic neoplasms.
in less advanced forms of MC disease, including CM, as well as ISM
and SSM. CD30 is not only expressed in the cytoplasm of neoplastic
MCs but also on the cell surface, which has clinical implications as Nonhematologic Organ Damage
a CD30 antibody-toxin conjugate is available and is currently being
tested in patients with advanced SM. The challenge of defining response parameters related to hepatic
function is several-fold. First, for patients with SM with associated
myeloid neoplasm, it is unclear whether liver dysfunction is related
Serum Tryptase Level to the SM or the accompanying myeloid disease. Concomitant dis-
eases such as MPN or MDS/MPN such as CMML, CEL, or AML
Tryptase is considered to be a most reliable and robust initial param- may (also) involve the liver and result in a hepatitis-like syndrome
eter with which to screen patients with suspected SM. 18,19 Tryptase is or obstructive liver disease. It is unknown what level of liver
a serine protease primarily produced by MCs, and to a lesser extent involvement by MC consistently results in liver dysfunction. Liver
by mature basophils and myeloid progenitors. Commercially avail- biopsy is sometimes performed and may help to assess the grade
able ELISA-based assays measure total serum tryptase levels which and extent of liver involvement by SM. Although liver biopsy may
consist of both mature tryptase (β-tryptase) and protryptases (e.g., be informative, the potential information gleaned from the proce-
α-tryptase). The basal serum tryptase level reflects the MC burden dure must be weighed against potential complications such as
in healthy individuals as well as in patients with SM, whereas the bleeding, especially in the setting of severe thrombocytopenia and/
event-related (further) increase in tryptase is a marker of MC activa- or coagulopathy.
tion. β-tryptase is stored in MCs and released together with all other Hypoalbuminemia is an adverse prognostic factor for overall
granular substances upon degranulation/anaphylaxis (tryptase levels survival (OS) in SM 3,11 ; it can reflect worsening synthetic function
peak 1–2 h after degranulation event and return to baseline after of the liver, and/or worsening nutritional status or even malabsorp-
24–48 h). The α-tryptase form is constitutively produced by MCs tion because of gastrointestinal infiltration by neoplastic MCs. The
and thus more reflects the total burden of MCs. For many centers, development of ascites in SM usually reflects aggressive liver disease
the upper normal reference range for the serum tryptase level is 10 and may be accompanied not only by hepatomegaly but also by
or 11.4 ng/mL. However, healthy individuals may exhibit levels in abnormal liver function test, often with an elevated alkaline phos-
the range of 5–15 ng/mL or higher, which may be confounded by phatase and/or portal hypertension. More uncommonly, ascites may
the association between advancing age and increasing serum tryptase develop without evidence for liver disease, or in conjunction with
levels. Although a serum tryptase level >20 ng/mL serves as a minor massive abdominal lymphadenopathy. Similar to ascites, pleural
diagnostic criterion for SM, a minority of patients with histopatho- effusions may develop in advanced SM, although it is an uncom-
logically proven SM can exhibit values lower than this threshold. In mon event. Every attempt should be made to establish that the
adult patients with MIS or hymenoptera allergy, a serum tryptase ascites or pleural effusion is related to SM and/or the associated