fibrous tumors of infancy and childhood: an update international...
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Fibrous Tumors of Infancy and Childhood: An Update
International Society of Bone and Soft Tissue Pathology 2011
Cheryl M. Coffin, M. D.
Goodpasture Professor of Pathology
Vice Chair and Executive Medical Director of Anatomic Pathology
Vanderbilt University, Nashville, TN
Key Words: Fibroblastic-myofibroblastic tumors, fibromas, fibromatoses, Gardner
fibroma, desmoid, lipofibromatosis, infantile fibrosarcoma, primitive myxoid
mesenchymal tumor of infancy, low grade fibromyxoid sarcoma, inflammatory
myofibroblastic tumor.
Introduction
Fibroblastic and myofibroblastic neoplasms account for approximately 12% of
soft tissue tumors in the first two decades of life, excluding the pseudosarcomas such as
nodular fasciitis and related lesions and inflammatory myofibroblastic tumor (1-8). The
histologic similarities, differences in biologic potential, and clinical and molecular
genetic variations among this group of lesions create clinical, diagnostic and therapeutic
challenges. The histologic spectrum encompasses reactive, malformative,
pseudosarcomatous, and neoplastic lesions. In recent decades, the concept of intermediate
or borderline fibroblastic-myofibroblastic tumors has been refined for neoplasms with a
tendency for local recurrence or rare metastases. This presentation focuses on recently
described fibroblastic neoplasms or new advances in the knowledge about these lesions in
young patients.
Gardner Fibroma and Desmoid Fibromatosis Gardner fibroma is a benign plaque-like mass with a predilection for children and
young adults, and a strong association with APC mutation and familial adenomatous
polyposis (9 and 10). It is associated with concurrent or subsequent development of
desmoids. The mass is composed of coarse collagen fibers separated by clear clefts and
interspersed with bland spindle cells and sparse mast cells. Although it is unknown
whether Gardner fibroma represents an overgrowth or a neoplasm, nuclear beta-catenin
reactivity has been observed in a subset of cases. There is over expression of beta-catenin
and other proteins in the APC and WNT pathways. The optimal therapeutic approach to
Gardner fibroma is not fully understood, since surgery may promote the growth of a
subsequent desmoid in the region of a Gardner fibroma.
Desmoid tumors are relatively frequent in children although they are categorized
among the so-called “adult fibromatoses” (11-16). Approximately 15-40% of desmoids
occur in patients in the first two decades of life, and 19-60% of pediatric fibroblastic-
myofibroblastic tumors are desmoids. Multiple desmoids occur in 3-12% of cases. The
trunk and extremities are the most common sites, although desmoids can occur in soft
tissue anywhere in the body. The grossly circumscribed mass is composed of sheets and
fascicles of fibroblasts and myofibroblasts in a variably collagenized and myxoid
background. The microscopic borders are often infiltrative. A pattern of elongated
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slender blood vessels at the periphery of fascicles is distinctive. Nuclear beta-catenin
reactivity is frequently demonstrated. The recurrence rate in children and adolescents in
60% overall, and 20% of patients have multiple recurrences. Fewer than 2% die of local
complications. Up to 25% of young patients have adenomatous polyposis coli. This may
be an underestimate of the frequency of APC mutation since other manifestations of APC
may not be obvious in children and adolescents. Other genetic aberrations in desmoids
include beta-catenin mutations, chromosome 5q deletion, and trisomies 8 and 20.
Desmoid fibromatoses are treated with surgery; chemotherapy may be effective in
selected cases.
Lipofibromatosis
Lipofibromatosis is a recently described intermediate, locally recurrent neoplasm
(17-19). It has a predilection for infancy and early childhood, and approximately 25% are
congenital. The distal extremities are the favored site. Lipofibromatosis has a male
predilection. The poorly circumscribed mass is composed of slender interfacing bundles
of mature fibroblasts interspersed with mature adipose tissue. 75% recur locally. Little is
known about the cytogenetics or molecular genetic aspects of lipofibromatosis, although
a complex translocation involving chromosomes 4, 6, and 9 has been reported in one
case.
Infantile Fibrosarcoma
Infantile fibrosarcoma is an intermediate rarely metastasizing neoplasm that
occurs mainly in infancy and very early childhood (20-29). Approximately 50% are
congenital and the sex distribution is equal. Infantile fibrosarcoma can arise on the
extremities, trunk, or head and neck as a rapidly growing tumor that reaches a very large
size in proportion to the size of the child. Histologically, spindle, primitive angulated, and
round cell patterns may be seen, and zonal necrosis is frequent. A translocation between
chromosomes 12 and 15 with an ETV6-NTRK3 gene fusion is considered characteristic.
In addition, gains of chromosomes 8, 11, 17, and 21 may be observed. Surgery and
chemotherapy are effective treatments. It is now recognized that infantile fibrosarcoma
and cellular congenital mesoblastic nephroma are histologically identical tumors with the
same gene fusion and the same response to treatment.
Primitive Myxoid Mesenchymal Tumor of Infancy
Primitive myxoid mesenchymal tumor of infancy is a rare recently described
primitive tumor of infancy that occurs on the trunk, extremities, and head and neck (29).
The multinodular growth is composed of primitive cells with a myxoid background and
lacks characteristic immunohistochemical features. Recurrence and metastasis occur. No
information is yet available about cytogenetic or molecular genetic features. Primitive
myxoid mesenchymal tumor has been provisionally included among the intermediate or
low grade malignant potential fibroblastic-myofibroblastic tumors because of its
tendency for recurrence, rare frequency of metastasis, and ultrastructural features of
primitive fibroblasts.
Low Grade Fibromyxoid Sarcoma
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Low grade fibromyxoid sarcoma is a specific subtype of fibrosarcoma with a low
frequency of metastasis (30-36). Approximately 20% occur in the first two decades of
life. Although the proximal extremities and trunk are the most common sites, the head
and neck is a preferred site in children. The tumor may be superficial or deep, although
pediatric cases are more frequently located in superficial soft tissue. A variety of
histologic variants have been reported, including myxoid and cellular variants,
hyalinizing spindle cell with giant collagen rosettes, and perhaps sclerosing epithelioid
fibrosarcoma. A translocation between chromosomes 7 and 16 with a FUS-CREB3L2
gene fusion has been reported. The recurrence rate is 10%. Approximately 6% of patients
have late metastases. Complete surgical excision is effective treatment.
Inflammatory Myofibroblastic Tumor
Inflammatory myofibroblastic tumor is a distinctive lesion composed of
myofibroblastic spindle cells accompanied by an inflammatory infiltrate of plasma cells,
lymphocytes and eosinophils, according to the current WHO classification (2, 37-48). It
is currently regarded as an intermediate, rarely metastasizing neoplasm. The age
distribution is wide, but inflammatory myofibroblastic tumor is most frequent in the first
three decades of life. It can arise in the mesentery, omentum, retroperitoneum, lungs,
mediastinum, head and neck, live, and genitourinary tract as a solitary or multinodular
mass. Up to 25% of patients have a clinical syndrome of fever, weight loss, growth
failure, anemia, thrombocytosis, polyclonal hyperglobulinemia, and elevated
inflammatory markers.
Genetic abnormalities have been reported including chromosome 2p23
abnormalities with ALK gene rearrangements in 50-70% of inflammatory myofibroblastic
tumors. The fusion oncogenes are numerous and include tropomyosin, clathrin, RAN
binding protein 2, and other oncogenes. Detection of the ALK abnormality with
immunohistochemistry has high sensitivity and specificity. The ALK rearrangement can
be demonstrated with conventional tumor karyotype, fluorescent in situ hybridization,
and RT-PCR. Local recurrence has been reported in up to 25% of extrapulmonary
inflammatory myofibroblastic tumors. Metastases are rare. Although surgery is the
standard treatment, and chemotherapy may be effective, small molecule inhibitors of
ALK are a recent therapeutic option for inflammatory myofibroblastic tumor with an ALK
gene rearrangement.
Prognostic indicators have been elusive. Recent finding of clinical and prognostic
importance is the recognition of the round cell variant of inflammatory myofibroblastic
tumor. Round cell inflammatory myofibroblastic tumor is ALK positive with a distinctive
membranous and dot-like pattern of ALK reactivity and a gene fusion between ALK and
RANBP2, which has a predilection for males, involves intraabdominal sites, and has a
mean age of 35 years, with an age range of infancy to the sixth decade. The majority of
patients reported thus far with round cell inflammatory myofibroblastic tumor have
experienced rapid local recurrence, a metastatic rate of 25%, and a death rate of 38%.
One of the most important aspects of the diagnosis of inflammatory
myofibroblastic tumor is recognizing it from its many mimics. Many different reactive
infections, fibroinflammatory, and neoplastic conditions can simulate inflammatory
myofibroblastic tumor. Although the term “inflammatory pseudotumor” is embedded in
the literature, we recommend abandoning this term because of its lack of specificity and
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the significant potential for confusion about pathologic classification. IgG4-related
sclerosing disease encompasses a clinical syndrome with multiorgan system involvement
by a diffuse fibroinflammatory proliferation and is distinguished by its infiltrative growth
pattern, presence of abundant lymphoid aggregates, and obliterative phlebitis. The IgG4/
IgG plasma cell ratio in inflammatory myofibroblastic tumor can overlap with IgG-
related sclerosing disease and is not a reliable test for distinguishing between the two
lesions. There are many neoplastic mimics of inflammatory myofibroblastic tumor, such
as lymphoma (Hodgkin’s disease, anaplastic large cell lymphoma, other lymphomas, and
extramedullary myeloid sarcoma), dendritic cell neoplasms (especially follicular
dendritic cell tumor arising in the context of Castleman disease), sarcomatoid
carcinomas, malignant melanoma, plexiform fibromyxoma, and other sarcomas
(inflammatory liposarcoma, inflammatory leiomyosarcoma).
At this point in time, understood that inflammatory myofibroblastic tumor is
regarded as an intermediate rarely metastasizing neoplasm, and in 50-70% of cases it is
an ALKoma with the potential for targeted treatment with small molecule inhibitors. It is
also well recognized that inflammatory myofibroblastic tumor has a predilection for
younger patients and an origin in body cavities. Ongoing challenges include identification
of prognostic markers, optimal treatment, and appropriate classification of ALK-negative
inflammatory myofibroblastic tumors. The pathologic paradox is the neoplastic
proliferation of spindled myofibroblastic cells combined with the prominent
inflammatory infiltrate.
Summary and Conclusions Fibroblastic-myofibroblastic tumors in young patients are an important and
challenging group of lesions with extensive histologic and immunohistochemical
similarities. Cytogenetic and molecular genetic identification of mutations, deletions,
gene rearrangements, and alterations in receptor tyrosine kinases has yielded new insights
about this group of tumors. Whether non-round cell undifferentiated sarcomas in young
patients will eventually be recognized as primitive fibroblastic neoplasms and included
among the fibroblastic-myofibroblastic tumors in young patients is an important point for
future consideration. It is also evident that many tumors previously classified as
fibrohistiocytic tumors could be subsumed into the fibroblastic-myofibroblastic category
because of their cellular characteristics and phenotypes. Finally, the extent to which
treatment can be tailored to these individual tumors and to the individual patients will be
an important area for further investigation. The time will soon come for a revised
morphologic-genetic-managerial classification.
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Fibrous Tumors of Infancy and
Childhood: An Update
International Society of Bone and Soft
Tissue Pathology 2011Tissue Pathology 2011
Cheryl M. Coffin, M. D.
Goodpasture Professor of Pathology
Vice Chair and Executive Medical Director of Anatomic Pathology
Vanderbilt University, Nashville, TN
Key Facts and Challenges
• >10% of soft tissue tumors in newborns to 20
year olds have a fibroblastic-myofibroblastic
phenotype
• The clinicopathologic spectrum encompasses • The clinicopathologic spectrum encompasses
reactive, malformative, benign, intermediate,
and malignant lesions
• Morphologic and immunohistochemical
similarities
• Biologic, genetic, and therapeutic diversity
Objectives
• To review the current classification of
fibroblastic-myofibroblastic tumors
• To summarize new information and recently
described lesionsdescribed lesions
• To discuss evolving knowledge and ongoing
challenges of inflammatory myofibroblastic
tumor (IMT)
Classification
• Benign
Malformations/ overgrowths
Pseudosarcomas
Fibromas Fibromas
Fibromatoses, juvenile and adult
• Intermediate fibroblastic-myofibroblastic neoplasms (locally recurrent vs. rarely metastasizing)
• Fibroblastic-myofibroblastic sarcomas
Gardner Fibroma
• Benign plaquelike mass
• Predilection for children and young adults
• Strong association with FAP/APC
• Overexpression of beta-catenin and other • Overexpression of beta-catenin and other
proteins in the APC and Wnt pathways
• Association with concurrent or subsequent
desmoids
• Surgery vs. no treatment?
• Overgrowth or neoplasm?
Juvenile Desmoid Tumors
• 15-40% of desmoids occur in NB – 20 y.o
• 3-12% are multiple
• Trunk and extremities are most common sites
• 60% recur; 20% have multiple recurrences
• Death in < 2%
• APC known in 25%
Lipofibromatosis
• Intermediate, locally recurrent neoplasm
• Infancy and childhood; 25% congenital
• Distal extremities favored site
• Male predilection
• 75% local recurrence rate
• t(4;6;9) in one case
Infantile Fibrosarcoma
• Intermediate, rarely metastasizing neoplasm
• Infancy; 50% congenital
• Extremities, trunk, head/ neck
• Rapid growth, large size
• t(12;15) with ETV6-NTRK3 fusion
• Gains of chromosomes 8,11,17,21
• Surgery, chemotherapy effective
Primitive Myxoid Mesenchymal
Tumor of Infancy
• Rare primitive tumor of infancy
• Trunk, extremities, head, and neck
• Multinodular growth• Multinodular growth
• Recurrence, metastasis
• Intermediate or low grade malignant potential
Low Grade Fibromyxoid Sarcoma
• A specific subtype of fibrosarcoma
• 20% in first two decades of life
• Proximal extremities and trunk most common sites,
superficial or deep
• Predilection for head/ neck and superficial sites in
children
• Histologic variants
• Recurrence in 9%, metastases in 6% (late)
• t(7;16)(q34;p11) with FUS-CREB3L2 gene fusion
Inflammatory Myofibroblastic Tumor
• Intermediate, rarely metastasizing neoplasm
• Infancy to adulthood, most frequent in first 3 decades
• Mesentery, omentum, retroperitoneum, lung,
mediastinum, head/neck, liver, GU tract
• Clinical syndrome: fever, weight loss, growth failure, • Clinical syndrome: fever, weight loss, growth failure,
anemia, thrombocytosis, polyclonal hyperglobulinemia,
elevated ESR
• Local recurrence in 25%; metastasis rare
• Prognostic indicators elusive
Genetic Abnormalities
• Chromosome 2p23 abnormalities with ALK
gene rearrangements in 50- 70% of IMTs
• Fusion oncogenes: tropomyosin (TPM3,
TPM4), clathrin (CLTC), Ran-binding protein TPM4), clathrin (CLTC), Ran-binding protein 2 (RANBP2), CARS, ATIC, SEC31L1
• Detection: immunohistochemistry, FISH, RT-PCR
• Small molecule ALK inhibitors: a new therapeutic option
Round Cell IMT: A Morphologic-
Prognostic- Molecular Subtype?
• Males
• Intraabdominal
• Mean age 35 yr. (7mo.- 59 yr.)
• Rapid local recurrence in 100%
• Metastases in 25 %
• Death in 38%
• ALK- positive with RAN-BP2 fusion
IMT: What It Is Not
• A “pseudotumor” (abandon the term!)
• IgG4- related sclerosing disease
• Lymphoma, dendritic cell neoplasm, • Lymphoma, dendritic cell neoplasm,
carcinoma, melanoma, other sarcomas
IMT: What It Is
• An intermediate (rarely metastasizing) neoplasm
• An ALKoma with potential for targeted treatment
(sometimes)
• A tumor with a predilection for body cavities and younger
patients
• A pathologic paradox
• An ongoing challenge
Rethinking the Fibroblastic-
Myofibroblastic Tumors
• Mutations, deletions, rearrangements, receptor tyrosine kinases, and more?
• Is it time for a revised morphologic- genetic-managerial classification?managerial classification?
• Will non-round cell undifferentiated sarcomas in young patients eventually be recognized as primitive fibroblastic neoplasms?
• To what extent can treatment be tailored to tumors and to individual patients?
“There is a bright future for complexity,
what with one thing leading to another.”
E.B. White