1

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