PEDIATRIC

FIBROBLASTIC/MYOFIBROBLASTIC
NEOPLASMS: WHAT’S NEW?
Jason L Hornick, MD, PhD
Director of Surgical Pathology
and Immunohistochemistry
Brigham and Women’s Hospital
Professor of Pathology
Harvard Medical School
Boston, MA, USA
WHO CLASSIFICATION OF PEDIATRIC TUMORS (2021)
Fibroblastic/myofibroblastic tumors Intermediate (locally aggressive)
Benign Lipofibromatosis
Fasciitis/myositis DFSP and Giant cell fibroblastoma
Fibrodysplasia ossificans progressiva Plantar/palmar fibromatosis
Fibroma of tendon sheath Desmoid fibromatosis
Gardner fibroma Intermediate (rarely metastasizing)
Fibrous hamartoma of infancy Inflammatory myofibroblastic tumor
Inclusion body (infantile digital) fibromatosis NTRK-rearranged spindle cell neoplasm
Juvenile hyaline fibromatosis Malignant
Fibromatosis colli Infantile fibrosarcoma
Calcifying aponeurotic fibroma Low-grade fibromyxoid sarcoma/
Nasopharyngeal angiofibroma sclerosing epithelioid fibrosarcoma
EWSR1::SMAD3-positive fibroblastic tumor Low-grade myofibroblastic sarcoma
WHO CLASSIFICATION OF PEDIATRIC TUMORS (2021)
Fibroblastic/myofibroblastic tumors Intermediate (locally aggressive)
Benign Lipofibromatosis
Fasciitis/myositis DFSP and Giant cell fibroblastoma
Fibrodysplasia ossificans progressiva Plantar/palmar fibromatosis
Fibroma of tendon sheath Desmoid fibromatosis
Gardner fibroma Intermediate (rarely metastasizing)
Fibrous hamartoma of infancy Inflammatory myofibroblastic tumor
Inclusion body (infantile digital) fibromatosis NTRK-rearranged spindle cell neoplasm
Juvenile hyaline fibromatosis Malignant
Fibromatosis colli Infantile fibrosarcoma
Calcifying aponeurotic fibroma Low-grade fibromyxoid sarcoma/
Nasopharyngeal angiofibroma sclerosing epithelioid fibrosarcoma
EWSR1::SMAD3-positive fibroblastic tumor Low-grade myofibroblastic sarcoma
Fibroblastic/myofibroblastic Neoplasms

• Immunohistochemistry of limited diagnostic utility

(with several notable exceptions!)

• Recent discovery of gene rearrangements in many

tumor types

• Implications for diagnosis and targeted therapies

in select cases
Fibroblastic/myofibroblastic Neoplasms

Benign

Nodular fasciitis and related neoplasms

Fibrous hamartoma of infancy
Calcifying aponeurotic fibroma
EWSR1::SMAD3-positive fibroblastic tumor
 Nodular Fasciitis
Definition:
Self-limiting mesenchymal neoplasm that
usually occurs in subcutaneous tissue. It is
composed of plump, uniform fibroblastic/
myofibroblastic cells displaying a tissue
culture–like architectural pattern, and it
usually harbors USP6 rearrangement.
 Nodular Fasciitis
• All age groups, including children; wide distribution
(upper extremities, trunk, head and neck)

• Cranial fasciitis – infants < 2 yr; soft tissue of scalp

and outer table of skull

• Grows rapidly; usually < 2 cm (almost always < 5 cm)

• Spontaneous regression, typically 3 – 4 months

• Local recurrence rare

Nodular Fasciitis
Nodular Fasciitis
Nodular Fasciitis
Nodular Fasciitis
Nodular Fasciitis
Hiemcke-Jiwa et al. Int J Surg Pathol 2020
 Fibrous Hamartoma of Infancy
Definition:
Benign soft tissue neoplasm of infants and
young children, showing organoid, triphasic
morphology with bundles of bland fibroblastic/
myofibroblastic cells; nodules of primitive,
rounded or stellate cells with myxoid stroma;
and mature adipose tissue.
 Fibrous Hamartoma of Infancy
• Most children < 2 yr; can be congenital (20%)

• Male predominance

• Axilla, trunk, upper extremities, genital region

• Painless subcutaneous mass; sometimes overlying

skin discoloration, edema, hypertrichosis

• Mean size 3 cm (usually 1 – 6 cm)

• Local recurrence (non-destructive) in 15%

Fibrous Hamartoma of Infancy
Fibrous Hamartoma of Infancy
Fibrous Hamartoma of Infancy
Fibrous Hamartoma of Infancy
Fibrous Hamartoma of Infancy
 EGFR

Park et al. Am J Surg Pathol 2016

 Calcifying Aponeurotic Fibroma
Definition:
Rare benign tumor with potential for local
recurrence that typically arises on the distal
extremities of children and adolescents. It is
characterized by bland spindle cells and less
cellular zones of calcification with plump to
epithelioid fibroblasts.
 Calcifying Aponeurotic Fibroma
• Peak in children 5 – 15 yr; M > F

• Palmar hands/fingers >> plantar feet/toes >> wrists or

ankles

• Painless, poorly circumscribed mass; calcifications

on radiology

• Usually 1 – 3 cm

• Local recurrence up to 50%, sometimes following

prolonged interval; multiple recurrences rare
Calcifying Aponeurotic Fibroma
Calcifying Aponeurotic Fibroma
Calcifying Aponeurotic Fibroma
Calcifying Aponeurotic Fibroma
EWSR1::SMAD3–positive Fibroblastic Tumor
Definition:
Benign neoplasm with a strong predilection for
the hands and feet. Tumor nomenclature is
provisional.
EWSR1::SMAD3–positive Fibroblastic Tumor

• Wide age range, including children

• Female predominance

• Majority in hands and feet

• Small, painless superficial tumor

• Most 1 – 2 cm

• Local recurrence (non-destructive) in some cases

EWSR1::SMAD3-positive Fibroblastic Tumor
EWSR1::SMAD3-positive Fibroblastic Tumor
EWSR1::SMAD3-positive Fibroblastic Tumor
EWSR1::SMAD3-positive Fibroblastic Tumor
 ERG

Kao et al. Am J Surg Pathol 2018

Fibroblastic/myofibroblastic Neoplasms

Intermediate (Locally Aggressive)

Lipofibromatosis
Dermatofibrosarcoma protuberans
 Lipofibromatosis
Definition:
Rare, frequently recurring pediatric soft tissue
tumor with a predilection for the hands and
feet. It is composed of a distinctive admixture
of mature fat, short fascicles of bland spindle
cells, and lipoblast-like cells in the interface
between the spindle cell and lipomatous
components.
 Lipofibromatosis

• Children; 50% < 1 yr; 20% congenital; M:F 2:1

• Hands and feet >> trunk and head and neck

• Slow-growing, poorly demarcated subcutaneous mass

• Most between 1 – 6 cm

• High local recurrence rate (70%)

• No metastatic potential
Lipofibromatosis
Lipofibromatosis
Lipofibromatosis
Primary tumor Local recurrence (3 yr)

• FN1::EGF in 20%
• Some cases “early” calcifying
aponeurotic fibroma?

Al-Ibraheemi et al. Mod Pathol 2019

 Dermatofibrosarcoma Protuberans
Definition:
Superficial, locally aggressive fibroblastic
neoplasm, having a cellular storiform
appearance and carrying a COL1A1::PDGFB
or related fusion.
 Dermatofibrosarcoma Protuberans
• Young to middle-aged adults; also children; rarely
congenital

• Trunk, proximal extremities >> head and neck

• Slow but persistently growing nodular or multinodular

cutaneous mass; early lesions plaque-like

• Locally aggressive; often repeated local recurrence

(20-50%); wide margins advisable

• No metastatic potential in conventional form

Dermatofibrosarcoma Protuberans
Dermatofibrosarcoma Protuberans
Dermatofibrosarcoma Protuberans

CD34
Fibrosarcomatous Dermatofibrosarcoma Protuberans
• Histologic progression from storiform to fascicular
fibrosarcoma-like appearance

• Usually vesicular nuclei; increased mitotic activity

• Often loses expression of CD34

• FISH particularly useful in such tumors, especially when

no conventional component

• Acquires 10-15% risk for metastasis (most often lungs)

Fibrosarcomatous DFSP
Fibrosarcomatous DFSP
Fibrosarcomatous DFSP
Fibrosarcomatous DFSP

Myoid Nodules
 Dermatofibrosarcoma Protuberans Genetics
• Unbalanced translocation

• Often ring chromosomes

• der(17)(17;22)(q22;q13)

• COL1A1::PDGFB

• Strong promoter drives

expression of growth
factor

• FISH for PDGFB Simon et al. Nat Genet 1997

Metastatic Fibrosarcomatous Dermatofibrosarcoma Protuberans
Metastatic Fibrosarcomatous Dermatofibrosarcoma Protuberans
Dermatofibrosarcoma Protuberans Targeted Therapy

• Imatinib mesylate

• High rate of partial and low

rate of complete responses

• Neoadjuvant: “down-stage”
prior to surgery

• Shorter responses in
patients with metastatic
fibrosarcomatous DFSP Stacchioti et al. Clin Cancer Res 2016

Rutkowski et al. Eur J Surg Oncol 2017

Dermatofibrosarcoma Protuberans Genetics
• Small subset of DFSP (4%) negative for PDGFB
rearrangement by FISH

• Until recently, molecular pathogenesis unknown

• Around half of these cases (2%) harbor “cryptic”

COL1A1::PDGFB rearrangement

• Other half (2%) harbor novel gene fusions:

• COL6A3::PDGFD or EMILIN2::PDGFD
Dadone-Montaudié et al. Mod Pathol 2018

Dickson et al. Genes Chromosomes Cancer 2018

Dickson et al. Genes Chromosomes Cancer 2018
Fibroblastic/myofibroblastic Neoplasms

Intermediate (Rarely Metastasizing)

Inflammatory myofibroblastic tumor

NTRK-rearranged spindle cell neoplasm
 Inflammatory Myofibroblastic Tumor
Definition:
Distinctive, rarely metastasizing neoplasm
composed of myofibroblastic and fibroblastic
spindle cells accompanied by an inflammatory
infiltrate of plasma cells, lymphocytes, and/or
eosinophils.
 Inflammatory Myofibroblastic Tumor
• Primarily children, adolescents, and young adults
• Lung, abdominal cavity, retroperitoneum, pelvis >>
head and neck, GI tract, uterus, bladder
• Symptoms depend on anatomic site
• Around 20% present with constitutional symptoms
(fever, malaise, weight loss) and lab abnormalities
(anemia, thrombocytosis, hypergammaglobulinemia,
elevated ESR)
• Local recurrence in 25% (extrapulmonary);
metastasis in 2-3%
 Inflammatory Myofibroblastic Tumor

Lung
 Inflammatory Myofibroblastic Tumor

Lung
 Inflammatory Myofibroblastic Tumor

Mesentery
 Inflammatory Myofibroblastic Tumor

Colon
 Inflammatory Myofibroblastic Tumor

Stomach
 ALK in Inflammatory Myofibroblastic Tumor
• ALK rearrangement in 60% of IMT

• <10% in adults >50 yr

• Heterogeneous fusion partners

• Strong correlation between detection of ALK by IHC

and ALK rearrangement by FISH or NGS (new highly
sensitive antibodies better)

• ALK negative in other fibroblastic/myofibroblastic

tumors
Inflammatory Myofibroblastic Tumor
TPM3::ALK

ALK
8-year-old boy with IMT harboring TFG::ROS1 fusion

Lovly et al. Cancer Discovery 2014

Inflammatory Myofibroblastic Tumor
TFG::ROS1

ROS1
Inflammatory Myofibroblastic Tumor
NTRK-rearranged Spindle Cell Neoplasms
Definition:
Emerging family of rare spindle cell tumors showing
a wide morphologic spectrum, from lipofibromatosis-
like to infantile fibrosarcoma-like lesions, and
harboring NTRK1/2/3 gene rearrangements or other
gene alterations (such as RAF1, BRAF, or RET)
implicated in receptor tyrosine kinase pathway
activation. Our understanding of this category is
rapidly evolving; additional genetic alterations may
be discovered with further studies.
 NTRK-rearranged Spindle Cell Neoplasms
• Majority occur in first two decades; rarely in adults
• Most common in extremities (superficial > deep);
also trunk and GI tract
• May resemble lipofibromatosis, malignant peripheral
nerve sheath tumor, infantile fibrosarcoma
• Co-expression of S100 protein and CD34 common
• Pediatric tumors can recur locally; metastasis rare
• Prognostic significance of histologic features
(cellularity, mitotic rate, necrosis) not entirely clear
NTRK variant fusions
TPM3::NTRK1
LMNA::NTRK1
MIR584F1::NTRK1
SQSTM1::NTRK1
TPR::NTRK1
STRN::NTRK2
EML4::NTRK3
NTRK-rearranged Spindle Cell Neoplasm
NTRK-rearranged Spindle Cell Neoplasm
NTRK-rearranged Spindle Cell Neoplasm
NTRK-rearranged Spindle Cell Neoplasm

pan-TRK
WHO CLASSIFICATION OF SOFT TISSUE TUMORS
5TH EDITION 2020: NEW GENETICS
Fibroblastic/myofibroblastic tumors

Tumor type New genetic alterations

Fibrous hamartoma of infancy EGFR mutations
Calcifying aponeurotic fibroma FN1::EGF
RTK or EGFR ligand fusions
Lipofibromatosis
(EGFR, ROS1, PDGFRB, RET, BRAF)
Dermatofibrosarcoma protuberans COL6A3::PDGFD, EMILIN2::PDGFD
Infantile fibrosarcoma and NTRK- EML4::NTRK3, NTRK1, NTRK2,
rearranged spindle cell neoplasms BRAF, RAF1, RET fusions
[email protected]
@JLHornick

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