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Benign and Intermediate Fibroblastic/Myofibroblastic Lesions

Rita Alaggio

Fibroblastic/myofibroblastic tumors

Fibroblastic/myofibroblastic tumors account for about 12% of all pediatric soft tissue

tumors. The WHO classification recognizes 3 prognostic categories: Benign tumors,

tumors with intermediate prognosis (either locally aggressive or only rarely

metastasizing) and malignant tumors. The majority of myofibroblastic proliferations is

represented by benign or reactive/pseudo-neoplastic lesions; the remaining have an

intermediate prognosis. Malignant myofibroblastic tumors are very rare in children. The

histologic variation of Fibroblastic/myofibroblastic tumours, may be sometimes subtle

even between tumors with different clinical behavior and render the differential

diagnosis challenging.

This review will focus on benign and intermediate myofibroblastic lesions.

Table 1 summarizes the fibroblastic-myofibroblastic tumors more frequent in pediatric

age.

Table 1 FIBROBLASTIC / MYOFIBROBLASTIC TUMOURS

Pseudo-sarcomatous proliferations Nodular fasciitis Cranial Fasciitis Myositis ossificans/fibro-osseous pseudo-tumour of digits

Benign Lesions Fibromas

Fibroma of tendon sheath Gardner fibroma Fibromatoses (Juvenile type)

Fibrous hamartoma of infancy Myofibroma / Myofibromatosis Fibromatosis colli Juvenile hyaline fibromatosis/Inclusion body fibromatosis Calcifying aponeurotic fibroma

Lesions with intermediate prognosis (locally aggressive) Fibromatoses (Juvenile type)

Lipofibromatosis Fibromatoses (adult type) Palmar-plantar fibromatosis Desmoid-type fibromatoses

Lesions with intermediate prognosis (rarely metastasizing) Inflammatory myofibroblastic tumour Low-grade myofibroblastic sarcoma Infantile fibrosarcoma

Pseudosarcomas

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Nodular fasciitis

Nodular fasciitis is the most common pseudo-sarcomatous lesion in adults. It is rare in

children younger than 5 years, although infants and small children may be rarely

affected. There is a slight predominance in males. It may involve any site, including

head and neck, trunk and extremities. Nodules are located in deep subcutaneous tissue,

muscle and fascia, but dermal variants are also reported. A previous trauma may be

identified in less than 15% of cases.

Macroscopically nodular fasciitis is a small non-encapsulated, nodule, usually less than

3.0 cm in greatest diameter with a cut surface, varying from myxoid to firm and

leathery.

The histological features show variations according to the phase of the process (table 2).

Early lesions show a prominent myxoid matrix with spindle-stellate cells simulating

fibroblasts grown in tissue culture. Extravasated red blood cells, scattered lymphocytes

and plasma-cells are common.

In the florid phase, there is a higher cellularity, with myofibroblasts and ganglion-like

mesenchymal cells in short fascicles and sheets intermingled with collagen bundles.

Occasionally a zonation pattern may be observed, with a myxoid or hyalinized central

area and a densely cellular periphery. In late stage lesions myxoid matrix is minimal,

replaced by collagen with hyaline, keloid-like appearance. Broad fascicles of

myofibroblasts display a storiform pattern. Microcystic spaces containing mucoid

material may be found. Mitoses are more frequent in recent lesions, but are never

atypical. Cartilagineous metaplasia, osteoid, calcification, and heterotopic ossification

may be occasionally found.

Immunohistochemically myofibroblasts are reactive for vimentin, muscle-specific actin,

smooth muscle actin, and calponin, whereas h-caldesmon is negative. CD68 stains

histiocytes and rare osteoclast-like giant cells.

Unusual variants of nodular fasciitis include intra-articular and intravascular nodular

fasciitis. They closely resemble the common form of nodular fasciitis.

The differential diagnosis of nodular fasciitis includes a wide spectrum of benign and

malignant lesions (table 2). Nodular fasciitis is treated by surgical excision. In case of

incomplete resection, the lesion may spontaneously regress. Recurrences are extremely

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rare and may be related to the proliferation of reactive myofibroblasts present in the

residual lesion in response to the trauma of resection.

Table 2: differential diagnosis of Nodular Fasciitis

Histology Differential Diagnosis Diagnostic clues

Early lesion: Abundant myxoid matrix Fibroblasts in “cell culture-like” pattern Red cells, lymphocytes plasmacells Florid lesion:

High cellularity Occasional zonation (hyalinized center and cellular periphery) Older lesions: Abundant keloid-like collagen

Malignant peripheral nerve sheath tumor

Neurofibroma

Lipoblastoma

myxoid liposarcoma:

myxofibrosarcoma:

Myofibromatosis

Spindle cell sarcomas (embryonal rhabdomyosarcoma, fibrosarcoma, inflammatory myofibroblastic tumor)

Desmoid Fibromatosis:

Keloid

Inflammatory myofibroblastic tumor

cellular atypia, weavy nucley, necrosis, Antoni A and B areas.

absent inflammatory infiltrate and red cells, S100+ cells

lipoblasts, organoid pattern with collagen septa

lipoblasts, typical vascular network

cellular atypia, atypical mitoses

spindle cells in whorls, inflammatory infiltrate or extravased red cells not prominent

Larger lesions, deeply located, cytologic atypia, necrosis

Long fascicles, scattered mast cells, IHC: beta-catenin+

larger lesions, deeply located, ALK+ in some case

Fibromas

Gardner fibroma

Gardner fibroma, has been recognized by the 2002 World Health Organization

classification of soft tissue tumors as a distinctive benign lesion, typically associated

with desmoids and familial adenomatous polyposis coli or Gardner syndrome. A family

history of APC is found in 70% of patients and in 10% other members of family have a

history of desmoid fibromatosis.

It has a predilection for the first 2 decades of life, and is located in superficial and deep

soft tissues of the paraspinal region, back, chest wall, flank, head and neck, and

extremities. A desmoid fibromatosis may be found in continuity with the Gardner

fibroma at time of biopsy or may develop subsequently in about 50% of cases.

Macroscopically, it is a poorly circumscribed, plaque-like lesion with a rubbery, white

cut-surface.

Microscopically it is extremely hypocellular, densely collagenized, with scattered

spindle cells separated by clefts from the eosinophilic collagen fibers. At the periphery

the lesion is infiltrative with focal entrapment of fat, peripheral nerve fibers, and blood

vessels. Sparse mast cells may be present.

The spindled cells are positive for vimentin and CD34, but negative for muscle- specific

actin, smooth muscle actin, desmin, estrogen receptor, and progesterone receptor

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proteins. Nuclear beta-catenin reactivity is variable and can be positive in up to two-

thirds of cases. It may be negative in patients with APC mutation.

Nuchal- type fibroma typical of young adults is a lesion strictly related to Gardner

Fibroma. It may be associated with diabetes mellitus and shows an increased number of

small nerve bundles, absent in Gardner fibroma. Its presence in children may be

associated with FAP.

Gardner fibroma is a benign lesion, whether it is a malformation or a true neoplasm

representing a juvenile form of desmoid fibromatosis is yet to be determined. The

correct diagnsis is important because it may represent a sentinel event and should alert

clinicians to the possibility of an underlying Gardner Syndrome or FAP.

Fibromatoses

Fibromatoses represent an unique group of fibroblastic myofibroblastic lesions

accounting for over the 90% of fibroblastic-myofibroblastic tumors in children.They

include different clinico-pathologic entities, some typical of children (juvenile

fibromatoses), others occurring in adults and children (adult fibromatoses).

The juvenile fibromatoses are generally benign and some of them may have a

spontaneous regression. Some juvenile fibromatoses such as Juvenile hyaline

fibromatosis and gingival fibromatosis are hereditary.

The adult fibromatoses include superficial (palmar / plantar) and Desmoid-type

fibromatoses, which are considered as intermediate, locally aggressive lesions in 2002

WHO classification. In table 3 clinical features of fibromatoses are reported. We will

focus on the most common types.

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Table 3: Clinical features of Juvenile and Adult (*)Fibromatoses

Age M/F Site Prognosis Treatment

Myofibromatosis Solitary multicentric Generalized

Birth or later Congenital Congenital

3/1 1/2

Skin, soft tissue Skin, soft tissue, bone Skin, soft tissue, bone, viscera

Favorable Favorable Progression Death (75%)

Surgery, possible regression Surgery, possible regression Chemotherapy

Fibromatosis colli

Congenital Male predominance

Sternocleidomastoid muscle, right, may be bilateral

Self-limiting Physical therapy

Infantile digital fibroma/inclusion body fibromatosis

Infants/older children

No sex predilection

40-60% multiple dorso-lateral pprtion of digits,

Recurrence in xx%

Surgical resection

Fibrous Hamartoma of Infancy

Infants-2yr 1/1 Axilla, groin, upper arms, upper trunk, external genitalia

favourable Surgery

Lipofibromatosis Infants-2 yrs 2:1 distal extremities, trunk and head

Recurrence or persistent growth in 72%

Surgical resection

Juvenile nasopharingeal fibroma

10-20 yr male posterior nasal cavity ethmoid and maxillary sinuses

recurrence rate: 68%. Rare spontaneous regression.

Surgery, pharmacotherapy with anti-androgens. Embolization or chemotherapy.

Juvenile hyaline fibromatosis Juvenile Infantile systemic

First few years of life Infants

No sex predilection

Skin lesions: hands, scalp, ears, nose. Large subcutaneous tumors. Gingival hypertrophy

visceral involvement

progressive joint contractures osteopenia lethal

Interferon 2 alpha

Calcifying aponeurotic fibroma

0-64 yr Slight male predominance

Hands (fingers and palms), feet, and wrist. Proximal extremities and back occasionally involved

50% recurrence.. surgical excision

Palmar/plantar Fibromatosis*

Adults (10% in children between 2-12 yr)

1/2

plantar, less frequently palmar.

Recurrence: 83% Surgery reserved to lesions not responding to pharmacologic therapies and to early contractures in proximal inter-phalangeal joints of the hands

Desmoid-type fibromatosis*

Adults (20% in children between 0-19 yr)

1/1 Extremities, trunk, head, neck,shoulder, hip

Local growth, Relapse 20%

Surgery, CT/RT, Estrogen antagonists, Imatinib

Juvenile Fibromatoses Infantile myofibroma/myofibromatosis Infantile myofibroma or myofibromatosis is the most common type of fibromatosis in

infancy and childhood.

It occurs in 3 clinical forms: solitary, multicentric, and generalized. (table)The term

myofibromatosis is reserved to the last two forms. Solitary and multicentric IM are the

most common forms and manifest as isolated or multiple nodules localized in the skin,

soft tissues and bone. The most frequent regions involved are head and neck, followed

by trunk and extremities.

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Generalized IM shows concomitant lesions in lung, heart, gastrointestinal tract or even

central nervous system (Table 3).

Macroscopically myofibromas are nodules of variable size, with an average greatest

diameter of 1.5 cm, but large lesions may occur. Skin lesions are well circumscribed,

whereas those deeply located tend to have less defined margins. The nodules have firm

consistency and white-gray color, occasionally pinky, with cysts or central yellow

necrotic areas, which can be prominent in larger lesions. Scattered calcifications are also

found.

Histologically myofibromas/myofibromatosis are nodular proliferation variously

composed of myoid, elongated cells showing eosinophilic cytoplasm, nuclei with finely

dispersed chromatine and one or two small nucleoli and more primitive elongated-

polygonal cells with larger nuclei, uniform chromatine and amphophilic cytoplasms.

Their appearance varies according to the stage of the lesion.

Immature lesions are highly cellular and the primitive elongated-polygonal cells are

predominant. The cells are arranged in sheets or short fascicle, and only focal areas

show slightly more mature myofibroblasts. At the periphery the margins may be poorly

circumscribed or infiltrative. Delicate irregularly branching blood vessels in a

hemangiopericytomatous pattern may be present. In the past, such cases were regarded

as "infantile hemangiopericytoma", but they are now recognized as a variant of infantile

myofibromatosis.

A zonal microscopic appearance may be found in some cases charcaterized by immature

cells in a hemangiopericytomatous pattern in the center of lesion and myoid cells

arranged in short interlacing fascicles interspersed in a variable collagen or myxoid

matrix or forming whorls at the periphery. In the adjacent non-lesional tissue, peripheral

satellite nodules with a whorled pattern may be found. Focal perivascular and

intravascular proliferation of immature myofibroblastic and primitive mesenchymal cells

can give a false impression of vascular invasion.

Mitoses are rare, but occasianally are frequent. Necrosis may be extensive, with

associated dystrophic calcifications.

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Immunohistochemical staining of the tumor cells reveals alpha-smooth muscle actin

strong reactivity in the myoid component. S100 protein, epithelial membrane antigen,

keratin and desmin are negative.

Cytogenetic analyses or molecular genetics of infantile myofibroma/myofibromatosis

have demonstrated nonspecific findings with chromosome 8 abnormalities and

chromosome 6 deletions.

An autosomal dominant pattern of inheritance with variable penetrance has been

observed in rare cases.

The differential diagnosis includes other fibromatoses, particularly desmoid

fibromatosis, nodular fasciitis, myofibroblastic sarcoma (Table 4).

Solitary and multicentric myofibroma/myofibromatosis are frequently a self-healing

process, with spontaneous regression of nodules. Surgical excision is the treatment of

choice in those lesions that do not regress. Myofibromas with a destructive growth in

non-resectable sites may be responsive to chemotherapy. Generalized

myofibromatosis does not regress spontaneously and visceral involvement may be

fatal in about 70% of cases.

Fibrous hamartoma of infancy

Fibrous hamartoma is a subdermal fibromatous tumor of infants, generally

diagnosed within the first 2 years of life, with nearly 20% detected at birth. There is a

male prevalence, without familial or syndromic association. It commonly involves the

axillary and inguinal regions, upper arms, upper trunk and external genital areas.

Extremities are rarely involved. Fibrous hamartoma of infancy is generally a solitary

subcutaneous mass.

Grossly, it is poorly demarcated from the surrounding adipose tissue and has a pale,

gray-white fibrotic cut surface with focal soft yellow areas resembling fat.

The triphasic histologic pattern composed of primitive small rounded or stellate cells in

nests and whorls, mature fibrous tissue with collagen bands and islands of adipose tissue

is virtually diagnostic of fibrous hamartoma.

Morphologic variations include a prominent fat or collagen myxoid component,

simulating respectively a lipoblastoma or a neurofibroma. Immunohistochemistry may

be helpful in such cases, demonstrating their fibroblastic-myofibroblastic nature. In fact

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the primitive mesenchymal cells express only vimentin, whereas in the fibroblastic

component smooth muscle actin and desmin may be positive. CD34 is generally limited

to blood vessels, but primitive mesenchymal cells may be occasionally positive. A

reciprocal translocation t(2;3)(q31;q21) and a t(6;12;8)(q25;q24.3;q13) have been

reported in 2 cases.

Fibrous Hamartoma of infancy is treated with complete surgical excision. The

recurrence rate is 15%, mostly related to an incomplete resection. Spontaneous

regression has not been reported.

Lipofibromatosis

Lipofibromatosis has been described by Fetsch et al. in 2000.

In the past, lesions with morphologic features of lipofibromatosis had been variously

classified as infantile fibromatosis, fibrous hamartoma of infancy; calcifying aponeurotic

fibroma and lipoblastoma. Clinically lipofibromatosis manifests as a slow-growing

mass, arising in the upper and lower distal extremities and, less frequently, in the trunk

and head of infants and children. Up to 25% of cases are congenital. Males are affected

more often than females. Macroscopically the lesions are poorly demarcated, of variable

size, from 2 cm to 7 in maximum dimension, of firm consistency, with a gritty,

yellowish or tan–white cut surface.

Histologically, lipofibromatosis is composed of abundant adipose tissue, with thick

fibrous septa containing fascicles of fibroblasts embedded in a variable amount of

collagen. Focal myxoid changes may be present. Both the adipose tissue and the spindle

cell components are integral to the neoplastic process.

Uni-vacuolated cells in small aggregates may be found at the periphery of adipose

lobules, adjacent to the fibrous septa. These cells are pseudo-lipoblasts, probably

representing adipocytes with regressive changes or cells in transitional stage between

fibroblast and adipocyte. Lipoblasts are not found. At the periphery, the lesions are

poorly circumscribed with evidence of fibro-fatty tissue, infiltrating and entrapping the

adjacent structures. Mitoses are rare. Cytologic atypia is absent. The spindle cell

component shows a positive staining for CD99, CD34, alpha-smooth muscle actin.

BCL-2, S-100 protein, muscle specific actin and EMA may be occasionally expressed.

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One case has been reported with a complex translocation t(4;9;6). A similar region in

chromosome 6 is involved in a complex translocation found in a fibrous hamartoma of

infancy raising the possibility of a common pathogenetic link related to 6q

rearrangement.

The differential diagnosis of lipofibromatosis includes fibrous hamartoma of infancy,

lipoblastoma, calcifying aponeurotic fibroma, desmoid-type fibromatosis, and

fibrolipoma (table 4).

Surgical resection is the elective treatment for lipofibromatosis. Recurrence or persistent

growth has occurred in 72% of reported cases. Congenital onset, male sex, hands and

feet location, incomplete surgery, and a high mitotic activity are associated with a risk of

recurrence.

Adult Fibromatoses in children and adolescents

Desmoid fibromatosis

Desmoid tumors are monoclonal fibroblastic-myofibroblastic proliferations occurring

throughout the body, generally in association with the deep aponeurotic tissue. They

account for up to 60% of fibrous tumors in childhood, with an age range from the birth

to 19 years. Up to 30% occur in the first year of life, with a peak around 4.5 years.

Congenital cases have also been reported. In pediatric series a male predominance has

been observed.

Desmoid fibromatosis can be sporadic or arise in the setting of Familial Adenomatous

Polyposis (FAP) or the Gardner’s variant of the syndrome.

In children desmoid fibromatosis may involve extremities, trunk, head and neck,

shoulder and hip. Abdomen, retroperitoneum, breast and spermatic cord are rarely

involved. It is a slow growing, mass with an infiltrative growth with involvement of the

adjacent structures, without systemic symptoms. Desmoid tumors arising in Gardner

fibroma may be painful and have a rapid growth.

On gross examination, desmoid fibromatosis is a firm, gray-white mass with a

glistening, whorled cut surface. Hemorrhagic foci or necrosis are absent. The lesion may

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be apparently well circumscribed, but at a closer inspection, subtle trabeculae or wisps

dissect the surrounding tissues.

Histologically the lesions vary in cellularity and amount of collagen matrix. Uniform

spindle cells and subtle collagen bundles are arranged in long fascicles or sheets with

thin-walled blood vessels parallel to the fascicles. Morphologic variations include

lesions extensively collagenized or prominently myxoid lesions. Nuclear hypercromasia,

cellular atypia and pleomorphism are absent. Mitoses are rare. Mast cells may be

present, especially around blood vessels. At the periphery the tumors show a typical

infiltrative pattern, with subtle bands of collagen or cells in fascicles dissecting adipose

tissue or entrapping muscle fibers. Recurrent lesions show identical morphological

features. The extensive collagenization related to the scarring process may render

difficult the differential diagnosis with a recurrence and the evaluation of surgical

margins.

Immunostains confirm the fibroblastic-myofibroblastic nature of desmoid fibromatoses,

showing positive staining for vimentin and variable expression of muscle specific actin,

desmin and smooth muscle actin. S100 protein and cytokeratins are negative.

Cytogenetic investigation of desmoids in FAP has clarified the key role played by beta-

catenin. Beta catenin in mesenchymal tissues is important as a transcriptional activator

involved in the promotion of cell proliferation. In physiological conditions its cytosolic

levels are under control of adenomatosis polyposis coli (APC) complex, which

phosphorylates four critical aminoacids determining its proteosomal degradation. The

portion of beta-catenin involved in the phosphorylation is encoded by exon 3 of

CTNNB1 gene. Any interruption of phosphorylation results in the accumulation of beta-

catenin in the cytoplasm and its migration to the nucleus with a permanen activation of

genes involved in cell proliferation. In FAP-related desmoids germ-line mutations in

APC gene inhibit its ability to induce the phosphorilation of beta catenin. In sporadic

desmoids three different mutations resulting in a non-phosphorylated active beta-catenin

have been identified. The most frequent mutations in CTNNB1 gene involve codons 41

(41A) and 45 (45F and 45P). The mutated form of beta-catenin shows a positive nuclear

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immunostaing.

In a series of 42 pediatric desmoids Niero et al identified a mutation in APC gene in

17%, CTNNB1 in 64% and no mutations in 19%. A positive nuclear staining for beta-

catenin was present in about 85% of cases.

Some studies indicate that increased nuclear expression of beta-catenin, especially if

associated to p53 positivity may be predictive of a high recurrence rate, in other studies,

this correlation has not emerged and has been found a significant association between

CTNNB1 45F mutation and local recurrence.

The differential diagnosis includes a wide spectrum of benign and malignant

myofibroblastic proliferations.

The natural history of desmoid is that of a slow growing neoplasm, only locally

aggressive. It is unclear why some tumors continue to grow; others remain stable and

occasionally spontaneously regress. The therapeutic approach should take into account

the patient’s characteristics, the site and the observed aggressivity. Surgery remains the

mainstay for resectable sporadic desmoid tumors. The goal should be a radical resection

with negative margins, in order to reduce the risk of local recurrences. However, the

influence of positive margins on the local relapse is still debated, hence a mutilating

surgery should be avoided. In recent years the multi-modal approach including

radiotherapy and chemotherapy has contributed to the decrease of 5-year recurrence rate

to 20%. Mortality from locally aggressive desmoid is less than 10%. Estrogen

antagonists have been proven to be effective. Imatinib mesylate, a tyrosine-kinase

inhibitor, targeting c-kit and PDGFR have been recently used in a clinical trial. The

good clinical response reported in some cases is probably related to other mechanisms,

not involving c-kit and PGDFR. Clinical features associated with a higher risk of

recurrence include younger age, mesenteric lesions and occurrence in the setting of a

FAP or Gardner syndrome.

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Table 4: Differential diagnosis of Fibromatoses

Disease Histology Differential Diagnosis Diagnostic clues

myofibromatosis

Immature: primitive elongated-polygonaly cells in sheets or short fascicles;

Prevalent Hemangiopericytomatous pattern

Zonal Pattern: centrally immature cells in Hemangiopericytomatous pattern, at periphery. Myoid cells in whorls, intravascular myoid nodules

Fibromatosis

Infantile Fibrosarcoma

Pericytic tumor

Myofibroblastic sarcoma

Nodular Fasciitis

Slender fibroblasts in long fascicles, mitoses rare, infiltrative growth; IHC: beta catenin+

Spindle cells in herringbone pattern, t(12;15)

Multilobulated, cells arranged around thin-walled vessel; t(7;12)

Cellular atypia,

Scattered interstitial red cells and inflammatory infiltrate. Absence of whorls and myoid nodules

Fibrous hamartoma of Infancy

triphasic pattern:

primitive cells in nests and whorls in a

myxoid matrix, mature fibrous tissue

with collagen bands, adipose tissue

Lipoblastoma, Lipofibromatosis Absent primitive mesenchymal component

Lipofibromatosis mature adipose tissue

intersecting fascicles of spindled

mature fibroblasts.

Infiltrative growth

Desmoid fibromatosis

fibrous hamartoma of infancy.

fibrolipoma,

lipoblastoma

Fat is entrapped, not part of lesion.

Immature mesenchymal component

fibrous component not arranged in

strands and fascicles

myxoid areas or lipoblasts

Desmoid Fibromatosis

Uniform spindle cells in fascicle with thin-walled vessels running parallely. Scattered mast cells In hypocellular lesions: prominent collagen, hyalinization, abundant myxoid matrix

Nodular fasciitis Infantile fibrosarcoma Myofibroma/myofibromatosis Myofibrosarcoma Gardner fibroma Keloid Low-grade myofibroblastic sarcoma

Zonal pattern, interstitial red cells and inflammatory infiltrate Spindle cells in herringbone pattern, t(12;15) Zonal pattern, myoid cells in whorls, intravascular myoid nodules Cellular atypia, mitoses, occasionally atypical Extremely hypocellular, scattered bland cells Extremely hypocellular, coarse collagen bands Multinodular pattern with biphasic

morphology: myxoid hypocellular

areas with curvilinear vessels,

fibrous areas. IHC: EMA+, CD34-,

Inflammatory myofibroblastic tumor and Inflammatory pseudotumors.

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The generic term “inflammatory pseudotumor” includes reactive or infectious processes,

such as spindle cell nodules of genito-urinary tract, mycobacterial pseudotumor and

pseudotumors of lymph node and neoplastic clonal lesions such as the inflammatory

myofibroblastic tumor and follicular dendritic tumors of spleen, in the past diagnosed as

splenic pseudotumors.

In recent years a new group of inflammatory pseudotumors has emerged, including the

idiopathic fibro-sclerosing lesions related to a new syndrome with elevated serum levels

of IgG4.

Inflammatory myofibroblastic tumor.

IMT have been observed mainly in children and young adults, but can arise also in older

adults. The most frequent anatomic sites are the mesentery, omentum, retroperitoneum,

abdominal soft tissues, lung, mediastinum, liver, and head and neck.

In the current World Health Organization classification of soft tissue and bone tumors,

inflammatory myofibroblastic tumors are regarded as a neoplasm of intermediate

biologic potential with tendency for local recurrence and very rare metastases

A palpable mass may be the clinical presentation, but in up to a third of patients it is

discovered after the occurrence of an inflammatory syndrome associated with alteration

of laboratory exams (microcytic hypochromic anemia, thrombocytosis, polyclonal

hyperglobulinemia).

Macroscopically, inflammatory myofibroblastic tumors are nodular, circumscribed

lesions, with a firm consistency, and may reach a large size. Intra-abdominal IMTs are

generally larger, frequently multinodular, non-capsulated, adherent to and sometimes

infiltrating the intestinal wall. On cross-section, the surface is whitish with firm, fleshy,

or myxoid areas.

Histologically IMT are composed of long or intermediate-sized myofibroblasts with

eosinophilic-amphophilic cytoplasm and indistinct cellular borders, showing variable

cellularity and pattern of growth, intermixed with a prominent inflammatory infiltrate

composed of plasma cells, lymphocytes, and eosinophils. Coffin et al identified three

main morphologic patterns: fasciitis-like, fibrohistiocytoma-like and desmoid-like.

In the fasciitis-like pattern interlacing bundles of spindle cells or haphazardly arranged

plump to polygonal myofibroblasts are embedded in an abundant myxoid matrix

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containing a mixed inflammatory infiltrate A prominent network of small dilated vessels

and typical ganglion-like cells with evident nucleoli may be also present.

The fibrohistiocytoma-like pattern is more cellular with spindle cells in fascicles or in a

storiform pattern alternating with collagenized or myxoid areas. Scattered ganglion like

cells may be seen.

The desmoid-type pattern is hypocellular, with a rich dense collagenous matrix and

sparse spindle cells, intermixed with a discrete inflammatory infiltrate.

A rare variant of round cell inflammatory myofibroblastic tumor has been recently

described. It is characterized by non-cohesive round to polygonal cells with eccentric,

vesicular nuclei, prominent nucleoli and abundant eosinophilic cytoplasm.

Scattered foci of necrosis, calcifications and osseous metaplasia may be occasionally

found in inflammatory myofibroblastic tumors. Mitotic activity is generally low with

less than 2 mitoses per 10 HPF, and atypical mitoses are rare. Bizarre cells, large

atypical myofibroblasts may be seen.

Immunohistochemistry shows strong reactivity for vimentin and variable staining from

focal to diffuse for smooth muscle actin, muscle specific actin and desmin. Focal

positivity for CD68 may be found. Follicular dendritic cell markers, CD21, CD23 are

negative, whereas clusterin may be occasionally positive. Approximately one-third of

cases show focal keratin reactivity.

ALK-1 staining is detected in approximately half of inflammatory myofibroblastic

tumors and correlates with the presence of rearrangements of the gene. ALK is a

receptor tyrosine-kinase gene located on chromosome 2p23. When rearranged, it results

in a protein persistently activated. In inflammatory myofibroblastic tumors a variety of

fusion gene partners have been identified, including ATIC, CARS, TPM3, TMP4, TPM3

and TPM4, CLTC, RANBP2 and SEC31L genes, each one characteristically associated

with a peculiar pattern of immunostaining.

ALK gene rearrangements are more frequent in pediatric inflammatory myofibroblastic

tumors and in those arising in abdomen.

The differential diagnosis is extensive and varies according to the predominant

histologic pattern.

The recurrence rate varies according to the anatomical site. Extra-pulmonary lesions

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tend to recur more frequently, with a relapse rate of 25%. Distant metastases are rare,

occurring in less than 5% of cases, mostly in lung and brain, followed by liver and bone.

Tumor size, cellularity and histologic features do not appear to influence the clinical

behavior, even if some studies suggest that cellular atypia and prominent myxoid stroma

may be associated with an aggressive course. However cytologic atypia is frequently

found in IMT with a favorable prognosis. Aneuploidy may indicate a more aggressive

potential. There is no evidence of a prognostic significance of ALK expression.

Interestingly, intra-abdominal tumors, which are those with higher recurrence rate, tend

to show a prominent myxoid background, higher cytologic atypia and more frequent

ALK gene rearrangements. ALK negative tumors, on the other side, appear to have a

higher risk of metastasis. An aggressive behavior has been reporre in round cell IMT.

The fw tumors investigated showed an ALK- RANBP2 fusion gene.

IgG4 related fibro-sclerosing lesions (CASE 2 SLIDE SEMINAR)

Sclerosing mesenteritis, idiopathic retroperitoneal fibrosis, sclerosing mediastinitis, and

orbital inflammatory pseudo-tumor are lesions, which histologically can mimic

inflammatory myofibroblastic tumor.

After the report by Hamano et al in 2001 of elevated serum level of immunoglobulin G4

(IgG4) in patients affected by autoimmune sclerosing pancreatitis, there has been a

growing evidence that iper-IgG4 and sclerosing lesions affecting various organs,

represent an unique disease with different clinical manifestations. A recent study

reported the association of increased IgG4-positive plasma cells also in plasma cell-rich

pulmonary inflammatory pseudotumors.

Iper-IgG4 sclerosing diseases occur mainly in adults, nonetheless, retroperitoneal

fibrosis, autoimmune pancreatitis and orbital inflammatory pseudotumor have been

reported also in children.

Grossly, these processes form ill-defined masses often encasing adjacent structures.

Histologically there is a prominent fibrosclerosis extremely hypocellular, with a minimal

spindle cell component. A lymphoplasmacytic infiltrate is present with evidence of

lymphoid follicles. The fibrosis surrounds the parenchymal structures, such as pancreatic

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acini, with atrophy or loss. Obstructive phlebitis may be helpful in the differential

diagnosis from IMT.

The criteria to diagnose an IgG4-related disease on the basis of the degree of IgG4

positive plasma cells have not been clarified yet and the ratio IgG4+/IgG+ plasma cells

more than 0.1 is not reliable to discriminate from IMT (Coffin et al 2010).

Table 5: Inflammatory Pseudotumors

Inflammatory pseudotumors Histology Immunohistochemical key-features

Reactive, auto-immune, infectious processes

spindle cell nodules of genito-urinary tract

Pseudotumors of lung

Undistinguishable from IMT ALK negative

idiopathic fibro-sclerosing Iper-IgG4 syndromes

extremely hypocellular lesions minimal spindle cell component prominent fibrosclerosis lymphoplasmacytic infiltrate with lymphoid follicles

60/HPF IgG4 + plasma cells IgG4+/IgG+ plasma cells ratio >40%

neoplastic clonal lesions inflammatory myofibroblastic tumor

fasciitis-like fibrohistiocytoma-like desmoid-like

SMA, Desm, ALK (40%)

follicular dendritic tumors Interdigitating dendritic cell tumors

spindle cells in fascicles evenly distributed chronic inflammatory infiltrate

CD21, CD23, CD35, Clusterin

S100

Table 6: ALK staining in IMT

Partner gene

ALK immunohistochemical staining

TPM3 (1p23) TPM4 (19p13) ATIC (2q35) CARS (11p15) SEC31L1 (4q21)*

Diffuse cytoplasmic

CLTC (17q23)

Granular cytoplasmic

RANBP (2q13) Nuclear membrane

*Panagoupulous et al Int. J. Cancer, 2006 Zhigui et al. Genes, Chromosomes & Cancer, 2003

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