Advances in Anatomic Pathology:
Pediatric Fibroblastic and Myofibroblastic Lesions
Thway, Khin MBBS, BSc, FRCPath*; Fisher, Cyril MD, DSc, FRCPath*; Sebire, Neil J. MD, FRCPath†
*Department of Histopathology, The Royal Marsden NHS Foundation Trust
†Department of Paediatric Pathology, Camelia Botnar Laboratories, Great Ormond Street Hospital for Children, Great Ormond Street, London, UK
All figures can be viewed online in color at http://www.anatomicpathology.com.
The authors acknowledge NHS funding to the NIHR Biomedical Research Centre. The authors have no conflicts of interest to disclose.
Reprints: Khin Thway, MBBS, BSc, FRCPath, Department of Histopathology, The Royal Marsden NHS Foundation Trust, 203 Fulham Road, London SW3 6JJ, UK (e-mail: firstname.lastname@example.org).
Fibrous lesions of infancy and childhood are a heterogeneous group of entities composed predominantly of fibroblasts and myofibroblasts, ranging from reactive lesions to neoplasms with a range of malignant potential. Although rare, their correct recognition by histopathology is important clinically as they exhibit a wide range of behaviors and may be associated with distinct underlying syndromes. Contributions from molecular diagnostics have enabled more accurate diagnosis, and have changed our concepts of some tumor types. In this review, we discuss the clinicopathologic spectrum of fibroblastic and myofibroblastic lesions of childhood and adolescence.
Fibrous lesions of infancy and childhood are a heterogeneous group of neoplasms and pseudoneoplastic proliferations that often present with rapid growth, and which display varying degrees of cellularity, collagen production, and maturation. Lesions fall into 2 main groups; the first show similar morphology to those in adults, and the second occur uniquely, or predominantly, in infancy and childhood. These are rare lesions of fibroblasts and myofibroblasts, encompassing reactive entities through neoplasms with a range of malignant potential, and there is marked variation in typical age at presentation, with most myofibromatoses diagnosed in the first year of life, compared with 70% of desmoid-type fibromatoses occurring in the second decade.1 Some lesions are congenital or form part of distinct syndromes. Others are thought to occur secondary to surgical procedures or other types of trauma and some are known to regress spontaneously, hence their recognition is important clinically and in pediatric surgical pathology, for appropriate clinical management, prognostication, and clinicopathologic correlation. Although the histologic diagnosis of most childhood fibroblastic and myofibroblastic lesions remains largely based on morphologic features, with immunohistochemistry showing a general lack of specificity,2 contributions from molecular genetics and cytogenetics have enabled more accurate diagnosis for many entities, changing our understanding of some established tumor types. We discuss current concepts and the clinicopathologic spectrum of fibroblastic and myofibroblastic lesions of infancy, childhood, and adolescence.
FIBROMATOSIS/AGGRESSIVE DESMOID FIBROMATOSIS
The fibromatoses are characterized by proliferation of fibroblasts and myofibroblasts with marked collagen production.3 “Pediatric” fibromatosis is not clearly defined as a specific entity. Previously, usual-type fibromatosis was classified into adult and pediatric forms, with “juvenile” fibromatosis often used to denote childhood myofibroblastic lesions with similar morphology to desmoids, but not situated in the usual deep locations. “Juvenile” fibromatoses are not, however, categorized separately in the current World Health Organization Classification system,4 as they are indistinguishable morphologically and behaviorally from adult lesions. Deep (desmoid-type or aggressive) fibromatoses are rare, with an incidence of approximately 2 to 4 per million individuals per year,5 but rarer still in childhood. They usually arise as solid masses in skeletal muscle, fascia, or periosteum, typically involving the shoulder, upper arm, thigh, or head and neck region, occasionally involving adjacent bone. Intra-abdominal fibromatosis, and some examples with multiple tumors, can be associated with Gardner syndrome. Lesions can be large and are typically infiltrative, with invasion of subcutaneous fat, skeletal muscle and sometimes viscera. Fibromatoses have a high frequency of local recurrence, even when completely excised, but do not metastasize.
Histologically, lesions comprise long, sweeping fascicles of spindle, or sometimes stellate, myofibroblasts, with elongated or ovoid vesicular nuclei, small, punctate nucleoli and amphophilic fibrillary cytoplasm, within a variably collagenous stroma (Fig. 1A). Cells are usually uniform although sometimes plump, but no atypia is present. There is a distinct vascular pattern, with interspersed small, thick-walled vessels and larger, thin-walled slit-like vessels. Mitotic activity is usual, although rarely exceeds 5 mitoses per 10 high power fields, but necrosis is not a feature. Other features include small numbers of mast cells, often in perivascular spaces, focal myxoid or edematous stroma and thick, keloidal collagen fibers, particularly in intra-abdominal disease and after chemotherapy. Tumors express smooth muscle actin (SMA) (Fig. 1B), usually strongly although variably, and sometimes focal desmin, but lack h-caldesmon or CD34. Virtually all deep fibromatoses have somatic β-catenin or adenomatous polyposis coli (APC) gene mutations leading to intranuclear accumulation of β-catenin and most adult fibromatoses show diffuse nuclear (often granular) β-catenin expression.6 β-catenin immunohistochemistry separates deep fibromatosis from other entities in the differential diagnosis, a finding that can be exploited for diagnosis.6,7 High-level β-catenin expression is also seen in deep “adult-type” fibromatoses occurring in children (Fig. 1C), albeit to a lesser frequency than in adults,8 indicating that they share similar tumorigenic mechanisms to adult lesions. β-catenin has not been shown to be expressed in other common pediatric fibroblastic and myofibroblastic lesions.8 One study has reported that almost 90% of pediatric fibromatoses demonstrated increased expression of PDGF α and β relative to normal tissues, with 76% showing increased expression of corresponding PDGF α and β receptors; increased PDGF/R α and β expression may therefore play a role in the growth of these lesions, suggesting that novel therapeutic interventions could potentially be developed in the light of the expression patterns.9
Infantile digital fibromatosis (inclusion body fibromatosis) occurs predominantly in the first year of life and may be congenital, although it can arise later, including rarely in adults. Lesions may be multiple, and are painless, polypoid smooth nodules, usually <2 cm, in the dermis and subcutis, typically on the dorsal aspects of digits, more often the fingers, and most frequently the third to fifth digits. Extradigital soft tissue sites are rarely involved. The tumors are benign, although >50% recur, either at the same site or as a new lesion in an adjacent digit, and usually within a few weeks. However, untreated lesions have a tendency for spontaneous regression and the outcome is excellent.
Infantile digital fibromatoses are infiltrative dermal lesions comprising sparsely to moderately cellular distributions of bland, uniform myofibroblasts arranged in fascicles, sheets or more haphazard patterns within collagenous stroma.10 Many of the spindle cells contain distinctive round, 3 to 15 µm diameter eosinophilic cytoplasmic inclusions (Fig. 1D),11 often in a paranuclear distribution, which are possibly derived from abnormally contracted actin microfilaments.12,13 These inclusions are PAS negative, but typically stain red with Masson trichrome. Similar inclusions are, however, described in other soft tissue lesions with myofibroblastic or smooth muscle differentiation.14 There may be occasional mitoses, but atypia and necrosis are not seen. The myofibroblasts express desmin, SMA, calponin, and CD99, and occasionally CD34, h-caldesmon, and nuclear β-catenin.15
Juvenile hyaline fibromatosis/infantile systemic hyalinosis (JHF and ISH) represent a spectrum of rare autosomal recessive hereditary disease, characterized by extensive deposits of extracellular hyaline material containing collagen and glycosaminoglycans in the skin, gingiva, and other organs. Lesions can be congenital but usually appear between 2 and 5 years of age, with new lesions continuing to develop throughout life. There are typically multiple superficial and deep nodules involving the head and neck, trunk and extremities, and sometimes bone and viscera. Patients can present with severe pain with movement, joint contractures with motor disability, skin nodules, pearly papules of the face and neck, gingival hypertrophy, and macules/patches over bony prominences of the joints.16 Treatment is surgical, but lesions may recur after excision. ISH represents the more severe form of the disease with widespread visceral involvement, and children with this variant often die in early life, secondary to infections and complications of visceral disease with malabsorption and failure to thrive. Those with the milder JHF survive to adulthood.
The lesions, located in dermis, subcutis, gingiva, or sometimes viscera, are poorly defined collections of bland spindle fibroblasts evenly dispersed in homogeneous pale or eosinophilic, amorphous “glassy” collagenous stroma (Fig. 1E), the proportion of which increases in older lesions. The cells express vimentin but not other antigens, and the stroma is PAS positive and Alcian blue positive. Ultrastructurally lesions are fibroblasts with abundant dilated rough endoplasmic reticulum containing precursor stromal material. JHF and ISH are now known to be a consequence of germline mutations in the ANTXR2 gene (CMG2: capillary morphogenesis gene-2) on chromosome 4q21.17–19 Capillary morphogenesis protein-2 is an integrin-like cell surface receptor for laminins and type IV collagen, that may play a key role in cell-matrix or cell-cell interactions. Analysis of fibroblasts derived from patients with JHF or ISH suggests that CMG2 mutations abrogate normal cell interactions with the extracellular matrix19 and perturbation of basement-membrane matrix assembly has been implicated as the cause of the characteristic perivascular hyaline deposition seen in these conditions.17
Gingival fibromatosis may be sporadic but is familial in approximately a third of cases,20 and sometimes congenital, with autosomal dominant or recessive inheritance. It occurs equally in both sexes as a benign, progressive fibrous overgrowth of the gums, which can be extensive resulting in the teeth being partially or totally engulfed by keratinized gingiva, with ensuing aesthetic and functional problems that tend to require repeated resective periodontal surgical procedures over the patient’s lifetime.21,22 Although usually an isolated condition, approximately 10% of patients have hypertrichosis, and gingival fibromatosis can be 1 feature of several rare eponymous syndromes, including those of Zimmermann-Laband (which has a wide clinical spectrum including swelling of perioral tissues, nail hypo/aplasia, abnormalities of terminal phalanges and occasional mental retardation),23,24 Klippel-Trenaunay-Weber,25 Barber-Say,26 and Ramon syndromes.27 Lesions that are histologically similar, with varying degrees of fibrosis are also described associated with drugs such as phenytoin and calcium channel blockers. The disease can be localized or generalized, and histologically lesions are sparsely cellular, with dense, interlacing bundles of collagen, focal mild inflammation and sometimes microcalcifications. The overlying epidermis may show hyperplasia. Genetic loci for autosomal dominant forms of heriditary gingival fibromatosis (HGF) have been localized to chromosome 2p21-2222,28 (HGF1) and chromosome 5q13-22 (HGF2), for which mutations are described, including in the SOS1 (Son of sevenless-1) gene for HGF1.29
Calcifying (juvenile) aponeurotic fibroma can arise over a wide age range and at various anatomic sites, but most frequently occur in childhood or adolescence (median age of 12), in the distal extremities. Lesions present as slowly growing, firm painless masses most often in the hands (usually the palm or fingers) with about 15% in the feet, particularly plantar or ankle regions. Rarely other sites such as the forearm, popliteal fossa, elbow, supraclavicular region, and lower back are involved,30 generally with attachment to tendons or fasciae. Excision is usually curative, but lesions are prone to recurrence, and malignant transformation to fibrosarcoma with metastasis has been occasionally recorded.31 The lesions are pale, up to 3.5 cm in diameter, poorly defined and infiltrative, with processes extending into subcutaneous fat and infiltrating around vessels and nerves. They are composed of variably cellular fibrous tissue, with bland, plump spindled myofibroblasts, and epithelioid mesenchymal cells. Sometimes the cells show a linear or palisaded arrangement (particularly near calcified areas), with variable amounts of focally hyalinized collagen. In addition, there are centrally located deposits of amorphous calcification (Fig. 1F), ranging from fine granules to large deposits, and chondroid differentiation.32 More rounded cells are often present adjacent to the calcification. Osteoclast-like giant cells and ossification are more rarely seen (the latter especially in older children). Mitoses are rare. Lesions can express actins, CD99, and more rarely CD34 or EMA, but do not express β-catenin. Aneuploidy has been shown in 1 case,33 although no characteristic or reproducible genetic aberrations have been identified.
Fibromatosis colli is a rare fibrosing lesion of infants involving the muscles of the neck. It typically presents in the neonatal period, arising in the first 4 weeks of life as a firm, solitary 2 to 3 cm mass in the sternal or clavicular portion of the lower third of the sternomastoid muscle. It is more frequent in males, and on the right side, although cases are rarely bilateral and occasionally familial.34 Most are spontaneous, with approximately half arising after breech or forceps delivery, and very occasional cases are associated with congenital dislocation of the hip and anomalies of the foot. Torticollis, clinically characterized by a lateral head tilt and chin rotation toward the side opposite to the tilt, is caused by many conditions,35 and fibromatosis colli is a common cause of congenital torticollis. Patients may present simultaneously with, or progress to the development of congenital torticollis during childhood. After initial rapid growth, the mass remains static and the vast majority regress over months, without recurrence. Persistent lesions may require surgery, especially when torticollis occurs in the later phases. Lesions comprise diffuse, variably cellular proliferations of bland fibroblasts that infiltrate between skeletal muscle fibers that are atrophic and regenerating. No cytologic atypia, necrosis, or mitoses are seen, and inflammation is minimal. In later stages there is more prominent fibrosis that imparts a distinctive checkerboard-like pattern (Fig. 2A), with eventual confluent scarring. While the fibroblasts express SMA in the early stages of disease, the lesion is negative for β-catenin.8,36
Calcifying fibrous tumor is a benign fibrous lesion that occurs in children and young adults of either sex, characterized by the presence of abundant hyalinized collagen with psammomatous or dystrophic calcifications and a lymphoplasmacytic infiltrate.37 Tumors arise in subcutaneous, subfascial or deep tissue, most frequently in the extremities and trunk, and can reach large sizes of up to 15 cm.37 Tumors can also occur in viscera and body cavities, including paratesticular, mediastinal, and intra-abdominal sites, although this is rarer in the pediatric population than in adults. Although it has been suggested that calcifying fibrous tumor might represent the end stage of inflammatory myofibroblastic tumor (IMT), there is so far no convincing evidence to support an association between these entities.38,39 The prognosis is excellent, although lesions can recur locally after excision.
Tumors are generally well circumscribed, and composed of paucicellular densely collagenous tissue containing bland spindle cells. There is a variable interspersed lymphoplasmacytic infiltrate and sometimes lymphoid follicles, as well as scattered dystrophic or psammomatous calcification. The lesions appear histologically similar to “deep” or visceral calcifying aponeurotic fibroma. There is rare focal expression of SMA, desmin, or CD34 within spindle cells, but consistent negativity for anaplastic lymphoma kinase (ALK).39 Ultrastructurally, the dystrophic and psammomatous calcifications are observed as electron-dense amorphous masses and laminated bodies within fibroblast cytoplasm and collagenous stroma. Cytoplasmic degeneration is postulated to be an initial event of intracytoplasmic calcification.40
Fibrous hamartoma of infancy is a benign myofibroblastic tumor typically occurring in the axillary or shoulder region of male infants.41 Most lesions present in the first 2 years of life, in the superficial soft tissues of the upper body, typically in the anterior or posterior axillary fold. Other sites include the upper extremity, shoulder, groin, thigh, trunk, neck, and scalp. Lesions are usually solitary, or can rarely occur as multiple synchronous nodules. Less than one fifth of cases recur, and none is known to have metastasized. Rare cases are described in patients with tuberous sclerosis, although no conclusive familial or syndromic associations are characterized.
The lesion is infiltrative, involves the deep dermis or subcutis and has an organoid growth pattern, with 3 distinct components. There are cellular, intersecting bands of fibrous tissue, comprising spindle fibroblasts and myofibroblasts within collagenous stroma, as well as whorls or nests of more immature round, ovoid or spindle cells in a loose stroma that is often arranged around small vessels and lastly, interspersed mature fat (Fig. 2B). Each of the 3 components is present in variable amounts, and individual components may not be sampled in a biopsy. Actin is expressed in the fibrous areas,42 and more rarely CD34 or desmin.43 Ultrastructurally, the fascicular-fibroblastic areas show fibroblastic and myofibroblastic differentiation, with primitive mesenchymal cells present in immature-appearing regions.43 Chromosomal translocations have been described in 2 cases: a complex (6;12;8)(q25;q24.3;q13) translocation44 and reciprocal t(2;3)(q31;q21) translocation,45 whereas a further case has shown complex structural rearrangements involving chromosomes 1, 2, 4, and 17, but no diagnostic molecular feature is in present clinical use.46
Lipofibromatosis is a rare, benign, soft tissue tumor predominantly occurring in the extremities of infants. It has a male preponderance, and while it arises most frequently in the hands and feet, it can occur on the head and trunk and has been documented in rare sites such as the orbit.47 Complete excision may be difficult, and the recurrence rate is high. This is an ill-defined, slowly growing lesion, histologically comprising fibrous tissue bands of moderate cellularity, that intersect adipose tissue, dermis, and skeletal muscle (Fig. 2C),48 and surround nerves and adnexa. The lesion does not tend to cause the extensive architectural effacement of fat seen commonly in conventional fibromatoses. The component spindle cells are bland fibroblasts, and mitotic figures are rare. The adipose tissue has a lobulated appearance and is largely of mature type, although small univacuolated cells can be seen at the interface with the fibrous bands, and should not be mistaken for lipoblasts. The spindle cells can focally and variably express SMA, CD34, CD99, and EMA. Recurrence is fairly common, particularly in incompletely excised and congenital cases, in males, hand, and foot locations, and where there is mitotic activity in the fibroblastic element.48 A case with a 3-way t(4;9;6) translocation has been described but no diagnostic molecular changes are yet reported.49
Nasopharyngeal angiofibroma is a locally aggressive tumor that occurs predominantly in adolescent males, within the nasopharynx or paranasal sinuses. Patients present with local symptoms such as nasal obstruction and epistaxis. Some cases have been associated with familial adenomatous polyposis (FAP).50 Tumors recur in approximately 20% of patients and malignant transformation to sarcoma, while uncommon, is well documented after previous radiation therapy.51–53 The lesions are smooth, polypoid submucosal masses, and histologically comprise disorganized but well-formed large dilated, endothelial-lined vessels with focal or absent smooth muscle layers, within a sparsely to moderately cellular fibrous stroma (Fig. 2D). The cells within the stroma are plump, ovoid to spindled fibroblasts with vesicular nuclei and sometimes small nucleoli. Multinucleate cells and mild pleomorphism may be present, although mitotic figures are infrequent. The lesions show strong and diffuse nuclear β-catenin expression,54 and many show activating β-catenin gene mutations,54 indicating the role of β-catenin in pathogenesis. Tumors also show focal SMA immunoreactivity, as well as positivity for androgen receptors within both stromal and endothelial cells.
Gardner-associated fibroma is a benign lesion that occurs predominantly in childhood and adolescence, and may be an antecedent marker for Gardner syndrome (an autosomal dominant condition associated with mutations in the APC gene at 5q21, characterized by the presence of multiple colonic polyps and extracolonic lesions including osteomas, fibromas, epidermoid and sebaceous cysts, as well as the occurrence of desmoid tumors in approximately 15% of individuals), or for FAP.55 If undetected or untreated, virtually all patients with Gardner syndrome develop colonic carcinoma at a young age and hence early detection is essential. One large study of Gardner fibroma reported that 70% of patients had known FAP or APC, with 18% having documented desmoids concurrently or later.55 As osteomas appear later, followed by the colonic polyps, the possibility of Gardner syndrome and FAP should be raised in all young patients in whom such fibromas occur, and diagnosis of Gardner fibroma in a patient may identify children with spontaneous APC mutations, or identify Gardner syndrome kindreds and result in the diagnosis of unsuspected APC in older family members.56 Lesions present as painless, ill-defined, plaque-like subcutaneous masses, arising most commonly in the back and paraspinal region, but may also occur in head and neck, extremities, and trunk.55 Local excision is curative, although incompletely excised lesions can recur. Some lesions progress to classic desmoid fibromatoses, particularly after surgery.56
Microscopically, features are identical to those of nuchal-type fibromas,56 and comprise poorly defined, patternless or haphazard distributions of hypocellular, densely collagenized tissue with focal cracking artefact.57 Cell nuclei are small and hyperchromatic. There is variably entrapped adipose tissue, muscle and nerves. The lesions express CD34 and CD99, and two thirds express nuclear β-catenin55 (although the morphology is usually distinct from fibromatosis, which is more cellular and has a characteristic sweeping fascicular architecture).
Fibrodysplasia ossificans progressiva is a rare, autosomal dominant genetic disorder of congenital skeletal malformations and progressive heterotopic ossification, which primarily affects children below 10 years. It is caused by a recurrent mutation in the ACVR1 (activin receptor IA) gene on chromosome 2q23–24,58,59 which encodes a bone morphogenetic protein type I receptor involved in normal bone ossification, and there is overproduction of bone morphogenetic protein 4. Patients present congenitally or in childhood, typically with deformities of the toes.60 Following soft tissue injury, ossification occurs to skeletal muscle, tendons and ligaments. Ossification typically starts in the muscles of the upper back, spreading to other axial sites and to limbs. As biopsy can cause further bone formation, the diagnosis is best made clinically and radiologically. Histologically, there is initially a loose, nodular fasciitis-like fibroblastic proliferation (Fig. 2E), after which collagen is laid down, with calcification and formation of metaplastic bone and cartilage.
Myofibroma and Myofibromatosis
This category subsumes cases formerly termed infantile hemangiopericytoma, and although considered as part of the spectrum of myopericytic lesions,61,62 the morphology and immunophenotype suggest that the cells show myofibroblastic differentiation. Myofibromas are benign mesenchymal neoplasms that are mostly solitary and can occur at any age; the occurrence of multiple lesions in newborns and infants is termed infantile myofibromatosis. Multifocal lesions involve soft tissues and bone, or rarely viscera, where they are associated with an unfavorable prognosis. Lesions usually appear in the first year of life, particularly the first 3 months, and occur less frequently in older children and adults. Some cases are familial, with autosomal dominant inheritance. The dermis and subcutis are the commonest sites, and cutaneous nodules can reach up to 8 cm. Lesions in the skeletal muscle and bone are rarer. Solitary lesions occur on extremities or trunk, in the head and neck or rare sites such as the testis.63 When multiple, lesions involve the deeper soft tissues, bones, and viscera including lung, myocardium and gastrointestinal tract, producing local symptoms. The lesions are benign although can recur, and as the prognosis of the disease depends on whether visceral involvement is present, solitary and multicentric nodules without visceral involvement usually have excellent prognosis. Solitary lesions sometimes undergo spontaneous regression, and this and the characteristic necrosis are possibly mediated by massive apoptotic cell death.64
Histologically lesions usually show a nodular architecture, often beneath ulcerated mucosal surfaces, that display a “zoning” phenomenon (Fig. 2F). Although usually circumscribed, they may be locally infiltrative. There is a typical biphasic pattern, with a central zone comprising sheets and lobules of polygonal cells with scanty cytoplasm and mitoses, associated with a characteristic hemangiopericytic vascular pattern. Peripherally there are paler bundles of smooth muscle-like cells (which are generally actin positive but negative for desmin, h-caldesmon, S100 protein and CD34) arranged in short fascicles with variable amounts of collagen. Necrosis can be extensive, and lesions can show calcification, ossification and mature fat. There is sometimes intravascular extension of tumor, and a relationship with infantile hemangiopericytoma has been postulated.62,65,66 Ultrastructurally the spindle cells are myofibroblasts, with rough endoplasmic reticulum, stress fibers and rarely fibronexus structures.67,68
Inflammatory myofibroblastic tumor is a neoplasm of intermediate biological potential that most commonly arises in the abdomen, especially retroperitoneum or mesentery, as well as viscera, including the lung and deep soft tissue, although may occur in unusual sites including intravascularly.69 Tumors occur most frequently in the first decade, then adolescence and more rarely in older adults. Patients present with symptoms from the mass lesion or with B-type systemic features, including fever, anemia, and leukocytosis. Tumors can be solitary or multicentric and approximately a third recur after excision,70 but metastasis is rare. IMT may become more atypical with successive recurrences, and progression to metastasizing sarcoma after multiple recurrences has been rarely reported in soft tissue.71
Histologically, tumors are variably cellular, usually consisting of a proliferation of largely bland, spindle to stellate fibroblastic and myofibroblastic cells with a prominent lymphoplasmacytic inflammatory infiltrate (Fig. 3A). Appearances can vary within the same tumor, with fasciitis-like, fascicular and sclerosing areas.72 Fibrosis and calcification are commonly seen. Although cells usually lack pleomorphism, occasional atypical cells, sometimes with epithelioid morphology can be present.73 While plasma cells predominate in the inflammatory infiltrate, histiocytes and smaller numbers of neutrophils and eosinophils may also be found. There is no histologic distinction between IMT and inflammatory fibrosarcoma,74 the latter principally described in the mesentery and retroperitoneum, with a peak incidence in the first decade and comprising focally atypical fibroblasts and myofibroblasts with pleomorphic nuclei, prominent nucleoli and atypical mitoses, in sweeping fascicles or whorls, as well as marked, predominantly lymphoplasmacytic inflammation. Although the presence of nuclear pleomorphism and atypia and the occurrence of metastasis might indicate designation as inflammatory fibrosarcoma, no clinical or histologic factors have been identified that reliably predict behavior in IMT.
The spindle cells of IMT express SMA and sometimes focally desmin. Cytokeratin expression is occasionally seen, particularly in abdominal/submesothelial tumors. Up to 60% show immunoreactivity for ALK,75–78 (Fig. 3B) particularly those in intra-abdominal, visceral and pulmonary sites and occurring in childhood.79,80 There is a relationship between ALK expression and morphology and behavior of IMT: ALK-negative tumors occur more frequently in adults, display more nuclear pleomorphism and atypical mitoses72,80 and are associated with a worse outcome.80 ALK expression is not specific, however, and is seen in other tumors in the differential diagnosis, including some malignant peripheral nerve sheath tumors, rhabdomyosarcomas and leiomyosarcomas.76,81 The ALK gene on chromosome 2p23 encodes a receptor tyrosine kinase of the insulin growth factor receptor family, normally expressed only in the central nervous system.82 Gene rearrangements83 are present in about half of IMTs,84 and can be detected in fixed tissue using fluorescence in situ hybridization or reverse-transcription polymerase chain reaction techniques, which is useful diagnostically as they are generally absent from the other sarcomas that show sporadic ALK immunoreactivity.81 ALK can fuse with several partner genes, including TPM3 (tropomyosin 3) at 1p13,85 CLTC (clathrin heavy chain gene) at 17q23, ATIC at 2q35, and RANBP2 at 2q1386 and fusion results in a constitutively active kinase. Although ALK expression is usually diffuse and cytoplasmic, it varies with some fusion types and can be granular (CTLC) or show nuclear membranous accentuation (RANPB2). The latter is described in epithelioid inflammatory myofibroblastic sarcoma, an aggressive intra-abdominal variant of IMT with a predilection for males and a wide age range, but which can occur in infants and young children.87 Lesions have a tendency for rapid local recurrence and are often fatal. The tumor comprises sheets of round to epithelioid cells with vesicular nuclei and large nucleoli, and a minor spindle cell component within abundant myxoid stroma and prominent neutrophils. It displays a distinct nuclear membrane or perinuclear pattern of ALK immunoreactivity.87 Most cases show ALK gene rearrangements with fluorescence in situ hybridization, and a proportion harbor RANBP2-ALK fusions, detectable by reverse-transcription polymerase chain reaction.87
Low-grade and intermediate-grade myofibrosarcomas are fascicular spindle cell neoplasms resembling fibrosarcoma or leiomyosarcoma, that occur in deep soft tissue or bone with disproportionate involvement of head and neck sites and can recur locally but infrequently metastasize. They usually occur in adults, but can more rarely affect children.88,89 Their clinical importance lies in the resemblance, particularly of low-grade examples, to reactive or pseudosarcomatous conditions such as nodular fasciitis.90 Histologically tumors may be infiltrative or circumscribed, and are composed of spindle cells with ovoid vesicular nuclei and often small single nucleoli, with moderate amounts of amphophilic cytoplasm within collagenous stroma. Cells are mainly arranged in sweeping fascicles but can display a range of appearances from fasciitis-like to fibrosarcoma-like. Although cells are generally fairly uniform, there is at least focal nuclear pleomorphism (Fig. 3C), but necrosis is infrequent. Tumors express SMA, frequently with a subplasmalemmal “tram-track” accentuation, and calponin, and some express desmin but most lack h-caldesmon.73,91 Ultrastructurally they display the typical characteristics of myofibroblasts, including rough endoplasmic reticulum, peripheral contractile filaments and the cell-to-matrix junction known as the fibronexus.92
Dermatofibrosarcoma protuberans (DFSP) and giant cell fibroblastoma are thought to represent a histologic spectrum of CD34-positive neoplasms, which share similar genetic findings, with giant cell fibroblastoma more commonly affecting children. Foci of 1 tumor type may be present in the other, or they may be juxtaposed.93 DFSP occurs mostly in young adults, but sometimes in children or congenitally.94 Most arise on the trunk and proximal extremities, presenting as slowly enlarging dermal plaques and nodules. Lesions recur particularly if incompletely excised, and repeated local recurrence is common, although metastasis is rare. Occasional cases may, however, undergo fibrosarcomatous transformation, which is associated with a more aggressive course. Histologically, tumors infiltrate the dermis and subcutis, and are composed of monotonous spindle cells with elongated hyperchromatic nuclei and small amounts of amphophilic fibrillary cytoplasm in striking storiform distributions. No pleomorphism is present, and atypia is minimal. Lesions infiltrate subcutaneous fat in a distinctive honeycomb pattern, extending parallel to the surface. Paler nodules where tumors show “myoid” or myofibroblastic differentiation are sometimes seen, and there are also myxoid and pigmented variants.
Tumors characteristically show diffuse, strong CD34 expression and occasional focal SMA, CD117, or EMA. DFSP is associated with a characteristic t(17;22)(q22;q13) translocation, fusing the COL1A1 and PDGFB1 genes, which is found in all morphologic subtypes, in fibrosarcoma arising in DFSP,95 and in giant cell fibroblastoma.96 Other chromosomal rearrangements are more rarely seen. Fibrosarcoma in DFSP can occur either de novo or in recurrent disease. Cells show more fascicular or herringbone rather than tightly storiform patterns, and there is greater mitotic activity (>5/10 high power fields). They may lose CD34 expression and have a higher MIB1 proliferative index.
Giant cell fibroblastoma predominantly affects children in the first decade of life. It is genetically identical to DFSP,96 and is regarded as its juvenile variant. Like DFSP, it arises in the proximal lower limbs and trunk.97 It is locally aggressive, with frequent recurrence, although metastasis has not been reported. Tumors infiltrate the skin and subcutis, and are of sparse to moderate cellularity, comprising bland spindle and multinucleate cells in fibrous or myxoid stroma. There are characteristic irregular cystic spaces lined by tumor cells (rather than endothelium) (Fig. 3D). Like DFSP, lesional cells show diffuse and strong CD34 expression. Recurrent lesions may have the morphology of dermatofibrosarcoma, sometimes focally.
Congenital and infantile fibrosarcoma (CIFS) is a relatively rare tumor of low to intermediate malignant potential that usually occurs in the first year of life,98 especially the first 3 months, and may be present at birth. It is rare in children older than 2 years, and slightly more common in males. It presents as a painless, rapidly growing swelling that can arise in both superficial or deep soft tissues. Tumors occur most frequently in distal extremities, with smaller numbers in the trunk or head and neck. They can reach large sizes and there is often extensive local invasion with erosion of adjacent bone. There is well-documented potential for spontaneous regression of tumors. Most can be cured by wide local excision or amputation where unavoidable. The recurrence rate is up to 30%, but metastasis is rare, with a frequency of around 5%,99,100 and most deaths are secondary to local complications, with tumors in the head and neck or deep truncal soft tissues, including mesentery, having a poor prognosis because of local extension.98 Unlike adult fibrosarcoma, the overall clinical course for CIFS is favorable, with up to 94% 5-year survival.98
Lesions are lobular, circumscribed, or infiltrative cellular masses, composed of loose or herringbone fascicles of fairly uniform, minimally pleomorphic ovoid to spindle cells with hyperchromatic nuclei (Fig. 3E). A more primitive-appearing, round to ovoid cell component may be present, especially in young children and congenital cases. The stroma varies from collagenous to myxoid, and a lymphocytic infiltrate, hemorrhage (especially in vascular areas) and necrosis can be seen. Mitotic figures are usually frequent. Some cases show areas that resemble infantile myofibroma, and composite cases are described.
Ultrastructurally the cells are fibroblastic, although some tumors show myofibroblastic differentiation immunohistochemically, with expression of actins in almost a third. Desmin is expressed in about a quarter, with occasional cases expressing CD34 or S100 protein. Most tumors harbor a characteristic and diagnostic t(12;15)(p13;q26) translocation, which fuses ETV6, a member of the ETS family of transcription factors on chromosome 12p13, and NTRK3, which encodes a receptor tyrosine kinase for neurotropin-3101,102 on chromosome 15q25. The fusion protein results in ligand-independent chimeric protein tyrosine kinase activity with autophosphorylation, leading to constitutive activation of Ras-MAPK and PI3K-AKT pathways via insulin receptor substrate-1, which is tyrosine-phosphorylated,103–105 and through the activation of c-Src.106 The fusion protein also associates with TGF-β II receptor, which can be oncogenic by leading to inhibition of TGF-β receptor signals that mediate tumor suppression.107
The ETV6-NTRK3 fusion is also seen in congenital mesoblastic nephroma (CMN),108,109 secretory carcinoma of the breast,110 and acute myeloid leukemia,111 implying oncogenesis by lineage-independent activation of kinase-related signaling pathways. CMN is a renal spindle cell tumor of infants, the cellular variant of which is histologically identical to infantile fibrosarcoma.112 Both CMN and CIFS are associated with polysomies for chromosomes 8, 11, 17, and 20, suggesting a common pathogenetic pathway and that they perhaps represent a single neoplastic entity, arising in either renal or soft tissue locations.108
Adult-type fibrosarcoma is a malignant tumor showing purely fibroblastic and myofibroblastic differentiation, which occurs in older children. It differs from CIFS both histologically, by the presence of gradable atypia and pleomorphism, and clinically by aggressive behavior related to the usual factors of size, grade and depth from skin surface. It has metastatic potential, but fibrosarcoma before the age of 4 years is much less likely to metastasize than those in adults and has more in common with infantile forms of fibromatosis. With increasing age, fibrosarcomas tend to behave more like their adult counterparts.
Low-grade fibromyxoid sarcoma (LGFMS)113,114 is a rare variant of fibrosarcoma only rarely encountered in childhood. It occurs in deeper soft tissues or abdomen, mostly of young adults, although superficial examples have a higher incidence in childhood.115 It is characterized by deceptively benign-appearing histology, with bland spindle cells with angulated nuclei and even chromatin, within collagenous to myxoid matrix (Fig. 3F). 15% to 30% of lesions display distinctive, rosette-like collagenous nodules. There is a recurrence rate of up to 21%, and eventual metastasis, usually to lung, in almost one third of tumors. The recurrence rate is, however, lower in superficial cases, and there are no reported metastases in this subset. Tumors show diffuse and strong cytoplasmic expression of MUC4,116 a transmembrane glycoprotein that functions in cell growth signaling pathways and which has been shown by gene expression profiling to be upregulated in LGFMS. LGFMS is almost always negative for desmin, SMA, S100 protein, and cytokeratin, but some cases can express epithelial membrane antigen, CD34 and claudin-1,117 making distinction from perineurioma difficult, particularly for superficial cases. LGFMS harbor consistent and reproducible balanced translocations: t(7;16)(q34;p11) and t(11;16)(p11;p11), fusing FUS with CREB3L2 or CREB3L1, and show a distinct gene expression profile.118 Ultrastructurally, cells show features of fibroblasts.
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adolescence; childhood; fibromatosis; genetics; histopathology; myofibroblast
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