Fibrous Tumors of Infancy and Childhood





Fibrous tumors of infancy and childhood can be divided into two large groups: (1) lesions that correspond to similar lesions in adults in terms of clinical setting, microscopic picture, and behavior (e.g., nodular fasciitis, palmar/plantar fibromatosis, abdominal/extraabdominal fibromatosis) and (2) fibrous lesions that are peculiar to infancy and childhood and generally have no clinical or morphologic counterpart in adult life. The lesions in the second group are less common, and because of their unusual microscopic features, they pose a special problem in diagnosis. In fact, the microscopic picture often does not accurately reflect the biologic behavior, and features such as cellularity and rapid growth may be mistaken for evidence of malignancy, sometimes leading to unnecessary and excessive therapy. Therefore, accurate interpretation and diagnosis of fibrous lesions peculiar to infancy and childhood are essential for predicting clinical behavior and for selecting the proper forms of therapy ( Table 8.1 ).



Table 8.1

Clinicopathologic Characteristics of Fibrous Tumors of Infancy and Childhood



































































Histologic Diagnosis Age (Years) Location Solitary Multiple Regression
Fibrous hamartoma of infancy B-2 Axilla, upper arm +
Inclusion body fibromatosis B-2 Fingers, toes + /- +
Hyaline fibromatosis 2-A Dermis, subcutis +
Gingival fibromatosis B-A Gingiva, hard palate + + + (after tooth extraction)
Fibromatosis colli B-2 Sternocleidomastoid muscle + Bilateral +
Lipofibromatosis B-4 Musculature +
Congenital/infantile fibrosarcoma B-2 Musculature +
Calcifying aponeurotic fibroma 2-A Hands, feet + +

A, Adult life; B, birth.


Fibrous Hamartoma of Infancy


Fibrous hamartoma of infancy is a distinctive, benign neoplasm that most frequently occurs during the first 2 years of life. This lesion was first reported by Reye in 1956 as a subdermal fibromatous tumor of infancy . In 1965, Enzinger reviewed a series of 30 cases from the files of the Armed Forces Institute of Pathology (AFIP) and suggested the term fibrous hamartoma of infancy to emphasize its organoid microscopic appearance and its frequent occurrence at birth and during the immediate postnatal period.


Clinical Findings


The lesion usually develops during the first 2 years of life (median age: 10 months) as a small, rapidly growing mass in the subcutis or reticular dermis. A literature review of 197 cases found that 91% arose within the first year of life. Rare lesions have been reported in older infants and children. In the recent study of 145 cases by Al-Ibraheemi et al., the patients ranged in age from birth to 14 years (mean age: 15 months); six cases were congenital. As with other fibrous tumors in children, it is more common in boys, who are affected two to three times more often than girls. The mass is often freely movable; occasionally it is fixed to the underlying fascia but only rarely involves the superficial portion of the musculature. These lesions grow rapidly from the outset up to about age 5 years. The growth of the lesion then slows but does not cease or regress spontaneously.


Most fibrous hamartomas occur above the waist; the most common location is the anterior or posterior axillary fold, followed in frequency by the upper arm, thigh, inguinal and pubic region, shoulder, back, and forearm, although the anatomic spectrum continues to widen as larger clinicopathologic studies are published. In the Al-Ibraheemi study, 69 cases arose in typical sites (e.g., axilla, back, upper arm), but 76 arose in unusual locations. Few cases have been described in the feet or hands, a feature that helps distinguish this lesion from inclusion body fibromatosis, lipofibromatosis, and calcifying aponeurotic fibroma. Virtually all cases are solitary, with only rare reports of multiple lesions in the same patient. There is no evidence of increased familial incidence or associated malformations or other neoplasms, although there are reports of this lesion arising in the setting of a congenital nevus. Antecedent trauma is occasionally reported at presentation but is likely unrelated to pathogenesis.


Pathologic Findings


The excised lesion tends to be poorly circumscribed and consists of an intimate mixture of firm, gray-white tissue and fat. In some cases the fatty component is inconspicuous, whereas in others it occupies a large portion of the tumor, thereby resembling a fibrolipoma. Most measure 3 to 5 cm in greatest diameter, but tumors as large as 15 cm have been reported. Fibrous hamartoma of infancy is characterized by three distinct components forming a vague, irregular, organoid pattern ( Figs. 8.1 and 8.2 ):



  • 1.

    Well-defined intersecting trabeculae of fibrous tissue of varying size and shape and composed of well-oriented spindle-shaped cells (predominantly myofibroblasts) separated by varying amounts of collagen ( Figs. 8.3 and 8.4 )




    Fig. 8.3


    Fibrous hamartoma of infancy with interlacing fibrous trabeculae and interspersed myxoid zones.



    Fig. 8.4


    High-power view of spindle-shaped cells in fibrous trabeculae of fibrous hamartoma of infancy.


  • 2.

    Loosely textured areas consisting chiefly of immature small, round, or stellate cells in a myxoid matrix ( Figs. 8.5 to 8.7 )




    Fig. 8.5


    Fibrous hamartoma of infancy showing admixture of mature adipose tissue, fibrous trabeculae, and a nodule of spindle-shaped cells.



    Fig. 8.6


    Organoid pattern with a characteristic arrangement of the three distinct components typical of fibrous hamartoma of infancy.



    Fig. 8.7


    High-power view of cytologically bland, spindle-shaped cells deposited in a myxoid stroma in fibrous hamartoma of infancy.


  • 3.

    Varying amounts of interspersed mature fat, which may be present at only the periphery of the lesion or may be the major component




Fig. 8.1


Fibrous Hamartoma of Infancy.

The characteristic organoid pattern is composed of interlacing fibrous trabeculae, islands of loosely arranged spindle-shaped cells, and mature adipose tissue.



Fig. 8.2


Fibrous hamartoma of infancy with an organoid pattern but composed predominantly of mature adipose tissue.


Despite the lack of clear boundaries between the fat in the tumor and that in the surrounding subcutis, the fat is an integral part of the lesion. In many cases, its total amount exceeds many times the amount of fat normally present in the surrounding subcutis. In some cases, the immature small round cells in the myxoid foci are oriented around small veins.


Some tumors may have hyalinized zones with cracking artifact , imparting a pseudoangiomatous appearance resembling giant cell fibroblastoma ( Fig. 8.8 ). These areas were found in 30% of cases in the Al-Ibraheemi study and in more than 50% of cases in the Saab study. Adding to this confusion is that these pseudoangiomatous areas stain for CD34, a marker also consistently expressed in giant cell fibroblastoma. Unlike giant cell fibroblastoma, PDGFRB rearrangements have not been found in fibrous hamartoma of infancy.




Fig. 8.8


Fibrous hamartoma ( A ) with giant cell fibroblastoma–like areas ( B and C ).




Interestingly, two cases of fibrous hamartoma of infancy with sarcomatous foci have been described. These areas are characterized by high cellularity, high nuclear grade, and brisk mitotic activity ( Fig. 8.9 ). At the molecular level, those cases with sarcomatous features were found to be hyperdiploid/near-tetraploid, with both loss of heterozygosity of chromosomes 1p and 11p, and loss of 10p, chromosome 14, and a large portion of chromosome 22.




Fig. 8.9


Fibrous hamartoma with areas of sarcomatous transformation. Triphasic fibrous hamartoma ( A ) showing expansion of loose myxoid stroma by atypical cells ( B ) and adjacent sarcoma ( C ).




Immunohistochemical and Molecular Genetic Findings


On immunohistochemistry (IHC), smooth muscle actin (SMA) stains the spindled cells in the trabecular component, with only rare expression of desmin. The primitive myxoid matrix stains for CD34, with variable expression of actins. As mentioned previously, the pseudoangiomatous foci stain for CD34.


In 2016, Park et al. found 12 of 12 cases of fibrous hamartoma of infancy to harbor EGFR exon 20 insertion/duplication mutations, which were not found in 10 cases of other pediatric fatty tumors. This alteration was subsequently reported in a case of fibrous hamartoma of infancy with a predominant pseudoangiomatous pattern.


Differential Diagnosis


In most cases, the organoid pattern characteristic of fibrous hamartoma of infancy is readily recognized, so the lesion is not difficult to distinguish from other entities. On occasion, when the myofibroblastic area is predominant, the lesion may be difficult to distinguish from lipofibromatosis, the recently described lipofibromatosis-like neural tumor, diffuse myofibromatosis, and calcifying aponeurotic fibroma. Lipofibromatosis (detailed later) is characterized by either primitive cells or mature fibroblastic spindle-shaped cells that infiltrate the subcutis and skeletal muscle with fascicular growth, lacking the characteristic organoid pattern of fibrous hamartoma. Lipofibromatosis-like neural tumor (also described later) has features similar to lipofibromatosis but shows more cytologic atypia and nuclear hyperchromasia, S-100 protein immunoreactivity, and characteristic NTRK1 gene rearrangements. Diffuse myofibromatosis , typically nodular or multinodular, is characterized by light-staining nodules separated by or associated with hemangiopericytoma-like vascular areas. Calcifying aponeurotic fibroma may grow in the same trabecular manner, especially during its earliest phase, when there is still little or no calcification. However, the older age of the children and the distal extremity location should permit an unequivocal diagnosis.


Awareness of the characteristic organoid pattern also facilitates distinction from infantile fibrosarcoma and embryonal rhabdomyosarcoma. Because some fibrous hamartomas of infancy occur in the scrotal region, the spindle cell form of embryonal rhabdomyosarcoma enters the differential diagnosis; however, this lesion generally occurs in older children and is composed of cells with more cytologic atypia and myogenin immunoreactivity.


Discussion


It is important to recognize and distinguish fibrous hamartoma of infancy from other forms of fibromatosis because it is a benign lesion that, despite its focal cellularity, is usually cured by local excision. Up to 16% locally recur, but recurrences are nondestructive and are generally cured by local reexcision. Follow-up (median: 8 months) in 52 patients showed only 2 with local recurrence and no metastases. Because of the presence of extensive local disease in one patient (10-month-old female) with sarcomatous foci, a forequarter amputation was necessary. Additional cases of fibrous hamartoma of infancy with sarcomatous foci and clinical follow-up are needed before the clinical significance of sarcomatous histology can be determined.




Inclusion Body Fibromatosis (Infantile Digital Fibromatosis)


Inclusion body fibromatosis, also known as infantile digital fibromatosis, is a distinctive fibrous proliferation of infancy. It is characterized by occurrence in the fingers and toes, a marked tendency for local recurrence, and the presence of characteristic inclusion bodies in the cytoplasm of the neoplastic fibroblasts. In 1957, Jensen et al. reported seven patients whose presentations were consistent with this entity but referred to these lesions as digital neurofibrosarcoma in infancy . Enzinger subsequently reported seven cases in 1965 as infantile dermal fibromatosis .


Clinical Findings


Most patients present with a firm, broad-based, hemispheric or dome-shaped, nontender nodule with a smooth, glistening surface that is skin colored or pale red. It is usually small, rarely exceeding 2 cm in greatest diameter. Almost all lesions are noted within the first 3 years of life, with most recognized by 1 year. Up to one-third of cases are already present at birth. In the Laskin study, the 57 patients ranged in age from newborn to 10 years (median: 12 months) at surgery. Rare examples have been described in older children, adolescents, and even in adults. Unlike most other forms of fibromatosis, the condition has a roughly equal gender distribution, but no evidence of familial tendency. This lesion has been identified in patients with terminal osseous dysplasia (also known as digitocutaneous dysplasia) and pigmentary defects, a rare, lethal X-linked dominant disease that has been linked with mutations of the FLNA gene. However, it is unclear if the fibroblastic lesions in these patients are identical to inclusion body fibromatosis because the cells lack the characteristic inclusions and do not stain for smooth muscle actin.


The nodules are more often found in the fingers than the toes and usually are located on the sides or dorsum of the distal or middle phalangeal joints, especially of the third, fourth, and fifth digits. Although the thumb can be affected, cases involving the great toe have not been reported. The lesions may be single or multiple and often affect more than one digit of the same hand or foot. Occasionally, they involve both the fingers and the toes of the same patient. Very few cases have been described as occurring in areas other than the hands and feet. Purdy and Colby reported a case with typical eosinophilic perinuclear inclusions in the upper arm of a 2½-year-old child near an old injection site. Pettinato et al. described two cases of extradigital inclusion body fibromatosis in the breasts of 24- and 53-year-old women.


Although pain and tenderness are not typical symptoms, associated functional impairment or joint deformities may be present, including lateral deviation or flexion deformities of the adjacent joints, which typically remain unchanged after surgical removal of the lesions.


Pathologic Findings


The excised lesions are small, firm masses that are covered on one side by intact skin and have a solid white cut surface ( Fig. 8.10 ). The microscopic appearance varies little, consisting of a uniform proliferation of fibroblasts surrounded by a dense collagenous stroma ( Fig. 8.11 ). The lesions are poorly circumscribed and extend from the epidermis into the deeper portions of the dermis and subcutis, typically surrounding the dermal appendages. The overlying epidermis is usually minimally altered, with slight hyperkeratosis or acanthosis.




Fig. 8.10


Inclusion Body Fibromatosis.

Low-power view of a broad-based hemispheric dermal nodule composed of spindle-shaped cells, characteristic of infantile digital fibromatosis.



Fig. 8.11


Inclusion body fibromatosis, composed of a uniform proliferation of fibroblasts surrounded by a dense collagenous stroma.


The most striking feature of the tumor is the presence of small, round inclusions in the cytoplasm of the constituent spindle cells. The number of inclusions varies from case to case. Some are numerous and easily detected, whereas others are scarce and difficult to find with hematoxylin-eosin–stained slides. Typically, these inclusions are situated close to the nucleus, from which a narrow clear zone often separates them ( Fig. 8.12 ). They are eosinophilic and resemble erythrocytes, except for their more variable size (3-15 μm), intracytoplasmic location, and lack of refraction. Ultrastructurally the inclusions correspond to localized collections of non–membrane-bound, granular fibrillary material contiguous with the rough endoplasmic reticulum ( Fig. 8.13 ). Numerous histochemical preparations can be used to highlight these inclusions; they stain a deep red with Masson trichrome stain ( Fig. 8.14 ), but they do not stain with periodic acid–Schiff (PAS), Alcian blue, or colloidal iron stains. The spindle cells have pale, eosinophilic cytoplasm and elongated nuclei with fine chromatin. Mitotic figures are rare. Hayashi et al. suggested a relationship between the age of the lesion and the number of inclusion bodies found, with younger lesions having more inclusion bodies and less fibrosis, and the opposite with older lesions.




Fig. 8.12


Inclusion Body Fibromatosis.

Fibroblasts with characteristic intracytoplasmic inclusions separated by a narrow clear zone.



Fig. 8.13


Inclusion Body Fibromatosis.

Electron microscopy shows an inclusion within the fibroblast.

From Taxy JB, Battifora H. The electron microscope in the study and diagnosis of soft tissue tumors. In Trump BF, Jones RT, editors. Diagnostic Electron Microscopy. New York: Wiley; 1980, with permission.



Fig. 8.14


Masson trichrome stain demonstrating characteristic intracytoplasmic inclusions characteristic of inclusion body fibromatosis.


Immunohistochemical Findings


On IHC the spindled cells stain consistently for actin, but results have varied for actin immunoreactivity of the inclusion bodies themselves. Most of the earlier studies using formalin-fixed tissues were unable to demonstrate actin staining. However, actin staining of the inclusion bodies has been demonstrated using alcohol-fixed tissue as well as potassium hydroxide and trypsin-pretreated, formalin-fixed tissue. In the Laskin study, the cells consistently expressed calponin, SMA, desmin, and CD99. Most also expressed CD117, but stains for cytokeratins, estrogen, and progesterone receptors were negative. The Laskin study also indicated that rare, nuclear expression of beta-catenin may be present (2/11 = 18%), but a subsequent series by Thway et al. did not confirm this observation (0/6). Henderson et al. reported calponin immunoreactivity of the intracytoplasmic inclusions.


Discussion


The exact nature of the inclusions is not clear. Because of the resemblance of these inclusions to the viroplasm of fibroblasts infected with Shope fibroma virus , Battifora and Hines proposed a possible viral etiology. The IHC and ultrastructural findings strongly suggest that the inclusions are related to the intracellular bundles of microfilaments and represent densely packed masses of actin microfilaments. The occurrence of extradigital posttraumatic lesions that are histologically indistinguishable from those on the digits and antecedent trauma or surgery related to digital lesions suggests that trauma may stimulate development of the lesion. Inclusion bodies identical to those found in inclusion body fibromatosis have also been described in a variety of other tumors, including benign phyllodes tumor and fibroadenoma of the breast and endocervical polyps.


Although a significant percentage of these lesions recur locally, the ultimate prognosis is excellent. Recurrences usually appear at the same site within a few weeks or months after the initial excision. Although there is an initial period of growth, if watched long enough, many lesions regress spontaneously. In the Laskin study, 28 of 38 (74%) cases with follow-up information persisted or locally recurred at a median of 4 months after surgery. Most authors advocate conservative treatment because there is no evidence of aggressive behavior or malignant transformation. Some advocate a watch-and-wait approach following a diagnosis, given the high rate of spontaneous regression. Intralesional injection of corticosteroids or fluorouracil instead of surgical excision has also been advocated. Mohs micrographic surgery may be effective in minimizing the risk of local recurrence. Deformities and contractures develop in some patients, regardless of whether the lesions are removed surgically, and surgical correction of contractures and functional changes are sometimes necessary.




Juvenile Hyaline Fibromatosis/Infantile Systemic Hyalinosis


Juvenile hyaline fibromatosis (JHF) is another rare hereditary disease that bears a superficial resemblance to myofibromatosis but differs by its cutaneous distribution of the tumor nodules, the histologic picture, and associated clinical features. Murray first described the condition in 1873 as “molluscum fibrosum in children,” thought to represent an unusual variant of neurofibromatosis. Whitfield and Robinson offered a follow-up report of these three cases in 1903, but amazingly, no further reports occurred until 1962, when Puretic et al. reported a case under the name mesenchymal dysplasia . A variety of terms were used in subsequent reports, but Kitano coined the term juvenile hyaline fibromatosis , which has become the preferred term. For many years, the terms juvenile hyaline fibromatosis and infantile systemic hyalinosis (ISH) were used interchangeably, but the exact relationship between these two entities was unclear. Although they share a number of characteristics in common, there are some significant clinical differences. Genetic data (described later) clearly link these two diseases along a spectrum.


Clinical Findings


A number of clinical findings are common to both JHF and ISH, including joint contractures, gingival hyperplasia, osteopenia, and papular and nodular skin lesions. The skin lesions have been grouped into three types: (1) small pearly papules on the face and neck, (2) small nodules and large plaques with a translucent appearance and a gelatinous consistency developing on fingers and ears and around the nose, and (3) firm, large, subcutaneous tumors with a predilection for the scalp, trunk, and limbs ( Figs. 8.15 and 8.16 ). The lesions vary in size from 1 mm to up to 10 cm; they are slow-growing and painless and have a tendency to recur after excision. The number of cutaneous lesions varies from case to case, but some patients can have more than 100 lesions in various parts of the body. Most patients have extracutaneous findings, including painful flexion contractures of major joints and gingival hypertrophy, which may precede the development of skin lesions. More than 60% of patients reveal multiple osteolytic defects on radiographic examination. Most patients have painful, debilitating flexion contractures of large joints, resulting in marked deformity and generalized stiffness.




Fig. 8.15


Juvenile hyaline fibromatosis with gingival lesions.



Fig. 8.16


Juvenile hyaline fibromatosis with ear lesion.


As mentioned, some clinical features distinguish ISH from JHF. Patients with ISH usually present within the first 6 months of life and often die of intractable diarrhea or infection by age 2 years. In contrast, patients with JHF typically present later in infancy or childhood and often live into the third decade. Features unique to ISH include persistent diarrhea with a protein-losing enteropathy, presumably secondary to intestinal lymphangiectasia, hyperpigmentation over bony prominences, and failure to thrive.


Pathologic Findings


The lesions are poorly circumscribed and consist of cords of spindle-shaped cells embedded in a homogeneous eosinophilic matrix ( Figs. 8.17 and 8.18 ). They are often found in the dermis, subcutis, and gingiva, although the bone and joints may also be involved. Deposition of this amorphous eosinophilic matrix is widespread in some patients; Kitano et al. reported one patient with autopsy-proven deposition of this substance in the tongue, esophagus, stomach, intestine, thymus, spleen, and lymph nodes. Early lesions may be quite cellular ( Fig. 8.19 ), suggesting a fibromatosis. The cells resembling plump fibroblasts are arranged in indistinct fascicles. Over time the lesions acquire copious amounts of the characteristic PAS/Alcian blue–positive stroma, which widely separates the cells, some of which have a clear cytoplasm ( Fig 8.20 ). Despite the glassy appearance of the stroma, the material does not stain with Congo Red, as would amyloid. Occasional nodules reveal marked calcification, including calcospherites, and multinucleated giant cells may occasionally be seen.




Fig. 8.17


Juvenile hyaline fibromatosis with subepidermal hyaline deposits.



Fig. 8.18


Juvenile hyaline fibromatosis with widely spaced spindled cells in hyaline background.



Fig. 8.19


A, Juvenile hyaline fibromatosis showing variation in cellularity. B, Highly cellular areas resemble fibromatosis, whereas less cellular areas have abundant matrix material.



Fig. 8.20


PAS-positive matrix in juvenile hyaline fibromatosis.


The nature of this amorphous eosinophilic material is not clear. Ultrastructural studies have found this material to have a banding pattern identical to type II collagen. On IHC the spindled cells are generally negative for actins, but there is a conspicuous population of CD68-positive macrophages between the spindled cells.


Cytogenetic and Molecular Genetic Findings


Mutations of the capillary morphogenesis gene 2 ( CMG2 ) on 4q21 were identified in both JHF and ISH in 2003, confirming a long-suspected genetic link. The gene, also known as ANTXR2 , codes for a protein involved in basement membrane matrix assembly and morphogenesis of endothelial cells. Recently, this gene has been implicated as central to collagen VI homeostasis. Both ISH and JHF are associated with distinct mutations of this gene, suggesting a genotypic-phenotypic correlation. Given the clear relationship between JHF and ISH, some prefer the designation of hyaline fibromatosis syndrome .


These diseases are inherited in an autosomal recessive manner. Interestingly, there seems to be a preponderance of cases reported in patients of Middle Eastern descent, possibly as a result of a higher rate of consanguineous relationships.


Differential Diagnosis


Multicentric infantile myofibromatosis is composed of multiple nodules that are almost always present at birth or appear during the first year of life. In general, the nodules are better circumscribed and are found not only in the subcutis, but also in muscle, bone, and viscera. Microscopically, they consist of broad, interlacing bundles of plump myofibroblasts, often with a central hemangiopericytoma-like area composed of primitive-appearing cells. The gums or joints are never involved. Neurofibromatosis tends to make its first appearance in slightly older children and is associated with café au lait spots; the tumors are composed of generally bland, somewhat randomly arranged spindled cells with wavy or buckled nuclei in a fibrillary eosinophilic matrix and are positive for S-100 protein. Gingival fibromatosis , a lesion with a similar hereditary pattern, is limited to the gums of the upper and lower jaws and consists of dense, scarlike connective tissue rich in collagen. Cylindromas , or “turban tumors,” are confined to the head.


Winchester syndrome , a rare autosomal hereditary disease, is characterized by densely cellular, poorly demarcated fibrous proliferations in the dermis, subcutis, and joints without deposition of a hyaline matrix. Periarticular thickening and limited motion in the limbs and the spine, corneal opacities, and radiographic changes of bones and joints are also part of this disorder. The precise relation between JHF/ISH and Winchester syndrome is unclear, and some believe that these conditions represent different expressions of the same disorder, although mutations in the CMG2 gene have not been identified in this syndrome. Rather, mutations of membrane type 1 metalloproteinase have been identified in Winchester syndrome.


Discussion


Although most lesions in JHF/ISH are formed during childhood, new lesions may continue to appear into adult life. The nodules continue to grow slowly and may ulcerate the overlying skin. Surgical excision of lesions and hypertrophic gingival tissue is the treatment of choice, although the treatment can be as mutilating as the lesions themselves in those patients with innumerable nodules. Most patients with long-term follow-up are severely physically handicapped by joint contractures. Some patients can even develop upper airway obstruction because of the profound gingival hypertrophy that may occur.




Gingival Fibromatosis


Gingival fibromatosis is a rare benign fibroproliferative disorder that is clinically distinct, chiefly affecting young persons of both genders with a tendency for recurrent local growth. Lesions may be idiopathic or familial, and some are associated with a heterogeneous group of hereditary syndromes. Gingival fibromatosis has been classified into six categories: (1) isolated familial gingival fibromatosis; (2) isolated idiopathic gingival fibromatosis; (3) gingival fibromatosis associated with hypertrichosis; (4) gingival fibromatosis associated with hypertrichosis and mental retardation or epilepsy (or both); (5) gingival fibromatosis with mental retardation, epilepsy, or both; and (6) gingival fibromatosis associated with hereditary syndromes.


Clinical Findings


Patients with gingival fibromatosis present with a slowly growing, poorly defined enlargement or swelling of the gingivae, causing little pain but considerable difficulty in speaking and eating. The gingival overgrowth occurs to such a degree that the teeth are completely covered and the lips are prevented from closing. The lesions may also extend over the hard palate, resulting in a deformity of the contour of the palate; some also have marked swelling of the jaw bone. In some patients, the gingival swelling is minimal and limited to a small portion of the gum ( localized type ), but in most it is extensive and bilateral, involving the gingival tissues of both the upper and the lower jaw and the hard palate ( generalized type ). Idiopathic cases are slightly more common than familial cases. Among the idiopathic cases, the generalized type outnumbers the localized type by almost 2 to 1. The vast majority of familial cases are generalized. The condition occurs at any age, but most present at eruption of the deciduous or permanent teeth. In fact, it has been postulated that the erupting teeth trigger the fibrous growth, as evidenced by effective treatment with tooth extraction alone, at least in some cases. Patients with the familial form of the disease tend to be younger than those with the idiopathic form. Up to 8% of cases are found at birth or immediately after delivery.


Hypertrichosis is found in almost 10% of patients with this condition. Some patients also have mental retardation or epilepsy (or both), although the latter features can also be present in the absence of hypertrichosis. The gingival fibromatosis associated with these conditions generally occurs at a younger age than in the idiopathic form and is more common in females.


Gingival fibromatosis may also be associated with a variety of rare syndromes. Zimmermann-Laband syndrome is a rare autosomal dominant disorder characterized by gingival fibromatosis, hypertrichosis, intellectual disability, and various skeletal anomalies, including absence or hypoplasia of nails or terminal phalanges of the hands and feet. It appears to be inherited in an autosomal dominant manner and has been associated with mutations in KCNH1 and ATP6V1B2 . Gingival fibromatosis has also been associated with cherubism (Ramon syndrome), hearing loss and supernumerary teeth, Klippel-Trenaunay-Weber syndrome, prune-belly syndrome, and growth hormone deficiency.


Pathologic Findings


Grossly, the growth consists of dense scarlike tissue that cuts with difficulty and has a gray-white glistening surface. On microscopic examination, the lesions (which vary little in appearance) consist of poorly cellular, richly collagenous fibrous connective tissue underneath a normal or acanthotic squamous epithelium. Mild perivascular chronic inflammation and small foci of dystrophic calcification may be present. The histologic features of the familial and idiopathic forms are indistinguishable.


Differential Diagnosis


Gingival fibromatosis bears a striking resemblance to hypertrophy of the gums following prolonged therapy with phenytoin (diphenylhydantoin sodium, Dilantin). In epileptic patients treated with phenytoin, it is difficult if not impossible to determine the cause of the gingival overgrowth. However, patients with gingival fibromatosis and epilepsy were described before the use of phenytoin, indicating that the changes are not entirely drug induced. Other drugs, including immunosuppressives (cyclosporin A) and calcium channel blockers (nifedipine), can induce the same changes. Lesions of similar appearance may also be found during pregnancy and as the result of chronic gingivitis. In most of these cases, a detailed clinical and family history permits the correct diagnosis. JHF, a hereditary lesion that may involve the gingiva in a similar manner, can be distinguished by its association with multiple cutaneous tumors and the characteristic microscopic appearance, especially the prominent PAS-positive hyaline matrix.


Discussion


Surgical excision of the hyperplastic tissue is frequently followed by local recurrence. However, the overgrowth may recede or disappear with tooth extraction. Many authors recommend excision of the excess tissue and removal of all teeth in severe cases.


Approximately 35% of cases of gingival fibromatosis are familial; however, there is clearly genetic heterogeneity. Although some cases appear to be inherited in an autosomal recessive manner, most have an autosomal dominant pattern of inheritance. Several genes have been associated with gingival fibromatosis, including mutations of SOS1 , located at 2p21-p22, as well as alterations at 5q13-q22. The fibroblasts in this condition have a higher proliferative rate than normal gingival fibroblasts, possibly mediated by autocrine stimulation by transforming growth factor (TGF)-β1.




Fibromatosis Colli


Fibromatosis colli has long been recognized as a peculiar benign fibrous growth of the sternocleidomastoid muscle (SCM) that usually appears during the first weeks of life and is often associated with muscular torticollis , or wryneck . It bears a close resemblance to other forms of infantile fibromatosis but is sufficiently different in its microscopic appearance and behavior to warrant separation as a distinct entity. The finding of torticollis is not synonymous with the presence of fibromatosis colli because almost 80 entities have been reported to cause torticollis (acquired torticollis). In a retrospective study of 58 patients with infantile torticollis using magnetic resonance imaging (MRI), Parikh et al. found evidence of fibromatosis colli in only 7 patients.


Clinical Findings


The lesion usually manifests between the second and fourth weeks of life as a mass lying in or replacing the mid- to lower portion of the SCM, especially its sternal or clavicular portion. The lesion is movable only in a horizontal plane and never affects the overlying skin. Typically, a 1- to 3-cm-long, hard mass, or bulb, is palpable at the base of the SCM. Almost all cases are unilateral, with a slight predilection for the right side of the neck; rare cases of bilateral fibromatosis colli have been described. Most authors have found a slight predilection for this lesion in boys.


Initially the mass grows rapidly, but after a few weeks or months the growth slows and becomes stationary. In many cases, spontaneous regression occurs by age 1 to 2 years, and the lesion may no longer be palpable. During the initial growth period, torticollis (rotation and tilting of the head to the affected side) occurs in only about one-fourth to one-third of cases and usually is mild and transient. In addition, the face and skull on the affected side may begin to appear smaller, resulting in facial asymmetry and plagiocephaly ; there is flattening of the affected side of the face with posterior displacement of the ipsilateral ear. A number of patients with this lesion present with torticollis later in life because the affected SCM is incapable of keeping pace with the growth and elongation of the SCM on the opposite side, causing functional imbalance and torticollis.


Fibromatosis colli is associated with a high incidence of difficult deliveries, including breech (reported in up to 60% of patients) and forceps deliveries. Several reports have noted an association with other congenital anomalies, such as ipsilateral congenital dysplasia of the hip.


Pathologic Findings


When the growth is excised at an early stage, the specimen consists of a small mass of firm tissue averaging 1 to 2 cm in diameter. The cut surface is gray-white and glistening and blends imperceptibly with the surrounding skeletal muscle. Microscopic examination discloses partial replacement of the SCM by a diffuse fibroblastic proliferation of varying cellularity ( Figs. 8.21 and 8.22 ). The constituent cells lack nuclear hyperchromasia, pleomorphism, and mitotic activity. Scattered throughout the lesion are residual muscle fibers that have undergone atrophy or degeneration with swelling, loss of cross-striations, and proliferation of sarcolemmal nuclei. This intimate mixture of proliferated fibroblasts and residual atrophic skeletal muscle fibers is fully diagnostic of the lesion and should not be confused with the infiltrative growth of a malignant neoplasm. Lesions of longer duration typically show less cellularity and more stromal collagen, but there appears to be no correlation between histologic picture and patient age. Although present in some cases, hemosiderin deposits are never a prominent feature. Unlike fibrosing myositis , there is no inflammatory infiltrate; unlike fibrodysplasia ossificans progressiva , there are no associated malformations of the hands or feet. Fine-needle aspiration cytology is a useful diagnostic modality and may obviate the need for further surgery. As one might expect, the aspirate is characterized by bland, spindle-shaped fibroblasts of low cellularity admixed with degenerating skeletal muscle fibers. On IHC the cells stain for SMA but not for β-catenin.


Mar 10, 2020 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Fibrous Tumors of Infancy and Childhood
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