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Infantile Digital Fibroma: A Rare Fibromatosis.

Infantile digital fibroma is a rare benign tumor made up of mostly myofibroblasts, (1,2) with approximately 200 cases reported in the English-language literature. (3) This entity was first described by Reye (4) in 1965 as recurring digital fibrous tumor of childhood. It appears almost exclusively on the digits of the hands and feet, rarely involving the thumb or big toe. (5) However, there have been reports of infantile digital fibroma-like entities occurring outside of the digits. (6) Usually it presents at birth or within the first 2 years of life, but it has occasionally been reported to appear even as late as age 52 years. (7) These tumors have the unique histologic finding of small intracytoplasmic inclusions that appear similar to red blood cells. (6) Originally, it was unknown what these inclusion bodies were. There was some thought that they could have a viral origin, but human papilloma virus DNA types 6, 11, 16, and 18, and herpes simplex virus DNA types I and II could not be demonstrated. (8) The inclusions have been shown to be made up of densely packed vimentin and actin filaments. Currently it is thought that their presence most likely represents a deviation in the complex process of myofilament assemblage in myofibroblasts and smooth muscle cells. (9,10) Still, the etiology and pathogenesis of infantile digital fibroma remain unclear, with no large series demonstrating an association between infantile digital fibroma and genetic disorders or malformations. (11,12)

CLINICAL FEATURES

In the largest study, which included 57 patients, Laskin et al (5) found that the mean age at presentation was 22 months with ages ranging from newborn to 10 years. However, the tumor has been reported to appear much later in life as well. (7) The Laskin study found a slight male predominance, but other series have shown a female bias. (13,14) Typically, the lesion presents on the second through fifth digits of the hands or feet, on the dorsal or lateral aspect as an asymptomatic, firm, pinkish to flesh-colored nodule or growth that is commonly less than 2 cm (Figure 1). It can be associated with pain or can cause hindrance of activities, such as writing, if it is larger. (5,11) In some instances, more than one nodule can appear, usually as metachronous lesions affecting adjacent joints, (14,15) but simultaneously occurring lesions involving multiple fingers have been reported. (16) Rarely, this lesion can appear outside of the digit. (6) The lesion can be slow growing or have a rapid increase in size, with neither presentation imparting clinical significance. Although this lesion is benign and lacks a propensity for metastasis, it does often recur locally. (5,14) If left alone, there are some reports of spontaneous regression without any further intervention needed. (17)

GROSS AND HISTOLOGIC FEATURES

The tumor usually appears as a firm or rubbery dermal nodule with a white-gray cut surface located directly under the skin, and it has been reported to range in size from 3 to 35 mm. (5,12) The overlying epidermis can display a host of changes, including acanthosis, hyperkeratosis, parakeratosis, rete ridge flattening, entrapment of adnexal structures, and, rarely, ulceration. The lesion itself is made up of a proliferation of bland intradermal spindle cells arranged in whorls, fascicles, or a storiform pattern in a collagenous background of varying degrees (Figure 2). Also usually present are perpendicular tumor cell fascicles that extend to the epidermis. It often causes a dome-shaped elevation of the overlying structures, forming a protuberant or polypoid nodule (Figure 3).5,12,18 Tumor cells have pale eosinophilic cytoplasm with plump, elongated nuclei, a thin membrane, and finely granulated chromatin. In the superficial dermis there are ectatic thin-walled vessels that become slitlike in the deep dermis. Mast cells are usually present. Mitotic figures are rare, if present at all, and there is no cytologic atypia. The most pathognomonic feature of this entity is the perinuclear inclusion bodies, which usually are small, round, pale pink bodies on hematoxylin-eosin-stained slides that can indent the nucleus and appear similar to red blood cells (Figure 4). However, these inclusions vary in number, and in rare cases may be absent. (5,12) Tumors with decreased numbers of inclusion bodies often show an increase in fibrosis, and this process is thought to be related to the age of the lesion with younger lesions having more inclusions accompanied by less fibrosis and older lesions having less inclusions with more fibrosis. (19)

ANCILLARY STUDIES

Immunohistochemistry and special stains are very useful when trying to identify an infantile digital fibroma because the inclusions can be easily missed on regular hematoxylineosin staining. The inclusion bodies have been reported to stain best with Masson trichrome and appear bright red against a blue background (Figure 5). They stain deep purple with phosphotungstic and hematoxylin, yellow with elastica van Gieson, and bright red with Lendrum phloxine tartrazine. (20) Actin-related immunohistochemical stains have shown variable staining for the inclusions (Figure 6). (5,12,21) The spindle cells of the lesion typically show cytoplasmic staining for calponin, a-smooth muscle actin, and desmin, and membranous staining for CD99. (5,12,21)

ELECTRON MICROSCOPY

The ultrastructure of the spindle cells shows the presence of discrete bundles of microfilaments that contain many dense bodies that measure between 5 and 7 nm in diameter as well as filaments that are not bundled that measure 10 nm in diameter. The bundles run parallel to the long axis of the cells, appear like microtendons, and have been shown to attach to the cell membrane. (1,20,22) The characteristic feature present in most cells is the electron-dense, non-membrane-bound, spherical inclusions within the cytoplasm. The inclusions measure 1 to 10 nm in diameter and appear to vary in maturity, with the smaller inclusions having an irregular, poorly defined border, and the larger inclusions appearing round and sharply demarcated. (1,20,22) The inner core of the inclusions is composed of tightly packed filaments, which appear amorphous and finely granular, whereas the periphery appears looser and is composed of numerous fine filaments appearing feltlike. The inclusions frequently contain small, lucent membrane-bound vesicles, which resemble cell organelles or could represent entrapped cell organelles. (1,20,22) Fingerlike processes can be seen extending from the inclusions; these processes show the same structure as the bundles of microfilaments and sometimes contain dense bodies. Other features seen in the spindled cells are multiple indentations of the nucleus, abundant cisternae of rough endoplasmic reticulum, a prominent Golgi complex, many pinocytotic vesicles, and no viral particles.

GENETICS

There is no known syndrome or regular genetic abnormality that has been recognized with infantile digital fibromas. However, digitocutaneous dysplasia, also known as osseous terminal dysplasia with pigmentary defects, is a recently described pathology that occurs in young children and is reported to be associated with multiple digital fibromas. It is characterized as a syndrome of X-linked dominant transmission and is lethal in XY embryos. The genetic mutation was discovered by Sun et al (23) in 2010 to be in the FLNA gene when there is skin involvement. However, (the digital fibromas that have been biopsied in) these cases have always lacked the characteristic inclusion bodies, and the spindled cells usually lack immunohistochemical staining for a-smooth muscle actin, leading some to believe it is not the same entity as infantile digital fibroma. (5,24-27)

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of infantile digital fibroma is limited by the fact that it can rarely occur in adults and outside of the digits. In a classical infantile digital fibroma, the differential diagnosis includes infantile (desmoid-type and diffuse-type) fibromatosis, infantile lipofibromatosis, calcifying aponeurotic fibroma, and palmar-plantar fibromatosis. Infantile fibromatosis invades skeletal muscle and is usually present on the head, neck, or thigh. Infantile lipofibromatosis is composed mainly of fat, with spindled cells in fibrous septa and often has small univacuolated cells at the interface between fibroblasts and adipocytes. Calcifying aponeurotic fibroma is a lesion composed of cellular nodules with central chondroid differentiation and calcification. Palmar-plantar fibromatosis is a nodular, cytologically bland fibroproliferative process that involves the palmar or plantar aponeuroses. Infantile digital fibroma mainly differs from these other lesions by being centered in the dermis and exhibiting characteristic perinuclear cytoplasmic inclusion bodies.

TREATMENT

In the past, infantile digital fibroma was thought to be potentially malignant, leading to a more aggressive therapy with surgical excision of the tumor and digital amputation in some cases. (28) However, more recently it has been shown that the tumor does not metastasize and can even spontaneously regress. (5,14,17) These features combined with the high recurrence rate and complications after surgical excision has led to a much more conservative approach when asymptomatic. Many will use a watch and wait method, but others have advocated for some type of injection that may speed along the regression process. Holmes et al (29) compared intralesional corticosteroids, using a total of 0.5 to 2 mL of Triamcinolone, 10 mg/mL per patient under inhalational anaesthesia with further doses given depending on lesion response, to surgical excision. (29) They found that intralesional steroids had a lower recurrence rate with fewer complications, but because of the low patient volume (10 surgical interventions and 7 steroid interventions) the study lacked statistical significance. Oh et al (30) attempted to treat this lesion with 5 monthly intralesional injections of fluorouracil using undiluted fluorouracil (50 mg/dL) with a 30-gauge needle without any local or general anesthesia totaling 10 mg (0.2 mL) of fluorouracil injected at 2 or 3 sites. (30) They found a partial response after just 1 injection and that the lesion eventually regressed entirely after 5 injections, with no recurrence after 2 years. Laskin et al (5) concluded, based on their study involving the largest number of infantile digital fibroma cases, that the best course of action is to have clinical observation after an initial biopsy diagnosis, with additional intervention reserved for lesions causing functional impairment, showing continued growth, or creating cosmetic concerns.

CONCLUSIONS

Infantile digital fibromas are rare benign tumors that can appear worrisome. These lesions typically appear on the second to fifth digits of the hands and feet of children during the first 2 years of life, but they can appear much later and outside of the digits. Microscopically, they usually have pathognomonic inclusion bodies that help identify this lesion as a benign type of fibromatosis. The etiology of the inclusion bodies is, as of yet, unclear, but it is known that they are made up of actin filaments. Treatment options are limited, but the best approach is nonintervention because of their propensity to spontaneously regress and the complications that accompany surgery. However, new intralesional injections appear to be promising for inducing regression.

References

(1.) Bhawan J, Bacchetta C, Joris I, Majno G. A myofibroblasts tumor. Infantile digital fibroma (recurrent digital fibrous tumor of childhood). Am J Pathol. 1979; 94(1):19-36.

(2.) Liu B, Xu ZC, Bao PQ, Hu TZ, Li Y. A case of infantile digital fibromatosis: differential diagnosis and treatment. Int J Dermatol. 2014; 53(1):e16-e18.

(3.) Girgenti V, Restano L, Arcangeli F, Cambiaghi S, Gelmetti C. Infantile digital fibromatosis: a rare tumour of infancy: report of five cases. Australas J Dermatol. 2012; 53(4):285-287.

(4.) Reye RD. Recurring digital fibrous tumors of childhood. Arch Pathol. 1965; 80:228-231.

(5.) Laskin WB, Miettinen M, Fetsch JF. Infantile digital fibroma/fibromatosis: a clinicopathologic and immunohistochemical study of 69 tumors from 57 patients with long-term follow-up. Am J Surg Pathol. 2009; 33(1):1-13.

(6.) Purdy LJ, Colby TV. Infantile digital fibromatosis occurring outside the digit. Am J Surg Pathol. 1984; 8(10):787-790.

(7.) Plusje LG, Bastiaens M, Chang A, Hogendoorn PC. Infantile-type digital fibromatosis tumor in an adult. Br J Dermatol. 2000; 143(5):1107-1108.

(8.) Zhu WY, Xia MY, Huang YF, Leonardi C, Penneys NS. Infantile digital fibromatosis: ultrastructural human papillomavirus and herpes simplex virus DNA observation. Pediatr Dermatol. 1991; 8(2):137-139.

(9.) Mehregan AH, Babai H, Matthews JE. Recurring digital fibrous tumor of childhood. Arch Dermatol. 1972; 106(3):375-378.

(10.) McKenzie AW, Innes FL, RackJM, Breathnach AS, Gross M. Digital fibrous swellings in children. Br J Dermatol. 1970; 83(4):446-458.

(11.) Heymann WR. Infantile digital fibromatosis. J Am Acad Dermatol. 2008; 59(1):122-123.

(12.) Coffin CM, Alaggio R. Fibroblastic and myofibroblastic tumors in children and adolescents. Pediatr Dev Pathol. 2012; 15(suppl 1):127-180.

(13.) Ryman W, Bale P. Recurring digital fibromas of infancy. Australas J Dermatol. 1985; 26(3):113-117.

(14.) Beckett JH, Jacobs AH. Recurring digital fibrous tumors of childhood: a review. Pediatrics. 1977; 59(3):401-406.

(15.) Falco NA, Upton J. Infantile digital fibromas. J Hand Surg Am. 1995; 20(6): 1014-1020.

(16.) O'Gorman DJ. Infantile digital fibromatosis. Proc R Soc Med. 1974; 67(9): 880.

(17.) Niamba P, Leaute-Labreze C, Boralevi F, et al. Further documentation of spontaneous regression of infantile digital fibromatosis. Pediatr Dermatol. 2007; 24(3):280-284.

(18.) Rosenberg HS, Stenback WA, Spjut HJ. The fibromatoses of infancy and childhood. Perspect Pediatr Pathol. 1978; 4:269-348.

(19.) Hayashi T, Tsuda N, Chowdhury PR, et al. Infantile digital fibromatosis: a study of the development and regression of cytoplasmic inclusion bodies. Mod Pathol. 1995; 8(5):548-552.

(20.) Yun K. Infantile digital fibromatosis: immunohistochemical and ultrastructural observations of cytoplasmic inclusions. Cancer. 1988; 61(3):500-507.

(21.) Henderson H, Peng YJ, Salter DM. Anti-calponin 1 antibodies highlight intracytoplasmic inclusions of infantile digital fibromatosis. Histopathology. 2014; 64(5):752-755.

(22.) Iwasaki H, Kikuchi M, Mori R, et al. Infantile digital fibromatosis: ultrastructural, histochemical, and tissue culture observations. Cancer. 1980; 46(10):2238-2247.

(23.) Sun Y, Almomani R, Aten E, et al. Terminal osseous dysplasia is caused by a single recurrent mutation in the FLNA gene. Am J Hum Genet. 2010; 87(1):146-153.

(24.) Bloem JJ, Vuzevski VD, Huffstadt AJ. Recurring digital fibroma of infancy. J Bone Joint Surg Br. 1974; 56B(4):746-751.

(25.) Drut R, Pedemonte L, Rositto A. Noninclusion-body infantile digital fibromatosis; a lesion heralding terminal osseous dysplasia and pigmentary defects syndrome. Int J Surg Pathol. 2005; 13(2):181-184.

(26.) Horii E, Sugiura Y, Nakamura R. A syndrome of digital fibromas, facial pigmentary dysplasia, and metacarpal and metatarsal disorganization. Am J Med Genet. 1998; 80(1):1-5.

(27.) Cabrera Gonzalez M, Perez Lopez LM, Gutierrez de la Iglesia D, Rovira Zurriaga C, Martorell Sampol L, Gonzalez EnsenatA. Diagnosis and treatment of digitocutaneous dysplasia, a rare infantile digital fibromatosis: a case report. Hand (N Y). 2013; 8(4):473-478.

(28.) Dabney KW, MacEwen GD, Davis NE. Recurring digital fibrous tumor of childhood: case report with long-term follow-up and review of the literature. J Pediatr Orthop. 1986; 6(5):612-617.

(29.) Holmes WJ, Mishra A, McArthur P. Intra-lesional steroid for the management of symptomatic infantile digital fibromatosis. J Plast Reconstr Aesthet Surg. 2011; 64(5):632-637.

(30.) Oh CK, Son HS, Kwon YW, Jang HS, Kwon KS. Intralesional fluorouracil injection in infantile digital fibromatosis. Arch Dermatol. 2005; 141(5):549-550.

Etan Marks, DO; Michelle Ewart, MD

Accepted for publication January 11, 201 6.

From the Department of Pathology, Montefiore Medical Center/ Albert Einstein College of Medicine, Bronx, New York.

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Etan Marks, DO, Department of Pathology, Montefiore Medical Center/Albert Einstein College of Medicine, 111 E 210th St, Bronx, NY 10467 (email: emarks@montefiore.org).

Please Note: Illustration(s) are not available due to copyright restrictions.

Caption: Figure 1. Clinical picture of infantile digital fibroma.

Caption: Figure 2. Low-power image showing extensive fibromatosis in infantile digital fibroma (hematoxylin-eosin, original magnification X10).

Caption: Figure 3. Infantile digital fibroma forming protuberant nodule (hematoxylin-eosin, original magnification X2).

Caption: Figure 4. Higher magnification of the protuberant nodule shown in Figure 3 demonstrating red, round inclusion bodies (hematoxylin-eosin, original magnification X40).

Caption: Figure 5. Accentuating red round inclusion bodies (Masson trichrome, original magnification X40).

Caption: Figure 6. Smooth muscle actin, highlighting round inclusion bodies (original magnification X20).
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Author:Marks, Etan; Ewart, Michelle
Publication:Archives of Pathology & Laboratory Medicine
Date:Oct 1, 2016
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