Pediatric Dermatology Vol. 31 No. 3 298–304, 2014
Lipofibromatosis: An Institutional and Literature Review of an Uncommon Entity Markus D. Boos, M.D., Ph.D.,*,†,‡ Kudakwashe R. Chikwava, M.D.,§ John P. Dormans, M.D.,¶,** Nancy A. Chauvin, M.D.,††,‡‡ and Melinda Jen, M.D.*,†,‡ *Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, †Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, ‡Section of Dermatology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, §Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, ¶Department of Orthopedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, **Department of Orthopedic Surgery, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, ††Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, ‡‡Division of Radiology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania,
Abstract: We report six new cases of lipofibromatosis, an uncommon pediatric soft tissue neoplasm. This is the only series of patients to be described since the initial case series of 45 patients that characterized this entity in 2000. The purpose of this study was to characterize the presentation of lipofibromatosis to further define the clinical phenotype of this rare entity. Six patients were diagnosed with lipofibromatosis at our institution from 2000 to 2012. Patient age, sex, and ethnicity were recorded, along with tumor site and size, management, and recurrence data. Half of our patients were younger than 2 years old at presentation and the other half were school age. Boys and girls were affected with equal frequency. In five of six patients, lipofibromatosis presented in its “classic” form as a mass on the distal extremities. These tumors typically measured 1 to 2 cm in diameter, in contrast to case reports in the medical literature highlighting the occurrence of lipofibromatosis of greater size and at varied anatomic sites. The tumors in our series were managed using excision, with recurrence noted in 33%. Lipofibromatosis is an uncommon tumor typically found on the distal extremities of infants, although it can appear in various sizes and locations. It should be considered in the differential diagnosis of pediatric soft tissue neoplasms.
Lipofibromatosis is a rare pediatric neoplasm that was first described in 2000 (1). This soft tissue tumor presents from birth to childhood as an asymptomatic,
slowly growing subcutaneous mass on the distal extremities. Although benign, lipofibromatosis is often locally destructive. Herein we report a case of
Address correspondence to Melinda Jen, M.D., Children’s Hospital of Philadelphia, 3550 Market Street, 2nd Floor, Philadelphia, PA 19104, or e-mail: [email protected]. DOI: 10.1111/pde.12335
298
© 2014 Wiley Periodicals, Inc.
Boos et al: Lipofibromatosis: A Review
A
299
B
Figure 1. A 5-cm 9 5-cm subcutaneous nodule without overlying skin change was present on the right distal forearm (arrows): (A) dorsal view, (B) ventral view.
congenital lipofibromatosis and review the clinical features of six additional cases treated at our institution. By presenting the clinical, radiologic, and histologic characteristics of lipofibromatosis, we further characterize the clinical appearance and course of this entity while raising awareness of it among dermatologists. CASE REPORT A 2-month-old healthy girl presented with an asymptomatic, stable, congenital mass on her right forearm. Physical examination at presentation revealed a 5-cm 9 5-cm rubbery, nontender subcutaneous nodule fixed to the underlying bone on the ulnar aspect of the right distal forearm (Fig. 1). No overlying skin change, warmth, thrill, bruits, or pulsations were noted. Imaging was performed to characterize the lesion. Plain radiograph of the arm showed a radiolucent mass without evidence of calcification (Fig. 2). Magnetic resonance imaging (MRI) with and without contrast demonstrated a well-demarcated mass with internal septations that did not involve the surrounding musculature. The mass was hyperintense on T1and T2-weighted imaging and isointense with the adjacent subcutaneous fat (Fig. 3), suggestive of a lipoma or lipoblastoma. The patient was referred to plastic surgery for excision. Histologic examination revealed an unencapsulated lesion composed of lobules of adipose tissue admixed with streaks of thin to thick fibrous trabeculae. These fibrous strands were composed of benign-appearing spindle cells, with rare foci of myxoid areas. The adipose tissue contained mature adipocytes of varying sizes (Fig. 4). Lipoblasts, fat necrosis, immature mesenchymal tissue, and
Figure 2. Lateral radiograph of the right forearm. Along the posteromedial aspect of the distal forearm there is a focal mass (arrows) that demonstrates the same density as the adjacent subcutaneous fat (F). This mass contacts the ulna (*) without evidence of periosteal reaction or deformity of the bone.
arborizing vessels were not seen. These findings were consistent with a diagnosis of lipofibromatosis. Thirteen months after surgery the lesion had not recurred.
300 Pediatric Dermatology Vol. 31 No. 3 May/June 2014
A
Figure 3. Coronal T1-weighted image of the right forearm. There is a well-marginated ovoid mass (arrows) within the subcutaneous fat of the distal forearm. This mass is the same signal intensity as the subcutaneous fat (F). There are a few internal thin, dark septations (arrowheads). The mass abuts the ulna (*).
METHODS After institutional review board approval, the Children’s Hospital of Philadelphia pathology department records from January 1, 2000, to June 1, 2012, were queried for a diagnosis of lipofibromatosis. Cases were included if patients were younger than 19 years of age at diagnosis. Cases were excluded if the histologic diagnosis of lipofibromatosis was considered among other entities and was not definitive. All identified cases of lipofibromatosis had their pathology reviewed and the histologic diagnosis confirmed before inclusion in the study. Clinical, radiologic, and histologic information was extracted from the patients’ medical records. RESULTS Six cases of lipofibromatosis were identified at the Children’s Hospital of Philadelphia from 2000 to 2012 (Table 1) with follow-up of 7 months to 6 years. There were an equal number of boys and girls. Patients ranged in age from 2 months to 9 years at the time of presentation. The extremities were the most commonly involved site, with 83% located on
B
C
Figure 4. (A) Lobules of mature adipocytes are admixed with streaks of thin to thick fibrous trabeculae (hematoxylin and eosin [H&E] stain, 259). (B) Fibrous strands contain benign-appearing spindle cells with rare foci of myxoid areas (H&E, 1009). (C) Small, grouped, univacuolated cells are noted at sites of transition from fibroblast to adipose tissue (H&E, 2009).
the distal extremities and one lesion on the chin. The majority of tumors were approximately 1 to 2 cm in diameter. When noted, the lesions were asymptomatic
Boos et al: Lipofibromatosis: A Review
301
TABLE 1. Clinical Characteristics of Six Patients at the Children’s Hospital of Philadelphia with a Diagnosis of Lipofibromatosis Patient
Age
Sex
Ethnicity
Site
Duration
Size, cm*
Management
Recurrence
1
9 yrs
Female
Caucasian
Not reported
1.8 9 1.0 9 0.4
Excision
No (6 yrs PO)
2
9 yrs
Male
Caucasian
Right fourth digit Right ankle
Several months
1.7 9 1.8 9 2.0
No (3 yrs PO)
3
6 mos
Female
Caucasian
2 yrs 2 mos 7 yrs 2 mos
Male
Caucasian
6 mos (congenital) 2 mos
0.7 9 0.6 9 0.3
4
Right third digit Chin
Biopsy followed by excision Excision
1.0 9 0.8 9 0.5
Excision
Yes (15 mos PO)
Male Female
Caucasian African American
Right third digit Right distal forearm
2 mos 2 mos (congenital)
1.0 9 0.9 9 0.4 3.3 9 2.2 9 1.5
Excision Excision
Yes (7 mos PO) No (13 mos PO)
5 6†
No (5 yrs PO)‡
PO, postoperative. *Size was based on estimates made on magnetic resonance imaging; in cases in which imaging was not performed, the size of the excised specimen was used as a best approximation. †Patient is described in accompanying case report. ‡Patient had regrowth of a mass 13 mos postoperatively that was noted to be a traumatic neuroma upon excision. The specimen bore no histologic resemblance to the original lipofibromatous lesion.
or moderately painful after manipulation. All cases were treated using surgical excision, with tumor recurrence noted in two patients 7 and 15 months after primary excision. The other four patients remained disease free 13 months to 6 years after excision. DISCUSSION Lipofibromatosis (nondesmoid-type infantile fibromatosis) is a rare pediatric soft tissue neoplasm occurring in the subcutis and deep soft tissues (2). Fetsch et al (1) first described this entity as a series of 45 cases that had been classified as other soft tissue neoplasms. This initial series characterized lipofibromatosis as a solitary, firm, poorly demarcated, nontender, skincolored, subcutaneous nodule on the extremities, particularly the hands and feet, with a majority of tumors being 1 to 3 cm in diameter. The median age of onset was 1 year, with the majority of cases presenting before 3 years of age and 18% of patients presenting with congenital lesions. Boys were more commonly affected than girls, at a ratio of 2.7:1 (1). Clinical findings from our series of six patients support many of these characteristics of lipofibromatosis. Specifically, the majority of our patients had neoplasms on their extremities measuring 1 to 2 cm in diameter. Although half of our sample population was diagnosed before 2 years of age, the remaining half were school-age children (7–9 years old), corresponding to a smaller group of similarly aged patients in the original series (Table 1) (1). In contrast, the male-to-female ratio in our cohort was 1:1. Since the original series by Fetsch et al, 14 other cases of lipofibromatosis have been reported in the literature
(Table 2). Aggregate analysis of the 14 case reports of lipofibromatosis (Table 2) reflect an equal incidence between boys (57%) and girls (43%). These findings suggest that the male predominance of lipofibromatosis may be overstated. Of the additional 14 reported cases of lipofibromatosis, 6 were found at “classic” sites on the extremities, but the remainder presented at atypical locations, including the neck, orbit, back, and chin (3– 8) (Table 2). Many of these tumors were of significant size, being larger than 5 cm, with three instances of diffuse limb involvement (9–11). The overrepresentation of these large tumors in atypical locations in the medical literature may reflect a reporting bias. The clinical differential diagnosis of lipofibromatosis is broad (Table 3). Tumor appearance and site of involvement may provide a clue to differentiation among these diagnoses. Lipoblastoma and calcifying aponeurotic fibroma (CAF) often present as slowgrowing nodules on the extremities. Whereas lipoblastomas are soft, mobile masses, CAF is firm and fixed on the hands and feet (12,14). In contrast, myofibromas typically present as solitary, purplehued nodules of the head and neck, whereas fibrous hamartoma of infancy presents as soft, painless, solitary nodules, occasionally with hypertrichosis, in the axillae, proximal upper extremities, or groin (14). Lipofibromatous hamartoma is an intraneural tumor typically involving peripheral nerves of the distal (preferentially upper) extremities, but is frequently associated with digital enlargement or macrodactyly (15). It usually presents during the third decade of life (15). In diffuse lipofibromatosis involving an entire limb, vascular anomalies such as venolymphatic malformations should be considered (10,11).
1 day
2 wks
4 mos
10 mos
15 mos
16 mos
19 mos
21 mos
2 yrs
2 yrs 7 mos
8 yrs
8 yrs
8 yrs
14 yrs
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Female
Female
Female
Male
Male
Female
Male
Male
Female
Male
Male
Male
Male
Female
Sex
NR
NR
NR
NR
Caucasian
NR
Asian
Caucasian
NR
NR
NR
NR
Caucasian
Asian
Ethnicity
Right posterior neck Superolateral left orbit Back
Neck
Left iliac crest
Right plantar foot
Right submental
Right knee
Left scapula
Right forearm
Right upper extremity Right distal lower extremity Right lower extremity Left foot
Site
Several years
Several years
Approximately 2 yrs Approximately 8 yrs* At least 4 yrs†
9 mos
19 mos (congenital) 8 mos
6 wks
1 day (congenital) 2 wks (congenital) 4 mos (congenital) 10 mos (congenital) 5 mos
Duration
Excision Excision (incomplete) Biopsy followed by excision (incomplete) Excision (complete) Excision (incomplete) Excision Excision Excision (incomplete)/ debulking Excision (incomplete) Excision
3.3 9 3.0 9 0.7 2.2 9 1.7 9 1.0 9.3 9 3.8 9 5.8
Approximately 4.0 9 3.0 7.0 9 3.2 9 4.1 2.5 9 2.0 9 4.7 5.0 9 6.0 9 9.0
4.0 9 3.0 9 3.0
5.5 9 3.2 9 2.0
2.0 9 1.0 9 1.0
7.0 9 1.0
NR
Approximately 10.0 9 7.0
Management‡ Excision (incomplete)/ debulking Correction of bony limb deformity/observation Biopsy followed by observation Excision (incomplete)
NR
Size, cm
None (15 mos PO)
None (18 mos PO)
Yes† (1 yr PO)
NR
NR
Yes (8 mos PO)
None (2 yrs PO)
NR
NR
None (1 yr PO)
NR
N/A
N/A
None (3 yrs PO)
Recurrence
Teo et al (11) Joseph et al (9) Greene et al (10) Deepti et al (13) Sasaki et al (16) Walton et al (3) Costa Dias et al (12) Kabasawa et al (4) Sari et al (18) Kenney et al (2) Taran et al (5) Herrmann et al (8) Nuruddin et al (6) Ayadi et al (7)
Reference
NR, not reported; N/A, not applicable; PO, postoperative. *The mass was first clinically evident at 2 mos of age. †This report represents management of a recurrent lesion previously diagnosed as a hamartoma of infancy. Recurrence occurred after an initial debulking, but not after a subsequent complete reexcision. ‡Excisions are specified as complete or incomplete only if clearly noted in the publication. Otherwise the type of excision is not specified.
Age
Patient
TABLE 2. Clinical Characteristics of 14 Case Reports of Lipofibromatosis in the Medical Literature
302 Pediatric Dermatology Vol. 31 No. 3 May/June 2014
Boos et al: Lipofibromatosis: A Review
TABLE 3. Clinical Differential Diagnosis for Lipofibromatosis Calcifying aponeurotic fibroma Fibrous hamartoma of infancy Juvenile fibromatosis Lipoblastoma Lipofibromatous hamartoma Lipoma Macrocystic lymphatic malformation Myofibroma Rhabdomyosarcoma
Imaging can help distinguish lipofibromatosis from other entities. Ultrasound is a useful initial screen to determine whether the lesion is of vascular origin. On ultrasound, lipofibromatosis presents as a nonspecific hyperechoic mass suggestive of a fat-containing lesion (3). Plain radiographs are also often nonspecific, with subcutaneous opacities causing local distortion (Fig. 2) (13,16). MRI is the imaging modality of choice (3,10,13,16). A variably defined mass with hyperintense signaling that is isointense to fat on T1- and T2weighted imaging is typically seen on MRI (Fig. 3) (3,13), although these signals may vary if there is a prominent myxoid infiltrate within the adipose tissue (11,13). Enhancement with gadolinium is minimal, reflecting the low vascularity of the neoplasm (3). Ultimately MRI cannot definitively diagnose lipofibromatosis, but it can exclude other diagnoses and assist in preoperative planning (3). A diagnosis of lipofibromatosis can only be made histologically. The classic histologic appearance of lipofibromatosis is one of adipose tissue constituting at least 50% of the tumor separated into lobules by fascicles of spindled fibroblasts or myofibroblasts (Fig. 4A, B) (1,11,13). This fibroblastic tissue sometimes contains small amounts of collagen or evidence of myxoid change (1). Although lipofibromatosis can envelop regional structures such as skeletal muscle, nerves, and blood vessels, mitoses and nuclear pleomorphism are uncommon, and cytologic atypia, if present, is mild (1). Rarely, scattered pigmented cells can also be found in the fat septae (1,7,11). A common finding in lipofibromatosis is the presence of small, grouped, univacuolated cells found at sites of transition from fibroblast to adipose tissue (Fig. 4C). These are thought to be degenerating adipocytes or lipidrich fibroblasts (1). Immunohistochemistry is not required to establish the diagnosis, but spindled cells may demonstrate focal CD99 and CD34 positivity, whereas S100 highlights adipocytes (1,4,5,16). Expression of connective tissue growth factor (CCN2) is greater in the fibroblastic component of
303
lipofibromatosis (4,17), and cytogenetics from a case of lipofibromatosis demonstrate a balanced three-way translocation designated t(4,6,9)(q21;q22;q2?4) (2). Because CCN2 is located on chromosome 6q23.1, its role in the pathogenesis of lipofibromatosis warrants further investigation. The histologic differential diagnosis for lipofibromatosis includes fibrous hamartoma of infancy, CAF, juvenile fibromatosis, and lipoblastoma. Given the histologic overlap with these other pediatric soft tissue tumors, incisional or excisional biopsy specimens are preferred to provide adequate tissue for diagnosis. Lipofibromatosis has no known metastatic potential (1) but may exhibit progressive, infiltrative local growth and recurrence. It can become locally destructive and may be of cosmetic or functional significance (9–12). The gold standard of therapy is complete surgical resection, although modalities such as radiation have been attempted as adjunct therapy (1). In instances in which the lesion is diffusely infiltrative, partial resection with the lowest potential postoperative morbidity is recommended (1,12,13,18). Fetsch et al (1) reported male sex, presence at birth, incomplete excision, presence on the hands and feet, and mitotic activity on histology as predisposing factors for recurrence. In our series, both patients exhibiting tumor recurrence were male, but the two patients with congenital lipofibromatosis remain disease free (Table 1). One of the recurrences in our series was located on the chin, and four of the five tumors located on the distal extremities did not recur. The risk factors for recurrence are unknown and families should be counseled accordingly. In summary, lipofibromatosis is a rare pediatric soft tissue neoplasm that is commonly characterized by slow growth and local invasion. Although traditionally thought of as a 1- to 2-cm mass found on the distal extremities of boys, our study indicates that girls may be more frequently affected than previously appreciated. A variety of anatomic sites and sizes may also be seen in this process. It should be considered in the differential diagnosis of soft tissue tumors of childhood. CONFLICTS OF INTEREST JPD is a consultant for Shriner’s International Medical Advisory Board. He has received royalties from Elsevier, Mosby, and Brooke’s Publishing for services as an editor of medical textbooks. None of JPD’s interests are directly related to the diagnosis, management, or treatment of any condition discussed in this manuscript.
304 Pediatric Dermatology Vol. 31 No. 3 May/June 2014
REFERENCES 1. Fetsch JF, Miettinen M, Laskin WB et al. A clinicopathologic study of 45 pediatric soft tissue tumors with an admixture of adipose tissue and fibroblastic elements, and a proposal for classification as lipofibromatosis. Am J Surg Pathol 2000;24:1491–1500. 2. Kenney B, Richkind KE, Friedlaende G et al. Chromosomal rearrangements in lipofibromatosis. Cancer Genet Cytogenet 2007;179:136–139. 3. Walton JR, Green BA, Donaldson MM et al. Imaging characteristics of lipofibromatosis presenting as a shoulder mass in a 16-month-old girl. Pediatr Radiol 2010;40:43–46. 4. Kabasawa Y, Katsube K, Harada H et al. A male infant case of lipofibromatosis in the submental region exhibited the expression of the connective tissue growth factor. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:677–682. 5. Taran K, Woszczyk M, Kobos J. Lipofibromatosis presenting as a neck mass in eight-years old boy—a case report. Pol J Pathol 2008;59:217–220. 6. Nuruddin M, Osmani M, Mudhar HS et al. Orbital lipofibromatosis in a child: a case report. Orbit 2010;29:360–362. 7. Ayadi L, Charfi S, Ben Hamed Y et al. Pigmented lipofibromatosis in unusual location: case report and review of the literature. Virchows Arch 2008;452:465–467. 8. Herrmann BW, Dehner LP, Forsen JW. Lipofibromatosis presenting as a pediatric neck mass. Int J Pediatr Otorhinolaryngol 2004;68:1545–1549.
9. Joseph G, Zenios M. Congenital bowing of the tibia due to infantile lipofibromatosis corrected with a Taylor Spatial Frame. Musculoskelet Surg 2012 Dec 11 [Epub ahead of print]. 10. Greene AK, Karnes J, Padua HM et al. Diffuse lipofibromatosis of the lower extremity masquerading as a vascular anomaly. Ann Plast Surg 2009;62:703–706. 11. Teo HEL, Peh WCG, Chan M-Y et al. Infantile lipofibromatosis of the upper limb. Skeletal Radiol 2005;34:799–802. 12. Costa Dias S, McHugh K, Sebire NJ et al. Lipofibromatosis of the knee in a 19-month-old child. J Pediatr Surg 2012;47:1028–1031. 13. Deepti AN, Madhuri V, Walter NM et al. Lipofibromatosis: report of a rare paediatric soft tissue tumour. Skeletal Radiol 2008;37:555–558. 14. Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology. Philadelphia: Elsevier Saunders, 2012. 15. Razzaghi A, Anastakis DJ. Lipofibromatous hamartoma: review of early diagnosis and treatment. Can J Surg 2005;48:394–399. 16. Sasaki D, Hatori M, Hosaka M et al. Lipofibromatosis arising in a pediatric forearm—a case report. Ups J Med Sci 2005;110:259–266. 17. Leask A, Parapuram SK, Shi-wen X et al. J. Connective tissue growth factor (CTGF, CCN2) gene regulation: a potent clinical bio-marker of fibroproliferative disease? J Cell Commun Signal 2009;3:89–94. 18. Sari A, Tunakan M, Bolat B et al. Lipofibromatosis in a two-year-old girl: a case report. Turk J Pediatr 2007;49:319–321.
Lipofibromatosis: An Institutional and Literature Review of an Uncommon Entity Markus D. Boos, M.D., Ph.D.,*,†,‡ Kudakwashe R. Chikwava, M.D.,§ John P. Dormans, M.D.,¶,** Nancy A. Chauvin, M.D.,††,‡‡ and Melinda Jen, M.D.*,†,‡ *Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, †Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, ‡Section of Dermatology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, §Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, ¶Department of Orthopedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, **Department of Orthopedic Surgery, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, ††Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, ‡‡Division of Radiology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania,
Abstract: We report six new cases of lipofibromatosis, an uncommon pediatric soft tissue neoplasm. This is the only series of patients to be described since the initial case series of 45 patients that characterized this entity in 2000. The purpose of this study was to characterize the presentation of lipofibromatosis to further define the clinical phenotype of this rare entity. Six patients were diagnosed with lipofibromatosis at our institution from 2000 to 2012. Patient age, sex, and ethnicity were recorded, along with tumor site and size, management, and recurrence data. Half of our patients were younger than 2 years old at presentation and the other half were school age. Boys and girls were affected with equal frequency. In five of six patients, lipofibromatosis presented in its “classic” form as a mass on the distal extremities. These tumors typically measured 1 to 2 cm in diameter, in contrast to case reports in the medical literature highlighting the occurrence of lipofibromatosis of greater size and at varied anatomic sites. The tumors in our series were managed using excision, with recurrence noted in 33%. Lipofibromatosis is an uncommon tumor typically found on the distal extremities of infants, although it can appear in various sizes and locations. It should be considered in the differential diagnosis of pediatric soft tissue neoplasms.
Lipofibromatosis is a rare pediatric neoplasm that was first described in 2000 (1). This soft tissue tumor presents from birth to childhood as an asymptomatic,
slowly growing subcutaneous mass on the distal extremities. Although benign, lipofibromatosis is often locally destructive. Herein we report a case of
Address correspondence to Melinda Jen, M.D., Children’s Hospital of Philadelphia, 3550 Market Street, 2nd Floor, Philadelphia, PA 19104, or e-mail: [email protected]. DOI: 10.1111/pde.12335
298
© 2014 Wiley Periodicals, Inc.
Boos et al: Lipofibromatosis: A Review
A
299
B
Figure 1. A 5-cm 9 5-cm subcutaneous nodule without overlying skin change was present on the right distal forearm (arrows): (A) dorsal view, (B) ventral view.
congenital lipofibromatosis and review the clinical features of six additional cases treated at our institution. By presenting the clinical, radiologic, and histologic characteristics of lipofibromatosis, we further characterize the clinical appearance and course of this entity while raising awareness of it among dermatologists. CASE REPORT A 2-month-old healthy girl presented with an asymptomatic, stable, congenital mass on her right forearm. Physical examination at presentation revealed a 5-cm 9 5-cm rubbery, nontender subcutaneous nodule fixed to the underlying bone on the ulnar aspect of the right distal forearm (Fig. 1). No overlying skin change, warmth, thrill, bruits, or pulsations were noted. Imaging was performed to characterize the lesion. Plain radiograph of the arm showed a radiolucent mass without evidence of calcification (Fig. 2). Magnetic resonance imaging (MRI) with and without contrast demonstrated a well-demarcated mass with internal septations that did not involve the surrounding musculature. The mass was hyperintense on T1and T2-weighted imaging and isointense with the adjacent subcutaneous fat (Fig. 3), suggestive of a lipoma or lipoblastoma. The patient was referred to plastic surgery for excision. Histologic examination revealed an unencapsulated lesion composed of lobules of adipose tissue admixed with streaks of thin to thick fibrous trabeculae. These fibrous strands were composed of benign-appearing spindle cells, with rare foci of myxoid areas. The adipose tissue contained mature adipocytes of varying sizes (Fig. 4). Lipoblasts, fat necrosis, immature mesenchymal tissue, and
Figure 2. Lateral radiograph of the right forearm. Along the posteromedial aspect of the distal forearm there is a focal mass (arrows) that demonstrates the same density as the adjacent subcutaneous fat (F). This mass contacts the ulna (*) without evidence of periosteal reaction or deformity of the bone.
arborizing vessels were not seen. These findings were consistent with a diagnosis of lipofibromatosis. Thirteen months after surgery the lesion had not recurred.
300 Pediatric Dermatology Vol. 31 No. 3 May/June 2014
A
Figure 3. Coronal T1-weighted image of the right forearm. There is a well-marginated ovoid mass (arrows) within the subcutaneous fat of the distal forearm. This mass is the same signal intensity as the subcutaneous fat (F). There are a few internal thin, dark septations (arrowheads). The mass abuts the ulna (*).
METHODS After institutional review board approval, the Children’s Hospital of Philadelphia pathology department records from January 1, 2000, to June 1, 2012, were queried for a diagnosis of lipofibromatosis. Cases were included if patients were younger than 19 years of age at diagnosis. Cases were excluded if the histologic diagnosis of lipofibromatosis was considered among other entities and was not definitive. All identified cases of lipofibromatosis had their pathology reviewed and the histologic diagnosis confirmed before inclusion in the study. Clinical, radiologic, and histologic information was extracted from the patients’ medical records. RESULTS Six cases of lipofibromatosis were identified at the Children’s Hospital of Philadelphia from 2000 to 2012 (Table 1) with follow-up of 7 months to 6 years. There were an equal number of boys and girls. Patients ranged in age from 2 months to 9 years at the time of presentation. The extremities were the most commonly involved site, with 83% located on
B
C
Figure 4. (A) Lobules of mature adipocytes are admixed with streaks of thin to thick fibrous trabeculae (hematoxylin and eosin [H&E] stain, 259). (B) Fibrous strands contain benign-appearing spindle cells with rare foci of myxoid areas (H&E, 1009). (C) Small, grouped, univacuolated cells are noted at sites of transition from fibroblast to adipose tissue (H&E, 2009).
the distal extremities and one lesion on the chin. The majority of tumors were approximately 1 to 2 cm in diameter. When noted, the lesions were asymptomatic
Boos et al: Lipofibromatosis: A Review
301
TABLE 1. Clinical Characteristics of Six Patients at the Children’s Hospital of Philadelphia with a Diagnosis of Lipofibromatosis Patient
Age
Sex
Ethnicity
Site
Duration
Size, cm*
Management
Recurrence
1
9 yrs
Female
Caucasian
Not reported
1.8 9 1.0 9 0.4
Excision
No (6 yrs PO)
2
9 yrs
Male
Caucasian
Right fourth digit Right ankle
Several months
1.7 9 1.8 9 2.0
No (3 yrs PO)
3
6 mos
Female
Caucasian
2 yrs 2 mos 7 yrs 2 mos
Male
Caucasian
6 mos (congenital) 2 mos
0.7 9 0.6 9 0.3
4
Right third digit Chin
Biopsy followed by excision Excision
1.0 9 0.8 9 0.5
Excision
Yes (15 mos PO)
Male Female
Caucasian African American
Right third digit Right distal forearm
2 mos 2 mos (congenital)
1.0 9 0.9 9 0.4 3.3 9 2.2 9 1.5
Excision Excision
Yes (7 mos PO) No (13 mos PO)
5 6†
No (5 yrs PO)‡
PO, postoperative. *Size was based on estimates made on magnetic resonance imaging; in cases in which imaging was not performed, the size of the excised specimen was used as a best approximation. †Patient is described in accompanying case report. ‡Patient had regrowth of a mass 13 mos postoperatively that was noted to be a traumatic neuroma upon excision. The specimen bore no histologic resemblance to the original lipofibromatous lesion.
or moderately painful after manipulation. All cases were treated using surgical excision, with tumor recurrence noted in two patients 7 and 15 months after primary excision. The other four patients remained disease free 13 months to 6 years after excision. DISCUSSION Lipofibromatosis (nondesmoid-type infantile fibromatosis) is a rare pediatric soft tissue neoplasm occurring in the subcutis and deep soft tissues (2). Fetsch et al (1) first described this entity as a series of 45 cases that had been classified as other soft tissue neoplasms. This initial series characterized lipofibromatosis as a solitary, firm, poorly demarcated, nontender, skincolored, subcutaneous nodule on the extremities, particularly the hands and feet, with a majority of tumors being 1 to 3 cm in diameter. The median age of onset was 1 year, with the majority of cases presenting before 3 years of age and 18% of patients presenting with congenital lesions. Boys were more commonly affected than girls, at a ratio of 2.7:1 (1). Clinical findings from our series of six patients support many of these characteristics of lipofibromatosis. Specifically, the majority of our patients had neoplasms on their extremities measuring 1 to 2 cm in diameter. Although half of our sample population was diagnosed before 2 years of age, the remaining half were school-age children (7–9 years old), corresponding to a smaller group of similarly aged patients in the original series (Table 1) (1). In contrast, the male-to-female ratio in our cohort was 1:1. Since the original series by Fetsch et al, 14 other cases of lipofibromatosis have been reported in the literature
(Table 2). Aggregate analysis of the 14 case reports of lipofibromatosis (Table 2) reflect an equal incidence between boys (57%) and girls (43%). These findings suggest that the male predominance of lipofibromatosis may be overstated. Of the additional 14 reported cases of lipofibromatosis, 6 were found at “classic” sites on the extremities, but the remainder presented at atypical locations, including the neck, orbit, back, and chin (3– 8) (Table 2). Many of these tumors were of significant size, being larger than 5 cm, with three instances of diffuse limb involvement (9–11). The overrepresentation of these large tumors in atypical locations in the medical literature may reflect a reporting bias. The clinical differential diagnosis of lipofibromatosis is broad (Table 3). Tumor appearance and site of involvement may provide a clue to differentiation among these diagnoses. Lipoblastoma and calcifying aponeurotic fibroma (CAF) often present as slowgrowing nodules on the extremities. Whereas lipoblastomas are soft, mobile masses, CAF is firm and fixed on the hands and feet (12,14). In contrast, myofibromas typically present as solitary, purplehued nodules of the head and neck, whereas fibrous hamartoma of infancy presents as soft, painless, solitary nodules, occasionally with hypertrichosis, in the axillae, proximal upper extremities, or groin (14). Lipofibromatous hamartoma is an intraneural tumor typically involving peripheral nerves of the distal (preferentially upper) extremities, but is frequently associated with digital enlargement or macrodactyly (15). It usually presents during the third decade of life (15). In diffuse lipofibromatosis involving an entire limb, vascular anomalies such as venolymphatic malformations should be considered (10,11).
1 day
2 wks
4 mos
10 mos
15 mos
16 mos
19 mos
21 mos
2 yrs
2 yrs 7 mos
8 yrs
8 yrs
8 yrs
14 yrs
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Female
Female
Female
Male
Male
Female
Male
Male
Female
Male
Male
Male
Male
Female
Sex
NR
NR
NR
NR
Caucasian
NR
Asian
Caucasian
NR
NR
NR
NR
Caucasian
Asian
Ethnicity
Right posterior neck Superolateral left orbit Back
Neck
Left iliac crest
Right plantar foot
Right submental
Right knee
Left scapula
Right forearm
Right upper extremity Right distal lower extremity Right lower extremity Left foot
Site
Several years
Several years
Approximately 2 yrs Approximately 8 yrs* At least 4 yrs†
9 mos
19 mos (congenital) 8 mos
6 wks
1 day (congenital) 2 wks (congenital) 4 mos (congenital) 10 mos (congenital) 5 mos
Duration
Excision Excision (incomplete) Biopsy followed by excision (incomplete) Excision (complete) Excision (incomplete) Excision Excision Excision (incomplete)/ debulking Excision (incomplete) Excision
3.3 9 3.0 9 0.7 2.2 9 1.7 9 1.0 9.3 9 3.8 9 5.8
Approximately 4.0 9 3.0 7.0 9 3.2 9 4.1 2.5 9 2.0 9 4.7 5.0 9 6.0 9 9.0
4.0 9 3.0 9 3.0
5.5 9 3.2 9 2.0
2.0 9 1.0 9 1.0
7.0 9 1.0
NR
Approximately 10.0 9 7.0
Management‡ Excision (incomplete)/ debulking Correction of bony limb deformity/observation Biopsy followed by observation Excision (incomplete)
NR
Size, cm
None (15 mos PO)
None (18 mos PO)
Yes† (1 yr PO)
NR
NR
Yes (8 mos PO)
None (2 yrs PO)
NR
NR
None (1 yr PO)
NR
N/A
N/A
None (3 yrs PO)
Recurrence
Teo et al (11) Joseph et al (9) Greene et al (10) Deepti et al (13) Sasaki et al (16) Walton et al (3) Costa Dias et al (12) Kabasawa et al (4) Sari et al (18) Kenney et al (2) Taran et al (5) Herrmann et al (8) Nuruddin et al (6) Ayadi et al (7)
Reference
NR, not reported; N/A, not applicable; PO, postoperative. *The mass was first clinically evident at 2 mos of age. †This report represents management of a recurrent lesion previously diagnosed as a hamartoma of infancy. Recurrence occurred after an initial debulking, but not after a subsequent complete reexcision. ‡Excisions are specified as complete or incomplete only if clearly noted in the publication. Otherwise the type of excision is not specified.
Age
Patient
TABLE 2. Clinical Characteristics of 14 Case Reports of Lipofibromatosis in the Medical Literature
302 Pediatric Dermatology Vol. 31 No. 3 May/June 2014
Boos et al: Lipofibromatosis: A Review
TABLE 3. Clinical Differential Diagnosis for Lipofibromatosis Calcifying aponeurotic fibroma Fibrous hamartoma of infancy Juvenile fibromatosis Lipoblastoma Lipofibromatous hamartoma Lipoma Macrocystic lymphatic malformation Myofibroma Rhabdomyosarcoma
Imaging can help distinguish lipofibromatosis from other entities. Ultrasound is a useful initial screen to determine whether the lesion is of vascular origin. On ultrasound, lipofibromatosis presents as a nonspecific hyperechoic mass suggestive of a fat-containing lesion (3). Plain radiographs are also often nonspecific, with subcutaneous opacities causing local distortion (Fig. 2) (13,16). MRI is the imaging modality of choice (3,10,13,16). A variably defined mass with hyperintense signaling that is isointense to fat on T1- and T2weighted imaging is typically seen on MRI (Fig. 3) (3,13), although these signals may vary if there is a prominent myxoid infiltrate within the adipose tissue (11,13). Enhancement with gadolinium is minimal, reflecting the low vascularity of the neoplasm (3). Ultimately MRI cannot definitively diagnose lipofibromatosis, but it can exclude other diagnoses and assist in preoperative planning (3). A diagnosis of lipofibromatosis can only be made histologically. The classic histologic appearance of lipofibromatosis is one of adipose tissue constituting at least 50% of the tumor separated into lobules by fascicles of spindled fibroblasts or myofibroblasts (Fig. 4A, B) (1,11,13). This fibroblastic tissue sometimes contains small amounts of collagen or evidence of myxoid change (1). Although lipofibromatosis can envelop regional structures such as skeletal muscle, nerves, and blood vessels, mitoses and nuclear pleomorphism are uncommon, and cytologic atypia, if present, is mild (1). Rarely, scattered pigmented cells can also be found in the fat septae (1,7,11). A common finding in lipofibromatosis is the presence of small, grouped, univacuolated cells found at sites of transition from fibroblast to adipose tissue (Fig. 4C). These are thought to be degenerating adipocytes or lipidrich fibroblasts (1). Immunohistochemistry is not required to establish the diagnosis, but spindled cells may demonstrate focal CD99 and CD34 positivity, whereas S100 highlights adipocytes (1,4,5,16). Expression of connective tissue growth factor (CCN2) is greater in the fibroblastic component of
303
lipofibromatosis (4,17), and cytogenetics from a case of lipofibromatosis demonstrate a balanced three-way translocation designated t(4,6,9)(q21;q22;q2?4) (2). Because CCN2 is located on chromosome 6q23.1, its role in the pathogenesis of lipofibromatosis warrants further investigation. The histologic differential diagnosis for lipofibromatosis includes fibrous hamartoma of infancy, CAF, juvenile fibromatosis, and lipoblastoma. Given the histologic overlap with these other pediatric soft tissue tumors, incisional or excisional biopsy specimens are preferred to provide adequate tissue for diagnosis. Lipofibromatosis has no known metastatic potential (1) but may exhibit progressive, infiltrative local growth and recurrence. It can become locally destructive and may be of cosmetic or functional significance (9–12). The gold standard of therapy is complete surgical resection, although modalities such as radiation have been attempted as adjunct therapy (1). In instances in which the lesion is diffusely infiltrative, partial resection with the lowest potential postoperative morbidity is recommended (1,12,13,18). Fetsch et al (1) reported male sex, presence at birth, incomplete excision, presence on the hands and feet, and mitotic activity on histology as predisposing factors for recurrence. In our series, both patients exhibiting tumor recurrence were male, but the two patients with congenital lipofibromatosis remain disease free (Table 1). One of the recurrences in our series was located on the chin, and four of the five tumors located on the distal extremities did not recur. The risk factors for recurrence are unknown and families should be counseled accordingly. In summary, lipofibromatosis is a rare pediatric soft tissue neoplasm that is commonly characterized by slow growth and local invasion. Although traditionally thought of as a 1- to 2-cm mass found on the distal extremities of boys, our study indicates that girls may be more frequently affected than previously appreciated. A variety of anatomic sites and sizes may also be seen in this process. It should be considered in the differential diagnosis of soft tissue tumors of childhood. CONFLICTS OF INTEREST JPD is a consultant for Shriner’s International Medical Advisory Board. He has received royalties from Elsevier, Mosby, and Brooke’s Publishing for services as an editor of medical textbooks. None of JPD’s interests are directly related to the diagnosis, management, or treatment of any condition discussed in this manuscript.
304 Pediatric Dermatology Vol. 31 No. 3 May/June 2014
REFERENCES 1. Fetsch JF, Miettinen M, Laskin WB et al. A clinicopathologic study of 45 pediatric soft tissue tumors with an admixture of adipose tissue and fibroblastic elements, and a proposal for classification as lipofibromatosis. Am J Surg Pathol 2000;24:1491–1500. 2. Kenney B, Richkind KE, Friedlaende G et al. Chromosomal rearrangements in lipofibromatosis. Cancer Genet Cytogenet 2007;179:136–139. 3. Walton JR, Green BA, Donaldson MM et al. Imaging characteristics of lipofibromatosis presenting as a shoulder mass in a 16-month-old girl. Pediatr Radiol 2010;40:43–46. 4. Kabasawa Y, Katsube K, Harada H et al. A male infant case of lipofibromatosis in the submental region exhibited the expression of the connective tissue growth factor. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:677–682. 5. Taran K, Woszczyk M, Kobos J. Lipofibromatosis presenting as a neck mass in eight-years old boy—a case report. Pol J Pathol 2008;59:217–220. 6. Nuruddin M, Osmani M, Mudhar HS et al. Orbital lipofibromatosis in a child: a case report. Orbit 2010;29:360–362. 7. Ayadi L, Charfi S, Ben Hamed Y et al. Pigmented lipofibromatosis in unusual location: case report and review of the literature. Virchows Arch 2008;452:465–467. 8. Herrmann BW, Dehner LP, Forsen JW. Lipofibromatosis presenting as a pediatric neck mass. Int J Pediatr Otorhinolaryngol 2004;68:1545–1549.
9. Joseph G, Zenios M. Congenital bowing of the tibia due to infantile lipofibromatosis corrected with a Taylor Spatial Frame. Musculoskelet Surg 2012 Dec 11 [Epub ahead of print]. 10. Greene AK, Karnes J, Padua HM et al. Diffuse lipofibromatosis of the lower extremity masquerading as a vascular anomaly. Ann Plast Surg 2009;62:703–706. 11. Teo HEL, Peh WCG, Chan M-Y et al. Infantile lipofibromatosis of the upper limb. Skeletal Radiol 2005;34:799–802. 12. Costa Dias S, McHugh K, Sebire NJ et al. Lipofibromatosis of the knee in a 19-month-old child. J Pediatr Surg 2012;47:1028–1031. 13. Deepti AN, Madhuri V, Walter NM et al. Lipofibromatosis: report of a rare paediatric soft tissue tumour. Skeletal Radiol 2008;37:555–558. 14. Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology. Philadelphia: Elsevier Saunders, 2012. 15. Razzaghi A, Anastakis DJ. Lipofibromatous hamartoma: review of early diagnosis and treatment. Can J Surg 2005;48:394–399. 16. Sasaki D, Hatori M, Hosaka M et al. Lipofibromatosis arising in a pediatric forearm—a case report. Ups J Med Sci 2005;110:259–266. 17. Leask A, Parapuram SK, Shi-wen X et al. J. Connective tissue growth factor (CTGF, CCN2) gene regulation: a potent clinical bio-marker of fibroproliferative disease? J Cell Commun Signal 2009;3:89–94. 18. Sari A, Tunakan M, Bolat B et al. Lipofibromatosis in a two-year-old girl: a case report. Turk J Pediatr 2007;49:319–321.
