Pathology of Lipomatous Lesionsin Proteus Syndrome

TARIK TIHAN1* AND JONATHAN OKUN2

1Department of Pathology, Johns Hopkins Medical Institutions, Carnegie Building, Room 484, 600 N. Wolfe Street,Baltimore, MD 21287, USA2Department of Pathology, State University of New York at Stony Brook, Stony Brook, NY 11794, USA

Received May 6, 1997; accepted October 28, 1997.

ABSTRACTProteus syndrome is an extremely rare, complex hamar-tomatous disorder with markedly variable clinical expres-sion. We present a case of Proteus syndrome withmultiple disfiguring soft tissue masses that were presentsince early childhood. The lesions involved predomi-nantly the right side of the body and included scoliosis,macrodactyly, and limited hyperostosis in the right foot.There was no evidence of cranial or skin lesions. Thepatient underwent multiple resections of soft tissuemasses, including an amputation of the right foot be-cause of severe gait disturbance. All specimens exhibitedlipomatous lesions that were probably hamartomatousrather than neoplastic. She carried a diagnosis of neuro-fibromatosis for more than a decade, but a re-evaluationof clinical features and pathological findings promptedthe diagnosis of Proteus syndrome. We believe that amore informed evaluation of the pathology material mayhelp to identify this rare entity.

Key words: hamartoma, hyperostosis, lipomatosis, neu-rofibromatosis, plantar hyperplasia, Proteus syndrome

INTRODUCTIONProteus syndrome (PS) is a rare congenital hamar-tomatous disorder that can present with a varietyof skin, soft tissue, and musculoskeletal abnormali-ties [1,2]. Common findings include hemihypertro-phy, soft tissue hamartomas, macrocephaly, periar-ticular calcifications, hyperostosis, bony spurs,plantar or palmar hypertrophy, and macrodactyly

[1–5]. Less common manifestations, such as genito-urinary and pulmonary lesions, and linear verru-cous nevi have been described [6–8]. Neoplasiacommonly identified in PS included hemangiomas,lipomas, and lymphangiomas. Uncommon neo-plasms seen in PS were recently reviewed by Gor-don et al. [9].

First definition of PS was made by Cohen andHayden in 1979 [2]. In 1983, Wiedemann et al.coined the term ‘‘Proteus syndrome’’ after themythological figure that is capable of assumingdifferent forms [1]. Reported cases of PS exhibitremarkable variation in terms of extent of disease,progression, and associated lesions [3,5,10,11]. Thecause of this variation is believed to be the somaticmosaicism of the underlying genetic disorder [5,12].However, the exact genetic mechanism is unclear.

Histopathological findings associated with PShave been overlooked on many occasions, contrib-uting to misdiagnoses of cases for long periods oftime [6,13]. We report an 18-year-old female withPS who carried the diagnosis of neurofibromatosis(NF) for more than a decade, and we presenthistopathological findings that should help to estab-lish the diagnosis of PS when combined with theclinical data.

CASE REPORTThe patient is an 18-year-old female of normalintelligence who presented with gait difficulty due*Corresponding author

Pediatric and Developmental Pathology 1, 443–448, 1998 Pediatric and Developmental Pathology

r1998 Society for Pediatric Pathology

to an extremely deformed right foot. She was theproduct of an uncomplicated pregnancy, and nosignificant anomaly was detected at birth. Soonafter birth, she developed deformities of the rightextremity, right paraspinal region, buttocks, andthe foot. The deformities gradually increased inseverity over the next decade. She underwent mul-tiple surgical procedures to remove soft tissuemasses from the right buttock, perineum, andthigh at ages 7, 14, and 16, respectively. In addition,she underwent four prior foot surgeries, includingamputation of the last three digits of the right foot,which were recorded as ‘‘large and deformed.’’ Shehad no family history of musculoskeletal disease ordeformity.

On physical examination, the patient hadscoliosis of the thoracolumbar spine. There was anadjacent palpable paraspinal soft tissue mass thathad not changed in size for many years. Her rightfoot was markedly deformed by a large soft tissuemass involving the plantar and lateral aspect, pre-venting dorsiflexion and steady gait. Paresthesiawas present in the skin overlying the plantar sur-face. The deformity resulted in a significant limb-length inequality. No cafe-au-lait spots or axillaryfreckling was noted. Neurological examination wasunremarkable except in the right lower extremity.

Radiological examination of the deformedfoot revealed extensive soft tissue enlargement ofthe ankle and foot, a plantar heel spur, and hyperos-tosis of the posterior–superior aspect of the calca-neus. The vertebral column had a 457 thoracolum-bar curve. Multiple lipomatous masses wereidentified in the right paraspinal and pelvic regions(Fig. 1), extending into perirectal and perivesicularareas. Soft tissue masses (plantar and paraspinal)had the signal characteristics of adipose tissue onT1 and T2 weighted images.

The patient underwent a Syme’s amputationof the right foot. She had no evidence of progres-sion of soft tissue masses, scoliosis or additionallesions 9 months after surgery. She continues to befollowed up at regular intervals.

PATHOLOGICAL FINDINGSPathology materials and reports from previoussurgical interventions were reviewed. The first speci-men was from a wide excision of right buttockmass performed at age 7. It measured 16 3 10 3 10

cm, weighed 1210 g, and had the gross appearanceof indurated fat. It was diagnosed as consistentwith lipoma. The second specimen was obtainedfrom an excision of a soft tissue mass from theperineal region and right thigh at age 14. It mea-sured 33 3 25 3 2.5 cm, weighed 2998 g, and wasreported elsewhere as being composed of adiposetissue. At age 16, a third resection of a right thighmass was performed. The specimen weighed 2480g and measured 50 3 18 3 5.5 cm. The interpreta-tion was ‘‘lipoma associated with skeletal muscle.’’A report on the previous triple digit amputationrevealed macrodactyly described as ‘‘grossly en-larged and deformed digits with extensive fattyinfiltration.’’ No pathology material was availablefrom this surgery.

The amputation specimen consisted of theanterior four-fifths of the foot, measured 15 3 13 3

11 cm, and weighed 1510 g. The overlying skinparticularly on the plantar aspect was thickenedand had a lobular surface (Fig. 2B). An old scar atthe site of the triple digit amputation was identi-fied. The remaining digits were minimally de-formed but not enlarged (Fig. 2D). On serial cutsections, an ill-defined soft tissue mass measuring14 3 12 3 5 cm was present. It consisted of diffuse,non-encapsulated, mature adipose tissue and inter-mingled tan-white, fibrous areas forming lobules ofvarying sizes. The adipose tissue imperceptibly

Figure 1. Double echo T2 weighted MRI image of thepelvic region in transaxial plane demonstrates lipoma-tous masses involving the pelvis and the musculaturedisplacing the bladder and the rectum.

444 T. TIHAN AND J. OKUN

surrounded bones, tendons, and skeletal muscles.The talus and calcaneus bones were received sepa-rately and had surface irregularities suggestive ofhyperostosis. Specimen X-rays exhibited limitedhyperostosis of talus and calcaneus (Fig. 2C) andno significant deformity of the metatarsal or phalan-geal bones (Fig. 2A).

Microscopic examination of the previous andcurrent specimens was strikingly similar. All speci-mens showed a markedly thickened dermis withextensive collagen deposition and variable hyper-

keratosis. The soft tissue masses were composed ofmature adipose tissue arranged in lobules sur-rounded by thick fibrous septa (Fig. 3A–B). Theadipose tissue contained normal vessels and nerves,and surrounded the adnexa. In certain areas, theadipose tissue infiltrated into skeletal muscles,giving the appearance of an infiltrating lipoma (Fig.3C). None of the sections examined showed lipo-blasts, cellular atypia, or mitosis. Special stainsrevealed the extent of collagen deposition withinthe septa of the lobules and unremarkable nerves

Figure 2. A: X-ray obtainedafter amputation of the footshowing a large plantarmass vaguely defined by ra-diating fibrous tissue, andno significant bone defor-mity. B: Gross specimenshowing a large plantarmass with somewhat cere-briform-appearing skin.C: X-ray of the talus and cal-caneus showing hyperostosis(arrowheads). D: Gross pho-tograph of previous ampu-tation site and of the re-maining two digits.

Figure 3. Extensive lipoma-tous infiltration of the deepsoft tissues and a marked lobu-lar architecture formed by fi-brous tissue obtained from re-section specimen from thigh in1986 (A), and current amputa-tion specimen (B) (originalmagnification 340). C: Lipoma-tous infiltration of the skeletalmuscles causing atrophy andgiving the appearance of aninfiltrating lipoma (originalmagnification 3100). D: EVG-Trichrome stain showing theextent of fibrosis, unremark-able nerves, and adnexa sur-rounded by the fibrofatty infil-tration (original magnification340).

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and vessels (Fig. 3D). Sections from the bonesdemonstrated hyperostosis but no evidence of carti-laginous overgrowth or degeneration. On the basisof the clinical and histological features, a diagnosisof PS was rendered.

DISCUSSIONPS is an extremely rare congenital hamartomatoussyndrome that was first delineated by Cohen andHayden in 1979 [2]. It was further characterizedand named by Wiedemann et al. in 1983, after afigure in Greek mythology [1]. Since then, morethan 80 cases have been reported, the most famousbeing Joseph Merrick, the ‘‘Elephant Man,’’ whowas believed to have had neurofibromatosis type I[11].

The underlying genetic defect in PS is un-known. Case reports of transmission from father toson [13] or from mother to son [14] have suggestedpossible germline or autosomal dominant mode ofinheritance. However, PS does not appear to followa single Mendelian pattern, and somatic mosaicismwas suggested as the cause of extensive phenotypicvariation seen in reported cases [5,12]. There is noapparent sex predilection or link to paternal ormaternal age in cases reported to date.

Recently, many lesions have been added to theclassically described bone and soft tissue lesions ofPS. Newman et al. reported two cases with cysticlung disease and estimated an overall incidence of10% [8]. Hotamisligil and Ertogan reported anassociation with nephrogenic diabetes insipidus[7]. Neurological manifestations consisting of pre-dominantly mental deficits and seizures have alsobeen documented [10,12,15].

Clinically, the differential diagnosis for PSincludes Ollier’s disease, Maffucci syndrome, andother less well-defined entities, such as encephalo-craniocutaneous lipomatosis (ECCL), Bannayan-Zonana syndrome (BZS), Klippel-Trenaunay-Weber syndrome (KTWS), and macrodystrophialipomatosa (Table 1). However, the most frequentdysgenetic syndrome that can be confused withProteus syndrome is NF [6,11]. Large, disfiguringlesions can be interpreted as neurofibromas orother tumors associated with NF, and epidermalnevi of PS can be misidentified as cafe-au-lait spots.In addition, the extent of involvement can be

variable in both syndromes. Since absence of Lischnodules, axillary freckling, or a family history willnot exclude the possibility of NF, distinction mayrely on other clinical features, and finally on thehistological evaluation. Similar to our case, somecases in the literature were initially interpreted asNF [6,14].

Ollier’s disease and Maffucci syndrome areboth characterized by multiple chondroid lesionsthat may affect any bone. Ollier’s disease is usuallyunilateral and may resemble the hemihypertrophyof PS. However, radiological and histological dis-tinction from PS is almost always possible. On theother hand, Maffucci syndrome may be more diffi-cult to distinguish from PS because of the presenceof soft tissue tumors, specifically hemangiomas.However, the histopathology of lesions in Maffuc-ci’s syndrome are distinctive enough for correctdiagnosis.

Table 1. Pathological features of soft tissueproliferations in the differential diagnosisof proteus syndrome

Feature PS NF BZS ECCL ML LHN

Localized to oneanatomical site 2 2 2 2 1 1

Infiltrative lipo-matus over-growth 1 2 1 1 1 1

‘‘Lobulated,’’dense fibrosis 1 2 2 NR NR 2

Neurofibromas/neural over-growth 2 1 2 2 2 2

Angiomas/vascularlesions 1/2a 1/2b 1 1 2 2

Dilated lymphatics/lymphangiomata 2 2 1 1 2 2

Associated nevi/pigmentedlesions 1 1 1 2 2 2

Malignant trans-formation 2 1 2 2 2 2

PS, Proteus syndrome; NF, neurofibromatosis; BZS, Bannayan-Zonanasyndrome; ECCL, encephalocraniocutaneous lipomatosis; ML, macrodys-trophia lipomatosa; LHN, lipomatous hamartoma of nerve; NR, notreported.aEven though there are numerous reports of angiomatous lesions in theliterature, we were unable to find histological documentation of suchlesions in bona fide cases of PS.bIn rare occasions, angiomatous neoplasms have been documented in NF,but the overwhelming majority of soft tissue proliferations in NF areneurofibromas.

446 T. TIHAN AND J. OKUN

The most difficult and probably controversialdifferential diagnosis of PS is that from the hamar-tomatous entities, including ECCL [10,16], KTWS[2], BZS [17], and macrodystrophia lipomatosa[18]. To date, there is no consensus on the exactdefinition of the above entities, and the conclusionsin the literature are confusing.

KTWS presents with similar lesions, e.g., par-tial gigantism of digits, hemihypertrophy, soft tis-sue hemangiomas, or lipomas. Some consider thisentity as an incomplete expression of PS, even thoughWiedemann et al. reported to have easily excludedthis syndrome in their original report [1]. However,they did not discuss the basis of this exclusion.

ECCL is characterized by lipomas and malfor-mations of the central nervous system, mentaldefects, seizures, and other anomalies [15]. McCallet al. consider ECCL a distinct entity [16], whereasothers conclude that the entity seems to represent aform of PS [10,15]. Bialer et al. report a patientwith features of both PS and BZS, and they con-clude that these two syndromes may be etiologi-cally related [17].

Macrodystrophia lipomatosa is defined as acongenital unilateral lipomatosis of the foot withassociated bony changes that remains localized[18]. It is also tempting to suggest that macrodystro-phia lipomatosa is a very limited expression of PS,but sufficient evidence for this conclusion as wellas for the contrary is lacking. More detailed analy-sis of these cases may clear this uncertainty.

It is certain that these discussions will con-tinue until a molecular pathologic definition of theabove-mentioned entities is made. Currently thereis more overlap among the hamartomatous syn-dromes with the addition of new cases, and distin-guishing one entity from another may no longer beas easy. It may be practical, albeit reductionist, toinclude cases reported as ECCL, BZS, and macro-dystrophia lipomatosa in the family of PS.

All available pathologic specimens in our pa-tient revealed a striking resemblance to each other,which was different from a classical lipoma. Thelack of an obvious vascular component beyond thevascularity seen in lipomatosis, the remarkablylobulated appearance imposed by marked fibrosis,diffuse infiltrative nature of the adipose tissuerather than circumscription, and lack of encapsula-tion distinguish the pathology. It is of no surprise to

find the hyperlobulated architecture of adiposetissue, given the macroscopically gyriform appear-ance of the skin. We did not find any componentother than that of lipomatosis in the sectionsexamined. Similar observations were made by Bar-makian et al. [4]. The overall architecture of theselesions are quite different from lipomas, which aremostly encapsulated, circumscribed, and expan-sive rather than infiltrating, and they lack thelobulated architecture seen in PS. The infiltrating(intramuscular) lipomas may show some resem-blance to lipomatoses but can be distinguished bytheir deep, intramuscular location, occurrence inlater age-groups, and localized growth [19]. Infiltrat-ing lipomas are not associated with hyperostosis,and we are not aware of a case report of multipleinfiltrating lipomas. Microscopically, they may infil-trate muscle fibers, but they do not exhibit alobulated architecture.

We have identified a critical histopathologicalevaluation of the soft tissue lesions of PS only in afew of the reports in the literature [4,6]. Since mostreports of lipomas in PS patients lack histopatho-logical description, it is not clear to us whetherthese lesions are neoplastic or hamartomatous.

Recent advances in the pathology and genet-ics of lipomatous tumors underline the importanceof identifying genomic changes in characterizingcertain entities [20]. Recognition of cytogeneticalterations in such neoplasms may result in betterclassifications. Given the possibility of somaticmosaicism, the nature of PS may be revealed ifgenetic studies are conducted in the lesions as wellas in ‘‘normal’’ tissues from patients. We are awareof only one such case report [12]. Such studies mayanswer the question whether these lipomatouslesions are neoplastic (lipoma) or hamartomatous(lipomatosis). We do not find sufficient histologicalevidence to classify the lesions as neoplastic in ourpatient. Furthermore, we believe that these lesionsare distinctive enough to raise the suspicion of PS.Nevertheless, lack of sufficient cases and reports of‘‘lipomas’’ in PS prompted us to use the term‘‘lesion’’ rather than hamartoma or neoplasm.

In conclusion, we wish to underline the impli-cations of a pathological diagnosis of lipoma, orconsistent with lipoma, in a patient with question-able NF. Sometimes, the surgical pathology reportmay reflect the typical changes without awareness

LIPOMATOUS LESIONS IN PROTEUS SYNDROME 447

of the patient’s condition. In such cases, the diagno-sis of NF may remain unchallenged. An informedevaluation of the surgical material will lead to thecorrect diagnosis.

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