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Maffucci syndrome: an interesting case and a review of the literature.

Enchondromatosis is characterized by the proliferation of enchondromas-benign intramedullary cartilaginous tumors that occur near the growth plate in long bones. It has been proposed that they occur due to abnormalities in the signaling pathways that control chondrocyte differentiation and proliferation. Because they are usually asymptomatic and often occur as solitary lesions, they are generally found incidentally on radiographs. These lesions replace normal bone with hyaline cartilage, which appears radiolucent with internal calcifications on plain radiographs. (1) Due to a risk of malignant degeneration, (1,2) skeletal deformity, (2,3) and pathologic fractures, (2) careful surveillance is essential.

There are many different subtypes of enchondromatosis, each characterized by its particular mode of inheritance and other tumor characteristics. Maffucci syndrome is a rare, non-hereditary sporadic subtype characterized by hemangiomas in addition to multiple enchondromas. Hemangiomas are benign vascular tumors that are also usually asymptomatic; they, too, require close monitoring due to the risk of malignant progression. Here we present an interesting case of Maffucci syndrome with a history of malignant transformation of enchondromas and recurrent hemangiomas that required multiple prophylactic surgical excisions. The known literature regarding this rare, but potentially lethal, disease is reviewed. The investigators have obtained the patient's informed written consent for print and electronic publication of the case report.

Case

A 58-year-old male with multiple enchondromas experienced malignant degeneration of one into a chondrosarcoma of the distal femur. He underwent a right distal femoral re placement 10 years ago (Fig 1). Two years later, he presented with new masses (1 x 1 cm and 2 x 2 cm) over his left hand. At that time, these masses were asymptomatic and conservative therapy was initiated. Over the next year, these masses continued to increase in size and became more painful. As a result, surgical excision of the masses was performed without complications. Pathology confirmed the masses as hemangiomas. At his postoperative visit, the patient then complained of a left foot mass between the heads of the second and third metatarsals that was causing him pain and difficulty walking. Again, the patient underwent surgical excision of the masses without complications. Pathology again confirmed the mass to be a spindle cell hemangioma.

Over the next 2 years, the patient had masses removed from his left forearm, left small finger, and left ankle. All the pathology, except for the left small finger, returned as spindle cell hemangiomas. The left small finger mass was reported as an enchondroma or low grade chondrosarcoma (Fig 2). Discussion was had with the patient regarding a finger amputation, which the patient declined. Follow-up has revealed no recurrence in the left small finger.

Discussion

First described by Angelo Maffucci in 1881, Maffucci syndrome is an exceedingly rare disease with less than 200 cases reported. (2) Considered a subtype of enchondromatosis, Maffucci syndrome presents with multiple enchondromas that are associated with soft tissue hemangiomas. Enchondromas are benign growths commonly in the small bones of the fingers and toes, long tubular bones, and flat bones such as the pelvis. They grow in close proximity to the growth plate cartilages and are therefore thought to result from abnormal regulation of proliferation and terminal differentiation of chondrocytes. (3) The most common type of enchondromatosis is Ollier disease-enchondromas of the long bones sparing the spine and skull-which occurs in 1/100,000 patients. (12)

Maffucci syndrome is a sporadic disorder occurring only in isolated patients without familial transmission. It remains unclear whether it is caused by a single gene defect or by combinations of germ-line or somatic mutations. (3) There are studies that show mutations of the gene encoding the parathyroid hormone receptor 1 (PTH1R) occur in a small subset of patients with enchondromatosis. (4) In fact, 10% of patients with enchondromatosis harbor a mutation in the PTH1R receptor; these mutations were shown to decrease the function of the receptor by 30%. (2,3,5,6) Additionally, Pansuriya and coworkers recently found that there are also mutations in the gene encoding isocitrate dehydrogenase 1 and 2 in enchondromas and spindle cell hemangiomas. Eighty-one percent of patients with Ollier disease and 77% of patients with Maffucci syndrome carried IDH1 (98%) and IDH2 (2%) mutations. Thus far, however, genome wide screens have not yet identified a causative gene. (4)

The presentation of the enchondromas in Maffucci syndrome is asymmetrically distributed and can be extremely variable in terms of size, number, location, age, and evolution. Clinical problems caused by these cartilage lesions include skeletal deformities, limb-length discrepancy, and potential risk for malignant change. (5) Complications can include spontaneous fractures through an area of advanced disease in 26% and sarcomatous degenerations of enchondromas to chondrosaromas in 15% to 40%. (2,4,7) However, Schwartz and colleagues conducted life table analyses that showed that malignant degeneration is almost a certainty for patients who have Maffucci syndrome. (8) Although chondro sarcoma is the most frequent musculoskeletal malignancy encountered in Maffucci syndrome, malignant transformation of skeletal lesions into fibrosarcomas and of vascular lesions into hemangiosarcomas, hemangioendotheliomas, and lymphangiosarcomas have also been reported. (8,9)

Radiography is crucial in making the diagnosis of Maffucci syndrome. X-rays, particularly of the hands and feet, are often pathognomonic for Maffucci syndrome. Images show well-demarcated radiolucent skeletal lesions and re-modeling of the affected bone with predominant thinning of the cortex and endosteal scalloping. (10) Frequently, there is matrix mineralization in the osseous lesions and typical "ring- and arc" appearance of the chondroid lesions. (11) By definition, these multiple enchondromas are associated with soft tissue swelling and calcifications and phleboliths, which are typical of hemangiomas. (10)

Grossly, enchondromas show round-shaped cartilaginous nodules that look like fragments of gray tissue. (1,10) All of them are surrounded peripherally with a osseous rim and centrally with myxoid or elastic tissue. Microscopically, enchondromas are characterized by a heterogeneous chondrocyte phenotype with diverse cellularity. Due to this increased cellularity and the similarity between enchondromas and malignant chondrosarcomas, distinction between them can be difficult based on histopathology alone. Therefore, it is critical that the diagnosis must rely on the combination of clinical, radiographic and histological features. (1) For hemangiomas, there are several histologic variants that have been described with this syndrome. The patient presented here has the spindle cell type, which is much more specific for Maffucci syndrome (12) and comprised of cavernous vascular spaces with organized thrombi and phleboliths. These cavernous spaces are unencapsulated, largely dilated blood vessels that are separated by very little connective tissue. This vascular tumor is also mixed in with solid areas composed of predominantly spindle cells. The spindle cells interact with epitheloid cells and some have intracytoplasmic vacuoles (13,14) (Fig 3).

One of the main concerns of patients with Maffucci syndrome is the malignant transformation of the enchondromas into chondrosarcomas and the hemangiomas into vascular malignancies. Verdegaal and associates (6) conducted a retrospective multicenter study that looked into the incidence, predictive factors, and prognosis of chondrosarcomas in patients with Maffucci syndrome. One of their main analyses grouped patients by the location and distribution of enchondromas. Group 1 involved enchondromas in short tubular bones only in hands and feet, group 2 involved only long tubular bones and flat bones (scapula and pelvis), and group 3 involved both short and long flat bones. They found that the percentage of patients developing chondrosarcomas in groups 1, 2, and 3 were 15%, 43%, and 46%, respectively. One patient mortality was noted in their study with metastases of a chondrosarcoma located in the humerus. (6) This emphasizes the need for vigilant surveillance (Fig. 4) of the masses and the importance of surgical resection of the enchondromas before they develop into the malignant chondrosarcomas.

According to the current literature, many other malignancies are associated with Maffucci syndrome, such as pancreatic and hepatic adenocarcinoma, mesenchymal ovarian tumors, brain gliomas and astrocytomas, and many kinds of sarcomas. (6) Schwartz and coworkers (8) did a retrospective study on 44 patients with enchondromatosis, 7 had Maffucci syndrome while 37 had Ollier disease. Four out of seven patients with Maffucci syndrome developed other malignancies in addition to chondrosarcomas. Additionally, none of the patients in their study actually died of the skeletal sarcoma, but four out of the five total patients in their study who had a non-skeletal malignant lesion died. (8) Surgery is indicated when a patient develops clinical symptoms such as growth of a mass by clinical and or radiographic criteria or if the patient develops pain over a new or preexisting lesion. At that time, the tumor mass should be removed and histology performed on the tissue to confirm the diagnosis. Currently, there is no medical therapy for the treatment of Maffucci syndrome, and surgery remains the only therapeutic option.

Conclusion

The treatment of a patient with Maffucci syndrome is a lifelong task. As demonstrated by our case study, these patients require frequent surveillance to monitor their multiple enchondromas and hemangiomas to guard against the high life time risk of malignant degeneration. Radiographs should be periodically performed to evaluate the stability of the tumors. This allows for early detection of malignant transformations. Treatment and management should focus on symptomatic relief as well as biopsies of suspicious lesions.

Disclosure Statement

None of the authors have a financial or proprietary interest in the subject matter or materials discussed, including, but not limited to, employment, consultancies, stock ownership, honoraria, and paid expert testimony

References

(1.) Silve C, Juppner H. Ollier Disease. Orphanet J Rare Dis. 2006 Sep 22; 1:37.

(2.) Gao H, Wang B, Zhang X, et al. Maffucci syndrome with unilateral limb: a case report and review of the literature. Chin J Cancer Res. 2013 Apr; 25(2); 254-8.

(3.) Hopyan S, Gokgoz N, Poon R, et al. A mutant PTH/PTHrP type I receptor in enchondromatosis. Nat Genet. 2002 Mar; 30(3):306-10.

(4.) Pansuriya TC, Van Eijk R, D'Adamo P, et al. Somatic mosaic IDH1 or IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome. Nat Genet. 2012 Nov 6; 43(12):1256-61.

(5.) Couvineau A, Wouters V, Bertrand G, et al. PTHR1 mutations associated with Ollier disease result in receptor loss of function. Hum Mol Genet. 2008 Sep 15; 17(18):2766-75.

(6.) Verdegaal SHM, Bovee JVMG, Pansuriya TC, et al. Incidence, predictive factors, and prognosis of chondrosarcoma in patients with Ollier disease and Maffucci syndrome: An international multicenter study of 161 patients. Oncologist. 2011; 16(12):1771-9.

(7.) Garzon MC, Huang JT, Enjolras O, Frieden IJ. Vascular malformations. Part II: associated syndromes. J Am Acad Dermatol. 2007 Apr; 56(4):541-64.

(8.) Schwartz HS, Zimmerman NB, Simon MA, et al. The malignant potential of enchondromatosis. J Bone Joint Surg Am. 1987 Feb; 69(2):269-74.

(9.) Lewis RJ, Ketcham AS. Maffucci's syndrome: functional and neoplastic significance-case report and review of the literature. J Bone Joint Surg Am. 1973 Oct; 55(7):1465-79.

(10.) Flach HZ, Ginai AZ, Oosterhuis JW. Best cases from AFIP. Maffucci syndrome: radiologic and pathologic findings. Ra diographics. 2001 Sep-Oct; 21(5):1311-6.

(11.) Flemming DJ, Murphey MD. Enchondroma and chondrosar coma. Semin Musculoskelet Radiol. 2000; 4(1):59-71.

(12.) Pansuriya TC, Kroon HM, Bovee JV. Enchondromatosis: insights on the different subtypes. Int J Clin Exp Pathol. 2010 Jun 26; 3(6):557-69.

(13.) Kumar V, Abbas AK, Aster JC. Robbins Basic Pathology (9th ed). Elsevier Saunders: Philadelphia, 2013.

(14.) Tomasini C, Aloi F, Soro E, Elia V. Spindle cell hemangioma. Dermatology. 1999; 199(3):274-6.

Calvin Ngai, B.A., Medical Student, NYU School of Medicine, New York, New York. David Y Ding, M.D., and Timothy B. Rapp, M.D., Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, New York, New York.

Correspondence: Calvin Ngai, B.A., NYU School of Medicine, 550 First Avenue, New York, New York 10016; Calvin.Ngai@ nyumc.org.

Caption: Figure 1 X-ray images of right femur after right distal femur replacement.

Caption: Figure 2 A and B, X-ray images of left ankle after removal of masses in 2013. C and D, X-ray images of left small finger mass in 2012.

Caption: Figure 3 A, The pathology of a spindle cell hemangioma in the left forearm in 2011. B, The pathology of a spindle cell hemangioma in the left ankle in 2013, which was similar in quality to the previous ones. To view this figure in color, see www.hjdbulletin.org.

Caption: Figure 4 A, A gross image of left hand mass during follow-up visit of surgery in 2013. B and C, Gross images of left foot and leg masses during follow-up visit of surgery in 2013. To view this figure in color, see www.hjdbulletin.org.

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Publication:Bulletin of the NYU Hospital for Joint Diseases
Article Type:Clinical report
Date:Oct 1, 2015
Words:2103
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