Immunostain Patterns of HER-2, EGFR and CD117 in Fibrous Dysplasia: A Six -Case Series And Literature Review

Nicole M. DeMers¹, Scott M. Schlauder¹, and Marilyn M. Bui^1,2

Abstract:

Introduction:Fibrous dysplasia is an uncommon bone disease that has a rare but clear potential for malignant transformation. The treatment of fibrous dysplasia is limited to maintenance of maximum bone density via diet, exercise and therapeutic medications (i.e. bisphosphonates), as well as surgical reinforcement of bowing deformities and fractures as they occur. Currently, there is no therapy for preventing advance of the disease or malignant transformation. In light of recent development in novel targeted therapy to HER2, epidermal growth factor receptor (EGFR) and CD 117 (C-KIT) have shown therapeutic promise in many neoplasms, both benign and malignant; we investigated the expression of these markers in six cases of fibrous dysplasia in hopes of finding new treatment methods for this uncommon and sometimes devastating disease. 
Methods: A retrospective computer assisted query of a large community hospital identified six cases of fibrous dysplasia in 3 years. Immunohistochemical analysis was performed on 4-5 µm sections of formalin fixed paraffin embedded tissue blocks from the above cases by Ventana autostainer using HER2, EGFR, and CD 117 antibodies (Ventana, Tucson, AR) with appropriate controls following the manufacture’s recommendation. Four of these cases had been decalcified. Positive reactivity is scored following generally accepted standards among pathologists. Other tumor tissue with known HER2, EGFR and CD117 expression before decalcification were also stained after decalcification in parallel with fibrous dysplasia cases to ensure that the decal process do not cause false negative immunohistochemical results. 
Result :Six cases of fibrous dysplasia are uniformly negative for all three biomarkers. The controls worked appropriately.

J.Orthopaedics 2009;6(2)e4

Keywords:

Fibrous Dysplasia treatment; CD117, EGFR; HER2Neu

Introduction:

Fibrous dysplasia is an uncommon bone disease that has a rare but clear potential for malignant transformation.  The treatment of fibrous dysplasia is limited to maintenance of maximum bone density via diet, exercise and therapeutic medications (i.e. bisphosphonates), as well as surgical reinforcement of bowing deformities and fractures as they occur.  Currently, there is no therapy for preventing advance of the disease or malignant transformation.  In light of recent development in novel targeted therapy to HER2, epidermal growth factor receptor (EGFR) and CD 117 (C-KIT) have shown therapeutic promise in many neoplasms, both benign and malignant; we investigated the expression of these markers in six cases of fibrous dysplasia in hopes of finding new treatment methods for this uncommon and sometimes devastating disease.

Methods:

A retrospective computer assisted query of a large community hospital identified six cases of fibrous dysplasia in 3 years. Immunohistochemical analysis was performed on 4-5 µm sections of formalin fixed paraffin embedded tissue blocks from the above cases by Ventana autostainer using HER2, EGFR, and CD 117 antibodies (Ventana, Tucson, AR) with appropriate controls following the manufacture’s recommendation.  Four of these cases had been decalcified.  Positive reactivity is scored following generally accepted standards among pathologists.  Other tumor tissue with known HER2, EGFR and CD117 expression before decalcification were also stained after decalcification in parallel with fibrous dysplasia cases to ensure that the decal process do not cause false negative immunohistochemical results.

Results :

Six cases of fibrous dysplasia are uniformly negative for all three biomarkers. The controls worked appropriately.

Discussion :

Fibrous dysplasia (FD) is a benign fibro-osseous lesion which may present in monostotic or polyostotic form, with or without additional morbidities (1),(2). The monostotic form (MFD) represents approximately 70-80% of fibrous dysplasia cases and most frequently occurs in the craniofacial bones, rib, femur, tibia, and humerus.  MFD usually presents with pain or pathologic fracture in patients aged 10-70 years, but most commonly occurs in those aged 10-30 years. The degree of bone deformity in MFD is relatively less severe compared with that of the polyostotic type. To date there is no documented evidence supporting the conversion of the monostotic form to the polyostotic form 1,(3).  Approximately 20-30% of fibrous dysplasia cases are polyostotic (PFD).  The common sites of involvement are the femur, tibia, skull and facial bones, pelvis, ribs, upper extremities, lumbar spine, clavicle, and cervical spine. The sites of dysplasia may be unilateral or, less commonly, bilateral.  Two-thirds of patients with PFD are symptomatic before adolescence. The initial symptom is commonly pain in the involved limb(s) associated with a limp in the case of lower extremity involvement, spontaneous fracture, or both. Leg-length discrepancy of varying degrees occurs in about 70% of patients with limb involvement due to the weakened structural integrity of the bone leading to significant bowing (1, 2, 4, 5).  Fibrous dysplasia often is associated with a shepherd’s crook deformity, curvature of the femoral neck and proximal shaft resulting in a coxa vara deformity, which can be severe and is a pathognomonic for fibrous dysplasia.  Pregnancy can reactivate dormant bony lesions and occurs more commonly in PFD than MFD. 

A small, but important subset of polyostotic fibrous dysplasia occurs along with endocrine abnormalities and coast of Maine café-au-lait spots, a triad called McCune-Albright syndrome,  named for two physicians who separately described the syndrome in 1937, Donovan McCune and Fuller Albright ⁴.  The most common endocrine abnormality is precocious puberty, once treated by removal of the active gonad, now treated with anti-hormonal medications.  Rarely, patients may have only two of the three characteristics and may have one or more of the numerous endocrine symptoms, which include disturbances of the thyroid gland, parathyroid calcium regulation, adrenal hormonal regulation, as well as an over-active pituitary. Approximately 3% of FD cases will qualify for McCune-Albright syndrome.  The disease is more common among females and holds no racial predilection.  Separate from McCune-Albright and involving an even smaller fraction (~1%) of FD patients are those with associated intramuscular myxomas, typically around the sites of the bony lesions, an entity called Mazabraud’s syndrome ⁵.  This disorder is also more common in women.   FD is generally thought of as a benign pediatric disease with dormancy of the lesions typically reached by early adulthood, however, patients with FD should be aware that malignant transformation may rarely occur (1% average, 4% in McCune Albright). Rapidly increasing pain without apparent trauma or a significant rapid change in radiological appearance should alert the clinician to further investigate. 

Currently, treatment of fibrous dysplasia is limited to maintenance of maximum bone density via diet, exercise and therapeutic medications (i.e. bisphosphonates), as well as surgical reinforcement of bowing deformities and fractures as they occur.  There is no therapy for preventing advance of the disease or malignant transformation, nor any role for chemotherapy, nor any study investigating the potential role of novel targeted therapy to HER2, EGFR and CD 117.  

Conclusion:

We studied the immunostain pattern of the above biomarkers in 6 cases of fibrous dysplasia and found  uniformly negative immunoreactivity.  We also have confirmed that the negative results of the above markers was not caused by the decalcification process.  This signifies that therapies targeted against these biomarkers should have no utility in the treatment of FD. We strongly encourage further investigations to discover optimal therapy for FD. This disease may cause not only bone deformity with associated pain and morbidity, but also has clear potential malignant transformation.

Reference :

1. DiCaprio MR, Enneking WF. Fibrous dysplasia. Pathophysiology, evaluation, and treatment. Bone Joint Surg Am. 2005 Aug;87(8):1848-64.

2. Fletcher CDM Unni KK, Mertens F Pathology and genetics of tumours of soft tissue and bone. Lyon: IARC Press; 2002.

3. Horvai A, Unni KK. Premalignant conditions of bone. J Orthop Sci. 2006 Jul;11(4):412-23.

4. Daneman A, Daneman D. McCune-Albright syndrome. J Pediatr Endocrinol Metab. 2007 Dec;20(12):1265.

5. Zoccali C, Teori G, Prencipe U, Erba F. Mazabraud's syndrome: a new case and review of the literature. Int Orthop. 2008 Jan 24.

This is a peer reviewed paper 

Please cite as: Nicole M. DeMers: Immunostain Patterns of HER-2, EGFR and CD117 in Fibrous Dysplasia: A Six -Case Series And Literature Review.

J.Orthopaedics 2009;6(2)e4

URL: http://www.jortho.org/2009/6/2/e4

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