Metastatic Cancer of Bone Author: Patrick O'Donnell

Introduction

Metastatic cancer is the most common reason for a destructive bone lesion in adults o carcinomas that commonly spread to bone include breast lung thyroid renal prostate Epidemiology o incidence bone is the third most common site for metastatic disease (behind lung and liver) o demographics metastatic bone lesions are usually found in older patients (> 40 yrs) o locations common sites of metastatic lesions include axial skeleton (vertebral bodies, pelvis, ribs) thoracic spine is most common site of bony metastasis proximal limb girdle proximal femur is most common site of fracture secondary to metastatic bone lesions Pathophysiology o mechanism of bone destruction (osteolysis) osteolytic bone lesions are caused by tumor induced activation of osteoclasts occurs through the RANK, RANK ligand (RANKL), osteoprotegrin pathway PTHrP positive breast cancer cells activate osteoblastic RANKL production osteoblastic bone metastases are due to tumor-secreted endothelin 1

Prognosis o median survival in patients with metastatic bone disease thyroid: 48 months prostate: 40 months breast: 24 months kidney: variable depending on medical condition but may be as short as 6 months lung: 6 months Associated conditions o metastatic hypercalcemia a medical emergency symptoms include confusion muscle weakness polyuria & polydipsia nausea/vomiting dehydration treatment treat with hydration and loop diuretics Metastatic cancer is the most common reason for a destructive bone lesion in adults o carcinomas that commonly spread to bone include breast lung thyroid renal prostate Epidemiology o incidence bone is the third most common site for metastatic disease (behind lung and liver) o demographics metastatic bone lesions are usually found in older patients (> 40 yrs) o locations common sites of metastatic lesions include axial skeleton (vertebral bodies, pelvis, ribs) thoracic spine is most common site of bony metastasis proximal limb girdle proximal femur is most common site of fracture secondary to metastatic bone lesions Pathophysiology o mechanism of bone destruction (osteolysis) osteolytic bone lesions are caused by tumor induced activation of osteoclasts occurs through the RANK, RANK ligand (RANKL), osteoprotegrin pathway

PTHrP positive breast cancer cells activate osteoblastic RANKL production osteoblastic bone metastases are due to tumor-secreted endothelin 1

Prognosis o median survival in patients with metastatic bone disease thyroid: 48 months prostate: 40 months breast: 24 months kidney: variable depending on medical condition but may be as short as 6 months lung: 6 months Associated conditions o metastatic hypercalcemia a medical emergency symptoms include confusion muscle weakness polyuria & polydipsia nausea/vomiting dehydration treatment treat with hydration and loop diuretics

Principles of metastasis

Mechanism of metastasis o tumor cell intravasation E cadherin cell adhesion molecule (on tumor cells) modulates release from primary tumor focus into bloodstream o avoidance of immune surveillance o target tissue localization attaches to target organ endothelial layer via integrin cell adhesion molecule (expressed on tumor cells) o extravasation into the target tissue o induction of angiogenesis via vascular endothelial growth factor (VEGF) expression o genomic instability o decreased apoptosis Vascular spread o Batson's vertebral plexus valveless venous plexus of the spine that provides a route of metastasis from organs to axial structure including vertebral bodies, pelvis, skull, and proximal limb girdles o arterial tree metastasis mechanism by which lung and renal cancer spread to the distal extremities

Symptoms

Symptoms o pain may be mechanical pain due to bone destruction or tumorigenic pain which often occurs at night o pathologic fracture occurs at presentation in 8-30% of patients with metastatic disease o metastatic hypercalcemia Physical exam o neurologic deficits caused by compression of the spinal cord with metastatic disease to the spine

Evaluation Workup for older patient with single bone lesion and unknown primary includes

imaging o plain radiographs in two planes of affected limb o CT of chest / abdomen / pelvis o technetium bone scan to detect extent of disease myeloma and thyroid carcinoma are often cold on bone scan - evaluate with a skeletal survery labs o CBC with differential o ESR o basic metabolic panel o LFTs, Ca, Phos, alkaline phosphatase o serum and urine immunoelectrophoresis (SPEP, UPEP) biopsy o in patients where a primary carcinoma is not identified, obtaining a biopsy is necessary to rule out a primary bone lesion should not treat a bone lesion without tissue diagnosis of the lesion o metastatic adenocarcinoma not identified by CT of the chest, abdomen, and pelvis is most likely from a small lung primary tumor

Imaging

Radiographic o recommended views AP and lateral of involved area o findings purly lytic or mixed lytic/blastic lesions lung, thyroid, and renal are primarily lytic 60% of breast CA is blastic

90% of prostate CA is blastic cortical metastasis are common in lung cancer lesions distal to elbow and knee are usually from lung or renal primary

CT scan o helpful to identify metastatic lesions to the spine MRI o useful to show neurologic compromise of the spine

Studies Histology

characteristic findings o epithelial cells in clumps or glands in a fibrous stroma immunohistochemical stains positive o Keratin o CK7 (breast and lung cancer) o TTF1 (lung cancer)

Treatment - Metastatic Extraspinal Bone Lesion

Goals goal of treatment in metastatic disease is pain control and maintainence of patient independence Nonoperative o bisphosphonate therapy indications symptomatic care by preventing osteoclatic bone destruction technique IV pamidronate most commonly used Operative o stabilization of complete fracture, postoperative radiation indications most complete fractures are treated if operative stabilization leads to improved quality of life postoperative radiation all patients require postop radiation unless death is imminent or area has previously been irradiated begin radiation therapy after surgery area of irradiation should include the entire fixation device (e.g. entire femur after intramedullary nailing of femoral lesion) o prophylactic stabilization of impending fracture, postoperative radiation indications impending fx that meets criteria criteria for impending fractures o preoperative embolization indications is indicated inpatients with renal cell carcinoma or thyroid carcinoma prior to operative intervention because these cancers are very vascular.
o

Treatment - Metastatic Spine Lesion

Nonoperative o palliative care indications life expectancy of < 6 months Takuhashi scoring system can be used to determine life expectancy Operative o neurologic decompression, spinal stabilization, and postoperative radiation indications metastatic lesions to spine with neurologic deficits in patients with life expectancy of > 6 months. technique preoperative embolization indicated in metastatic renal CA to spine

Techniques

Prophylactic IM nailing of proximal femur lesions o indications impending and complete peritrochanteric fractures that do not involve the femoral head o technique statically locked cephalomedullary IM nail for peritrochanteric fractures Hemiarthroplasty vs.Total Hip Arthroplasty o indications both impending and complete pathologic fractures of the femoral head and neck can be management with replacement arthroplasty

Differentials & Groups

Location Case A Prox femur

Xray

Xray

CT

B. Scan

MRI

MRI

Histo (1)

Case B

pelvis

Case C

Hand (thyroid CA)

Case D

Hand (lung CA)

Case E

Femur (lung CA)

Case F

pelvis

Case G

Renal CA (angio)

Qbank (27 Questions) (OBQ12.124) A 68-year-old male presents to the emergency room with neck pain and progressive weakness to the point that he is unable to walk. Prior to this event he was in good health and active. On physical exam he is an ASIA C. Radiographs, computed tomography, and an MRI are show in Figure A,B, and C respectively. A CT of the chest, abdomen, and pelvis shows a single resectable lesion in the rectum consistent with a primary malignancy. Sagittal images of the spine show a single metastatic lesion in the thoracic spine, but no signs of thoracic canal compromise. He has no other metastatic bone lesions. What is the best treatment for this patient? Review Topic FIGURES: A B C 1. 2. 3. 4. 5. Surgical decompression and stabilization followed by radiation Radiation followed by surgical decompression and fusion Radiation alone Chemotherapy alone Palliative measures

PREFERRED RESPONSE 1 DISCUSSION: The clinical presentation is consistent with metatatic cancer to the spine in a patient with a life expectancy of greater than six months. Therefore surgical decompression and stabilization followed by radiation is the most appropriate treatment. There is good evidence to support surgical decompression followed by radiation for patients with metastatic cancer to the spine leading to a neurologic deficit if their life expectancy is greater than six months. Using the Tokuhashi scoring system, this patient has a score equal to 11, and therefore a life expectancy of > 6 months. A score of 11 was calculated in the following way: 11 = Good health (2 points) + No Extra-spinal bone lesions (2 points) + 2 Spinal Lesions (1 point) + Removable visceral lesion (1 points) + Primary Rectal Lesion (4 points) + Incomplete Palsy (1 point). Patchell et al. published a prospective, randomized study comparing patients who received surgery followed by radiation to patients who only received radiation. The results were so dramatically in favor of surgery and radiation that the study was stopped early. Importantly, patients with extremely radiosensitive tumors such as multiple myeloma were excluded from the study. Ghogawala et al. retrospectively reported on 123 patients with spinal metastases. They also found significantly improved neurologic results and life expectancy for patients who had surgery. Additionally, they found a three-fold higher risk of serious wound complications for patients who underwent radiation prior to surgery. Kim et al., in a more recent systematic review of the literature, verified the results of the previous studies. They identified 33 well-designed studies. It was noted that paraplegic patients (from spinal metastasis) who underwent surgery had greater pain relief and 4-fold greater return to ambulation. Tokuhashi et al. published a scoring system to help develop a treatment algorithm for patients with metastatic spinal lesions. They used a patient's general condition, the number of extraspinal bone metastases, the number of metastases in the vertebral body, the metastases to other major internal organs, the primary site of the tumor, as well as the degree of neurologic compromise to determine the life expectancy. They recommended against surgical intervention for patients with less than six months to live. Illustration A is a table showing the Tokuhashi scoring system. Incorrect Answers: Answer 2: Radiation prior to surgery leads to a three-fold increase in wound complications. Answer 3: In patients who do not have highly radiosensitive tumors (i.e. multiple myeloma) the neurologic recovery and life expectancy are improved with surgery. Answer 4: While chemotherapy is a standard treatment for metastatic disease, it has a slow onset and is an inappropriate choice for a patient with acute neurologic deterioration. Answer 5: Palliative care is the appropriate choice for patients with less than 6 months to live. If

this patient was in poor health with multiple unresectable metastatic lesions, along with multiple spinal and metastatic bone lesions, this would be the appropriate choice. Illustrations: A REFERENCES: 1. Patchell RA, Tibbs PA, Regine WF, Payne R, Saris S, Kryscio RJ, Mohiuddin M, Young B. Direct decompressive surgical resection in the treatment of spinal cord compression caused by metastatic cancer: a randomised trial.Lancet. Aug 20-26 2005;366(9486):643-648. PubMed PMID: 16112300. PMID:16112300 (Link to Abstract) 2. Ghogawala Z, Mansfield FL, Borges LF. Spinal radiation before surgical decompression adversely affects outcomes of surgery for symptomatic metastatic spinal cord compression. Spine (Phila Pa 1976). 2001 Apr 1;26(7):818-24. PubMed PMID: 11295906. PMID:11295906 (Link to Abstract) 3. Kim JM, Losina E, Bono CM, Schoenfeld AJ, Collins JE, Katz JN, Harris MB. Clinical outcome of metastatic spinal cord compression treated with surgical excision radiation versus radiation therapy alone: a systematic review of literature. Spine (Phila Pa 1976). 2012 Jan 1;37(1):78-84. doi: 10.1097/BRS.0b013e318223b9b6. Review. PubMed PMID: 21629164. PMID:21629164 (Link to Abstract) 4. Tokuhashi Y, Ajiro Y, Umezawa N. Outcome of treatment for spinal metastases using scoring system for preoperative evaluation of prognosis. Spine (Phila Pa 1976). 2009 Jan 1;34(1):69-73. doi: 10.1097/BRS.0b013e3181913f19. PubMed PMID: 19127163. PMID:19127163 (Link to Abstract) Question Authors: Greg Schroeder, Derek Moore MD, AFSHIN RAZI MD, Felasfa Wodajo MD,

Giant Cell Tumor Author: Patrick O'Donnell

Introduction

A benign aggressive tumor typically found in the epiphysis of long bones Age & sex o more common in females (unlike most bone tumors which show male predominance) o ages 30-50 years Location o 50% occur around knee (distal femur or proximal tibia) o 10% in sacrum and vertebrae (sacrum is most common site in axial skeleton) while GCT can rarely occur in the spine, it usually occurs in the vertebral body o distal radius is third most common location o phalanges of the hand is also a very common location o may arise in the apophysis (like chondroblastoma) o spinal GCT typically occurs in the vertebral body Malignancy o primary malignant giant cell tumor metastatic to lung in 2-5% hand lesions have greater chance of metastasis secondary malignant giant cell tumor occurs following radiation or multiple resections of giant cell tumor

Symptoms

Symptoms

pain referable to involved joint Physical exam o palpable mass o decreased range of motion around affected joint

Imaging

Radiographs o eccentric lytic epiphyseal/metaphyseal lesion that often extends into the distal epiphysis and borders subchondral bone "neo-cortex" is characteristic of benign aggressive lesions, and not unique to GCT Bone scan o is very hot MRI o shows clear demarcation on T1 image between fatty marrow and tumor
o

Histology Characteristic findings o neoplastic cell is the mononucleur stromal cell o hallmark giant cells are numerous nuclei of giant cell appears same as stromal cells o secondary aneurysmal bone cyst degeneration is not uncommon

Treatment Nonoperative o radiation alone indications only indicated for inoperable or multiply recurrent lesions outcomes leads to 15% malignant transformation o medical management indications medical therapy can be used to augment or replace surgical management depending on the specific clinical scenario medications bisphosphonates osteclast inhibitors which may decrease the size of the defect in giant cell tumors denosumab monoclonal antibody against RANK-ligand recent clinical trials suggest denosumab can decrease the size of the bone defect in giant cell tumor Operative o extensive curettage and reconstruction (with adjuvant treatment) indications lesions amenable to currettage hand lesion treatment is controversial if no cortical breakthrough treat with curettage and cementing if significant cortical breakthrough consider intercalary resection (with free fibular graft) vs. amputation technique challenge of treatment is to remove lesion while preserving joint and providing support to subchondral joint extensive exterioration (removal of a large cortical window over the lesion) is required can fill lesion with bone cement or autograft/allograft bone outcomes 10-30% recurrence with curettage alone verses 3% with adjuvant treatment (phenol, hydrogen peroxide, argon beam, etc) o amputation indications hand lesions with cortical breakthrough who are not amendable to intercalary resection

Location Case A Kneerecurrence

Xray

Xray

CT

B. Scan

MRI

MRI

Histo (1)

Case B

Knee

Case C

Distal radius

Case D

Hand

Case B

Knee

Case B

Ankle

Case A

Humerus

Qbank (9 Questions) (OBQ10.204) A 29-year-old female complains of increasing severity back pain for the past 4 months. Radiograph, CT scan, T1 and T2 MRI, and biopsy specimen are shown in Figures A through E. What is the most likely diagnosis? Review Topic FIGURES: A B C D E

1. 2. 3. 4. 5.

Osteosarcoma Ewing's sarcoma Lymphoma Giant cell tumor Chordoma

PREFERRED RESPONSE 4 DISCUSSION: The history, radiographs, CT scan, MRI, and histology slide are consistent with a diagnosis of giant cell tumor of the sacrum. Outside the appendicular skeleton, the sacrum is a common location for giant cell tumor of bone. The radiographs and CT scan show a well defined lytic lesion. The characteristic MRI signal pattern of a lesion which isn't too bright nor too dark is seen on T2 and T1 MRI. This MRI signal is characteristic for giant cell tumor, lymphoma, and Ewing's sarcoma. The histology specimen shows multinucleated giant cells on a mononuclear stromal background. While the MRI appearance may be suggestive of either giant cell tumor, lymphoma, or Ewing's sarcoma, the histology specimen is classic for giant cell tumor. Histology slides for lymphoma and Ewing's sarcoma are shown in illustrations A and B. Note the classic Reed-Sternberg cells of lymphoma with granular cytoplasm and a eosinophilic nucleolus and the small round blue cells of Ewing's sarcoma. Illustrations: A B

REFERENCES: 1. Mirra JM. Bone Tumors. Philadelphia, PA: Lea and Febiger; 1989:941-1022. 2. McDonald DJ, Weber KL. Giant cell tumor of bone. In: Schwartz HS, ed. Orthopaedic Knowledge Update: Musculoskeletal Tumors 2. Rosemont, IL: American Academy of Orthopaedic Surgeons; 2007:133-140.

Question Authors: Patrick O'Donnell MD/PhD, John Badylak MD, Jan Szatkowski MD,

Ewing's Sarcoma
Author: Patrick O'Donnell

Introduction

A distinctive small round cell sarcoma Epidemiology o demographics typically found in patients from 5-25 years of age second most common bone tumor in children uncommon in African Americans and Chinese o locations ~50% are found in the diaphysis of long bones the most common locations include pelvis, distal femur, proximal tibia, femoral diaphysis, and proximal humerus Genetics o t(11:22) translocation found in all cases leads to the formation of a fusion protein (EWS-FLI1) can be identified with PCR and useful to differentiate Ewing sarcoma from other round cell lesions Prognosis

survival 60-70% long term survival with isolated extremity disease at presentation and appropriate treatment/tumor response to chemotherapy 40% long term survival with pelvis lesions 15% long term survival if patient presents with metastatic disease poor prognostic factors spine and pelvic tumors tumors greater than 100cm3 < 90% necrosis with chemotherapy elevated lactic dehydrogenase levels p53 mutation in addition to t(11:22) translocation

Symptoms Presentation o pain often accompanied by fever o often mimics an infection Physical exam o swelling and local tenderness

Imaging Radiographs o large destructive lesion in the diaphysis or metaphysis with a moth-eaten appearance o lesion may be purely lytic or have variable amounts of reactive new bone formation o periosteal reaction may give "onion skin" or "sunburst" appearance Bone scan o required as part of staging workup - will show very "hot" lesion MRI o necessary to identify soft-tissue extension and marrow involvement o often shows a large soft tissue component CT chest o is required for appropriate staging to look for pulmonary metastasis

Evaluation Labs ESR is elevated WBC is elevated anemia is common lactic dehydrogenase Bone marrow biopsy o required as part of workup for Ewing's to rule out metastasis to the marrow
o o o o

Histology Gross appearance o may have liquid consistency mimicking pus Characteristic findings o sheets of monotonous small round blue cells o prominent nuclei and minimal cytoplasm o may have pseudo-rosettes (circle of cells with necrosis in center) Immunostaining o CD99 reactivity

Treatment Operative o chemotherapy and limb salvage resection indications standard of care in most patients chemotherapy preoperative chemotherapy given for 8-12 weeks followed by surgical resection and maintenance chemotherapy for 6-12 months irradiation current trend is towards surgical resection and away from irradiation due to long term morbidity associated with radiation situations where radiation may be used non-resectable tumors (eg. large spinal tumors) patients who present with widely metastatic disease

Location Case A Tibia

Xray

Xray

CT

B. Scan

MRI

MRI

Histo (1)

Case B

femur

Case C

Humerus

Case D

Pelvis

Case E

Pelvis

Case F

Qbank (9 Questions) (OBQ12.222) A 10-year-old male presents with ongoing complaints of left thigh pain after falling during a soccer game. A clinical photo is seen in Figure A. He has tenderness and general warmth over the lateral aspect of his left thigh. His ESR is 82 and his WBC is 15. A radiograph and histology slide are shown in Figures B and C. What is the most likely translocation and fusion protein associated with this condition? Review Topic FIGURES: A B C 1. 2. 3. 4. 5. t (x:18), EWS-FL1 t (2:13), PAK3-FKHR t (11: 22), EWS-FL1 t (11: 22), EWS-CHN t (9: 22), EWS-CHN

PREFERRED RESPONSE 3 DISCUSSION: Based on the presentation and clinical findings, the most likely diagnosis is Ewings sarcoma. The associated translocation and fusion protein is t (11:22), EWS-FL1. Ewings sarcoma, the second most common primary tumor of bone in children, is the result of a translocation event; the resulting protein, EWS-FL1, is seen in all cases. PCR can be used to detect the protein, which can help to discern this from other round cell tumors. Elevated LDH levels and concomitant p53 mutations are noted to be poor prognostic factors. Burchill et al. reviews the histologic, diagnostic and prognostic considerations of Ewings sarcoma. Under light microscopy the tumor is found to be composed of small round cells containing finely dispersed chromatin. They emphasize the importance of research into the fusion proteins as targets for therapeutic intervention. Figure A shows a swollen limb in a patient with Ewings sarcoma of the thigh. Figure B is an AP radiograph of a femur, where significant periosteal reaction is giving the femoral diaphysis an onion skin appearance. Figure C demonstrates the small blue cells that comprise Ewings sarcoma on a histological level. Ewings will also have CD99 immunostaining reactivity. Incorrect Answers 1: t (x:18) is the translocation associated with synoval sarcoma. The fusion protein is SYT-SSX1 2: t (2: 13), PAK3-FKHR is the translocation and associated protein for rhabdomyosarcoma 4, 5: t (9:22) and EWS-CHN are the translocation and associated fusion protein for chondromyxoid sarcoma REFERENCES: 1. Burchill SA. Ewings sarcoma: diagnostic, prognostic, and therapeutic implications of molecular abnormalities. J Clin Pathol. 2003 Feb;56(2):96-102. Review. PubMed PMID: 12560386. PMID:12560386 (Link to Abstract) 2. Hopyan S, Wunder JS, Randall RL. Molecular biology in musculoskeletal neoplasia. In: Schwartz HS, ed. Orthopaedic Knowledge Update: Musculoskeletal Tumors 2. Rosemont, IL: American Academy of Orthopaedic Surgeons Question Authors: Amiethab Aiyer, Ben Taylor MD, Patrick O'Donnell MD/PhD, Jeff Shilt MD,

Adamantinoma
Author: Patrick O'Donnell

Introduction Rare low-grade malignant tumor of unknown etiology that is almost always located in the mid-tibia Epidemiology o incidence less than 300 cases have been documented o demographics occurs in young adults (20 - 40 years of age) Associated conditions o osteofibrous dysplasia historically, it was thought that osteofibrous dysplasia (OFD) was a precursor to this adamantinoma, however current studies have cast doubt on this theory Prognosis o may metastasize to lungs (25%), therefore long-term followup is recommended o recurrence is uncommon with negative margin excision

Presentation Symptoms o pain of months to years duration Physical exam o bowing deformity or a palpable mass of tibia is common

Imaging Radiographs o multiple sharply circumscribed lucent lesions ("soap bubble" appearance) with interspersed sclerotic bone in mid tibia some lesions may destroy cortex o may see bowing of the tibia o radiographic evolution of lesions is helpful in the diagnosis as lesions may continue to grow and erode thru the cortex o unlike other primary bone tumors, adamantinoma typically shows no periosteal reaction

Studies Histology o characteristic fibrous and epithelial tissue in gland like pattern o contains both epithelial and mesenchymal cells nests of epithelial-like cells arranged in palisading or glandular pattern background of fibrous stroma

Treatment

Operative o wide-margin surgical resection indications standard of care in most patients techniques often requires intercallary resection with allograft or intercallary megaprosthesis reconstruction as adamantinoma is a low-grade malignancy, radiotherapy and/or chemotherapy is not typically used for local control of disease

Location Case A tibia

Xray

Xray

CT

B. Scan

MRI

MRI

Histo (1)

Case B

tibia

Case C

tibia

Case D

tibia

Qbank (3 Questions) (OBQ12.31) An 28-year-old male presents for evaluation of leg pain. He denies trauma, and is otherwise healthy. A lateral radiograph of the affected leg is shown in Figure A. A biopsy is taken, and the low and high power histology specimens are shown in Figures B and C. The pathology report states the presence of islands and cords of basaloid epithelial cells in a fibrous stroma with nuclear atypias and mitotic figures. Which of the following should be offered as definitive treatment of this lesion? Review Topic FIGURES: A B C 1. 2. 3. 4. 5. Continued observation Radiation and chemotherapy Bracing to prevent tibial deformity and pathologic fracture Immediate above the knee amputation En bloc resection with wide margins followed by appropriate reconstruction

PREFERRED RESPONSE 5 DISCUSSION: The clinical history and figures are consistent with a diagnosis of adamantinoma. This is best treated initially by en bloc resection with wide margins followed by appropriate reconstruction to prevent local recurrence or metastasis. Differentiating between adamantinoma (AD) and osteofibrous dysplasia (OFD) can be difficult, as the two lesion share many similar characteristics. AD is a rare, low-grade malignant primary bone tumor that occurs most often in the tibia and/or fibula of adolescent persons and young adults; however, it has been reported in other long bones, as well. Histologically, AD is composed of islands of epithelial cells in a spindle-cell stroma and nuclear atypia with mitotic figures may be present as well. OFD is a rare, benign, fibro-osseous lesion that typically is seen within the cortex of the tibia in children. Microscopically, OFD is characterized by a loose, often storiform fibrous background containing spicules of woven bony trabeculae that are lined by a layer of osteoblasts. Treatment of OFD in children usually consists of observation. Kashima et al. assessed expression of podoplanin, a glycoprotein found in osteocytes, in OFD and AD as well as in fibrous dysplasia and metastatic cancer. Podoplanin expression was found in OFD and AD only, and the authors concluded that expression of podoplanin in an osteolytic tumour of the tibia may be useful as a diagnostic discriminant in distinguishing OFD from fibrous dysplasia and ALB from metastatic adenocarcinoma. Most et al. completed a review article discussing the features associated with OFD and AD. They state that management of OFD varies from observation to surgical intervention, depending on the age of the patient and the extent of the lesion. Management of AD requires surgical resection with wide margins, followed by appropriate reconstruction, to minimize the risk of local recurrence or metastasis. Figure A shows a lateral radiograph of a tibia with multifocal lytic lesions and areas of intervening sclerosis, which can give a soap bubble appearance. Figures B and C show the characteristic histological findings of AD including islands and cords of basaloid epithelial cells in a fibrous stroma with nuclear atipias and mitotic figures. Illustration A shows an example of OFD for comparison. Note the classic intracortical anterior tibial lesion which is well marginated and surrounded by an area of sclerosis. Illustration B demonstrates the histology of OFD, showing a loose, storiform fibrous background containing

spicules of woven bony trabeculae that are lined by a layer of osteoblasts. Incorrect Answers: Answer 1: Observation would be appropriate for a diagnosis of OFD in a child. Answer 2: Radiation and chemotherapy are not effective treatments for adamantinoma. Answer 3: Bracing would be appropriate treatment for OFD in the setting of tibial bowing or pending pathologic fracture. Answer 4: Above the knee amputation would be appropriate as a salvage operation if en bloc resection and reconstruction failed. Illustrations: A B

REFERENCES: 1. Kashima TG, Dongre A, Flanagan AM, Hogendoorn PC, Taylor R, Athanasou NA. Podoplanin expression in adamantinoma of long bones and osteofibrous dysplasia. Virchows Arch. 2011 Jul;459(1):41-6. Epub 2011 Apr 16. PubMed PMID: 21499851 PMID:21499851 (Link to Abstract) 2. Most MJ, Sim FH, Inwards CY. Osteofibrous dysplasia and adamantinoma. J Am Acad Orthop Surg. 2010 Jun;18(6):358-66. Review. PubMed PMID: 20511441. PMID:20511441 (Link to Abstract) Question Authors: Joshua Blomberg MD, Patrick O'Donnell MD/PhD, Derek Moore MD,

Neurilemoma
Author: Derek Moore

Introduction A benign encapsulated tumor composed of Schwann cells o tumor is well encapsulated on the surface of a peripheral nerve o also known as Schwannoma Age & location o peak incidence is in the 3rd to 6th decades previous test question ages: 40, 45 o affect males and females equally o often occurs on flexor surfaces of extremities and head and neck o larger lesions may occur in the pelvis Pathoanatomy o can affect motor or sensory nerves Genetics o often associated with mutations affecting NF2 gene Malignant transformation o extremely rare

Presentation Symptoms o usually asymptomatic o may have paresthesia in the distribution of the peripheral nerve Physical exam o may have positive Tinels sign in the distribution of the nerve affected may be present

Imaging MRI
o

sequences

low intensity (dark) T1 high intensity (bright) on T2 diffuse enhancement with gadolinium findings may show string sign difficult to differentiate from neurofibroma

Histology Gross pathology o the lesion is well encapsulated in a nerve sheath o gray in color Histology o Antoni A structure a pattern of spindle cells arranged in intersecting bundles (spindle cell battle formation) o Antoni B areas with less cellularity with loosely arranged cells o Verocay bodies pathognomonic composed of two rows of aligned nuclei in a palisading formation Immunochemistry o strongly uniform S100 antibody staining

Treatment Nonoperative o observation indications asymptomatic lesions Operative o marginal excision indications symptoms or interfering with quality of life technique nerve function may be preserved by careful dissection, excising the lesion parallel to the nerve fascicles so the lesion may be extruded. complications small risk of sensory deficits outcomes recurrence is rare

Neuroma
Author: Derek Moore Introduction Common neuromas include

Interdigital (Morton's) Neuroma Recurrent neuroma

Interdigital (Morton's) Neuroma

Introduction

demographics

more common in females (9:1) location o most frequently between the 3rd and 4th metatarsals o 2nd most common is between 2nd and 3rd metatarsal

poorly understood o compression/tension around the transverse intermetatarsal ligament o repetitive microtrauma o excessive bursal tissue o endoneural edema o all the above can lead to neural fibrosis

Anatomy 3rd and 4th inter-metatarsal space o unique anatomy in that medial branch of LPN and lateral branch of MPN merge and share a common perineurium

Presentation Symptoms o pain 60% of patients report pain radiating into toe distally often pain elicited during push-off phase of running athletes and demipointe position in dancers shoes with narrow toe box or high heels can make symptoms worse patients often complain of feeling like there is a stone or similar under the ball of their foot o paresthesia 40% report numbness or dysesthesia in plantar aspect of web space Physical exam o plantar tenderness with palpation just distal to metatarsal heads o check sensation in affected region as it may be altered in some patients o a bursal click (Mulder's click) may be elicited by squeezing metatarsals together o metatarsalgia and MTP synovitis or instability must be ruled out (use drawer test at MTPJ)

Imaging Radiographs o recommended views three weight bearing views of foot to rule out bony deformity MRI o indications rule out other pathology not required for diagnosis Ultrasound o Many find helpful to evaluate nerve o dependent on size o also not necessary for diagnosis

Studies Pathology shows o perineural fibrosis o thickened and hyalinized walls o demyelination o degeneration of nerve fibers o endoneural edema o absence of inflammatory cells o frequent bursal tissue Differential

MTP synovitis o can mimic an interdigital neuroma o important to differentiate between the two because treatment of interdigital neuroma with a steroid injection can exacerbate pathologic condition at the MTP joint

Treatment

Nonoperative o wide shoe box with firm sole and metatarsal pad indications first line of treatment o corticosteroid injection usually approached dorsal nerve is below intermetatarsal ligament avoid injection of MTPJ due to risk of iatrogenic instability Operative o neuroma resection indications when nonoperative management fails technique dorsal incision used most commonly resection of neuroma 2-3 cm proximal to deep transverse intermetatarsal ligament (incise transverse intermetatarsal ligament) bury proximal stump within intrinsic muscles o neuroma decompression alternative to resection, especially if adjacent neuromas resection of adjacent neuromas will lead to complete numbness of toe

Complication Stump neuroma o causes include inadequate retraction (traction neuritis) most common caused by tethering of plantar neural branches that prevent retraction following resection inadequate resection (not proximal enough) o resect through plantar or dorsal incision Painful plantar scar o increased risk (5%) with plantar incision

Malignant Peripheral Nerve Sheath Tumor

Author: Paul D. Kim

Introduction Overview o arises from a peripheral nerve or neurofibroma o also known as neurofibrosarcoma or malignant schwannoma Epidemiology o demographics 30 to 55 years for solitary neurofibromas 20 to 40 years for neurofibromatosis type 1 (NF-1) Genetics o most cases associated with NF-1 4% incidence in these patients Prognosis o survival for solitary lesion is 75% (5-year survival) o survival associated with NF-1 is 30% (5-year survival)

Presentation Presentation o soft-tissue mass o most arise from large nerves (sciatic, brachial plexus) o motor and sensory deficit of the affected nerve

Imaging Radiograph o usually normal or non-specific soft-tissue mass MRI o low-intensity on T1-weighted images o high intensity on T2-weighted images

serial MRI may show enlargement of previous benign nerve sheath lesion suggesting malignant transformation Bone scan o mildly positive

Studies Histology o classic characteristics are spindle cells with wavy nuclei resembling fibrosarcoma o Immunohistochemistry positive S100 stain keratin staining is negative

Treatment Operative o wide surgical resection + radiation indications standard of care in most patients in general, treated as high-grade sarcoma technique wide resection should include entire affected nerve radiation perform preoperative adjuvant radiation chemotherapy not useful

Neurofibroma
Author: Derek Moore Introduction Benign nerve sheath tumors with multiple cell types o fibroblasts (predominant cell) o nonmyelinating Schwann cells cell of origin, arises from this cell o perineural cells o differentiate from Schwannoma, which involves Schwann cell alone Molecular biology o arise in nonmyelinating Schwann cells with biallelic inactivation of NF1 tumorsuppressor gene o loss of expression of protein neurofibromin neurofibromin negatively regulates RAS-mediated pathway loss of neurofibromin leads to increased Ras activity affects Ras-dependent MAPK activity which is essential for osteoclast function and survival o rapid hyperplasia of nonmyelinating Schwann cells into neurofibromas after NF1 inactivation recruits perineural cells, fibroblasts, mast cells, endothelial cells

Presentation Symptoms o asymptomatic

stinging, itching, pain, disfiguration Physical exam o reduced sensation o cutaneous lesions can "button hole" through skin defect using finger pressure o signs of neurofibromatosis (2 of 7) (NIH criteria) 2 or more neurofibromas, or 1 plexiform neurofibroma axillary or groin freckling (Crowe's sign) 6 or more coast of California cafe-au-lait spots 5mm diameter in prepubertal >15mm diameter in postpubertal sphenoid wing dysplasia or thinning of long bone cortex (anterolateral tibial bowing) 2 or more Lisch nodules (iris hamartomas) on slit lamp optic glioma 1st degree relative with NF1 o associated with NF1 dystrophic kyphoscoliosis rib penciling intraspinal neurofibromas and dumbbell lesions dural ectasia meningiomas

Histology Characteristics o cells

o

predominantly fibroblasts mixed Schwann cells, mast cells, lymphocytes elongated, wavy nuclei

stroma rich wire-like collagen fiber network may be myxoid distorted structures resembling Pacini or Meissner corpuscles variable S100 staining

o o

Malignancies MPNST (malignant peripheral nerve sheath tumor or neurofibrosarcoma) o 5% of patients with NF, 10-25% lifetime risk o symtoms include painful, enlarging soft tissue mass o usually from plexiform neurofibroma 10% of plexiform neurofibromas transform into MPNST o associated with loss of expression of CDKN2A or TP53 genes in non-myelinating Schwann cells (that also have biallelic inactivation of NF1) o poor prognosis widespread metastasis high rate of local recurrence Wilms tumor melanoma leukemia

rhabdomyosarcoma pheochromocytoma

Imaging MRI with and without contrast

Treatment Non operative o observe if asymptomatic Operative o surgical excision if symptomatic may require nerve grafting

Neuroblastoma
Author: Patrick O'Donnell

Introduction Neuroblastoma is a malignant tumor which develops from sympathetic neural tissue o it is the most common solid tumor of childhood o most cases of neuroblastoma arise in the adrenal gland or near the spinal cord Epidemiology o occurs in approximately 1 out of 100,000 children o slight male predominance o the majority of cases occur in children younger than 2 years of age Metastasis o metastasis to the bone are common and a poor prognostic sign Prognosis o the majority of children are cured o metastatic disease is a poor prognostic factor o in very young children, spontaneous regression of the tumor without treatment is known to occur

Presentation

Symptoms o fever, malaise, weight loss, diarrhea o if the adrenal glands are affected, the child may present with significant tachycardia o abdominal mass Exam o may reveal abdominal mass or hepatosplenomegaly Biopsy o needle or open incisional biopsy is required to obtain lesional tissue and make the histological definitive diagnosis

Imaging

Radiographs o may show bone lesions in cases of metastatic disease o bone lesions are often permeative and lytic in nature o may occur anywhere in the skeleton CT o chest/abd/pelvis is the most common initial imaging sequence for evaluation of the extent of disease o helpful in determining the extent of visceral metastasis MRI o MRI scan of the chest/abdomen may be useful to delineate anatomic structures Bone scan o helpful in determining the extent of metastatic bone disease

Histology Small round blue cells forming rosette patterns o other small round blue cell tumors of childhood include rhabdomyosarcoma non-Hodgkin's lymphoma Ewing's sarcoma/PNET blastemic component of Wilms tumor

Treatment Nonoperative o observation indications very young infants with low risk tumors a significant portion of neuroblastomas can spontaneously regress o chemotherapy and stem cell transplant alone indications children with high grade or metastatic neuroblastomas in a location not amenable to surgical resection technique treat with chemotherapeutics like platinum (cisplatin) or alkylating agents (ifosfamide) followed by stem cell transplant Operative o surgical excision indications low grade tumors which can be easily excised with a wide surgical margin while not damaging critical neurovascular structures o chemotherapy, stem cell transplant, and surgical excision indications high grade tumors which arise in close proximity to critical neurovascular structures and therefore cannot be easily excised with a wide surgical margin

Qbank (1 Questions)
(OBQ11.15) What is the most common malignant solid tumor of childhood? 1. 2. 3. Leukemia Lymphoma Neuroblastoma Review Topic

4. 5.

Ewing's Sarcoma Eosinophilic granuloma

PREFERRED RESPONSE 3 DISCUSSION: The most common malignant SOLID tumor of childhood is neuroblastoma, developing from neoplastic transformation of neural-crest derived cells. While leukemia and lymphoma are common pediatric cancers, they are not "solid" tumors. Eosinophilic granuloma is not a malignant tumor but rather described as a tumor like condition secondary to an increase in histiocytes. While Ewing's sarcoma is a common solid neoplasm, it is not as common as neuroblastoma. Dormans and Moroz review the diagnosis, management, and outcomes of spinal tumors and infections in children. While neuroblastoma is derived from neural crest cells, it most frequently originates in one of the adrenal glands, neck, chest, abdomen, or pelvis. Illustration A shows a large mass growing in the area of the right kidney which was biopsy proven to be neuroblastoma. Note how large the pediatric liver is in relation to the rest of the abdominal cavity. Illustration B is a histology slide of a neuroblastoma with its characteristic small round blue cells (like Ewing's sarcoma) with rosette formation.

Illustrations: A

REFERENCES: 1. Khanna G, El-Khoury GY, Menda Y. Imaging in pediatric orthopaedics. In: Morrissy RT, Weinstein SL, eds. Lovell and Winter's Pediatric Orthopaedics. 6th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:67-96. 2. Dormans JP, Moroz L. Infection and tumors of the spine in children. J Bone Joint Surg Am. 2007 Feb;89 Suppl 1:79-97. Review. PMID:17272426 (Link to Abstract) Question Authors: Patrick O'Donnell MD/PhD, Jan Szatkowski MD, Dave Marcu MD,