Metastatic Disease

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Ovid: Oncology and Basic Science

Editors: Tornetta, Paul; Einhorn, Thomas A.; Damron, Timothy A.

Title: Oncology and Basic Science, 7th Edition

> Table of Contents > Section II – Specific Bone Neoplasms and Simulators > 8 – Metastatic Disease

Metastatic Disease

Timothy A. Damron

Metastatic disease to bone accounts for the largest
number of bone lesions in patients greater than 40 years of age. In
fact, the differential diagnosis for an aggressive bone lesion in an
adult is “mets, mets, mets, myeloma, lymphoma, and sarcoma,” in
decreasing order of frequency. Even solitary bone lesions in this age
group are most commonly due to metastatic carcinoma. The role of the
orthopaedist is to establish or confirm the diagnosis, evaluate for
risk of fracture, and stabilize or otherwise surgically treat
pathological fractures and impending fractures. Pathologic fractures
are discussed in Chapter 4, Treatment Principles.

Despite the prevalence of metastatic carcinoma as a
cause of bone lesions in this age group, bone lesions should never be
assumed to be due to metastatic disease without compelling evidence.
One of the most important pitfalls in the evaluation and treatment of
bone lesions in adults is the erroneous treatment of a sarcoma under
the mistaken assumption that the lesion is due to metastatic carcinoma.
Because the principles for treatment differ so greatly between sarcomas
and metastatic carcinomas, the specific diagnosis must be established
before initiation of care. Hence, an aggressive bone lesion in an
adult, while frequently due to metastatic disease, should be considered
a sarcoma until proven otherwise.

Pathogenesis

Etiology

Common sources of bone carcinomas metastasizing to bone in adults
- Most common “osteophilic” carcinomas
  - Breast, prostate, lung, kidney, thyroid (the “big 5”)
  - Melanoma: emerging osteophilic tumor
  - Common sources of metastatic carcinoma (Fig. 8-1)
- Most common when there is an established history of cancer:
  - Breast and prostate
- Most common when there is no established history of cancer
  - Lung and kidney, respectively
Common sources of metastases to bone in pediatric patients
- Neuroblastoma (<5 years old) > rhabdomyosarcoma > retinoblastoma
Common sources for unusual patterns of distribution (any primary may)
- Most common metastases distal to the elbows and knees (“acral” mets)
  - Lung and kidney, respectively
  - 50% of acral mets due to lung carcinomas
- Most common metastases to soft tissue
  - Lung and kidney, respectively

Epidemiology

Frequency of common sources of bone carcinoma metastases (Table 8-1)
New cases: prostate > breast > lung > kidney > thyroid

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Frequency of metastases and survival according to primary source (Table 8-2)

Figure 8-1 Body diagram showing breast, prostate, lung, kidney, and thyroid with arrows to bone.

Table 8-1 Epidemiology of The “Big Five” Most Common Primary Sources of Metastases to Bone

Site	% New Cases (Rank in Top 10)
Site	Female	Male	Number Annual Cases
Prostate	—	33 (1)	230,110
Breast	32 (1)	<1 (-)	215,990
Lung	12 (2)	13 (2)	173,770
Kidney	1 (-)	3 (7)	35,710
Thyroid	3 (8)	2 (-)	23,600
Data from Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin 2004;54:8–29.

Pathophysiology

While the local “soil” in which the metastases deposit
is very important to allowing the establishment of a tumor growth, the
distribution of metastases is intimately related to the route that
metastases take from their site of origin to get to their ultimate
destination (Fig. 8-2 and Table 8-3).
Most metastases escape the circulation by traversing thin-walled venous
structures, so they follow the distribution of the systemic (caval),
portal, or vertebral venous circulation (Batson’s plexus; Box 8-1) to arrive within the lung, liver, or bone, respectively (see Table 8-3).
The axial pattern of distribution of the vertebral venous circulation
is reflected in the predominance of axial locations for the most common
sites of bone metastases (see Fig. 8-2). Lung
carcinomas, given their location, have a relatively greater frequency
of accessing the arterial circulation by means of eroding the pulmonary
venous vasculature within the lungs. Hence, lung carcinomas are the
most common source of bone metastases to the acral skeleton (distal to
the elbow and knee).

Distribution of Metastases Overall

Common sites
- Thoracolumbar spine > sacrum > proximal femur > pelvis > ribs > sternum > proximal humerus > skull

“Soil and seed” versus circulation controversy

Classic argument: idea that certain
tissues are better “soil” for cancer cells versus idea that the
circulation determines the patterns of metastases

“Soil hypothesis” from Paget (1889) with modern considerations

Metastatic tumors have a predilection for red marrow (proximal sites) over yellow marrow.

Adhesion molecules favor recruitment of tumor cells.

For example, stromal cell–derived
factor-1 (SDF-1) recruits prostate cancer cells via interaction with
chemokine receptor (CXCR4) on tumor cells.

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Table
8-2 Fraction of Patients with Each Primary Source Who Will Develop
Metastases, Fraction of Those That Will Involve Bone, and Survival With
Metastases

Primary Tumor	Pts. with Metastatic Disease (%)	Pts. with Metastases who Have Bone Involvement Clinically (%)	Median Survival After Diagnosis of Metastases (mo)	Mean 5-year Survival Rate (%)
Breast carcinoma	65–75		24	20
Prostate carcinoma	65–75	30–40	40	25
Lung carcinoma	30–40	20–40	<6	<5
Renal carcinoma	20–25	15–25	6	10
Thyroid carcinoma	60	20–40	48	40
Multiple myeloma	95–100	100	20	10
Data from Coleman RE. Skeletal complications of malignancy. Cancer 1997;80:1588–1594.

Figure 8-2 Common sites of metastases to bone, in order of relative frequency.

Table 8-3 Circulation Theory of Metastatic Distribution

Circulatory Component	Consequent Site of Metastases
Systemic (caval) venous circulation	Lung
Portal venous circulation	Liver
Batson’s vertebral venous plexus	Bone
Pulmonary venous circulation	All organs, bones

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Figure 8-3 Disruption by tumor cells of normal osteoblast–osteoclast interaction via OPG-ligand.

Algorithm 8-1 Diagnostic work-up of metastatic tumors.

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Growth factors capable of stimulating tumor proliferation are replete in bone.
- Insulin-derived growth factor (IGF)
- Bone morphogenic proteins (BMP)
- Transforming growth factor-beta (TGF-β)

“Circulation theory” from Ewing (1928) (see Table 8-3)

Source of Destruction: Role of the Osteoclast

Osteoclasts, not tumor cells, destroy bone.
Osteoclasts mediate tumor cell attachment to bone.
Breast cancer cells recruit osteoclasts via parathyroid hormone–related protein (PTHrP) (Fig. 8-3).
- Tumor cells produce PTHrP and osteoprotegerin ligand (OPG-L).
- PTHrP stimulates osteoblasts to release osteoprotegerin (OPG) and receptor activator of nuclear factor kappa ligand (RANK-L).
- RANK-L stimulates the RANK receptor on
  osteoclast precursors to cause differentiation into osteoclasts, which
  leads to resorption.
- Osteoprotegerin inhibits the interaction of RANK-L with RANK, decreasing the bone resorption.
Myeloma cells stimulated by interleukin-6 (IL-6) released by osteoclasts

Algorithm 8-2
Evaluation for metastatic disease of unknown primary site. (Adapted
from Rougraff BT, Kneisl JS, Simon MA. Skeletal metastases of unknown
origin: A prospective study of a diagnostic strategy. J Bone Joint Surg [Am] 1993;75:1276–1281.)

Classification

Metastatic disease to bone represents the most advanced
stage of any primary malignancy and carries a similar weight in staging
systems for these cancers as metastases to other distant sites. While
the TLM (tumor, lymph node, metastasis) classification systems differ
in their details between sarcomas and the common carcinomas that
metastasize to bone, spread to bone in all cases shifts the disease to
the highest level.

Diagnosis

The diagnosis of metastatic disease to bone relies on assimilation of data from numerous sources (Algorithms 8-1 and 8-2). In some cases, the diagnosis is apparent on review of only the history, physical examination, and radiographs.

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However, in many cases in which the orthopaedic surgeon will be
involved, the diagnosis will require a more comprehensive evaluation
and biopsy for confirmation.

Physical Examination

Key examinations search for common sources of bone metastases:
- Breast, prostate, lungs, flank (kidney), thyroid
Comprehensive evaluation for other less common sources of bone metastases and sites of concurrent metastases (Table 8-4):
- Skin (melanoma), lymphatics (lymphoma), guaiac examination (colon)

History

Pain
- The most common presenting clinical symptom of bone metastases
- Night pain characteristic
Less common presentations of metastases
- Soft tissue mass (from soft tissue extension or soft tissue metastasis)
- Incidental findings on staging studies coincident with primary tumor diagnosis
- Paraplegia (spine metastases with or without pathologic spinal fracture)
- Pathological fracture (usually preceded by pain, even of short duration)
Soft tissue metastases: more frequently painful rather than painless, whereas most soft tissue sarcomas are painless

Table
8-4 Comprehensive Systemic Approach for Physical Examination and Review
of Systems Relative to Patients with Potential Metastatic Disease

System Examination	Potential Primary Tumor Source	Other Potential Findings
HEENT	Oropharyngeal tumors
Neck	Thyroid carcinoma	Lymphatic metastases
Neurologic		Brain metastases
Lymphatic	Lymphoma	Lymphatic metastases
Skin	Melanoma	Skin metastases
Musculoskeletal
Extremities	Sarcomas	Bone and soft tissue metastases
Back	Renal carcinoma	Bone and soft tissue metastases
Endocrine	Thyroid carcinoma
Cardiovascular		Cardiovascular fitness
Pulmonary	Lung carcinoma	Lung metastases
Abdominal	Colon carcinoma
Rectal	Prostate and colorectal carcinoma	Stool guaiac
Psychiatric	Brain tumors	Brain metastases

Radiologic Features

Most common radiographic appearance: aggressive features (Box 8-2)
- Typical margins: moth-eaten to permeative
- Typical effects on bone: cortical destruction, soft tissue extension (variable)
- Typical bone reactions: nonlaminar periosteal reaction (variable), Codman’s triangle (unusual) (Fig. 8-4, onion-skinning (rare), sunburst (rare)
- Matrix: lytic (Fig. 8-5), sclerotic (Fig. 8-6), or mixed (Fig. 8-7)
- Bone scan: increased uptake (see Fig. 8-4), except in very aggressive lytic tumors (e.g., renal, thyroid, myeloma)
- Radioiodide nuclear medicine study: increased uptake for thyroid carcinoma
Differentiation from myeloma
- Myeloma classic features not typical in metastases
- Myeloma classic features: multiple punched-out lytic defects, raindrop pattern, diffuse osteopenia (Fig. 8-8)
- Only 20% to 30% of lesions “hot” on bone scan

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Differentiation from lymphoma
- Paucity of radiographic changes typical for lymphoma
- Magnetic resonance imaging (MRI) marrow replacement with subtle plain radiographic findings
- Predilection for ends of long bones
- Confluent epiphyseal/metaphyseal/adjacent diaphyseal uptake on bone scan (Fig. 8-9)
Differentiation from Paget’s disease
- Paget’s disease shows classic features of expansion with coarsening of trabeculae and cortical thickening in blastic phase (Fig. 8-10), which are atypical for metastases.
- Paget’s disease lytic phase classic features: blade-of-grass advancing edge sharply delineated from normal bone
- Predilection: ends of long bones, pelvis, spine
- Bone scan: increased uptake on bone scan if untreated

Box 8-2 Typical Radiologic Appearance of Common Metastatic Carcinomas and Their Differential Diagnoses

LYTIC
Lung*
Kidney
Thyroid
Adrenal
Gastrointestinal tract
Melanoma
Head and neck
Chordoma
Mesothelioma
Fibrosarcoma
Malignant fibrous histiocytoma
Ewing sarcoma
Hepatoma
Pheochromocytoma
Differential diagnosis
Myeloma
Lymphoma
Paget’s disease (lytic phase)
Hyperparathyroidism
MIXED (MAINLY LYTIC)
Lung
Breast
Cervix
Ovary
Testicles
Neuroblastoma
Chondrosarcoma
Differential diagnosis
Paget’s disease
OSTEOBLASTIC†
Breast
Bronchial carcinoid
Bowel (stomach)
Bladder
Brain (medulloblastoma)
Bone (osteosarcoma)
Lymphoma
Prostate
Differential diagnosis
Paget’s disease

*Classic, most common osteophilic tumors are shown in italics.
†Mnemonic: “Six bees lick pollen.”
Data from Tuite MJ. Radiologic evaluation. In: Heiner JP, Kinsella TJ, Zdeblick TA, eds. Management of Metastatic Disease to the Musculoskeletal System. St. Louis: Quality Medical Publishing, 2002:55–81.

Laboratory Features

Laboratory tests play a role in the initial evaluation of any patient suspected to have a metastatic bone lesion (Table 8-5).
A limited number of specific laboratory tests are helpful in seeking a
specific diagnosis, while others seek information that may be related
to visceral involvement and potential complications of the malignancy.

Role of specific serum tumor markers in primary work-up: unclear
- Examples: prostate specific antigen (PSA) for prostate cancer, carcinoembryonic antigen (CEA) for colon carcinoma
Tests to seek potential visceral involvement and/or complications
- Complete blood count (CBC) and platelets:
  marrow replacement by tumor or the adverse effects of tumor treatment
  (radiation, chemotherapy) may result in anemia, thrombocytopenia, or
  neutropenia
- Metabolic panel: either visceral
  involvement or the toxicities of treatment may result in electrolyte
  disturbances such as hypercalcemia and/or alterations in renal or
  hepatic function
- Erythrocyte sedimentation rate (ESR):
  elevations in ESR are frequently seen in lymphoma and myeloma, but only
  uncommonly in metastatic carcinoma

Hypercalcemia of Malignancy

Hypercalcemia is common in patients with bone metastases.
It is important to recognize for treatment and as a prognostic factor.
Hypercalcemia can be seen in primary or
secondary hyperparathyroidism, which can create multifocal bone lesions
that may be confused with metastatic carcinoma.
Two types of hypercalcemia of malignancy
- Local osteolytic hypercalcemia: effect of bone metastases
- Humoral hypercalcemia: systemically mediated effect without bone metastases
- Common tumors: squamous cell carcinoma of lung, head and neck carcinoma, kidney cancer, ovarian cancer
Mediators of hypercalcemia of malignancy
- PTHrP, IL6, TNF-β, vitamin D
Interpreting serum calcium levels
- Ionized calcium is the portion of the total (“uncorrected”) calcium not bound to albumin.
- Serum calcium reflects calcium both bound and not bound to albumin.
- If serum albumin is low, an elevated ionized calcium level may be masked by a normal total uncorrected calcium level.
Symptoms of hypercalcemia: weakness, urinary frequency, thirst, nausea, constipation
Treatment of hypercalcemia of malignancy: hydration, bisphosphonates
Prognostic importance: hypercalcemia in metastatic cancer is a poor prognosticator, especially for metastatic lung cancer

Hematologic Complications of Malignancy

Hypercoagulable states are much more common in malignancy than are coagulopathies.

Hypercoagulability may be due to
paraneoplastic erythrocytosis or thrombocytosis from tumor-produced
circulating erythropoietin and thrombopoietin, respectively.

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Figure 8-4 (A)
An isolated left distal femoral bone lesion in an elderly woman without
a history of cancer demonstrates increased uptake on bone scan,
permeative borders, Codman’s triangle, and soft tissue extension.
Biopsy showed metastatic adenocarcinoma. (B) Computed tomography scan of the lung revealed a mediastinal mass consistent with a lung carcinoma primary.

Figure 8-5 A lytic, relatively well-defined metastatic lesion of the right humerus in a patient with renal cell carcinoma.

Figure 8-6 A pelvic radiograph shows typical blastic metastases from prostate cancer.

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Figure 8-7
Multiple bone lesions in a woman with breast cancer show the wide
variation in appearance of breast cancer metastases to bone, from the
predominately lytic appearance in the ischium, the mixed lytic and
blastic proximal femur metastases, and the sclerotic distal femur
metastases.

Figure 8-8
Radiographs from humerus and femur of a patient with multiple myeloma
show classic raindrop pattern of punched-out lytic defects throughout
the bones.

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Figure 8-9
An isolated left proximal femoral bone lesion shows a permeative lytic
process involving the proximal femur with confluent uptake on bone scan
involving the femoral epiphysis, metaphysis, and proximal diaphysis.
Biopsy showed lymphoma.

Figure 8-10
Paget’s disease of bone in its sclerotic phase can be confused with
prostate cancer. This patient with Paget’s disease of the entire right
hemipelvis shows the typical coarsening of trabeculae and bony
expansion (both best seen in the pubic rami) as well as confluent
uptake on the bone scan.

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Table 8-5 Laboratory Tests Important in The Evaluation of Metastatic Disease

Laboratory Test	Positive Finding	Disease Association
Serum protein electrophoresis	Monoclonal spike (monoclonal gammopathy)	Multiple myeloma
Urine protein electrophoresis	Bence Jones proteins	Multiple myeloma
Lactate dehydrogenase	Elevated	Lymphoma (nonspecific; depends on disease load; also with osteogenic sarcoma, Ewing sarcoma)
Prostate specific antigen	Elevated	Prostate carcinoma
Urinalysis	Hematuria	Renal cell carcinoma
Alkaline phosphatase	Elevated	Paget’s disease of bone (nonspecific; also with osteogenic sarcoma)

Common tumors: adenocarcinomas, especially lung, pancreas, and stomach
Diagnosis: no helpful screening laboratory tests available

Biopsy of Lesions Suspected to be Metastatic (also see Chapter 3, Biopsy of Musculoskeletal Tumors)

Biopsy of bone and soft tissue lesions suspected to be
metastatic in origin should follow the same principles as those for a
sarcoma. If a biopsy is to be done prior to the stabilization of an
impending or actual pathologic fracture, care should be taken to avoid
contaminating tissue or bone regions not already involved by the tumor.
Do not send reamings from the femur or
humerus as a biopsy specimen to establish the diagnosis; in addition to
being histologically inferior to a standard biopsy, if the patient has
a sarcoma, the lesion will then have been unnecessarily spread
throughout the reamed region of bone and possibly disseminated into the
caval venous system as well. The best solution in the case of an
impending or pathologic fracture is to establish the diagnosis first by
way of a direct approach to the tumor for an incisional biopsy,
contaminating the fewest tissue planes and compartments possible. In
the proximal femur, this is done through a lateral approach at or near
the ridge between the gluteus maximus insertion and the vastus
lateralis origin. In the proximal humerus, a proximal biopsy should be
performed through the anterior aspect of the deltoid but not exposing
the cephalic vein.

Table 8-6 Metastatic Tumors with Histopathology of Specific Origin

Tumor	Source	Histopathology
Clear cell carcinoma	Kidney	Groups of clear cells separated by delicate arborizing vasculature
Well-differentiated follicular carcinoma	Thyroid	Colloid-filled follicles
Metastatic pigmented malignant melanoma	Skin	Intracytoplasmic melanin

Pathology Features

The histology of metastatic carcinoma usually does not
reveal the specific site of origin. There are a limited number of
exceptions to that rule (Table 8-6 and Fig. 8-11).
More importantly, when an appropriate metastatic work-up has been done
in advance, the pathology only needs to confirm the presence of
metastatic carcinoma consistent with the identified probable source to
allow surgical treatment to

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proceed.
Since many of these cases rely upon frozen section for diagnosis, the
pathologist does not have the luxury of waiting for
immunohistochemistry staining results, which can be very helpful (Table 8-7).

Figure 8-11 Representative pathology sections from typical metastatic lesions. Metastatic adenocarcinoma of lung (A), follicular thyroid carcinoma (B), malignant melanoma (low power) (C), squamous cell carcinoma (D), clear cell renal carcinoma (E), and melanoma (high power) (F).

Table 8-7 Immunohistochemistry for Metastatic Carcinomas and Tumors in Their Differential

Primary Tumor	Immunohistochemistry Marker
Carcinomas in general	Cytokeratins, epithelial membrane antigen (EMA)
Prostate carcinoma	Prostate specific antigen
Lung carcinoma	Thyroid transcription factor (TTF-1)
Malignant melanoma	HMB45
Lymphoma	Leukocyte common antigen

Histopathology that identifies the specific source of origin (see Table 8-6)
Histopathology suggestive of source of origin
- Adenocarcinoma of breast
- Adenocarcinoma of colon

Histopathology of nonspecific origin (Table 8-8)

Table 8-8 Tumors With Histopathology of Nonspecific Origin

Tumor	Potential Sources
Metastatic squamous cell carcinoma	Lung, head and neck, esophagus, cervix
Metastatic adenocarcinoma without differentiating features	Breast, colon, prostate, ovary, endometrium, stomach, lung
Metastatic clear cell adenocarcinoma	Ovary, endometrium, lung
Poorly differentiated carcinomas	Lung, prostate, pancreas, thyroid, breast, colon, ovary, endometrium, stomach, etc.

Differential pathology diagnoses
Anaplastic large cell lymphoma
Poorly differentiated angiosarcoma
Primary and metastatic sarcoma

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Treatment

Surgical and Nonoperative Options

The three main indications for surgical treatment of
patients with metastases are for diagnosis, prophylactic fixation of
impending fractures, and stabilization of pathologic fractures. Many
patients with bone involvement by metastatic disease or myeloma can be
treated nonoperatively. Both surgical and nonsurgical options are
discussed in more detail in the chapter on pathologic fractures (Chapter 4).

Indications for Biopsy of Suspected Metastatic Disease

Solitary new destructive lesion with or without history of cancer
- Biopsy first before proceeding with treatment!
- Other processes seen in adults that
  should not be treated the same as a metastatic lesion and therefore
  must be considered in the differential diagnosis
  - Bone sarcomas: chondrosarcomas, malignant fibrous histiocytoma, fibrosarcoma, postradiation sarcoma, Paget’s sarcoma
  - Most common mistake: placement of an intramedullary nail through a bone sarcoma without biopsy
  - Most common result: unnecessary amputation
- Other processes seen in adults that may require medical intervention prior to surgical procedure
  - Hyperparathyroidism
  - Paget’s disease
Multiple bone lesions without biopsy-proven metastatic bone disease (even with history of cancer)
- Biopsy first before proceeding with treatment!
- Multiple other scenarios mimic metastatic carcinoma! (Box 8-3)
Situation that does not require biopsy of new bone lesion
- Established histologically proven mets to bone and/or viscera

Indications for Stabilization of Pathologic Fracture

The site and type of pathologic fracture
determine to a large extent the need for surgical stabilization, and
those specific details are discussed in Chapter 4.5, Pathologic Fractures.
- Sites that frequently require stabilization
  - Upper extremity: humerus
  - Lower extremity: femur, tibia
Patient factors should be considered as well.
- Moribund, immediately preterminal patients are a contraindication to surgery.
- Minimum expected survival: 6 to 12 weeks

Indications for Prophylactic Fixation of Impending Fractures

These factors are discussed in detail in Chapter 4.5.

Preoperative Planning

Search for Concomitant Lesions Requiring Prevention or Intervention

Other coexisting metastatic lesions may require
modification of the technique for anesthesia and/or difficulty with
postoperative care. These lesions and the potential problems they may
create should be investigated. Review of the most recent bone scan is
useful in this regard.

Cervical spine disease: an anesthesia concern
- History and examination: Does patient have neck pain or tenderness?
- Radiologic investigation: Review most recent bone scan, consider new plain cervical spine radiographs.
Impending upper extremity pathologic
fractures: may cause postoperative pain and/or fracture if recovery
period requires ambulatory aids for weight bearing.
- History and examination: Does patient have shoulder or arm pain and/or tenderness?
- Radiologic investigation: Review most recent bone scan; consider new shoulder or humeral radiographs.

Search for Hematologic Abnormalities

Hematologic abnormalities may result from marrow replacement by tumor, chemotherapy, and/or radiotherapy.

Anemia management guidelines
- Consider preoperative transfusion if hemoglobin is <10.0 mg/dL or large amount of blood loss anticipated.
- Use leukodepleted, irradiated red blood cells if patient has been on chemotherapy.
Thrombocytopenia management guidelines
- Preoperative platelet transfusion if platelet count is <50,000/mm³
Leukopenia management guidelines
- Consider canceling major operation if absolute neutrophil count (ANC) is <1,000/mm³.
- Avoid major operations at time of typical nadir in white blood cell count following chemotherapy.

Search for Hypercalcemia

Most common primary malignancies: lung carcinoma, head and neck, kidney, ovarian
Early symptoms are flu-like: fatigue, lethargy, anorexia, constipation, nausea, polyuria

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Late symptoms of stupor and dysrhythmias
Treatment: hydration, bisphosphonates

Does the Patient Need Preoperative Embolization?

Highest risk of bleeding during intralesional procedures: renal carcinoma metastases
Increased risk of bleeding (others): myeloma and thyroid carcinoma metastases
Consider embolization.
- Especially for renal carcinoma intralesional procedures
- Also myeloma and thyroid carcinoma of spine, pelvis

Surgical Goals and Approaches

Patients with metastatic disease to bone or myeloma have
limited ability to heal fractures, shortened life spans, and the
potential to develop other sites of bone involvement, which may
compromise prior surgery. Therefore, these patients cannot be treated
the same as those with routine fractures. The specific approaches to
achieving these goals are discussed in Chapter 4.5.

Goals of surgical intervention:

Achieve immediately rigid fixation to allow early use.
Achieve durable fixation to last the patient’s expected shortened lifetime.
Protect the entire bone when feasible.

Techniques

Internal Fixation

Intramedullary fixation
- Diaphyseal fractures and impending fractures
- Metaphyseal fractures with adequate epiphyseal bone
- Consider bone cement supplementation.
Plate fixation
- Metaphyseal and diaphyseal fractures
- Supplement with bone cement in most cases.

Prosthetic Replacement

Indications
- Failure of or inability to achieve goals
  by internal fixation (e.g., extensive peritrochanteric destruction not
  necessarily involving femoral head)
- Joint surface destruction (e.g., femoral head, femoral condyles, humeral head)
- Need for resection and reconstruction, such as sometimes indicated for the solitary renal carcinoma metastasis

Complications

Orthopaedic operative intervention for patients with
metastatic disease and myeloma entails all of the usual risks. Only
those with specifically increased or unique risks are detailed below.

Infection
- Administer prophylactic cephalosporin antibiotics in all cases.
- Consider adding aminoglycoside for patients with neutropenia or large prosthetic reconstructions.
Failure of internal fixation
- Avoid by achieving goals of surgical intervention in operating room.
- Administer postoperative radiotherapy to avoid disease progression that may compromise result.
Cardiovascular collapse from cementing
- Especially with long-stem cemented femoral stems
- Communicate with anesthesia prior to cementing.

Results and Outcome (Prognosis)

The recovery period for any operative intervention in a
patient with metastatic disease should not be longer than the patient’s
expected survival. However, prediction of survival is difficult at best.

Prognostication for Surgical Candidates

Nonspinal sites postoperative survival
(patients undergoing surgical intervention for metastatic bone disease
of any site other than spine)
- Postoperative survival rates over time
  - 1 year: 40%
  - 2 years: 30%
  - 3 years 20%
- 1-year survival rates (Table 8-9)
- Negative prognostic factors (multivariate analysis)
  - Pathologic fracture
  - Visceral metastases
  - Hemoglobin <7 mmol/L
  - Lung cancer
- Positive prognostic factors (multivariate analysis)
  - Myeloma
Proximal femur (patients undergoing hip arthroplasty for femoral and/or acetabular metastatic bone disease)
- Survival rates over time following hip arthroplasty for metastatic disease
  - 1 year: 40%
  - 2 years: 20%
  - 3 years: 15%
- Negative prognostic factors (multivariate analysis)
  - Time from diagnosis of primary to hip surgery (shorter interval = poorer prognosis)

Table 8-9 Postoperative 1-Year Survival Rates

Primary Tumor with Metastases	Survival Rate (%)
Myeloma	65
Lymphoma	50
Breast	50
Kidney	43
Prostate	26
Lung	24
Unknown primary	20
Data from Hansen BH, Keller J, Laitinen M, et al. The Scandinavian Sarcoma Group Skeletal Metastasis Register. Survival after surgery for bone metastases in the pelvis and extremities. Acta Orthop Scand Suppl 2004;311:11–15.

Disease-Specific Prognostication

Metastatic breast cancer
- Poor prognostic factors
  - Caudal metastases: 5-year survival rate
    is 16% for those with bone mets below lumbosacral junction versus 36%
    for those above lumbosacral junction
  - Extraosseous metastases: median survival 5 months after identified
  - Lytic metastases: 5-year survival 23% versus 42% with blastic metastases
  - Hypercalcemia: harbinger of subsequent visceral metastases
- Good prognostic factors
  - Cranial metastases (above lumbosacral junction)
  - No extraosseous metastases
  - Blastic metastases
  - No hypercalcemia
Metastatic prostate cancer
- Number of metastatic sites inversely proportional to expected survival duration
- Best prognoses: (1) pelvis only, (2) thoracic vertebra only
- Worst prognoses: (1) skull combined with other sites, (2) sternum combined with other sites

Postoperative Management (Guidelines)

Antibiotics
- Routine cases: 24 to 48 hours intravenous cephalosporin coverage or until drain discontinued
Mobilization
- Strive for goal of early mobilization with full weight bearing when feasible.
External-beam radiotherapy
- Radiotherapy as an adjunct to operative treatment
  - There are documented benefits in metastatic disease patients treated surgically for bone disease.
    - Reduces need for subsequent surgical procedures (3% versus 15%)
    - Improves postoperative functional status
  - Postoperative timing
    - After wound healing completed
    - Typically 2 to 4 weeks postoperatively
  - Doses
    - 3,000 cGy in 10 fractions or 2,000 cGy in 5 fractions
    - 4,500 cGy in 180-cGy fractions for patients with renal and thyroid carcinoma and life expectancy of 12 months or more