weakness, and swelling or varicosities in the lower extremities.

Complete history and physical examination should exclude signs and symptoms of lymphoma (e.g., Bsymptoms such as fevers and night sweats) and presence of scrotal masses concerning for testes cancer.

Serum laboratory testing can be helpful if lymphoma (e.g., elevated lactate dehydrogenase [LDH]),

germ-cell tumors (e.g., elevated beta-human chorionic gonadotropin (B-HCG) or alpha-fetoprotein

[AFP]), or adrenal tumors (i.e., cortisol levels or adrenocorticotropic hormone [ACTH]) are in the

differential diagnosis. High-quality cross-sectional imaging with CT or MRI is critical for diagnosis and

treatment planning. Use of oral and intravenous contrast defines extent of primary disease and the

relationship of the tumor to nearby structures. Chest imaging should be obtained to assess for presence

of pulmonary metastases. Hepatic involvement is the second most common site of distant spread in

intra-abdominal and retroperitoneal sarcomas, so a CT scan that includes the proper contrast phasing for

examination of the liver should be done.

4 For large tumors, preoperative image-guided biopsy can almost always be performed by

experienced interventional radiologists (Fig. 108-11). However, preoperative biopsy is not

mandatory5,97 if management would not be altered by findings. Use of biopsy is reserved for cases in

which a diagnosis of sarcoma is in question or if neoadjuvant approaches are being considered for large,

high-grade lesions or lesions which are locally advanced and potentially unresectable. Complete

resection is the treatment of choice for intra-abdominal (visceral) and retroperitoneal sarcomas

whenever possible. Only complete resection is associated with long-term survival benefit, with

retroperitoneal liposarcomas being a possible exception.98,99 For retroperitoneal sarcomas, median

survival for those with an incomplete resection is similar to those who were observed (unresectable)100

(Fig. 108-12). In general, incomplete resection should only be considered for palliation of intractable

symptoms. While successful palliation may be achieved in carefully selected patients, aggressive tumor

biology limits the ability to maintain sustained relief of symptoms.101

In order to attain complete removal of the sarcoma, en bloc resection of nearby structures should be

considered when necessary. Resectability is more a function of location than of size, grade, or histologic

subtype. Common reasons for unresectability include distant metastasis, peritoneal metastasis, extensive

multifocality, and prohibitive vascular involvement. Though sarcomas do not uniformly invade other

structures, involvement of vascular structures or mesentery (mesocolon) may lead to resection of solid

organs or bowel that may not be directly involved. When nephrectomy may be necessary, it is

important to assess bilateral renal function with preoperative contrast scanning. Concomitant

nephrectomy, when necessary, is associated with comparable outcomes for retroperitoneal sarcomas

overall.102 Commonly resected organs include the following: kidney, colon, adrenal gland, pancreas,

and spleen.103 For tumors located in the pelvis, it may be necessary to perform en bloc resection of the

colon/rectum, bladder, and uterus. When vascular structures limit complete resection of tumor,

resection with ligation or reconstruction of vessels must be considered if technically feasible (Fig. 108-

13).

Even when surgical resection is possible and complete gross resection is achieved, margin status is

often compromised by constraints of visceral anatomy. A transperitoneal approach allows for excellent

exposure and facilitates en bloc resection of with early control of the vascular supply to the tumor.

Analyses of relatively aggressive approaches to resection include complete compartmental resections

and liberal use of en bloc visceral resection shows better local control, but high-grade tumors tend to

recur systemically. Proper patient selection for so-called “aggressive resection” needs to be weighed

against the natural history of sarcoma.104–106 It is generally agreed that the best chance for curative

intent resection is at the time of first operation. Complex multivisceral operations should be referred to

higher-volume centers with experienced sarcoma surgeons when possible.

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Figure 108-11. Biopsy can be helpful in the workup of retroperitoneal masses. A: CT scan shows a retroperitoneal mass encasing

the IVC and aorta. B: Image-guided biopsy is demonstrated here. Pathology confirmed a diagnosis of large B-cell lymphoma.

Even with aggressive surgical management, local recurrence rates range from 40% to 70% for highgrade tumors.13,107 Unlike extremity sarcomas, local progression is associated with decreased survival.

Difficulty obtaining negative margins and high recurrence rates support a role for carefully selected

multimodality treatments. The benefits of radiation for extremity sarcomas have not been similarly

appreciated for retroperitoneal sarcomas and no improvement in disease-free intervals have been

noted.108 Large field sizes and the dose-limiting toxicity of abdominal viscera limit the utility of

postoperative radiation, and preoperative radiation warrants consideration. The major advantage of

preoperative radiation is the displacement of small bowel and other structures by the in situ tumor.

Similar to preoperative radiation for extremity tumors, a possible advantage in the

abdomen/retroperitoneum is that the radiation may prevent later seeding of tumor cells because

radiation is administered to tumor and surrounding peritoneum. With the advent of conformal

technology, or intensity-modulated radiation therapy (IMRT), further selective application of

radiotherapy may be possible with minimal toxicity.109,110 The role of chemotherapy, either in the

preoperative or postoperative setting, is unproven for intra-abdominal and retroperitoneal

sarcomas.111,112 Several trials of postoperative adjuvant chemotherapy do not show any benefit for

patients with retroperitoneal sarcoma, and in one series, treated patients fared worse than those not

receiving chemotherapy.113 In one trial of an aggressive multimodality approach, there was an

improvement in locoregional control but no overall survival advantage and significant toxicity from the

chemotherapy and radiation therapy.114 Though some histologic subtypes, such as leiomyosarcoma,

pleomorphic sarcoma, or myxoid/round cell liposarcoma, may be relatively more responsive to systemic

treatments, a paucity of data exist to guide appropriate use of therapy. Randomized controlled trials

have been notoriously difficult to accrue patients to.

Special consideration is also given to complete resection with functional preservation in head and

neck sarcomas and genitourinary sarcomas. As is true of sarcomas in other anatomic locations,

histologic grade and size adversely affect prognosis for head and neck sarcomas.115 Resections with

negative margins may not require adjuvant radiotherapy treatments. Similarly, grade, size, location,

and histologic subtype similarly predict disease-specific survival for genitourinary sarcomas.116 Regional

relapse is influenced by margin status so radical resections are necessary. Unfortunately, recurrences are

not uncommon and may be difficult to control due to anatomic location.

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Figure 108-12. Kaplan–Meier plot of disease-specific survival for patients with retroperitoneal sarcomas treated at Memorial Sloan

Kettering Cancer Center. Disease-specific survival is 103 months in patients who underwent complete resection of retroperitoneal

sarcomas, compared to 18 months in those who had an incomplete resection or just observation. (From Lewis JJ, Leung D,

Woodruff JM, et al. Retroperitoneal soft-tissue sarcoma: analysis of 500 patients treated and followed at a single institution. Ann

Surg 1998;228(3):355–365.)

Figure 108-13. Inferior vena cava (IVC) leiomyosarcoma. A: CT scan demonstrates a 9.2- × 6.4- × 4.4-cm mass within the lumen

of the retrohepatic IVC. B: Photograph of the gross specimen. Cross-sectional view from the superior aspect of the specimen

demonstrates the extensive filling of the lumen with multilobulated tumor. C: Photomicrograph demonstrating intraluminal highgrade leiomyosarcoma with nuclear atypia and pleomorphism. Uninvolved smooth muscle of the IVC is shown (right lower

quadrant). (Courtesy of Jason Carvalho, MD and David R. Lucas, MD, University of Michigan, Ann Arbor, MI.)

RECURRENT OR METASTATIC DISEASE

About two-thirds of soft tissue sarcoma recurrences occur in the first 2 years after diagnosis and

treatment, though recurrences may be seen at any time.117 Recurrences may be classified as

locoregional or distant. Though no standardized follow-up regimens exist, routine history and physical

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examination (clinical follow-up) and interval chest imaging are recommended for the first 2 to 3 years.

Site-specific imaging guidelines are less clear. Directed cross-sectional imaging studies are helpful if

location of tumor precludes early detection of recurrence on clinical evaluation alone. Of course, the

choice of imaging study depends on availability, cost, and anatomic site being examined. MRI of the

extremity or trunk can help detect locoregional recurrences when they are relatively small. CT scans

may be useful for detection of intra-abdominal or retroperitoneal recurrences which would otherwise be

undetectable. However, there is no evidence that earlier detection improves survival for retroperitoneal

sarcomas,100 so a less aggressive imaging schedule may be appropriate.

If chest radiography is used, abnormal findings should be followed with a CT scan of the chest. Lowgrade lesions infrequently metastasize in the absence of local recurrence, though can recur locally up to

20 years after original resection. For high-grade lesions, surveillance should be directed toward

detecting recurrence and metastatic disease. Patients with locally recurrent or even metastatic sarcomas

can be considered for surgical resection if tumor biology supports potential cure or effective palliation

with removal of known disease. Recurrent disease, especially within the abdomen or retroperitoneum,

becomes more difficult to treat with each recurrence.117

If a recurrence is suspected, a biopsy should be performed to confirm diagnosis and review histologic

subtype as well as tumor grade, with reference to the original tumor if possible. In the absence of

distant disease, an aggressive surgical approach is warranted with the goal being the same as with a

primary sarcoma – control of the tumor and preservation of as much function as possible. For patients

who were initially treated with surgery alone and who failed locally, multimodality treatment with

repeat resection, radiation, and sometimes chemotherapy is associated with survival rates close to those

of previously untreated patients.118–120 Independent predictors of survival in patients with locally

recurrent extremity soft tissue sarcomas include histologic grade, size of recurrent disease, and

recurrence-free interval.121

The most common site of distant metastatic disease is the lung, and its presence is not detectable by

symptoms. Again, CT is the preferred imaging modality, though its very high sensitivity for detecting

pulmonary nodules as small as 2 mm decreases its specificity.122,123 Occasional patients have liver,

bone, or central nervous system metastases though these sites of disease are relatively uncommon. Once

diagnosed, metastatic disease is best approached with systemic chemotherapy, either as a single agent

or with combination treatments. Pulmonary metastases are the most common form of distant disease,

and metastasectomy in carefully selected patients seems to improve outcomes. Taking patient selection

into account, resection of pulmonary metastases in combination with radiation and/or chemotherapy,

may improve outcomes compared to resection alone124,125 (Fig. 108-14).

Figure 108-14. Kaplan–Meier plot of disease-specific survival for patients with pulmonary metastases treated at Memorial Sloan

Kettering Cancer Center. Patients treated with complete resection had a median survival of 33 months. Patients who underwent

incomplete resection or who did not undergo resection had median survival of 16 months and 11 months, respectively. (From

Billingsley KG, Burt ME, Jara E, et al. Pulmonary metastases from soft tissue sarcoma: analysis of patterns of diseases and

postmetastasis survival. Ann Surg 1999;229(5):602–610.)

GASTROINTESTINAL STROMAL TUMORS

Another subtype of sarcoma which deserves separate consideration is GIST. Prior to modern molecular

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diagnostic techniques, these tumors were likely to have been considered leiomyosarcomas based on

histologic features.13 It is now known that GISTs are differentiated from GI leiomyosarcoma based on

lack of well-differentiated smooth muscle cells. GISTs are composed of more primitive mesenchmyal

cells and originate from the interstitial cell of Cajal, which functions within the GI autonomic nervous

system. Immunohistologic diagnosis is made via expression of KIT (CD 117) cellular markers. KIT

overexpression is usually related to mutations in the KIT gene, although PDGFR-α mutations can also

result in KIT overexpression in approximately 3% to 5% of GIST. KIT-negative GISTs have been

reported, though tumor genotyping should be done to either KIT or PDGFR-α mutations even with

negative immunohistochemistry for KIT.126

The KIT proto-oncogene encodes for KIT protein, a transmembrane glycoprotein receptor with an

intracellular tyrosine kinase domain. Binding of the KIT ligand induces dimerization and

autophosphorylation of KIT, activating a cascade of intracellular signaling which results in cell

proliferation and tumorigenesis. A gain of function mutation in KIT occurs in up to 90% of GIST127 and

results in ligand-independent (constitutive) activation of tyrosine kinase function.128 KIT mutation is

found in 90% of GIST and the most frequent sites of mutation are found in exon 11 (70%) or exon 9

(10%), whereas rare mutations are found in exon 13 or exon 17.129 Mutation status may affect

prognosis, and testing has become more routine in the evaluation of GIST.

Swedish epidemiologic data estimates 14.5 cases per million, which translates to an annual US

incidence of 4,000 to 5,000 new cases of GIST per year.130 GISTs are largely sporadic, but they have

been seen in association with hereditary syndromes such as von Recklinghausen disease and Carney

triad, and familial germline mutations have been identified. Clinical presentation can be indolent – most

patients have nonspecific symptoms such as nausea, emesis, or abdominal discomfort. Infrequently,

GIST can rupture or bleed, leading to a more emergent presentation. GISTs are most commonly found in

the stomach (50% to 60%), with 30% to 40% of tumors in the small bowel, 5% in the colon or rectum,

and 5% in the esophagus. Rarely, GISTs develop within the mesentery, omentum, or retroperitoneum.

Most GISTs are found in adults over the age of 40, with a median age of 60 years. Tumors found in

children or young adults are considered a separate entity since pediatric GISTs have a more epithelioid

histology and wild-type KIT or PDGFR-α genotype.131

Complete surgical resection is the treatment of choice for GIST, but recurrences are common and 5-

year survival following resection of a localized tumor is approximately 50%.132 Recurrences are

common and thought to occur at 18 to 24 months from the time of the index operation. Lymph node

dissection is not warranted because GIST very rarely metastasizes to regional nodes. Treatment of GIST

was revolutionized with the development of imatinib mesylate (Gleevec), a selective tyrosine kinase

inhibitor, representative of the emerging paradigm of molecularly targeted therapies. The proof of

concept for this treatment paradigm was demonstrated in 2000 when a patient with diffuse metastatic

disease achieved a near-complete metabolic response133 on PET and with 75% reduction in tumor size at

8 months and histologic evidence of myxoid degeneration and lack of mitotic activity. Contemporary

use of imatinib in patients with metastatic GIST is considered appropriate first-line treatment of

metastatic disease (Fig. 108-15).

For patients who present with localized tumors, resection remains the mainstay of treatment.

Interestingly, emerging evidence suggests that incidentally discovered, very small GISTs (<2 cm) may

be successfully managed expectantly.

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Figure 108-15. 18FDG-PET scan showing response of metastatic GIST to imatinib mesylate. This patient presented with primary

disease in the small bowel and synchronous metastatic disease in the liver. The scan at presentation (left) compared to the one

obtained after 3 weeks of therapy (right) shows decrease in size of tumors and decreased 18FDG uptake in both the small bowel

and liver tumors consistent with a good response to imatinib. The patient eventually went on to complete surgical resection. (From

Gold JS, Dematteo RP. Combined surgical and molecular therapy: the gastrointestinal stromal tumor model. Ann Surg 2006;

244(2):176–184.)

5 The use of imatinib in the adjuvant setting has been informed by a number of clinical trials.

Mutation status is predictive of treatment success; KIT exon 11 mutations are associated with better

response rates and survival endpoints than exon 9 mutations and wild-type GISTs. Because of high rates

(>50%) of recurrence or metastasis following resection, at least 3 years of imatinib is recommended for

high-risk tumors, including tumors which are greater than 5 to 10 cm in size or contain more than 5

mitoses per 50 HPFs. Risk stratification must be approached with care; other factors which need to be

considered include location of tumor and mutation status. It is reasonable to consider the use of imatinib

for large or borderline resectable lesions prior to surgical resection. Most of these cases require

continued treatment after resection given the high risk of recurrence or metastasis. Second- and thirdline (and beyond) therapies are available for drug-resistant disease, but as expected, responses following

failure of first-line therapy are highly variable.

DESMOID TUMORS/DESMOID FIBROMATOSIS

Desmoid tumors warrant separate notation in the discussion of soft tissue tumors because of their

distinct biologic behavior.15,134 Desmoid tumors, or aggressive deep-seated fibromatosis, are part of a

rare group of fibrous tissue proliferations which have no propensity for metastasis but tend to be locally

aggressive. The natural history of desmoid tumors is not well defined and poorly understood. Clinical

behavior and therefore, recommended treatments, are often dictated by anatomic site. Location of

tumors can limit therapeutic options and result in significant morbidity with or without surgical

resection.

Desmoid tumors are uncommon with an estimated incidence rate of 2 to 4 cases per million per year.

The median age of diagnosis is 35, range 16 to 79 years. Desmoids are slightly more common in women

than men. Desmoid tumors are classically described as an abdominal wall tumor, seen in young women

during the postpartum period.135 However, desmoids can occur at any site in the body and three main

anatomic sites are described: (1) trunk or extremity, (2) abdominal wall, and (3) intra-abdominal

(bowel and mesentery). Fibromatosis is usually seen sporadically, but can be associated with FAP.

Desmoids are characterized by a monoclonal fibroblastic proliferation arising from muscular or

aponeurotic structures. On gross examination, the tumors appear firm and smooth, with a surrounding

pseudocapsule. However, microscopically, the tumor characteristically extends beyond this

pseudocapsule, with fibrous septae of tumor extending radially. Desmoid tumors had previously been

classified as an unchecked reactive process rather than a neoplastic process, but uniform patterns of Xchromosome inactivation seems to confirm tumors of clonal composition.136 There appears to be an

increased estrogen receptor-β, but not estrogen receptor-α, expression in 80% of desmoid specimens.137

These findings lend some support for the treatment of tumors with adjuvant agents such as tamoxifen.

Tumors tend to be located deep in the muscles or along fascial planes, such as at a point of muscular

insertion. Patients will usually present with a greater than 5 cm, localized, firm mass with an indolent

pattern of growth, which can be minimally painful. Intra-abdominal presentations can be associated

with mass effect, intestinal obstruction, or mucosal ischemia. Desmoid tumors are notoriously

infiltrative, and microscopically involved margins are seen in a significant number of patients.

Complete resection is considered the best course of treatment, though resection is sometimes

constrained by anatomic boundaries. For intra-abdominal tumors, extensive association with the

mesentery limits the extent of resection and could predispose to significant morbidity and ultimately,

mortality due to bowel involvement. Resection of large abdominal wall tumors often requires prosthetic

reconstruction of the resulting defect. Ability to accomplish complete resection at the first attempt

defines likelihood of recurrence, so it is important to have a sufficient preoperative suspicion of

fibromatosis and to be circumspect in surgical technique. Positive margins do not inevitably lead to

recurrent disease, just as patients with a complete microscopic resection are often found to have local

recurrences.138 Given the natural history of desmoid fibromatosis, emerging management strategies for

selected tumors which are small, asymptomatic, and located such that growth would not change ability

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to resect or lead to functional limitations are increasingly discussed. Surveillance plans must be adhered

to and progression prompts resection or other treatment.

There are no data to support the use of radiation therapy in the adjuvant setting following a complete

surgical resection. The utility of radiation in the setting of positive resection margins is thought to be

quite minimal given the difficulty in predicting risk of recurrence in these patients. A number of

systemic treatment regimens have been used in the past and in present practice with varying results.

BONE SARCOMAS

A variety of primary bone tumors are well described (Table 108-5). The vast majorities (>70%) of bone

malignancies represent metastasis from another site or are of hematologic origin (lymphoma or

myeloma). Primary bone cancers, however, are an extremely rare type of cancer, with only an

estimated 3,300 new cases in 2016.1 The three main types of bone sarcomas are osteosarcoma (which

arises from bone), chondrosarcoma (which arises from cartilage), and Ewing sarcoma (which have an

undefined origin). As with soft tissue sarcomas, a GTNM staging system is used by the AJCC45 (Table

108-6). Modern multimodality treatment approaches have been associated with excellent outcomes,

including possibility of cure for many osteosarcoma cases.

Table 108-5 Histologic Classification of Bone Tumors

Table 108-6 American Joint Commission on Cancer (AJCC): GTNM Classification

and Stage Grouping of Bone Sarcomas

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Osteosarcomas are the most common primary bone tumor. Osteosarcomas occur most commonly

around the knee, either in the distal femur or proximal tibia, but they can be encountered in any bone

(Table 108-7). Osteosarcomas originate in the metaphyseal ends of the involved bone. While there are

eleven known variants of osteosarcoma, classic osteosarcoma accounts for nearly 80% of incident cases.

They are commonly seen in children and young adults. Other important variants include osteosarcoma

associated with Paget disease,139 which corresponds to a later peak in incidence at 60 years of age.

Other well-described etiologies of osteosarcoma include prior radiation or history of retinoblastoma.140

Classic osteosarcomas are of intramedullary origin and are high grade. Osteosarcoma patients are at

high risk for metastatic disease; metastases to the lung are the most common, though bony metastases

are not uncommon. Low-grade variants do exist and these less aggressive tumors are usually parosteal

or periosteal in location. Elevated serum alkaline phosphatase and lactate dehydrogenase is associated

with reduced disease-free survival and overall survival rates.

Table 108-7 Distribution of Anatomic Locations of Osteosarcoma

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Chrondrosarcomas are typically classified as either (1) primary or central tumors arising from

previously normal-appearing bone, or (2) secondary or peripheral tumors that develop from pre-existing

benign cartilage lesions.141,142 The secondary or peripheral lesions are usually low grade and

infrequently metastasize. Chrondrosarcomas are usually seen in middle-aged or elderly people, though

can be seen at any age. Ewing sarcomas are broadly considered a family of small round cell neoplasms

and include the following subtypes: Ewing sarcoma, primitive neuroectodermal tumor (PNET), and

extraosseous Ewing sarcoma. Most Ewing sarcomas occur in adolescents and young adults but can be

seen in older individuals. These tumors may arise in soft tissues as well as bone, and are most

commonly seen in the femur, pelvic bones, and chest wall (Askin tumor).

CLINICAL PRESENTATION

A painful mass is the most common presenting complaint with an extremity osteosarcoma, though

symptoms of chrondrosarcoma may be quite mild. Tumor location in the axial skeleton may also be

associated with a more insidious presentation. Limitation of motion is often present when the tumor

arises in proximity to a joint. Patients occasionally present with a pathologic fracture of the involved

bone. Plain radiographs of the affected area often suggest a diagnosis. High-grade osteosarcomas lead to

rapid destruction of bone evidenced by cortical destruction and demonstrate periosteal reaction with

new bone formation; an extensive, poorly defined destructive bony lesion, often with an extraosseous

component is often seen (Fig. 108-16). Ewing sarcomas have a classic “onion skin” periosteal reaction

and underlying bone often appears mottled. Primary or central chrondrosarcomas show cortical

destruction and calcification. Further radiologic evaluation with MRI (or CT scan) provides excellent

detail of the anatomic extent of tumor and aids operative planning. Chest imaging should be used to

determine if there is metastatic disease. Evaluation with radionuclide bone scanning and/or PET scans

may also be useful depending on clinical context.

After the radiologic evaluation establishes the extent of the bony lesion, diagnostic biopsy should be

performed. Either CNB or open biopsy techniques can be used. Placement of the incision should be

carefully planned to avoid jeopardizing subsequent options for a limb-sparing procedure. Consideration

should also be given to stabilization techniques if there is risk of pathologic fracture during treatment.

Cytogenic analysis for evaluation of the t(11;22) translocation should be done if Ewing sarcoma is

suspected.13 Presenting features associated with poor prognosis in Ewing sarcoma include elevated

serum lactate dehydrogenase levels, fever, anemia, large tumor volume, mutation in p53 or deletion of

p16/p14ARF, and pelvic location. Most patients have at least micrometastatic disease at presentation,

and bone marrow biopsy can be considered because it is a common site of distant disease.

TREATMENT

6 Standard treatment for Ewing sarcoma involves combination chemotherapy, followed by surgical

resection. Regimens have evolved over time and currently involve some combination (or all) of the

following agents: ifosfamide, cyclophosphamide, etoposide, doxorubicin, and vincristine.143

Investigations continue to define the trade-offs between survival benefit and toxicity of high-dose

combination chemotherapy.144 Adjuvant radiation can be considered or used as definitive treatment in

some cases. Most patients will receive additional chemotherapy in the postoperative period as well. The

aggressive use of multimodality therapy has led to excellent outcomes for patients with localized

disease over time. Five-year survival rates have improved from 44% in the 1970s to 68% in the 1990s.

Even outcomes with advanced disease at presentation has improved dramatically, increasing from 16%

to 39% over the same time period.145

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