Cancer, Sarcoma


Article Author:
John Popovich


Article Editor:
Sebastiano Cassaro


Editors In Chief:
Yvonne Carter
Jason Wallen


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
2/1/2019 10:08:09 PM

Introduction

Soft tissue sarcomas (STS) are a group of more than 60 different neoplasms that can originate from any location throughout the human body, and they can affect individuals at the extremes of age. From skeletal muscle, adipose tissue, blood, and lymphatics to connective tissue and peripheral nerves; these neoplasms can span a range of clinical presentations from benign lipomas to aggressive metastatic angiosarcomas. [1],[2],[3] The real challenge in diagnosing these conditions is that there are several, non-neoplastic conditions that mimic STS. Soft tissue sarcomas are separated categorically as trunk and extremity from retroperitoneum. The majority of STS occur spontaneously. However, germline mutations, radiation and environmental exposure(s) have been causative. [4],[5],[6],[7]

Etiology

While the majority of these cases occur sporadically, there have been several causative factors identified. 

Germline Mutations

Neurofibromatosis Type 1 (NF1) Von Recklinghausen Disease

  • Autosomal dominant (AD) condition caused by mutations in the NF1 gene which codes for a protein called neurofibromin
  • A tumor suppressor of the ras oncogene signaling pathway
  • Mutations in NF1 gene result in multiple cutaneous neurofibromas

Li-Fraumeni Syndrome

  • Rare AD disorder caused by mutations in the TP53 gene (17p13.1) which codes for p53 (tumor suppressor gene)
  • p53 functions to clear damaged cellular DNA
  • This manifests in a wide array of phenotypes and clinical presentations; some patients will develop rhabdomyosarcoma by the age of 4

Familial Adenomatous Polyposis (FAP)

  • AD disorder with a mutation in the APC gene (5q21-q22)
  • Tumor suppressor gene, inhibiting localization of B-catenin to the nucleus
  • Mutant protein fails to inhibit this localization which results in unchecked cell cycling and cellular proliferation
  • Clinically this manifests in innumerable colonic polyps with extracolonic manifestations such as epidermoid cysts, osteomas and desmoid tumors
  • Desmoid tumors typically arise approximately 5 years post-prophylactic colectomy and represent a major source of morbidity and mortality; often arising in previous surgical sites

Radiation

  • Significantly contributes to a patient's long-term risk for developing STS
  • The effects are dose-dependent, and they typically occur at the periphery of the radiation field
  • Shorter disease-specific survival as compared to the spontaneous counterparts
  • Children who develop STS post-radiation do so at a median 11.8 years later and in a dose-dependent fashion

Carcinogens 

  • Thorotrast (thorium-based IV contrast 1930 to 1955): Patients diagnosed approximately 20 to 30 years post-exposure associated with hepatic angiosarcoma
  • Polyvinyl chloride, a common form of plastic: Prolonged exposure
  • Arsenic

Epidemiology

Soft tissue sarcomas are a rare entity as there were 12,020 new cases and 4740 deaths reported in 2014 in the United States. They account for approximately 1% of all cancer incidence in the United States and represent approximately 2% of cancer-related deaths. As mentioned earlier, they are categorically separated regarding location within the body and extremity, and trunk STS are more common than intraperitoneal and retroperitoneal cases. In regards to the extremities, they occur more frequently on the proximal limb with the thigh being the most common location in 44% of cases. The age at diagnosis and histological subtype are often linked with rhabdomyosarcoma, hemangioma, neurofibroma, and alveolar sarcoma affecting children and young adults more. [8]

Pathophysiology

Sarcomas are tumors of the connective tissue, and thus the tumors may occur in bone, cartilage, fat, muscle, or vascular or hematopoietic tissues. Sarcomas are much rarer compared to carcinomas. Most tend to grow locally and invade the adjacent tissues. Most patients present with complaints of a hard mass or a pain, chiefly because of pressure on nearby nerves and soft tissues.

History and Physical

Several different STS subtypes can affect the trunk and, or extremities. The most common presentation is a patient with a painless mass which, upon initial evaluation, requires a detailed history and physical examination. Of note, there are several conditions that may mimic a soft tissue sarcoma. Some of these conditions are hypertrophic scars, hematoma, benign lipoma, cyst, abscess, and melanoma. All of these can confuse the clinician when trying to work up an STS. Neoplasms that are small, superficial, and mobile are highly suggestive of a soft tissue sarcoma. These are separate from skeletal or neurovascular structures and may be surgically resected with grossly wide margins. Tumors which are closer to vital organs or vascular structures are typically referred to a tertiary care center where surgeons specifically trained in such resections can intervene. In such cases, preoperative biopsies are encouraged as there are several factors that may ultimately affect patient outcome.

Evaluation

Indications for preoperative imaging and biopsy takes into consideration the extent of the mass on physical examination as well as the anticipated neurovascular involvement. The clinician also has to consider the likelihood of nodal involvement or distant metastases as well as the relative resectability and potential postoperative functional deficits as seen with STS of the extremities.

In regards to imaging, MRI is generally considered most informative for trunk and extremity STS. Chest CT with contrast is considered in cases where the metastatic potential is high as the lungs are often involved.

If a biopsy is recommended, then the choice is a core-needle biopsy, and if this is nondiagnostic, then an incisional biopsy may need to take place. The core-needle biopsy should be approached such that the entire needle trajectory can be incorporated into the forthcoming surgical resection volume to maximize diagnostic potential. It has been determined that approximately 74% of patients who undergo an unplanned trunk or extremity sarcoma resection have residual disease at the time of the following resection.

The high risk of recurrence warrants close postoperative surveillance with a physical exam every 3 to 6 months for 2 to 3 years and after that every 6 months for the next 2 years and finally annually. Radiographic surveillance of the chest, abdomen, and pelvis and indications for follow-up MRI is based upon individual patient and tumor characteristics.

Treatment / Management

Lipomatous Tumors

Benign adipocytic tumors that can arise from any part within the body and can cause symptoms primarily through mass effect. They are usually encapsulated, homogenous without evidence of nodularity or septations and may contain calcifications or hemorrhage as a result of trauma. Treatment consists of excision beyond the capsule of the tumor. There is some degree of clinical overlap with the potentially malignant form and most common soft tissue sarcoma, the liposarcoma. Liposarcomas are defined as those tumors which are greater than 10 cm in size, has thick internal septations and those lesions that are generally less than 75% adipose tissue. They represent 45% of retroperitoneal sarcomas. Treatment for the liposarcoma is surgical resection with wide margins. Local recurrence is common. Malignant behavior attributed to the amplification of (12q13-15), which leads to the upregulation of MDM2 and CKD4. Tumor-promoting pathways MET, RET and PI3K/Akt are thought to be activated. Liposarcomas of the extremities, the goal of care is limb-sparing resection with a gross negative margin. Retroperitoneal liposarcomas the goal is complete resection. Typically, well-differentiated liposarcomas have a low risk of distant metastases whereas de-differentiated extremity liposarcoma are generally benefit from neoadjuvant radiation therapy.[1]

Trunk and Extremity Sarcoma

There is a fine balance between preserving limb function and tumor control. Many types are chemoresistant, and several studies have reported conflicting results regarding the utility of neoadjuvant and adjuvant chemotherapy. Several studies have supported a surgical margin of 1 cm in regards to adequate resection.[9]

Desmoid Tumors

An rare form of fibroblastic tumors. Approximately 80% are sporadic, whereas others are related to familial adenomatous polyposis (FAP). Sporadic cases are related to pregnancy and prior trauma. They are 2 to 3 times more common in women than men and usually diagnosed between the ages of 30 to 40. They can originate in the extremities, intraperitoneal space, abdomen, and/or chest wall. They are usually slow growing, however can be quite aggressive. They utilize the WNT signaling pathway. Clinically, they can range from an asymptomatic firm mass to a painful mass resulting in bowel obstructions or ischemia. Radiographically they are usually homogenous and solid in appearance with a distinct or infiltrating boundary. Despite resection these tumors have a high incidence of recurrence.[10]

Angiosarcoma

Malignant tumor arising from the endothelial lining of blood vessels and can arise from essentially any region within the body. Two percent are considered soft tissue sarcomas, and 40% are radiation-induced. They usually occur in the scalp, head, neck (scalp), and viscera and generally occur during the seventh or eighth decade of life. There is usually regional lymphatic nodal involvement. Histologically they can range from well-differentiated to poorly differentiated. Again, therapy is aimed at surgical resection with negative margins. Tumors that are larger than 5 cm and with evidence of epitheliod are considered indicators of poor prognosis. These tumors are often locally advanced and beyond resection at presentation; however, there has been some noted benefit from chemoradiation. [11]

Retroperitoneal and Visceral Sarcomas

Retroperitoneal sarcomas represent approximately 15% of all soft tissue sarcomas with the average tumor size at presentation measuring 15 cm. Average age at presentation is 54 with an equal male to female distribution. There are a variety of clinical presentations depending on the size and location of the tumor. Many are asymptomatic and only incidentally discovered. Symptoms can range from abdominal pain, weight loss, early satiety, nausea, emesis, back or flank pain, paresthesias and weaknesses. CT is the study of choice. Gross resection is the treatment of choice with or without neoadjuvant or adjuvant chemoradiation. Most frequent subtype is the liposarcoma. Predominant intraperitoneal subtype is the Gastrointestinal stromal tumor. Despite optimal surgical resection, approximately 70% will relapse. [12]

Gastrointestinal Stromal Tumor (GIST)

GIST tumors are the most common visceral soft tissue sarcoma. The majority occur sporadically. They originate from the interstitial cells of Cajal within the gastrointestinal myenteric plexus and can occur any location along the GI tract. The most prevalent location is the stomach, small bowel, and rectum. They function as the pacemaker cells of the bowel. GIST tumors have a marker for CD117 (also known as KIT gene), which codes for a tyrosine kinase transmembrane receptor called c-kit. Classically a spindle cell neoplasm of smooth muscle origin. Clinically, they can range from asymptomatic to symptomatic with pain, nausea, hematemesis and gastrointestinal (GI) blood loss. Endoscopically they appear as a smooth submucosal tumor that can impinge on the visceral lumen. Radiographically, it appears well encapsulated with heterogeneous areas of enhancement secondary to patchy necrosis within the tumor. Metastases are common with common sites being the liver and peritoneal surface. Localized lesions are taken to the operating room for complete excision with negative margins with empiric lymphadenectomy. Adjuvant therapy after resection and neoadjuvant therapy for unresectable or locally advanced disease requires Imatinib (an oral tyrosine kinase inhibitor of c-kit).[13]

Leiomyosarcoma

Malignant smooth muscle tumor that can originate from any part of the body. It is the second most common soft tissue sarcoma subtype. They occur during the sixth and seventh decades. The retroperitoneum and uterus are the most common locations in women; whereas, in males, they originate in other locations. On gross inspection, they are heterogeneous, well-circumscribed tumors with cystic or necrotic central areas. They stain positive for desmin and smooth muscle actin. First-line therapy is surgical resection with negative margins.

Surgical Oncology

Current recommendations for sarcomas are as follows:

  • Surgery is the treatment of choice for stages 1A and 1B
  • Margins of more than 1 cm should be obtained; postoperative radiation is necessary if the margins are less than 1 cm [1],[14],[15],[16],[17],
  • Rehabilitation is necessary for most patients after surgery to achieve maximal function.
  • Follow up at 3 to 6 months for 2 years is necessary
  • Baseline imaging should be obtained
  • For stages II and III, the treatment depends on patient age, comorbidity, grade of the tumor, and patient performance status. Options include surgical resection followed by postoperative radiation and adjuvant chemotherapy.
  • For high-grade tumors, preoperative radiation or chemoradiation is an option.
  • Regional node dissection in patients with stage III malignancies with known lymph nodes is recommended.
  • PET scan has been shown to be useful for large lesions and deep tumors to determine the response to neoadjuvant chemotherapy.[18],[19],[20]
  • Tumors that are large and unresectable or present in the patient not deemed to be a surgical candidate may be observed if there are no symptoms. However, in symptomatic individuals, palliative surgery, radiation or chemotherapy may be used.[21],[22],[23]

Radiation Oncology

Sarcomas are heterogeneous lesions, and the response to radiation is dependent on the type of lesion. While overall these lesions are less sensitive to radiation, refinements and advances have improved outcomes. Radiation helps improve local control and is of most benefit when surgical margins are not clear.

Medical Oncology

Not all sarcomas respond to chemotherapy. However, because of their heterogeneous nature, some may respond. The 2 chemotherapeutic drugs approved to manage sarcomas include ifosfamide and doxorubicin. Current, standard, second-line therapy is fixed dose rate gemcitabine with or without docetaxel. Recently, the targeted agents eribulin and trabectedin have also been approved for managing patients with liposarcoma and leiomyosarcoma. However, the response depends on optimal dosing and timing. While the role of adjuvant chemotherapy remains questionable, most oncologists administer it.

Prognosis

For localized and early-stage lesions, curative resection can be done with good long-term survival, but recurrences are common. The risk of recurrence even persists after 10 to 15 years, and patients need indefinite follow up.

The majority of recurrences occur within the first 5 years.

For those with advanced disease, a cure is not possible, and the median survival is 12 to 18 months, depending on the subtype.

The majority of sarcomas show a poor response to chemotherapy (10% to 50% response). The response also depends on histological subtype, grade, and patient.

Complications

Besides the invasion of the sarcoma into the adjacent tissues and causing neurovascular compromise, the tumor has many other complications.

  • Chemotherapy-induced neurotoxicity, infertility, cardiac toxicity, infertility, and bone thinning
  • Surgery can lead to severe disfigurement, disability, pain, and poor cosmesis.
  • Radiation can lead to dry, leathery skin, avascularity, and poor healing.
  • There is also a risk for development of secondary malignancies.

Postoperative and Rehabilitation Care

All patients with sarcoma should enter a rehabilitation program after surgery. These patients often have marked functional deficits and can be confined to a bed or chair. To regain some functionality rehab is vital.

Pearls and Other Issues

The staging of STS is based on the American Joint Committee on Cancer (AJCC) Staging System where multiple histological subtypes are considered together. Various scoring systems have been employed that essentially take into account the same key elements or different tumor characteristics such as the following:

  1. Tumor differentiation 
  2. The rate of mitosis of individual tumor cells 
  3. The amount of tumor necrosis 
  4. Tumor depth 
  5. Lymph node involvement
  6. Distant metastases

There are limitations to the current system as the 7th edition AJCC encompasses the diverse heterogeneity of all soft tissue sarcomas, which decreases their prognostic potential and does not differentiate between categorical differences, for example, extremity and retroperitoneum. Of importance, tumor depth is not relevant to visceral or retroperitoneum STS. In regards to the extremities, superficial and deep refer to their relationship with the fascial plane. There has been shown to be a statistically significant decrease regarding disease-free survival when considering an extremity STS that is deep to the fascial layer and larger than 5 cm in size.

Enhancing Healthcare Team Outcomes

Management of sarcomas involves a multidisciplinary team of doctors and nurses. The team should discuss each patient should before making any treatment decisions. In addition to the oncologist, a surgeon, an orthopedist, neurologist, pain consultation, an internist, and a plastic surgeon should be consulted before any major surgery. When a patient is suspected of having a sarcoma, a referral to an oncologist should be the first step. Sarcomas are resistant to chemotherapy and radiation and surgery is the definitive treatment. However, they are known to occur and the prognosis for most patients is guarded.[24] (Level V)


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Cancer, Sarcoma - Questions

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Which of the following is a true statement about soft tissue sarcoma?



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Cancer, Sarcoma - References

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