Kaposi sarcoma is an angioproliferative tumor that is associated with human herpes virus-B (HIV-B). Mucocutaneous disease is the most common site for manifestation of AIDS-related Kaposi sarcoma, commonly affecting the lower extremeties, oral mucosa, face, and genitalia. Pleural effusions can occur in 36%-60% of patients with Kaposi sarcoma, and it has been documented that chylothorax is a rare, but plausible presentation in patients with Kaposi sarcoma.¹  We present here a case of bilateral chylothorax in a patient with AIDS-related Kaposi sarcoma.

Case presentation and summary

A 52-year-old MSM male with AIDS (CD4, <20 mm3 ; viral load, 58 copies/ml) presented to the emergency department with complaints of shortness of breath, productive cough, and diarrhea for 2 days prior to presentation. His medical history also included chronic obstructive pulmonary disease, coronary artery disease, and hyperlipidemia.The patient was not on HAART because of his history of noncompliance. The results of a chest X-ray and computed-tomography (CT) scan showed that the patient had bilateral pleural effusion and a spiculated 14-mm nodule in the left upper lobe.

The patient underwent ultrasound-guided placement of a 12-French left-sided chest catheter, and a milky white fluid was aspirated from the left pleural space. Laboratory analysis of the pleural fluid confirmed an exudate with an elevated triglyceride level of 120 mg/dL (chylous, >110 mg/dL) indicating chylothorax.

On close physical examination, the patient was found to have multiple irregular plaques on the back and lower extremities. As described by dermatology, there was a violaceous indurated plaque on the left axillae, violaceous indurated plaques with superficial scale grouped on the left midlateral back, and hyperpigmented lichenified plaques and papules on bilateral shins, with some with plate-like scale. Two punch biopsies were taken of the skin lesions, which confirmed Kaposi sarcoma, plaque stage from the lesion biopsied on the back, and patch stage from the lesion biopsied in the left axilla. Cytology of the pleural fluid was negative for malignant cells. On review by the radiologist of the CT scan of the chest, there was no indication of gross distention of the thoracic duct. Treatment options were offered to the patient, and the patient was considering options for chemotherapy and home hospice given his advanced disease state at the time of discharge.

Discussion

Chylothorax occurs with a thoracic duct obstruction, which results in leakage of lymphatic fluid into the pleural cavity. The two leading causes of chylothorax are trauma and malignancy, with lymphoma being the most common cause of chylothorax among those with malignancy.²  Chylothorax, however, is a rare but documented complication of Kaposi sarcoma. Marais and colleagues reported the case of a 3-year-old HIV-positive patient with newly diagnosed Kaposi sarcoma who was found to have tumor infiltration in the thoracic duct leading to bilateral chylothorax.3  Maradona and colleagues described a 40-year-old man with AIDS-related Kaposi sarcoma who was found to have pleural and pericardial Kaposi sarcoma with chylothorax.⁴  Priest and colleagues wrote about a 32-year-old patient with AIDS with biopsy-proven Kaposi sarcoma who required multiple therapeutic thoracenteses for rapidly recurrent left chylothorax effusions.⁵

There are two leading discussions as to the pathophysiology of chylothorax that is related to Kaposi sarcoma: chylothorax developing secondary to metastatic disease or the development of chylothorax secondary to primary Kaposi sarcoma arising from the pleural region.⁶ One case report examined pleural and lung biopsies in a 34-year-old patient with AIDS-related Kaposi sarcoma that showed immunohistochemical staining that was suggestive of early-stage Kaposi sarcoma of lymphatic endothelial origin. The authors were attempting to illustrate that Kaposi sarcoma may have a stem-cell origin which can differentiate into lymph cells. Kontantinopoulos and colleagues postulated that in situ Kaposi sarcoma can arise from the lymphatic system with a resultant clinical presentation of chylothorax.⁷ The more mainstream thought however, is that chylothorax has been found to develop secondary to metastatic disease. The present case, therefore, illustrates an unusual presentation of cytology negative chylothorax in a patient with AIDS-related Kaposi sarcoma. TSJ

Correspondence

Rebecca E Neril, MD; Department of Internal Medicine, SBH Health System, Bronx, New York.

Kaposi sarcoma is an angioproliferative tumor that is associated with human herpes virus-B (HIV-B). Mucocutaneous disease is the most common site for manifestation of AIDS-related Kaposi sarcoma, commonly affecting the lower extremeties, oral mucosa, face, and genitalia. Pleural effusions can occur in 36%-60% of patients with Kaposi sarcoma, and it has been documented that chylothorax is a rare, but plausible presentation in patients with Kaposi sarcoma.¹  We present here a case of bilateral chylothorax in a patient with AIDS-related Kaposi sarcoma.

Case presentation and summary

A 52-year-old MSM male with AIDS (CD4, <20 mm3 ; viral load, 58 copies/ml) presented to the emergency department with complaints of shortness of breath, productive cough, and diarrhea for 2 days prior to presentation. His medical history also included chronic obstructive pulmonary disease, coronary artery disease, and hyperlipidemia.The patient was not on HAART because of his history of noncompliance. The results of a chest X-ray and computed-tomography (CT) scan showed that the patient had bilateral pleural effusion and a spiculated 14-mm nodule in the left upper lobe.

The patient underwent ultrasound-guided placement of a 12-French left-sided chest catheter, and a milky white fluid was aspirated from the left pleural space. Laboratory analysis of the pleural fluid confirmed an exudate with an elevated triglyceride level of 120 mg/dL (chylous, >110 mg/dL) indicating chylothorax.

On close physical examination, the patient was found to have multiple irregular plaques on the back and lower extremities. As described by dermatology, there was a violaceous indurated plaque on the left axillae, violaceous indurated plaques with superficial scale grouped on the left midlateral back, and hyperpigmented lichenified plaques and papules on bilateral shins, with some with plate-like scale. Two punch biopsies were taken of the skin lesions, which confirmed Kaposi sarcoma, plaque stage from the lesion biopsied on the back, and patch stage from the lesion biopsied in the left axilla. Cytology of the pleural fluid was negative for malignant cells. On review by the radiologist of the CT scan of the chest, there was no indication of gross distention of the thoracic duct. Treatment options were offered to the patient, and the patient was considering options for chemotherapy and home hospice given his advanced disease state at the time of discharge.

Discussion

Chylothorax occurs with a thoracic duct obstruction, which results in leakage of lymphatic fluid into the pleural cavity. The two leading causes of chylothorax are trauma and malignancy, with lymphoma being the most common cause of chylothorax among those with malignancy.²  Chylothorax, however, is a rare but documented complication of Kaposi sarcoma. Marais and colleagues reported the case of a 3-year-old HIV-positive patient with newly diagnosed Kaposi sarcoma who was found to have tumor infiltration in the thoracic duct leading to bilateral chylothorax.3  Maradona and colleagues described a 40-year-old man with AIDS-related Kaposi sarcoma who was found to have pleural and pericardial Kaposi sarcoma with chylothorax.⁴  Priest and colleagues wrote about a 32-year-old patient with AIDS with biopsy-proven Kaposi sarcoma who required multiple therapeutic thoracenteses for rapidly recurrent left chylothorax effusions.⁵

There are two leading discussions as to the pathophysiology of chylothorax that is related to Kaposi sarcoma: chylothorax developing secondary to metastatic disease or the development of chylothorax secondary to primary Kaposi sarcoma arising from the pleural region.⁶ One case report examined pleural and lung biopsies in a 34-year-old patient with AIDS-related Kaposi sarcoma that showed immunohistochemical staining that was suggestive of early-stage Kaposi sarcoma of lymphatic endothelial origin. The authors were attempting to illustrate that Kaposi sarcoma may have a stem-cell origin which can differentiate into lymph cells. Kontantinopoulos and colleagues postulated that in situ Kaposi sarcoma can arise from the lymphatic system with a resultant clinical presentation of chylothorax.⁷ The more mainstream thought however, is that chylothorax has been found to develop secondary to metastatic disease. The present case, therefore, illustrates an unusual presentation of cytology negative chylothorax in a patient with AIDS-related Kaposi sarcoma. TSJ

Correspondence

Rebecca E Neril, MD; Department of Internal Medicine, SBH Health System, Bronx, New York.

Kaposi sarcoma is an angioproliferative tumor that is associated with human herpes virus-B (HIV-B). Mucocutaneous disease is the most common site for manifestation of AIDS-related Kaposi sarcoma, commonly affecting the lower extremeties, oral mucosa, face, and genitalia. Pleural effusions can occur in 36%-60% of patients with Kaposi sarcoma, and it has been documented that chylothorax is a rare, but plausible presentation in patients with Kaposi sarcoma.¹  We present here a case of bilateral chylothorax in a patient with AIDS-related Kaposi sarcoma.

Case presentation and summary

A 52-year-old MSM male with AIDS (CD4, <20 mm3 ; viral load, 58 copies/ml) presented to the emergency department with complaints of shortness of breath, productive cough, and diarrhea for 2 days prior to presentation. His medical history also included chronic obstructive pulmonary disease, coronary artery disease, and hyperlipidemia.The patient was not on HAART because of his history of noncompliance. The results of a chest X-ray and computed-tomography (CT) scan showed that the patient had bilateral pleural effusion and a spiculated 14-mm nodule in the left upper lobe.

The patient underwent ultrasound-guided placement of a 12-French left-sided chest catheter, and a milky white fluid was aspirated from the left pleural space. Laboratory analysis of the pleural fluid confirmed an exudate with an elevated triglyceride level of 120 mg/dL (chylous, >110 mg/dL) indicating chylothorax.

On close physical examination, the patient was found to have multiple irregular plaques on the back and lower extremities. As described by dermatology, there was a violaceous indurated plaque on the left axillae, violaceous indurated plaques with superficial scale grouped on the left midlateral back, and hyperpigmented lichenified plaques and papules on bilateral shins, with some with plate-like scale. Two punch biopsies were taken of the skin lesions, which confirmed Kaposi sarcoma, plaque stage from the lesion biopsied on the back, and patch stage from the lesion biopsied in the left axilla. Cytology of the pleural fluid was negative for malignant cells. On review by the radiologist of the CT scan of the chest, there was no indication of gross distention of the thoracic duct. Treatment options were offered to the patient, and the patient was considering options for chemotherapy and home hospice given his advanced disease state at the time of discharge.

Discussion

Chylothorax occurs with a thoracic duct obstruction, which results in leakage of lymphatic fluid into the pleural cavity. The two leading causes of chylothorax are trauma and malignancy, with lymphoma being the most common cause of chylothorax among those with malignancy.²  Chylothorax, however, is a rare but documented complication of Kaposi sarcoma. Marais and colleagues reported the case of a 3-year-old HIV-positive patient with newly diagnosed Kaposi sarcoma who was found to have tumor infiltration in the thoracic duct leading to bilateral chylothorax.3  Maradona and colleagues described a 40-year-old man with AIDS-related Kaposi sarcoma who was found to have pleural and pericardial Kaposi sarcoma with chylothorax.⁴  Priest and colleagues wrote about a 32-year-old patient with AIDS with biopsy-proven Kaposi sarcoma who required multiple therapeutic thoracenteses for rapidly recurrent left chylothorax effusions.⁵

There are two leading discussions as to the pathophysiology of chylothorax that is related to Kaposi sarcoma: chylothorax developing secondary to metastatic disease or the development of chylothorax secondary to primary Kaposi sarcoma arising from the pleural region.⁶ One case report examined pleural and lung biopsies in a 34-year-old patient with AIDS-related Kaposi sarcoma that showed immunohistochemical staining that was suggestive of early-stage Kaposi sarcoma of lymphatic endothelial origin. The authors were attempting to illustrate that Kaposi sarcoma may have a stem-cell origin which can differentiate into lymph cells. Kontantinopoulos and colleagues postulated that in situ Kaposi sarcoma can arise from the lymphatic system with a resultant clinical presentation of chylothorax.⁷ The more mainstream thought however, is that chylothorax has been found to develop secondary to metastatic disease. The present case, therefore, illustrates an unusual presentation of cytology negative chylothorax in a patient with AIDS-related Kaposi sarcoma. TSJ

Correspondence

Rebecca E Neril, MD; Department of Internal Medicine, SBH Health System, Bronx, New York.

The Diagnosis: Fibroblastic Rheumatism

Routine histologic sections stained with hematoxylin and eosin demonstrated a noncircumscribed dermal proliferation of fibroblasts and myofibroblasts with thickened collagen bundles (Figure, A and B). Focally fragmented elastin fibers were noted with Verhoeff elastic tissue stain. Alcian blue stain did not show increased dermal mucin. With the clinical presentation and histologic findings described, we diagnosed the patient with fibroblastic rheumatism (FR). To date, the patient's condition has stabilized overall with skin lesions fading and minimal to no joint pain. Current therapies include adalimumab, mycophenolate mofetil 500 mg 3 times daily, and low-dose prednisone.

Fibroblastic rheumatism is a rare arthropathy with cutaneous findings initially described by Chaouat et al¹ in 1980. Age of onset varies, and the condition also has been observed in pediatric patients.² Fibroblastic rheumatism is characterized by sudden onset of firm, flesh-colored, subcutaneous nodules on periungual and periarticular surfaces.² Neck lesions rarely are described,^2-4 and cordlike plaques previously have not been reported in FR. Typically, patients develop diffusely swollen fingers, palmar thickening, sclerodactyly, and contractures. The eruption may be accompanied by Raynaud phenomenon as well as a progressive symmetric erosive arthropathy.^2,5

The clinical course in FR is variable. The cutaneous findings spontaneously may regress in months to years.^3,4 However, polyarthropathy often is destructive and progresses to disability.³ Response to therapy has been unpredictable, and the following treatments have been tried, generally with poor efficacy: aspirin, nonsteroidal anti-inflammatory drugs, hydroxychloroquine, colchicine, methotrexate, prednisone, infliximab, D-penicillamine, interferon alfa, and intensive physical therapy.^2-4,6 Histologic characteristics may include thickened collagen bundles along with a fibroblastic and myofibroblastic proliferation. Elastic fibers may be decreased or absent.^2,3,5

Clinical and histologic features in FR may mimic other entities; thus, clinical pathological correlation is essential in determining the correct diagnosis. Considerations in the differential diagnoses include multicentric reticulohistiocytosis (MRH), palisaded neutrophilic and granulomatous dermatitis, and scleroderma.

In MRH, a symmetric erosive arthritis of mainly distal interphalangeal joints typically precedes the cutaneous disease. Occurrence of arthritis mutilans is reported in approximately half of patients.⁴ Cutaneous manifestations typically include the presence of coral bead-like papules and nodules over the dorsal aspect of the hands, face, and neck. Unlike FR, MRH has a concomitant autoimmune disease in up to 20% of cases and an associated malignancy in up to 31% of cases, with breast and ovarian carcinomas most common. On histology, MRH is characterized by a nodular infiltrate of histiocytes and multinucleated giant cells with eosinophilic ground-glass cytoplasm.⁴ No notable collagen changes or fibroblastic proliferations typically are present.

Palisaded neutrophilic and granulomatous dermatitis, usually associated with rheumatoid arthritis or connective tissue disease, classically presents as annular plaques and indurated linear bands over the trunk and extremities. However, its clinical presentation is quite variable and may include pink to violaceous urticarialike; livedoid-appearing; or nonspecific papules, plaques, or nodules. Histology in palisaded neutrophilic and granulomatous dermatitis shows a dense dermal neutrophilic infiltrate associated with interstitial histiocytes having a palisading arrangement around degenerated collagen.⁷ No fibroblastic proliferation typically is present.

Scleroderma can be distinguished based on additional clinical and laboratory findings as well as histology showing thickened collagen bundles without fibroblastic proliferation.2 The histologic findings also may suggest inclusion of dermatofibroma or a scar in the differential diagnosis, though the clinical presentation of these entities would not support these diagnoses.  
 
Acknowledgments
We thank the patient for granting permission to share this information. We also thank Sheng Chen, MD, PhD (Lake Success, New York), for his dermatopathological contributions to the case.

The Diagnosis: Fibroblastic Rheumatism

Routine histologic sections stained with hematoxylin and eosin demonstrated a noncircumscribed dermal proliferation of fibroblasts and myofibroblasts with thickened collagen bundles (Figure, A and B). Focally fragmented elastin fibers were noted with Verhoeff elastic tissue stain. Alcian blue stain did not show increased dermal mucin. With the clinical presentation and histologic findings described, we diagnosed the patient with fibroblastic rheumatism (FR). To date, the patient's condition has stabilized overall with skin lesions fading and minimal to no joint pain. Current therapies include adalimumab, mycophenolate mofetil 500 mg 3 times daily, and low-dose prednisone.

Fibroblastic rheumatism is a rare arthropathy with cutaneous findings initially described by Chaouat et al¹ in 1980. Age of onset varies, and the condition also has been observed in pediatric patients.² Fibroblastic rheumatism is characterized by sudden onset of firm, flesh-colored, subcutaneous nodules on periungual and periarticular surfaces.² Neck lesions rarely are described,^2-4 and cordlike plaques previously have not been reported in FR. Typically, patients develop diffusely swollen fingers, palmar thickening, sclerodactyly, and contractures. The eruption may be accompanied by Raynaud phenomenon as well as a progressive symmetric erosive arthropathy.^2,5

The clinical course in FR is variable. The cutaneous findings spontaneously may regress in months to years.^3,4 However, polyarthropathy often is destructive and progresses to disability.³ Response to therapy has been unpredictable, and the following treatments have been tried, generally with poor efficacy: aspirin, nonsteroidal anti-inflammatory drugs, hydroxychloroquine, colchicine, methotrexate, prednisone, infliximab, D-penicillamine, interferon alfa, and intensive physical therapy.^2-4,6 Histologic characteristics may include thickened collagen bundles along with a fibroblastic and myofibroblastic proliferation. Elastic fibers may be decreased or absent.^2,3,5

Clinical and histologic features in FR may mimic other entities; thus, clinical pathological correlation is essential in determining the correct diagnosis. Considerations in the differential diagnoses include multicentric reticulohistiocytosis (MRH), palisaded neutrophilic and granulomatous dermatitis, and scleroderma.

In MRH, a symmetric erosive arthritis of mainly distal interphalangeal joints typically precedes the cutaneous disease. Occurrence of arthritis mutilans is reported in approximately half of patients.⁴ Cutaneous manifestations typically include the presence of coral bead-like papules and nodules over the dorsal aspect of the hands, face, and neck. Unlike FR, MRH has a concomitant autoimmune disease in up to 20% of cases and an associated malignancy in up to 31% of cases, with breast and ovarian carcinomas most common. On histology, MRH is characterized by a nodular infiltrate of histiocytes and multinucleated giant cells with eosinophilic ground-glass cytoplasm.⁴ No notable collagen changes or fibroblastic proliferations typically are present.

Palisaded neutrophilic and granulomatous dermatitis, usually associated with rheumatoid arthritis or connective tissue disease, classically presents as annular plaques and indurated linear bands over the trunk and extremities. However, its clinical presentation is quite variable and may include pink to violaceous urticarialike; livedoid-appearing; or nonspecific papules, plaques, or nodules. Histology in palisaded neutrophilic and granulomatous dermatitis shows a dense dermal neutrophilic infiltrate associated with interstitial histiocytes having a palisading arrangement around degenerated collagen.⁷ No fibroblastic proliferation typically is present.

Scleroderma can be distinguished based on additional clinical and laboratory findings as well as histology showing thickened collagen bundles without fibroblastic proliferation.2 The histologic findings also may suggest inclusion of dermatofibroma or a scar in the differential diagnosis, though the clinical presentation of these entities would not support these diagnoses.  
 
Acknowledgments
We thank the patient for granting permission to share this information. We also thank Sheng Chen, MD, PhD (Lake Success, New York), for his dermatopathological contributions to the case.

The Diagnosis: Fibroblastic Rheumatism

Routine histologic sections stained with hematoxylin and eosin demonstrated a noncircumscribed dermal proliferation of fibroblasts and myofibroblasts with thickened collagen bundles (Figure, A and B). Focally fragmented elastin fibers were noted with Verhoeff elastic tissue stain. Alcian blue stain did not show increased dermal mucin. With the clinical presentation and histologic findings described, we diagnosed the patient with fibroblastic rheumatism (FR). To date, the patient's condition has stabilized overall with skin lesions fading and minimal to no joint pain. Current therapies include adalimumab, mycophenolate mofetil 500 mg 3 times daily, and low-dose prednisone.

Fibroblastic rheumatism is a rare arthropathy with cutaneous findings initially described by Chaouat et al¹ in 1980. Age of onset varies, and the condition also has been observed in pediatric patients.² Fibroblastic rheumatism is characterized by sudden onset of firm, flesh-colored, subcutaneous nodules on periungual and periarticular surfaces.² Neck lesions rarely are described,^2-4 and cordlike plaques previously have not been reported in FR. Typically, patients develop diffusely swollen fingers, palmar thickening, sclerodactyly, and contractures. The eruption may be accompanied by Raynaud phenomenon as well as a progressive symmetric erosive arthropathy.^2,5

The clinical course in FR is variable. The cutaneous findings spontaneously may regress in months to years.^3,4 However, polyarthropathy often is destructive and progresses to disability.³ Response to therapy has been unpredictable, and the following treatments have been tried, generally with poor efficacy: aspirin, nonsteroidal anti-inflammatory drugs, hydroxychloroquine, colchicine, methotrexate, prednisone, infliximab, D-penicillamine, interferon alfa, and intensive physical therapy.^2-4,6 Histologic characteristics may include thickened collagen bundles along with a fibroblastic and myofibroblastic proliferation. Elastic fibers may be decreased or absent.^2,3,5

Clinical and histologic features in FR may mimic other entities; thus, clinical pathological correlation is essential in determining the correct diagnosis. Considerations in the differential diagnoses include multicentric reticulohistiocytosis (MRH), palisaded neutrophilic and granulomatous dermatitis, and scleroderma.

In MRH, a symmetric erosive arthritis of mainly distal interphalangeal joints typically precedes the cutaneous disease. Occurrence of arthritis mutilans is reported in approximately half of patients.⁴ Cutaneous manifestations typically include the presence of coral bead-like papules and nodules over the dorsal aspect of the hands, face, and neck. Unlike FR, MRH has a concomitant autoimmune disease in up to 20% of cases and an associated malignancy in up to 31% of cases, with breast and ovarian carcinomas most common. On histology, MRH is characterized by a nodular infiltrate of histiocytes and multinucleated giant cells with eosinophilic ground-glass cytoplasm.⁴ No notable collagen changes or fibroblastic proliferations typically are present.

Palisaded neutrophilic and granulomatous dermatitis, usually associated with rheumatoid arthritis or connective tissue disease, classically presents as annular plaques and indurated linear bands over the trunk and extremities. However, its clinical presentation is quite variable and may include pink to violaceous urticarialike; livedoid-appearing; or nonspecific papules, plaques, or nodules. Histology in palisaded neutrophilic and granulomatous dermatitis shows a dense dermal neutrophilic infiltrate associated with interstitial histiocytes having a palisading arrangement around degenerated collagen.⁷ No fibroblastic proliferation typically is present.

Scleroderma can be distinguished based on additional clinical and laboratory findings as well as histology showing thickened collagen bundles without fibroblastic proliferation.2 The histologic findings also may suggest inclusion of dermatofibroma or a scar in the differential diagnosis, though the clinical presentation of these entities would not support these diagnoses.  
 
Acknowledgments
We thank the patient for granting permission to share this information. We also thank Sheng Chen, MD, PhD (Lake Success, New York), for his dermatopathological contributions to the case.

Introduction

Soft tissue sarcomas (STSs) are rare adult tumors, with 3.4 new cases per 100,000 persons or 12,310 expected new cases in 2016.¹ Sarcomas are a heterogeneous collection of tumors that affect fat, muscle, nerve, nerve sheath, vascular, and connective tissues. There are more than 50 histological subtypes that comprise this diverse category of tumors. Treatment varies by stage, with limb-sparing surgery representing the mainstay of curative-intent treatment. Radiation and chemotherapy may also be considered depending on the size, grade, and location of the tumor. Survival rates have been stagnant until recently, with a disease-specific survival hovering around 65%.¹ Given the complexity of these cases, all patients ideally should be evaluated and treated by a multidisciplinary team at an institution with extensive experience treating STS.²

Epidemiology and Classification

The most common STS subtypes are gastrointestinal stromal tumor (GIST), undifferentiate pleomorphic sarcoma (previously referred to as malignant fibrous histiocytoma), liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, and unclassified sarcoma.³ Liposarcoma is one of the most common subtypes, comprising 20% of all STSs; it is subdivided into well-differentiated/dedifferentiated liposarcomas, myxoid/round cell liposarcomas, and pleomorphic liposarcomas. Well-differentiated liposarcomas tend to occur in the retroperitoneum and limbs, while both myxoid and round cell as well as pleomorphic liposarcomas more commonly originate on the limbs. Histology varies based on subtype and ranges from mature-appearing adipocytes and fibroblasts to undifferentiated cells with minimal lipogenic differentiation.⁴

Leiomyosarcomas are smooth muscle tumors and are usually located in the retroperitoneum, but have also been associated with peripheral soft tissue and vasculature. Typical histology ranges from well-defined areas of spindle-shaped cells to poorly differentiated anaplastic spindle cells.^5,6 Synovial sarcomas are a distinct type of STS that can show epithelial differentiation and account for 5% of adult STSs. The extremities are the most common presenting location (90%).⁷

Rhabdomyosarcomas are skeletal muscle tumors and are further subdivided into embryonal, alveolar, and pleomorphic subtypes. Embryonal histology ranges from primitive mesenchymal-appearing cells to highly differentiated muscle cells. Alveolar rhabdomyosarcoma has the worst prognosis of the subtypes and consists of round cells with high nuclear-to-chromatin ratios that form “glandular-like” or “alveolar” spaces.⁸ Pleomorphic rhabdomyosarcomas are composed of rhabdomyoblasts that can affect many different locations, but most commonly present on the lower extremities.⁹

Malignant peripheral nerve sheath tumor (MPNST) comprises 5% to 10% of all STSs. These tumors are associated with neurofibromatosis type 1 (NF-1), with 25% to 50% of tumors occurring in NF-1 patients. Additionally, most patients have a truncating lesion in the NF1 gene on chromosome 17.¹⁰ Anghileri et al in their single institution analysis of 205 patients with MPNSTs found the 2 most common presenting sites were the trunk and extremities. Histologically, these tumors have dense fascicles of spindle cells.¹⁰

GISTs are the most common STS of the gastrointestinal (GI) tract. Previously, GISTs were classified as smooth muscle tumors and were not accounted for in the literature as a separate entity distinct from leiomyomas, leiomyoblastomas, and leiomyosarcomas.¹¹ GISTs are found throughout the GI tract: the most common sites are the stomach (60%) and small intestine (30%). Less common sites include duodenum (4%–5%), esophagus (1%), rectum (1%–2%), and appendix (< 0.2%).¹² GISTs can be spindle cell, epithelioid, or mesenchymal tumors. Immunohistochemically, GISTs are KIT (CD117) positive. Other cell markers that are also commonly positive include CD34 (60%–70%) and smooth muscle actin (SMA) (25%).¹¹ The majority of GISTs (80%) have an activating c-KIT gene mutation. The most common mutation site is exon 11, with less common c-KIT gene mutations also occurring at exon 9 or 13. Not all GISTs have KIT mutations. The second most common mutation is the PDGFRA mutation (5%–10% of GISTs).² A minority of GISTs are negative for both KIT and PDGFRA mutations. These tumors were previously called wild-type, but as the majority have either a succinate dehydrogenase (SDH) loss of function or loss of SDHB protein expression, they are now referred to as SDH-deficient GISTs.² GISTs vary in aggressiveness from incidental to aggressive. Typically, small intestine and rectal GISTs are more aggressive than gastric GISTs. Both size and mitotic rate help to predict the metastatic potential of the tumor. Tumors less than 2 cm in size and having a mitotic rate of less than 5 per 50 high-power fields (hpf) have the lowest risk of metastases, while tumors greater than 5 cm and with more than 5 mitoses per 50 hpf have the highest rates of metastases.¹²

Angiosarcomas are rare tumors comprising 4% of all STSs. Although they can occur in any site, the majority are cutaneous and occur most frequently in the head and neck regions. These tumors are either of vascular or lymphatic origin and are comprised of abnormal, pleomorphic, malignant endothelial cells. The most useful immunohistochemical markers include von Willebrand factor, CD31, and Ulex europaeus agglutinin 1. The majority of these tumors occur sporadically; however, radiation exposure, chronic lymphedema, and certain toxins including vinyl chloride and thorium dioxide are known risk factors.¹³

Undifferentiated sarcomas have no specific features and typically consist of primitive mesenchymal cells.

Clinical Evaluation

›  Case Presentation

Initial Presentation and History

A 55-year-old man presents to his primary care physician with a painless mass in his anterior thigh. The mass has been present for the past 3 months and he believes that it is enlarging. The patient has a history of well-controlled hypertension and hyperlipidemia. His medications include atorvastatin and hydrochlorothiazide. He has no known drug allergies. Family history is notable for diabetes and hypertension. He drinks 4 to 5 alcoholic drinks a week and he is a former smoker. He quit smoking in his 30s and only smoked intermittently prior to quitting. He denies any illicit drug use. He works as a high school principal. Currently, he feels well. His review of systems is otherwise noncontributory.

Physical Examination

On physical exam, he is afebrile with a blood pressure of 132/75 mm Hg, respiratory rate of 10 breaths/min, and oxygen saturation of 99% on room air. He is a well appearing, overweight male. His head and neck exam is unremarkable. Lung exam reveals clear breath sounds, and cardiac exam reveals a regular rate and rhythm. His abdomen is obese, soft, and without hepatosplenomegaly. There is a large, fixed mass on the anterior lateral aspect of his right thigh. He has no appreciable lymphadenopathy. His neurological exam is unremarkable.

• What are risk factors for sarcoma?

There are few known risk factors for sarcoma. Established risks factors include prior radiation therapy, chronic lymphedema, viruses, and genetic cancer syndromes including Li-Fraumeni syndrome, hereditary retinoblastoma, and NF-1. Other environmental exposures include phenoxyacetic acids and chlorophenols.¹⁴ The majority of cases are sporadic, with only a minority of patients having one of these known risk factors.¹⁵ Up to one third of sarcomas have a specific translocation and are driven by fusion oncogenes (Table 1).

• What is the typical presentation for sarcomas?

A painless mass is the most typical presenting symptom. Size at presentation varies based on location, with extremity and head and neck locations typically presenting at smaller sizes than retroperitoneal tumors.¹⁴ Patients may experience pain and numbness as the mass enlarges and impinges on surrounding structures including nerves and vasculature. The vast majority of patients are without systemic symptoms.

• How is sarcoma staged?

The American Joint Committee on Cancer (AJCC) staging system is the most widely used staging system in the United States. The latest AJCC manual was updated in 2010 to include a 3-tiered grading system where the tumor is classified according to tumor size, lymph node involvement, metastases, and grade at time of diagnosis (Table 2 and Table 3). Additionally, tumor depth in relation to deep fascia is also taken into account, with superficial tumors being assigned a designation of “a” and deep tumors a designation of “b.”

Previously, 2 of the most widely used grading systems were the National Cancer Institute (NCI) and French Federation of Cancer Centers Sarcoma Group (FNCLCC) systems, both 3-tier grading systems. The main components that determine the NCI grade are the tumor’s histologic type and location and the amount of tumor necrosis. The FNCLCC system evaluation focuses on tumor differentiation, mitotic rate, and amount of tumor necrosis. A study that compared the NCI and FNCLCC grading systems found that FNCLCC was a better predictor of mortality and distant metastasis.¹⁶ Previously, the AJCC was a 4-tier grading system, but the 2010 version was updated to the 3-tier FNCLCC grading system. Additionally, the AJCC system has reclassified single lymph node disease as stage III as it confers better survival than metastatic disease.¹⁷ It is important that pathology be evaluated by a sarcoma specialist as disagreements with regard to histologic subtype and grade are common.^18,19

• What are the most important prognostic factors?

Prognostic factors include grade, size, and presence of metastases at presentation. Best survival is associated with low-grade, small tumors with no metastases at time of diagnosis.¹⁴

• What imaging should be considered?

Imaging should be undertaken to help differentiate between benign and malignant lesions. Ideally, it should be undertaken before a biopsy is planned as the imaging can be used to plan biopsy as well as provide invaluable prognostic information. There are several imaging modalities that should be considered during the preliminary work-up and staging of STSs. Conventional imaging includes magnetic resonance imaging (MRI) of the original tumor site; computed tomography (CT) to evaluate for pulmonary metastases and, depending on location, liver metastases; and in the case of small, low-grade tumors, chest radiography. MRI is considered the test of choice for soft tissue masses and can help delineate benign masses such as hematomas, lipomas, and hemangiomas from sarcomas.²⁰ It is difficult to compare the accuracy of positron emission tomography (PET)/CT to CT and MRI because most studies have evaluated PET/CT in parallel with CT and MRI.²¹ Tateishi et al compared the accuracy of conventional imaging, PET/CT, and PET/CT combined with conventional imaging at determining the TNM staging for 117 patients. They found that conventional imaging correctly classified 77% of patients, PET alone correctly classified 70%, PET/CT correctly classified 83%, and PET/CT combined with conventional imaging correctly staged 87%.²²

• Which subtypes are most likely to metastasize?

Although the vast majority of sarcomas spread hematogenously, 3 have a propensity to spread lymphogenously: epithelioid sarcoma, rhabdomyosarcoma, and clear-cell sarcoma. Additionally, certain subtypes are more likely to metastasize: leiomyosarcomas, synovial sarcomas, neurogenic sarcomas, rhabdomyosarcomas, and epithelioid sarcomas.²³ Sarcomas metastasize to the lungs more frequently than to the liver. The metastatic pattern is defined primarily by sarcoma subtype and site of primary tumor. Sarcomas rarely metastasize to the brain (~1%).

Management

›  Case Continued

The patient undergoes an ultrasound to better visualize the mass. Given the heterogeneous character of the mass, he is referred for an MRI to evaluate the mass and a CT scan of the chest, abdomen, and pelvis to evaluate for distant metastases. MRI reveals a 5.1 cm × 4.6 cm heterogeneous mass invading the superficial fascia of the rectus femoris muscle. No suspicious lymph nodes or other masses are identified on imaging. The patient next undergoes an image-guided core needle biopsy. Pathology from that procedure is consistent with a stage III, T2bNxMx, grade 3, dedifferentiated liposarcoma.

• What is the best management approach for this patient?

Surgery

Surgery is the mainstay of treatment for STS. Patients with the best prognosis are those who undergo complete resection with negative surgical margins.^24,25 Goal tumor-free margin is 1 to 3 cm.²⁶ Complete resection confers the best long-term survival. Both local and metastatic recurrence is higher in patients with incomplete resection and positive margins.^24,25 In a study that analyzed 2084 localized primary STSs, patients with negative margins had a local recurrence rate of 15% versus a rate of 28% in patients with positive margins. This translated into higher 5-year local recurrence-free survival for patients with negative surgical margins (82%) compared to patients with positive margins (65%).²⁷ Another study similarly found that patients with negative margins at referral to their institution who underwent postoperative radiation had high local control rates of 93% (95% confidence interval [CI] 87% to 97%) at 5, 10, and 15 years.²⁶ Although radiation improves local control, neither preoperative or postoperative radiation has been shown to improve progression-free or overall survival.²⁸ Other factors that are associated with risk of recurrence are tumor location, history of previous recurrence, age of patient, histopathology, tumor grade, and tumor size. Approximately 40% to 50% of patients with high-grade tumors (defined as size > 5 cm, deep location, and high grade) will develop distant metastases.²⁹

Zagars et al found that positive or uncertain resection margin had a relative risk of local recurrence of 2.0 (95% CI 1.3 to 3.1; P = 0.002), and presentation with locally recurrent disease (vs new tumor) had a relative risk of local recurrence of 2.0 (95% CI 1.2 to 3.4; P = 0.013).²⁶ Patients with STS of head and neck and deep trunk have higher recurrence rates than those with superficial trunk and extremity STS. A single-institution retrospective review demonstrated that patients with completely resectable retroperitoneal sarcomas have longer median survival (103 months) compared to patients with incompletely resected abdominal sarcomas (18 months).²⁵Rosenberg and colleagues compared amputation to limb-sparing surgery and radiation.²⁴ Their prospective analysis of 65 patients found no difference in disease-free and overall survival between the 2 treatment groups.The limb-sparing treatment group had higher rates of local recurrence, which was highly correlated with positive surgical margins on pathology.²⁴ Evidence from this and similar studies has resulted in radical amputations being replaced by conservative limb-sparing procedures and radiation therapy. In those found to have positive margins, re-resection is an option for some. Patients who undergo re-resection have higher local control rates than patients with positive margins who do not undergo re-resection. The 5-year control rate for patients who undergo re-resection is 85% (95% CI 80% to 89%) compared to 78% (95% CI 71% to 83%) for those who do not undergo re-resection. Similarly, patients who undergo re-resection have lower rates of metastases at 5, 10, and 15 years as well as higher 5-, 10-, and 15-year disease-free survival rates.²⁶

›  Case Continued

The patient is referred for limb-sparing surgery after presentation at a multidisciplinary tumor board. Prior to undergoing resection of the tumor, he is also referred to radiation-oncology to discuss the risks and benefits of combination radiotherapy and surgery as opposed to surgical resection alone.

• What is the evidence for radiation therapy?

Radiation THERAPY

Radiation therapy is used in the preoperative, intraoperative, and postoperative settings to reduce the risk of local recurrence. There are several options for radiation, including external beam radiation therapy (EBRT), intraoperative radiation, and brachytherapy. A newer strategy, intensity-modulated radiation therapy (IMRT), utilizes 3-dimensional modeling to reduce radiation dosages. Overall there are no differences in overall survival or local recurrence rates between preoperative and postoperative radiation in STS.²⁸

The rationale behind preoperative radiation is that it reduces seeding of tumor cells, especially at the time of surgery.³⁰ Additionally, for EBRT, preoperative radiation has smaller field sizes and lower radiation doses. It can also help to reduce the size of the tumor prior to resection. Intraoperative radiation is often paired with preoperative radiation as a boost dose given only to the area of residual tumor.

Suit et al reviewed patients treated at a single institution with limb-sparing surgery and different radiation strategies. Local control rates between preoperative and postoperative radiation groups were not statistically significant. Local recurrence was linked to grade and size of the tumor in both groups. The authors did note, however, that the preoperative radiation group tended to have larger tumor sizes at baseline compared to the patients who received postoperative radiation.³⁰ A study that compared 190 patients who received preoperative and postoperative EBRT or brachytherapy (primary end point was wound complications, and local control was a secondary end point) showed a trend towards greater local control with preoperative radiation; however, the preoperative radiation group had significantly more wound complications compared to the postoperative radiation group.³¹

Yang et al found that postoperative EBRT decreases rates of local recurrence compared to surgery alone in high-grade extremity sarcomas.³² However, there were no differences in rates of distant metastases and overall survival between the 2 treatment groups. Similarly, in patients with low-grade sarcoma, there were fewer local recurrences in those who received EBRT and surgery as compared to surgery alone.³² Another study that evaluated 164 patients who received either adjuvant brachytherapy or no further therapy after complete resection found that brachytherapy reduced local recurrence in high-grade sarcomas. No difference in local recurrence rates was found in patients with low-grade sarcomas, nor was a significant difference found in the rates of distant metastases and overall survival between the 2 treatment groups.³³ With regards to IMRT, a single institution cohort experience with 41 patients who received IMRT following limb-sparing surgery had similar local control rates when compared to historical controls.³⁴

›  Case Continued

After discussion of the risks and benefits of radiation therapy, the patient opts for preoperative radiation prior to resection of his liposarcoma. He receives 50 Gy of EBRT prior to undergoing resection. Resection results in R1 margin consistent with microscopic disease. He receives 16 Gy of EBRT as a boost after recovery from his resection.²

• What is the evidence for neoadjuvant and adjuvant chemotherapy for stage I tumors?

Chemotherapy

Localized Sarcoma

For localized sarcoma, limb-sparing resection with or without radiation forms the backbone of treatment. Studies have evaluated chemotherapy in both the neoadjuvant and adjuvant settings, with the vast majority of studies evaluating doxorubicin-based chemotherapy regimens in the adjuvant settings. Due to the rare nature of sarcomas, most studies are not sufficiently powered to detect significant benefit from chemotherapy. Several trials evaluating chemotherapy regimens in the neoadjuvant and adjuvant settings needed to be terminated prematurely due to inadequate enrollment into the study.^35,36

For stage IA (T1a-Tb, N0, M0, low grade) tumors, no additional therapy is recommended after limb-sparing surgery with appropriate surgical margins. For stage IB (T2a-2b, N0, M0, low grade) tumors with insufficient margins, re-resection and radiation therapy should be considered, while for stage IIA (T1a-1b, N0, M0, G2-3) tumors preoperative or postoperative radiation therapy is recommended.² Studies have not found benefit of adjuvant chemotherapy in these low-grade, stage I tumors in terms of progression-free survival and overall survival.³⁷

• At what stage should chemotherapy be considered?

For stage IIb and stage III tumors, surgery and radiation therapy again form the backbone of therapy; however, neoadjuvant and adjuvant chemotherapy are also recommended as considerations. Anthracycline-based chemotherapy with either single-agent doxorubicin or doxorubicin and ifosfamide in combination are considered first-line chemotherapy agents in locally advanced STS.^2,29,37

Evidence regarding the efficacy of both neoadjuvant and adjuvant chemotherapy regimens in the setting of locally advanced high-grade STS has been mixed. The Sarcoma Meta-analysis Collaboration evaluated 14 trials of doxorubicin-based adjuvant chemotherapy and found a trend towards overall survival in the treatment groups that received chemotherapy.³⁷ All trials included in the meta-analysis compared patients with localized resectable soft-tissue sarcomas who were randomized to either adjuvant chemotherapy or no adjuvant chemotherapy after limb-sparing surgery with or without radiation therapy. None of the individual trials showed a significant benefit, and all trials had large confidence intervals; however, the meta-analysis showed significant benefit in the chemotherapy treatment groups with regard to local recurrence, distant recurrence, and progression-free survival. No significant difference in overall survival was found.³⁷ Pervais et al updated the Sarcoma Meta-analysis Collaboration’s 1997 meta-analysis with the inclusion of 4 new trials that evaluated doxorubicin combined with ifosfamide and found that both patients who received doxorubicin-based regimens or doxorubicin with ifosfamide had significant decreases in distant and overall recurrences. Only the trials that utilized doxorubicin and ifosfamide had an improved overall survival that was statistically significant (hazard ratio 0.56 [95% CI 0.36 to 0.85]; P = 0.01).²⁹ Although no significant heterogeneity was found among the trials included in either meta-analysis, a variety of sarcomas were included in each clinical trial evaluated. Given the extremely small number of each sarcoma subtype present in each trial, subgroup analysis is difficult and prone to inaccuracies. As a result, it is not known if certain histological subtypes are more or less responsive to chemotherapy.^37–39

One randomized controlled trial evaluated neoadjuvant chemotherapy in high-risk sarcomas defined as tumors greater than 8 cm or grade II/III tumors. This study evaluated doxorubicin and ifosfamide and found no significant difference in disease-free and overall survival in the neoadjuvant therapy group compared to the control group.³⁵ There remains controversy in the literature with regards to adjuvant chemotherapy. Many oncologists offer adjuvant chemotherapy to patients with certain stage III subtypes. Examples of subtypes that may be offered adjuvant therapy include myxoid liposarcomas, synovial sarcomas, and leiomyosarcomas.² With regards to how many cycles of chemotherapy should be considered, a noninferiority study compared 3 cycles of epirubicin and ifosfamide to 5 cycles of epirubicin and ifosfamide in patients with high-risk locally advanced adult STSs. Three cycles of preoperative epirubicin and ifosfamide was found to be noninferior to 5 cycles with regards to overall survival.³⁸

• What is this patient’s risk for recurrence?

The patient is at intermediate risk for recurrence. Numerous studies have demonstrated that tumor size, grade, and location are the most important factors to determine risk of recurrence, with larger size, higher grades, and deeper locations being associated with higher risk of recurrence. In an analysis of 1041 patients with STS of the extremities, high grade was the most important risk factor for distant metastases.³⁹ The highest risk of recurrence is within the first 2 years. Given that the patient’s initial tumor was located in the extremity, he is more likely to have a distant metastasis as his site of recurrence; individuals with retroperitoneal tumors and visceral tumors are more likely to recur locally.⁴⁰ For STSs of the extremity, distant metastases determine overall survival, whereas patients with retroperitoneal sarcomas can die from complications of local metastases.⁴¹ Once a patient develops distant metastases, the most important prognostic factor is the size of the tumor, with tumors larger than 10 cm having a relative risk of 1.5 (95% CI 1.0 to 2.0).³⁹

• What are the recommendations for surveillance?

Surveillance recommendations are based on the stage of the sarcoma. Stage I tumors are the least likely to recur either locally or distally. As a result, it is recommended that stage I tumors be followed with history and physical exam every 3 to 6 months for the first 2 to 3 years, and then annually after the first 2 to 3 years. Chest x-rays should be considered every 6 to 12 months.² For stage II–IV tumors, history and physical exam is recommended every 3 to 6 months for the first 2 to 3 years. Chest and distant metastases imaging should also be performed every 3 to 6 months during this time frame. For the next 2 years, history and physical exam and imaging are recommended every 6 months. After the first 4 to 5 years, annual follow-up is recommended.²

A study that followed 141 patients with primary extremity STSs for a median interval of 49 months found that high-grade tumors were most likely to recur during the first 2 years, with 20% of their patients recurring locally and 40% recurring distally. Chest x-rays performed during surveillance follow-up found distant lung metastases in 36 asymptomatic patients and had a positive predictive value of 92%, a negative predictive value of 97%, and a quality-adjusted life-year of $30,000.^40,41 No laboratory testing was found to aid in detection of recurrence.

›  Case Continued

The patient does well for 1 year. With physical therapy, he regains most of the strength and coordination of the lower extremity. He is followed every 3 months with chest x-rays and a MRI of the thigh for the first year. On his fourth follow-up clinic visit, he describes increased dysp-nea on exertion over the previous few weeks and is found to have multiple lung metastases in both lungs on chest x-ray. He undergoes further evaluation for metastases and is not found to have any other metastatic lesions. Bronchoscopy and biopsy of 1 of the lung nodules confirms recurrent dedifferentiated liposarcoma.

• Should this patient undergo metastectomy?

An analysis of 3149 patients with STS treated at Memorial Sloan-Kettering who developed lung metastases found that patients with pulmonary metastases have survival rates of 25%. The most important prognostic factor for survival was complete resection of all metastases.⁴² For stage IV disease, surgery is used only in certain instances. In instances where tumor is more localized or limited, removal of metastases or metastectomy can play a role in management.²

›  Case Continued

Because the patient’s metastases are limited to the lungs, he is referred for metastectomy. He undergoes wedge resection for definitive diagnosis but it is not possible to completely resect all of the metastases. He is thus referred to a medical oncologist to discuss his treatment options.

• What are treatment options for unresectable or metastatic disease?

Metastatic Disease

Unlike local and locally advanced disease, chemotherapy forms the backbone of treatment in stage IV disease. Doxorubicin and olaratumab or doxorubicin and ifosfamide in combination are considered first line in metastatic disease. Response rates for single-agent doxorubicin range from 16% to 27%, while phase 2 and phase 3 studies of doxorubicin and ifosfamide have found response rates ranging from 18% to 36%.⁴³ In addition, the effectiveness of doxorubicin and ifosfamide phase 2 and 3 trials varied. Edmonson et al found a tumor regression rate of 34% for doxorubicin and ifosfamide as compared to 20% for doxorubicin alone.⁴⁴ In comparison, Santoro et al found a response rate of 21.3% for doxorubicin alone and 25.2% for doxorubicin and ifosfamide.⁴⁵ Neither study found increased survival benefit for doxorubicin and ifosfamide when compared to doxorubicin alone. In a Cochrane review evaluating randomized trials that compared doxorubicin and combination chemotherapy regimens, response rates varied from 14% for doxorubicin in combination with streptomycin to 34% for doxorubicin and ifosfamide. Most trials did not show a significant benefit for combination therapies when compared to doxorubicin alone.⁴³ Mean survival with doxorubicin or doxorubicin and ifosfamide is 12 months. High rates of recurrence highlight the need for additional chemotherapy regimens.

The newest approved agent is olaratumab, a monoclonal antibody that binds platelet-derived growth factor receptor alpha and prevents receptor activation. A phase 1-b and phase 2 trial evaluated patients with locally advanced and metastatic STS and randomly assigned them to either olaratumab and doxorubicin or doxorubicin alone.⁴⁶ Progression-free survival for olaratumab/doxorubicin was 6.6 months (95% CI 4.1 to 8.3) compared to 4.1 months (95% CI 2.8 to 5.4) for doxorubicin alone. The objective response rate was 18.2% (95% CI 9.8 to 29.6) for olaratumab/doxorubicin compared to 7.5% (95% CI 2.5 to 6.6) for doxorubicin alone. Furthermore, the median overall survival for olaratumab plus doxorubicin was 26.5 months (95% CI 20.9 to 31.7) compared to 14.7 months for doxorubicin alone (95% CI 5.5 to 26.0). Impressively, this improved response was notable across histological types. Furthermore, patients who had previously been treated with more than 1 regimen and those who were treatment naïve had similar response rates.⁴⁶

• What are second-line treatment options?

Doxorubicin has been used in combination with several other agents including dacarbazine (DTIC) as well as DTIC and ifosfamide (MAID). Borden et al evaluated patients with metastatic STS and randomly assigned the patients to either doxorubicin or doxorubicin and DTIC. Combination therapy demonstrated better tumor response than doxorubicin alone: 30% complete or partial response for combination therapy and 18% for doxorubicin alone.⁴⁷ However, Omura et al found similar rates of efficacy between doxorubicin and combination doxorubicin and DTIC in women with recurrent or nonresectable uterine sarcomas.⁴⁸ MAID has never been directly compared in a randomized trial to doxorubicin alone. In a study that compared MAID to doxorubicin and DTIC (AD) in patients with unresectable or metastatic sarcomas, MAID had superior response rates (32% versus 17%), but there was no difference with regards to overall survival (mean survival of 12.5 months).⁴⁹

Several additional regimens have undergone evaluation in metastatic and recurrent STSs. Gemcitabine has been used both as a single agent and as part of combination therapy in many studies. Studies with gemcitabine in combination with either docetaxel or DTIC have been the most efficacious. In a phase 2 trial, patients with metastatic STS were randomly assigned to either gemcitabine alone or gemcitabine and docetaxel. Combination therapy had a higher response rate (16% versus 8%) and longer overall survival (17.9 months versus 11.5 months) than gemcitabine alone.⁵⁰ Furthermore, a phase 2 trial of gemcitabine and docetaxel in patients with unresectable leiomyosarcoma showed an overall response rate of 56%, with 3 complete and 15 partial responses among the 34 patients enrolled in the study.⁵¹ A phase 2 trial randomly assigned patients with unresectable or metastatic STS to either DTIC or combination gemcitabine and DTIC.⁵² Gemcitabine-DTIC had a superior progression-free survival at 3 months (56% [95% CI 43% to 69%]) as compared to DTIC alone (37% [95% CI 23.5% to 50%]). Furthermore, mean progression-free survival and overall survival were improved in the gemcitabine-DTIC group (4.2 months and 16.8 months) as compared to the DTIC group (2.0 months and 8.2 months).⁵² DTIC has a single-agent response rate of 16%, but has been shown to be particularly effective in the setting of leiomyosarcomas.⁴⁹

• Does response to treatment regimens differ by histologic subtype?

The majority of STS trials include many different histologic subtypes. Given the rarity of sarcomas as a whole, many trials have had difficulty recruiting adequate numbers of patients to have sufficient power to definitely determine if the treatment under investigation has clinical benefit. Furthermore, the patients recruited have been heterogeneous with regard to subtype. Many older studies hypothesized that the efficacy of chemotherapeutic agents vary based on histologic subtype; however, for most subtypes the number of individuals included in those trials was too low to evaluate efficacy based on subtype.

Some exceptions exist, however. For example, both gemcitabine-DTIC and gemcitabine-docetaxel have been found to be particularly effective in the treatment of leiomyosarcomas.^50,52 Additionally, a retrospective study found a 51% overall response rate for patients with myxoid liposarcomas treated with trabectedin.⁵³ Studies of patients with angiosarcoma treated with paclitaxel have demonstrated response rates of 43% and 53%.^54,55

• What are the newest approved and investigational agents?

A recently approved agent is trabectedin, a tris tetrahydroisoquinoline alkaloid isolated from ascidians that binds to the minor groove of DNA and causes disruptions in the cell cycle. Samuels et al reported data from a single-arm, open-label expanded access trial that evaluated patients with advanced metastatic sarcomas.⁵⁶ In this study, patients with liposarcomas and leiomyosarcomas had an objective response rate of 6.9% (95% CI 4.8 to 9.6) as compared to a rate of 5.9% (95% CI 4.4 to 7.8) for all assessable patients. Median survival was 11.9 months for all patients, with improved median survivals for liposarcoma and leiomyosarcomas of 16.2 months (95% CI 14.1 to 19.5) compared to 8.4 months (95% CI 7.1 to 10.7 months) for other subtypes.⁵⁶

Schöffski et al evaluated eribulin, a chemotherapeutic agent that affects microtubule dynamics, in a phase 2 trial of patients with progressive or high-grade STS with progression on previous chemotherapy. They found a median progression-free survival of 2.6 months (95% CI 1.7 to 6.2) for adipocytic sarcoma, 2.9 months (95% CI 2.4 to 4.6) for leiomyosarcoma, 2.6 months (95% CI 2.3 to 4.3) for synovial sarcoma, and 2.1 months (95% CI 1.4 to 2.9) for other sarcomas.⁵⁷

Van der Graaf and colleagues randomly assigned patients with metastatic nonadipocytic STS to pazopanib or placebo in a phase 3 trial. Pazopanib is a small-molecule endothelial growth factor inhibitor with activity against vascular endothelial growth factors 1, 2, and 3 as well as platelet-derived growth factors. Median progression-free survival was 4.6 months (95% CI 3.7 to 4.8) with pazopanib compared to 1.6 months (95% CI 0.9 to 1.8) with placebo.⁵⁸ Adipocytic sarcomas (liposarcomas) were excluded from the trial because phase 2 trials had found a lower rate of progression-free survival (26%) for them compared to other subtypes.

• What are the most common toxicities associated with the approved and investigational chemotherapeutic agents?

Toxicities were seen with each of the regimens studied and were common in the randomized trials, with higher rates of toxicities in the combination chemotherapy regimens. The most common toxicities are myelosuppression, nausea, and vomiting. In the doxorubicin trials, the most common toxicities were myelosuppression, nausea, and vomiting.⁴⁴

Ifosfamide both as an individual agent and in combination with doxorubicin has higher rates and higher grades of toxicity than doxorubicin alone. Myelosuppression is the most common toxicity associated with ifosfamide, and the most commonly affected cell line is leukocytes.⁴⁴ Combination doxorubicin and ifosfamide also had high rates of nausea and vomiting (95%) and alopecia (100%).³⁵Neutropenia is the most common toxicity associated with gemcitabine and dacarbazine, while their most common nonhematologic toxicities are fatigue and nausea.^52,59 Trabectedin’s most common toxicities are nausea (29%), neutropenia (24%), and fatigue (23%). It has also been shown to cause increased alkaline phosphatase (20%) and alanine aminotransferase (19%) levels.⁵⁶ In a phase 2 study of eribulin, 50% of patients had neutropenia, and other toxicities included fatigue, alopecia, nausea, sensory neuropathy, and thrombocytopenia.⁵⁷ Pazopanib is generally well tolerated; the most common toxicities are fatigue (65%), diarrhea (58%), nausea (54%), and hypertension (41%).⁵⁸ Higher rates of neutropenia, mucositis, nausea, vomiting, diarrhea, and transfusion reactions were seen with olaratumab and doxorubicin compared to doxorubicin alone in phase 1b and 2 studies.⁴⁶

›  Case Continued

Given his poor prognosis with unresectable metastatic undifferentiated liposarcoma, the patient considers a clinical trial prior to undergoing combined therapy with doxorubicin and ifosfamide. He tolerates therapy well with stable disease at 6 months.

Conclusion

STSs are a heterogeneous collection of rare tumors. Low-grade, localized tumors have the best prognosis, and patients who undergo complete resection have the best long-term survival. Due to the rarity of STSs, trials often have limited enrollment, and little progress has been made with regards to treatment and survival rates for metastatic and unresectable disease. All patients should be evaluated and treated at specialized sarcoma centers. This case highlights the need for continued research and clinical trials to improve overall survival of patients with sarcoma. TSJ

CORRESPONDENCE

Ashley Pariser, MD, Resident, Department of Medicine, Northwestern University Feinberg School of Medicine Chicago, IL. Accepted for publication Jan/Feb 2017; Hosp Phys; Vol. 12, Part1

Introduction

Soft tissue sarcomas (STSs) are rare adult tumors, with 3.4 new cases per 100,000 persons or 12,310 expected new cases in 2016.¹ Sarcomas are a heterogeneous collection of tumors that affect fat, muscle, nerve, nerve sheath, vascular, and connective tissues. There are more than 50 histological subtypes that comprise this diverse category of tumors. Treatment varies by stage, with limb-sparing surgery representing the mainstay of curative-intent treatment. Radiation and chemotherapy may also be considered depending on the size, grade, and location of the tumor. Survival rates have been stagnant until recently, with a disease-specific survival hovering around 65%.¹ Given the complexity of these cases, all patients ideally should be evaluated and treated by a multidisciplinary team at an institution with extensive experience treating STS.²

Epidemiology and Classification

The most common STS subtypes are gastrointestinal stromal tumor (GIST), undifferentiate pleomorphic sarcoma (previously referred to as malignant fibrous histiocytoma), liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, and unclassified sarcoma.³ Liposarcoma is one of the most common subtypes, comprising 20% of all STSs; it is subdivided into well-differentiated/dedifferentiated liposarcomas, myxoid/round cell liposarcomas, and pleomorphic liposarcomas. Well-differentiated liposarcomas tend to occur in the retroperitoneum and limbs, while both myxoid and round cell as well as pleomorphic liposarcomas more commonly originate on the limbs. Histology varies based on subtype and ranges from mature-appearing adipocytes and fibroblasts to undifferentiated cells with minimal lipogenic differentiation.⁴

Leiomyosarcomas are smooth muscle tumors and are usually located in the retroperitoneum, but have also been associated with peripheral soft tissue and vasculature. Typical histology ranges from well-defined areas of spindle-shaped cells to poorly differentiated anaplastic spindle cells.^5,6 Synovial sarcomas are a distinct type of STS that can show epithelial differentiation and account for 5% of adult STSs. The extremities are the most common presenting location (90%).⁷

Rhabdomyosarcomas are skeletal muscle tumors and are further subdivided into embryonal, alveolar, and pleomorphic subtypes. Embryonal histology ranges from primitive mesenchymal-appearing cells to highly differentiated muscle cells. Alveolar rhabdomyosarcoma has the worst prognosis of the subtypes and consists of round cells with high nuclear-to-chromatin ratios that form “glandular-like” or “alveolar” spaces.⁸ Pleomorphic rhabdomyosarcomas are composed of rhabdomyoblasts that can affect many different locations, but most commonly present on the lower extremities.⁹

Malignant peripheral nerve sheath tumor (MPNST) comprises 5% to 10% of all STSs. These tumors are associated with neurofibromatosis type 1 (NF-1), with 25% to 50% of tumors occurring in NF-1 patients. Additionally, most patients have a truncating lesion in the NF1 gene on chromosome 17.¹⁰ Anghileri et al in their single institution analysis of 205 patients with MPNSTs found the 2 most common presenting sites were the trunk and extremities. Histologically, these tumors have dense fascicles of spindle cells.¹⁰

GISTs are the most common STS of the gastrointestinal (GI) tract. Previously, GISTs were classified as smooth muscle tumors and were not accounted for in the literature as a separate entity distinct from leiomyomas, leiomyoblastomas, and leiomyosarcomas.¹¹ GISTs are found throughout the GI tract: the most common sites are the stomach (60%) and small intestine (30%). Less common sites include duodenum (4%–5%), esophagus (1%), rectum (1%–2%), and appendix (< 0.2%).¹² GISTs can be spindle cell, epithelioid, or mesenchymal tumors. Immunohistochemically, GISTs are KIT (CD117) positive. Other cell markers that are also commonly positive include CD34 (60%–70%) and smooth muscle actin (SMA) (25%).¹¹ The majority of GISTs (80%) have an activating c-KIT gene mutation. The most common mutation site is exon 11, with less common c-KIT gene mutations also occurring at exon 9 or 13. Not all GISTs have KIT mutations. The second most common mutation is the PDGFRA mutation (5%–10% of GISTs).² A minority of GISTs are negative for both KIT and PDGFRA mutations. These tumors were previously called wild-type, but as the majority have either a succinate dehydrogenase (SDH) loss of function or loss of SDHB protein expression, they are now referred to as SDH-deficient GISTs.² GISTs vary in aggressiveness from incidental to aggressive. Typically, small intestine and rectal GISTs are more aggressive than gastric GISTs. Both size and mitotic rate help to predict the metastatic potential of the tumor. Tumors less than 2 cm in size and having a mitotic rate of less than 5 per 50 high-power fields (hpf) have the lowest risk of metastases, while tumors greater than 5 cm and with more than 5 mitoses per 50 hpf have the highest rates of metastases.¹²

Angiosarcomas are rare tumors comprising 4% of all STSs. Although they can occur in any site, the majority are cutaneous and occur most frequently in the head and neck regions. These tumors are either of vascular or lymphatic origin and are comprised of abnormal, pleomorphic, malignant endothelial cells. The most useful immunohistochemical markers include von Willebrand factor, CD31, and Ulex europaeus agglutinin 1. The majority of these tumors occur sporadically; however, radiation exposure, chronic lymphedema, and certain toxins including vinyl chloride and thorium dioxide are known risk factors.¹³

Undifferentiated sarcomas have no specific features and typically consist of primitive mesenchymal cells.

Clinical Evaluation

›  Case Presentation

Initial Presentation and History

A 55-year-old man presents to his primary care physician with a painless mass in his anterior thigh. The mass has been present for the past 3 months and he believes that it is enlarging. The patient has a history of well-controlled hypertension and hyperlipidemia. His medications include atorvastatin and hydrochlorothiazide. He has no known drug allergies. Family history is notable for diabetes and hypertension. He drinks 4 to 5 alcoholic drinks a week and he is a former smoker. He quit smoking in his 30s and only smoked intermittently prior to quitting. He denies any illicit drug use. He works as a high school principal. Currently, he feels well. His review of systems is otherwise noncontributory.

Physical Examination

On physical exam, he is afebrile with a blood pressure of 132/75 mm Hg, respiratory rate of 10 breaths/min, and oxygen saturation of 99% on room air. He is a well appearing, overweight male. His head and neck exam is unremarkable. Lung exam reveals clear breath sounds, and cardiac exam reveals a regular rate and rhythm. His abdomen is obese, soft, and without hepatosplenomegaly. There is a large, fixed mass on the anterior lateral aspect of his right thigh. He has no appreciable lymphadenopathy. His neurological exam is unremarkable.

• What are risk factors for sarcoma?

There are few known risk factors for sarcoma. Established risks factors include prior radiation therapy, chronic lymphedema, viruses, and genetic cancer syndromes including Li-Fraumeni syndrome, hereditary retinoblastoma, and NF-1. Other environmental exposures include phenoxyacetic acids and chlorophenols.¹⁴ The majority of cases are sporadic, with only a minority of patients having one of these known risk factors.¹⁵ Up to one third of sarcomas have a specific translocation and are driven by fusion oncogenes (Table 1).

• What is the typical presentation for sarcomas?

A painless mass is the most typical presenting symptom. Size at presentation varies based on location, with extremity and head and neck locations typically presenting at smaller sizes than retroperitoneal tumors.¹⁴ Patients may experience pain and numbness as the mass enlarges and impinges on surrounding structures including nerves and vasculature. The vast majority of patients are without systemic symptoms.

• How is sarcoma staged?

The American Joint Committee on Cancer (AJCC) staging system is the most widely used staging system in the United States. The latest AJCC manual was updated in 2010 to include a 3-tiered grading system where the tumor is classified according to tumor size, lymph node involvement, metastases, and grade at time of diagnosis (Table 2 and Table 3). Additionally, tumor depth in relation to deep fascia is also taken into account, with superficial tumors being assigned a designation of “a” and deep tumors a designation of “b.”

Previously, 2 of the most widely used grading systems were the National Cancer Institute (NCI) and French Federation of Cancer Centers Sarcoma Group (FNCLCC) systems, both 3-tier grading systems. The main components that determine the NCI grade are the tumor’s histologic type and location and the amount of tumor necrosis. The FNCLCC system evaluation focuses on tumor differentiation, mitotic rate, and amount of tumor necrosis. A study that compared the NCI and FNCLCC grading systems found that FNCLCC was a better predictor of mortality and distant metastasis.¹⁶ Previously, the AJCC was a 4-tier grading system, but the 2010 version was updated to the 3-tier FNCLCC grading system. Additionally, the AJCC system has reclassified single lymph node disease as stage III as it confers better survival than metastatic disease.¹⁷ It is important that pathology be evaluated by a sarcoma specialist as disagreements with regard to histologic subtype and grade are common.^18,19

• What are the most important prognostic factors?

Prognostic factors include grade, size, and presence of metastases at presentation. Best survival is associated with low-grade, small tumors with no metastases at time of diagnosis.¹⁴

• What imaging should be considered?

Imaging should be undertaken to help differentiate between benign and malignant lesions. Ideally, it should be undertaken before a biopsy is planned as the imaging can be used to plan biopsy as well as provide invaluable prognostic information. There are several imaging modalities that should be considered during the preliminary work-up and staging of STSs. Conventional imaging includes magnetic resonance imaging (MRI) of the original tumor site; computed tomography (CT) to evaluate for pulmonary metastases and, depending on location, liver metastases; and in the case of small, low-grade tumors, chest radiography. MRI is considered the test of choice for soft tissue masses and can help delineate benign masses such as hematomas, lipomas, and hemangiomas from sarcomas.²⁰ It is difficult to compare the accuracy of positron emission tomography (PET)/CT to CT and MRI because most studies have evaluated PET/CT in parallel with CT and MRI.²¹ Tateishi et al compared the accuracy of conventional imaging, PET/CT, and PET/CT combined with conventional imaging at determining the TNM staging for 117 patients. They found that conventional imaging correctly classified 77% of patients, PET alone correctly classified 70%, PET/CT correctly classified 83%, and PET/CT combined with conventional imaging correctly staged 87%.²²

• Which subtypes are most likely to metastasize?

Although the vast majority of sarcomas spread hematogenously, 3 have a propensity to spread lymphogenously: epithelioid sarcoma, rhabdomyosarcoma, and clear-cell sarcoma. Additionally, certain subtypes are more likely to metastasize: leiomyosarcomas, synovial sarcomas, neurogenic sarcomas, rhabdomyosarcomas, and epithelioid sarcomas.²³ Sarcomas metastasize to the lungs more frequently than to the liver. The metastatic pattern is defined primarily by sarcoma subtype and site of primary tumor. Sarcomas rarely metastasize to the brain (~1%).

Management

›  Case Continued

The patient undergoes an ultrasound to better visualize the mass. Given the heterogeneous character of the mass, he is referred for an MRI to evaluate the mass and a CT scan of the chest, abdomen, and pelvis to evaluate for distant metastases. MRI reveals a 5.1 cm × 4.6 cm heterogeneous mass invading the superficial fascia of the rectus femoris muscle. No suspicious lymph nodes or other masses are identified on imaging. The patient next undergoes an image-guided core needle biopsy. Pathology from that procedure is consistent with a stage III, T2bNxMx, grade 3, dedifferentiated liposarcoma.

• What is the best management approach for this patient?

Surgery

Surgery is the mainstay of treatment for STS. Patients with the best prognosis are those who undergo complete resection with negative surgical margins.^24,25 Goal tumor-free margin is 1 to 3 cm.²⁶ Complete resection confers the best long-term survival. Both local and metastatic recurrence is higher in patients with incomplete resection and positive margins.^24,25 In a study that analyzed 2084 localized primary STSs, patients with negative margins had a local recurrence rate of 15% versus a rate of 28% in patients with positive margins. This translated into higher 5-year local recurrence-free survival for patients with negative surgical margins (82%) compared to patients with positive margins (65%).²⁷ Another study similarly found that patients with negative margins at referral to their institution who underwent postoperative radiation had high local control rates of 93% (95% confidence interval [CI] 87% to 97%) at 5, 10, and 15 years.²⁶ Although radiation improves local control, neither preoperative or postoperative radiation has been shown to improve progression-free or overall survival.²⁸ Other factors that are associated with risk of recurrence are tumor location, history of previous recurrence, age of patient, histopathology, tumor grade, and tumor size. Approximately 40% to 50% of patients with high-grade tumors (defined as size > 5 cm, deep location, and high grade) will develop distant metastases.²⁹

Zagars et al found that positive or uncertain resection margin had a relative risk of local recurrence of 2.0 (95% CI 1.3 to 3.1; P = 0.002), and presentation with locally recurrent disease (vs new tumor) had a relative risk of local recurrence of 2.0 (95% CI 1.2 to 3.4; P = 0.013).²⁶ Patients with STS of head and neck and deep trunk have higher recurrence rates than those with superficial trunk and extremity STS. A single-institution retrospective review demonstrated that patients with completely resectable retroperitoneal sarcomas have longer median survival (103 months) compared to patients with incompletely resected abdominal sarcomas (18 months).²⁵Rosenberg and colleagues compared amputation to limb-sparing surgery and radiation.²⁴ Their prospective analysis of 65 patients found no difference in disease-free and overall survival between the 2 treatment groups.The limb-sparing treatment group had higher rates of local recurrence, which was highly correlated with positive surgical margins on pathology.²⁴ Evidence from this and similar studies has resulted in radical amputations being replaced by conservative limb-sparing procedures and radiation therapy. In those found to have positive margins, re-resection is an option for some. Patients who undergo re-resection have higher local control rates than patients with positive margins who do not undergo re-resection. The 5-year control rate for patients who undergo re-resection is 85% (95% CI 80% to 89%) compared to 78% (95% CI 71% to 83%) for those who do not undergo re-resection. Similarly, patients who undergo re-resection have lower rates of metastases at 5, 10, and 15 years as well as higher 5-, 10-, and 15-year disease-free survival rates.²⁶

›  Case Continued

The patient is referred for limb-sparing surgery after presentation at a multidisciplinary tumor board. Prior to undergoing resection of the tumor, he is also referred to radiation-oncology to discuss the risks and benefits of combination radiotherapy and surgery as opposed to surgical resection alone.

• What is the evidence for radiation therapy?

Radiation THERAPY

Radiation therapy is used in the preoperative, intraoperative, and postoperative settings to reduce the risk of local recurrence. There are several options for radiation, including external beam radiation therapy (EBRT), intraoperative radiation, and brachytherapy. A newer strategy, intensity-modulated radiation therapy (IMRT), utilizes 3-dimensional modeling to reduce radiation dosages. Overall there are no differences in overall survival or local recurrence rates between preoperative and postoperative radiation in STS.²⁸

The rationale behind preoperative radiation is that it reduces seeding of tumor cells, especially at the time of surgery.³⁰ Additionally, for EBRT, preoperative radiation has smaller field sizes and lower radiation doses. It can also help to reduce the size of the tumor prior to resection. Intraoperative radiation is often paired with preoperative radiation as a boost dose given only to the area of residual tumor.

Suit et al reviewed patients treated at a single institution with limb-sparing surgery and different radiation strategies. Local control rates between preoperative and postoperative radiation groups were not statistically significant. Local recurrence was linked to grade and size of the tumor in both groups. The authors did note, however, that the preoperative radiation group tended to have larger tumor sizes at baseline compared to the patients who received postoperative radiation.³⁰ A study that compared 190 patients who received preoperative and postoperative EBRT or brachytherapy (primary end point was wound complications, and local control was a secondary end point) showed a trend towards greater local control with preoperative radiation; however, the preoperative radiation group had significantly more wound complications compared to the postoperative radiation group.³¹

Yang et al found that postoperative EBRT decreases rates of local recurrence compared to surgery alone in high-grade extremity sarcomas.³² However, there were no differences in rates of distant metastases and overall survival between the 2 treatment groups. Similarly, in patients with low-grade sarcoma, there were fewer local recurrences in those who received EBRT and surgery as compared to surgery alone.³² Another study that evaluated 164 patients who received either adjuvant brachytherapy or no further therapy after complete resection found that brachytherapy reduced local recurrence in high-grade sarcomas. No difference in local recurrence rates was found in patients with low-grade sarcomas, nor was a significant difference found in the rates of distant metastases and overall survival between the 2 treatment groups.³³ With regards to IMRT, a single institution cohort experience with 41 patients who received IMRT following limb-sparing surgery had similar local control rates when compared to historical controls.³⁴

›  Case Continued

After discussion of the risks and benefits of radiation therapy, the patient opts for preoperative radiation prior to resection of his liposarcoma. He receives 50 Gy of EBRT prior to undergoing resection. Resection results in R1 margin consistent with microscopic disease. He receives 16 Gy of EBRT as a boost after recovery from his resection.²

• What is the evidence for neoadjuvant and adjuvant chemotherapy for stage I tumors?

Chemotherapy

Localized Sarcoma

For localized sarcoma, limb-sparing resection with or without radiation forms the backbone of treatment. Studies have evaluated chemotherapy in both the neoadjuvant and adjuvant settings, with the vast majority of studies evaluating doxorubicin-based chemotherapy regimens in the adjuvant settings. Due to the rare nature of sarcomas, most studies are not sufficiently powered to detect significant benefit from chemotherapy. Several trials evaluating chemotherapy regimens in the neoadjuvant and adjuvant settings needed to be terminated prematurely due to inadequate enrollment into the study.^35,36

For stage IA (T1a-Tb, N0, M0, low grade) tumors, no additional therapy is recommended after limb-sparing surgery with appropriate surgical margins. For stage IB (T2a-2b, N0, M0, low grade) tumors with insufficient margins, re-resection and radiation therapy should be considered, while for stage IIA (T1a-1b, N0, M0, G2-3) tumors preoperative or postoperative radiation therapy is recommended.² Studies have not found benefit of adjuvant chemotherapy in these low-grade, stage I tumors in terms of progression-free survival and overall survival.³⁷

• At what stage should chemotherapy be considered?

For stage IIb and stage III tumors, surgery and radiation therapy again form the backbone of therapy; however, neoadjuvant and adjuvant chemotherapy are also recommended as considerations. Anthracycline-based chemotherapy with either single-agent doxorubicin or doxorubicin and ifosfamide in combination are considered first-line chemotherapy agents in locally advanced STS.^2,29,37

Evidence regarding the efficacy of both neoadjuvant and adjuvant chemotherapy regimens in the setting of locally advanced high-grade STS has been mixed. The Sarcoma Meta-analysis Collaboration evaluated 14 trials of doxorubicin-based adjuvant chemotherapy and found a trend towards overall survival in the treatment groups that received chemotherapy.³⁷ All trials included in the meta-analysis compared patients with localized resectable soft-tissue sarcomas who were randomized to either adjuvant chemotherapy or no adjuvant chemotherapy after limb-sparing surgery with or without radiation therapy. None of the individual trials showed a significant benefit, and all trials had large confidence intervals; however, the meta-analysis showed significant benefit in the chemotherapy treatment groups with regard to local recurrence, distant recurrence, and progression-free survival. No significant difference in overall survival was found.³⁷ Pervais et al updated the Sarcoma Meta-analysis Collaboration’s 1997 meta-analysis with the inclusion of 4 new trials that evaluated doxorubicin combined with ifosfamide and found that both patients who received doxorubicin-based regimens or doxorubicin with ifosfamide had significant decreases in distant and overall recurrences. Only the trials that utilized doxorubicin and ifosfamide had an improved overall survival that was statistically significant (hazard ratio 0.56 [95% CI 0.36 to 0.85]; P = 0.01).²⁹ Although no significant heterogeneity was found among the trials included in either meta-analysis, a variety of sarcomas were included in each clinical trial evaluated. Given the extremely small number of each sarcoma subtype present in each trial, subgroup analysis is difficult and prone to inaccuracies. As a result, it is not known if certain histological subtypes are more or less responsive to chemotherapy.^37–39

One randomized controlled trial evaluated neoadjuvant chemotherapy in high-risk sarcomas defined as tumors greater than 8 cm or grade II/III tumors. This study evaluated doxorubicin and ifosfamide and found no significant difference in disease-free and overall survival in the neoadjuvant therapy group compared to the control group.³⁵ There remains controversy in the literature with regards to adjuvant chemotherapy. Many oncologists offer adjuvant chemotherapy to patients with certain stage III subtypes. Examples of subtypes that may be offered adjuvant therapy include myxoid liposarcomas, synovial sarcomas, and leiomyosarcomas.² With regards to how many cycles of chemotherapy should be considered, a noninferiority study compared 3 cycles of epirubicin and ifosfamide to 5 cycles of epirubicin and ifosfamide in patients with high-risk locally advanced adult STSs. Three cycles of preoperative epirubicin and ifosfamide was found to be noninferior to 5 cycles with regards to overall survival.³⁸

• What is this patient’s risk for recurrence?

The patient is at intermediate risk for recurrence. Numerous studies have demonstrated that tumor size, grade, and location are the most important factors to determine risk of recurrence, with larger size, higher grades, and deeper locations being associated with higher risk of recurrence. In an analysis of 1041 patients with STS of the extremities, high grade was the most important risk factor for distant metastases.³⁹ The highest risk of recurrence is within the first 2 years. Given that the patient’s initial tumor was located in the extremity, he is more likely to have a distant metastasis as his site of recurrence; individuals with retroperitoneal tumors and visceral tumors are more likely to recur locally.⁴⁰ For STSs of the extremity, distant metastases determine overall survival, whereas patients with retroperitoneal sarcomas can die from complications of local metastases.⁴¹ Once a patient develops distant metastases, the most important prognostic factor is the size of the tumor, with tumors larger than 10 cm having a relative risk of 1.5 (95% CI 1.0 to 2.0).³⁹

• What are the recommendations for surveillance?

Surveillance recommendations are based on the stage of the sarcoma. Stage I tumors are the least likely to recur either locally or distally. As a result, it is recommended that stage I tumors be followed with history and physical exam every 3 to 6 months for the first 2 to 3 years, and then annually after the first 2 to 3 years. Chest x-rays should be considered every 6 to 12 months.² For stage II–IV tumors, history and physical exam is recommended every 3 to 6 months for the first 2 to 3 years. Chest and distant metastases imaging should also be performed every 3 to 6 months during this time frame. For the next 2 years, history and physical exam and imaging are recommended every 6 months. After the first 4 to 5 years, annual follow-up is recommended.²

A study that followed 141 patients with primary extremity STSs for a median interval of 49 months found that high-grade tumors were most likely to recur during the first 2 years, with 20% of their patients recurring locally and 40% recurring distally. Chest x-rays performed during surveillance follow-up found distant lung metastases in 36 asymptomatic patients and had a positive predictive value of 92%, a negative predictive value of 97%, and a quality-adjusted life-year of $30,000.^40,41 No laboratory testing was found to aid in detection of recurrence.

›  Case Continued

The patient does well for 1 year. With physical therapy, he regains most of the strength and coordination of the lower extremity. He is followed every 3 months with chest x-rays and a MRI of the thigh for the first year. On his fourth follow-up clinic visit, he describes increased dysp-nea on exertion over the previous few weeks and is found to have multiple lung metastases in both lungs on chest x-ray. He undergoes further evaluation for metastases and is not found to have any other metastatic lesions. Bronchoscopy and biopsy of 1 of the lung nodules confirms recurrent dedifferentiated liposarcoma.

• Should this patient undergo metastectomy?

An analysis of 3149 patients with STS treated at Memorial Sloan-Kettering who developed lung metastases found that patients with pulmonary metastases have survival rates of 25%. The most important prognostic factor for survival was complete resection of all metastases.⁴² For stage IV disease, surgery is used only in certain instances. In instances where tumor is more localized or limited, removal of metastases or metastectomy can play a role in management.²

›  Case Continued

Because the patient’s metastases are limited to the lungs, he is referred for metastectomy. He undergoes wedge resection for definitive diagnosis but it is not possible to completely resect all of the metastases. He is thus referred to a medical oncologist to discuss his treatment options.

• What are treatment options for unresectable or metastatic disease?

Metastatic Disease

Unlike local and locally advanced disease, chemotherapy forms the backbone of treatment in stage IV disease. Doxorubicin and olaratumab or doxorubicin and ifosfamide in combination are considered first line in metastatic disease. Response rates for single-agent doxorubicin range from 16% to 27%, while phase 2 and phase 3 studies of doxorubicin and ifosfamide have found response rates ranging from 18% to 36%.⁴³ In addition, the effectiveness of doxorubicin and ifosfamide phase 2 and 3 trials varied. Edmonson et al found a tumor regression rate of 34% for doxorubicin and ifosfamide as compared to 20% for doxorubicin alone.⁴⁴ In comparison, Santoro et al found a response rate of 21.3% for doxorubicin alone and 25.2% for doxorubicin and ifosfamide.⁴⁵ Neither study found increased survival benefit for doxorubicin and ifosfamide when compared to doxorubicin alone. In a Cochrane review evaluating randomized trials that compared doxorubicin and combination chemotherapy regimens, response rates varied from 14% for doxorubicin in combination with streptomycin to 34% for doxorubicin and ifosfamide. Most trials did not show a significant benefit for combination therapies when compared to doxorubicin alone.⁴³ Mean survival with doxorubicin or doxorubicin and ifosfamide is 12 months. High rates of recurrence highlight the need for additional chemotherapy regimens.

The newest approved agent is olaratumab, a monoclonal antibody that binds platelet-derived growth factor receptor alpha and prevents receptor activation. A phase 1-b and phase 2 trial evaluated patients with locally advanced and metastatic STS and randomly assigned them to either olaratumab and doxorubicin or doxorubicin alone.⁴⁶ Progression-free survival for olaratumab/doxorubicin was 6.6 months (95% CI 4.1 to 8.3) compared to 4.1 months (95% CI 2.8 to 5.4) for doxorubicin alone. The objective response rate was 18.2% (95% CI 9.8 to 29.6) for olaratumab/doxorubicin compared to 7.5% (95% CI 2.5 to 6.6) for doxorubicin alone. Furthermore, the median overall survival for olaratumab plus doxorubicin was 26.5 months (95% CI 20.9 to 31.7) compared to 14.7 months for doxorubicin alone (95% CI 5.5 to 26.0). Impressively, this improved response was notable across histological types. Furthermore, patients who had previously been treated with more than 1 regimen and those who were treatment naïve had similar response rates.⁴⁶

• What are second-line treatment options?

Doxorubicin has been used in combination with several other agents including dacarbazine (DTIC) as well as DTIC and ifosfamide (MAID). Borden et al evaluated patients with metastatic STS and randomly assigned the patients to either doxorubicin or doxorubicin and DTIC. Combination therapy demonstrated better tumor response than doxorubicin alone: 30% complete or partial response for combination therapy and 18% for doxorubicin alone.⁴⁷ However, Omura et al found similar rates of efficacy between doxorubicin and combination doxorubicin and DTIC in women with recurrent or nonresectable uterine sarcomas.⁴⁸ MAID has never been directly compared in a randomized trial to doxorubicin alone. In a study that compared MAID to doxorubicin and DTIC (AD) in patients with unresectable or metastatic sarcomas, MAID had superior response rates (32% versus 17%), but there was no difference with regards to overall survival (mean survival of 12.5 months).⁴⁹

Several additional regimens have undergone evaluation in metastatic and recurrent STSs. Gemcitabine has been used both as a single agent and as part of combination therapy in many studies. Studies with gemcitabine in combination with either docetaxel or DTIC have been the most efficacious. In a phase 2 trial, patients with metastatic STS were randomly assigned to either gemcitabine alone or gemcitabine and docetaxel. Combination therapy had a higher response rate (16% versus 8%) and longer overall survival (17.9 months versus 11.5 months) than gemcitabine alone.⁵⁰ Furthermore, a phase 2 trial of gemcitabine and docetaxel in patients with unresectable leiomyosarcoma showed an overall response rate of 56%, with 3 complete and 15 partial responses among the 34 patients enrolled in the study.⁵¹ A phase 2 trial randomly assigned patients with unresectable or metastatic STS to either DTIC or combination gemcitabine and DTIC.⁵² Gemcitabine-DTIC had a superior progression-free survival at 3 months (56% [95% CI 43% to 69%]) as compared to DTIC alone (37% [95% CI 23.5% to 50%]). Furthermore, mean progression-free survival and overall survival were improved in the gemcitabine-DTIC group (4.2 months and 16.8 months) as compared to the DTIC group (2.0 months and 8.2 months).⁵² DTIC has a single-agent response rate of 16%, but has been shown to be particularly effective in the setting of leiomyosarcomas.⁴⁹

• Does response to treatment regimens differ by histologic subtype?

The majority of STS trials include many different histologic subtypes. Given the rarity of sarcomas as a whole, many trials have had difficulty recruiting adequate numbers of patients to have sufficient power to definitely determine if the treatment under investigation has clinical benefit. Furthermore, the patients recruited have been heterogeneous with regard to subtype. Many older studies hypothesized that the efficacy of chemotherapeutic agents vary based on histologic subtype; however, for most subtypes the number of individuals included in those trials was too low to evaluate efficacy based on subtype.

Some exceptions exist, however. For example, both gemcitabine-DTIC and gemcitabine-docetaxel have been found to be particularly effective in the treatment of leiomyosarcomas.^50,52 Additionally, a retrospective study found a 51% overall response rate for patients with myxoid liposarcomas treated with trabectedin.⁵³ Studies of patients with angiosarcoma treated with paclitaxel have demonstrated response rates of 43% and 53%.^54,55

• What are the newest approved and investigational agents?

A recently approved agent is trabectedin, a tris tetrahydroisoquinoline alkaloid isolated from ascidians that binds to the minor groove of DNA and causes disruptions in the cell cycle. Samuels et al reported data from a single-arm, open-label expanded access trial that evaluated patients with advanced metastatic sarcomas.⁵⁶ In this study, patients with liposarcomas and leiomyosarcomas had an objective response rate of 6.9% (95% CI 4.8 to 9.6) as compared to a rate of 5.9% (95% CI 4.4 to 7.8) for all assessable patients. Median survival was 11.9 months for all patients, with improved median survivals for liposarcoma and leiomyosarcomas of 16.2 months (95% CI 14.1 to 19.5) compared to 8.4 months (95% CI 7.1 to 10.7 months) for other subtypes.⁵⁶

Schöffski et al evaluated eribulin, a chemotherapeutic agent that affects microtubule dynamics, in a phase 2 trial of patients with progressive or high-grade STS with progression on previous chemotherapy. They found a median progression-free survival of 2.6 months (95% CI 1.7 to 6.2) for adipocytic sarcoma, 2.9 months (95% CI 2.4 to 4.6) for leiomyosarcoma, 2.6 months (95% CI 2.3 to 4.3) for synovial sarcoma, and 2.1 months (95% CI 1.4 to 2.9) for other sarcomas.⁵⁷

Van der Graaf and colleagues randomly assigned patients with metastatic nonadipocytic STS to pazopanib or placebo in a phase 3 trial. Pazopanib is a small-molecule endothelial growth factor inhibitor with activity against vascular endothelial growth factors 1, 2, and 3 as well as platelet-derived growth factors. Median progression-free survival was 4.6 months (95% CI 3.7 to 4.8) with pazopanib compared to 1.6 months (95% CI 0.9 to 1.8) with placebo.⁵⁸ Adipocytic sarcomas (liposarcomas) were excluded from the trial because phase 2 trials had found a lower rate of progression-free survival (26%) for them compared to other subtypes.

• What are the most common toxicities associated with the approved and investigational chemotherapeutic agents?

Toxicities were seen with each of the regimens studied and were common in the randomized trials, with higher rates of toxicities in the combination chemotherapy regimens. The most common toxicities are myelosuppression, nausea, and vomiting. In the doxorubicin trials, the most common toxicities were myelosuppression, nausea, and vomiting.⁴⁴

Ifosfamide both as an individual agent and in combination with doxorubicin has higher rates and higher grades of toxicity than doxorubicin alone. Myelosuppression is the most common toxicity associated with ifosfamide, and the most commonly affected cell line is leukocytes.⁴⁴ Combination doxorubicin and ifosfamide also had high rates of nausea and vomiting (95%) and alopecia (100%).³⁵Neutropenia is the most common toxicity associated with gemcitabine and dacarbazine, while their most common nonhematologic toxicities are fatigue and nausea.^52,59 Trabectedin’s most common toxicities are nausea (29%), neutropenia (24%), and fatigue (23%). It has also been shown to cause increased alkaline phosphatase (20%) and alanine aminotransferase (19%) levels.⁵⁶ In a phase 2 study of eribulin, 50% of patients had neutropenia, and other toxicities included fatigue, alopecia, nausea, sensory neuropathy, and thrombocytopenia.⁵⁷ Pazopanib is generally well tolerated; the most common toxicities are fatigue (65%), diarrhea (58%), nausea (54%), and hypertension (41%).⁵⁸ Higher rates of neutropenia, mucositis, nausea, vomiting, diarrhea, and transfusion reactions were seen with olaratumab and doxorubicin compared to doxorubicin alone in phase 1b and 2 studies.⁴⁶

›  Case Continued

Given his poor prognosis with unresectable metastatic undifferentiated liposarcoma, the patient considers a clinical trial prior to undergoing combined therapy with doxorubicin and ifosfamide. He tolerates therapy well with stable disease at 6 months.

Conclusion

STSs are a heterogeneous collection of rare tumors. Low-grade, localized tumors have the best prognosis, and patients who undergo complete resection have the best long-term survival. Due to the rarity of STSs, trials often have limited enrollment, and little progress has been made with regards to treatment and survival rates for metastatic and unresectable disease. All patients should be evaluated and treated at specialized sarcoma centers. This case highlights the need for continued research and clinical trials to improve overall survival of patients with sarcoma. TSJ

CORRESPONDENCE

Ashley Pariser, MD, Resident, Department of Medicine, Northwestern University Feinberg School of Medicine Chicago, IL. Accepted for publication Jan/Feb 2017; Hosp Phys; Vol. 12, Part1

Introduction

Soft tissue sarcomas (STSs) are rare adult tumors, with 3.4 new cases per 100,000 persons or 12,310 expected new cases in 2016.¹ Sarcomas are a heterogeneous collection of tumors that affect fat, muscle, nerve, nerve sheath, vascular, and connective tissues. There are more than 50 histological subtypes that comprise this diverse category of tumors. Treatment varies by stage, with limb-sparing surgery representing the mainstay of curative-intent treatment. Radiation and chemotherapy may also be considered depending on the size, grade, and location of the tumor. Survival rates have been stagnant until recently, with a disease-specific survival hovering around 65%.¹ Given the complexity of these cases, all patients ideally should be evaluated and treated by a multidisciplinary team at an institution with extensive experience treating STS.²

Epidemiology and Classification

The most common STS subtypes are gastrointestinal stromal tumor (GIST), undifferentiate pleomorphic sarcoma (previously referred to as malignant fibrous histiocytoma), liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve sheath tumor, rhabdomyosarcoma, and unclassified sarcoma.³ Liposarcoma is one of the most common subtypes, comprising 20% of all STSs; it is subdivided into well-differentiated/dedifferentiated liposarcomas, myxoid/round cell liposarcomas, and pleomorphic liposarcomas. Well-differentiated liposarcomas tend to occur in the retroperitoneum and limbs, while both myxoid and round cell as well as pleomorphic liposarcomas more commonly originate on the limbs. Histology varies based on subtype and ranges from mature-appearing adipocytes and fibroblasts to undifferentiated cells with minimal lipogenic differentiation.⁴

Leiomyosarcomas are smooth muscle tumors and are usually located in the retroperitoneum, but have also been associated with peripheral soft tissue and vasculature. Typical histology ranges from well-defined areas of spindle-shaped cells to poorly differentiated anaplastic spindle cells.^5,6 Synovial sarcomas are a distinct type of STS that can show epithelial differentiation and account for 5% of adult STSs. The extremities are the most common presenting location (90%).⁷

Rhabdomyosarcomas are skeletal muscle tumors and are further subdivided into embryonal, alveolar, and pleomorphic subtypes. Embryonal histology ranges from primitive mesenchymal-appearing cells to highly differentiated muscle cells. Alveolar rhabdomyosarcoma has the worst prognosis of the subtypes and consists of round cells with high nuclear-to-chromatin ratios that form “glandular-like” or “alveolar” spaces.⁸ Pleomorphic rhabdomyosarcomas are composed of rhabdomyoblasts that can affect many different locations, but most commonly present on the lower extremities.⁹

Malignant peripheral nerve sheath tumor (MPNST) comprises 5% to 10% of all STSs. These tumors are associated with neurofibromatosis type 1 (NF-1), with 25% to 50% of tumors occurring in NF-1 patients. Additionally, most patients have a truncating lesion in the NF1 gene on chromosome 17.¹⁰ Anghileri et al in their single institution analysis of 205 patients with MPNSTs found the 2 most common presenting sites were the trunk and extremities. Histologically, these tumors have dense fascicles of spindle cells.¹⁰

GISTs are the most common STS of the gastrointestinal (GI) tract. Previously, GISTs were classified as smooth muscle tumors and were not accounted for in the literature as a separate entity distinct from leiomyomas, leiomyoblastomas, and leiomyosarcomas.¹¹ GISTs are found throughout the GI tract: the most common sites are the stomach (60%) and small intestine (30%). Less common sites include duodenum (4%–5%), esophagus (1%), rectum (1%–2%), and appendix (< 0.2%).¹² GISTs can be spindle cell, epithelioid, or mesenchymal tumors. Immunohistochemically, GISTs are KIT (CD117) positive. Other cell markers that are also commonly positive include CD34 (60%–70%) and smooth muscle actin (SMA) (25%).¹¹ The majority of GISTs (80%) have an activating c-KIT gene mutation. The most common mutation site is exon 11, with less common c-KIT gene mutations also occurring at exon 9 or 13. Not all GISTs have KIT mutations. The second most common mutation is the PDGFRA mutation (5%–10% of GISTs).² A minority of GISTs are negative for both KIT and PDGFRA mutations. These tumors were previously called wild-type, but as the majority have either a succinate dehydrogenase (SDH) loss of function or loss of SDHB protein expression, they are now referred to as SDH-deficient GISTs.² GISTs vary in aggressiveness from incidental to aggressive. Typically, small intestine and rectal GISTs are more aggressive than gastric GISTs. Both size and mitotic rate help to predict the metastatic potential of the tumor. Tumors less than 2 cm in size and having a mitotic rate of less than 5 per 50 high-power fields (hpf) have the lowest risk of metastases, while tumors greater than 5 cm and with more than 5 mitoses per 50 hpf have the highest rates of metastases.¹²

Angiosarcomas are rare tumors comprising 4% of all STSs. Although they can occur in any site, the majority are cutaneous and occur most frequently in the head and neck regions. These tumors are either of vascular or lymphatic origin and are comprised of abnormal, pleomorphic, malignant endothelial cells. The most useful immunohistochemical markers include von Willebrand factor, CD31, and Ulex europaeus agglutinin 1. The majority of these tumors occur sporadically; however, radiation exposure, chronic lymphedema, and certain toxins including vinyl chloride and thorium dioxide are known risk factors.¹³

Undifferentiated sarcomas have no specific features and typically consist of primitive mesenchymal cells.

Clinical Evaluation

›  Case Presentation

Initial Presentation and History

A 55-year-old man presents to his primary care physician with a painless mass in his anterior thigh. The mass has been present for the past 3 months and he believes that it is enlarging. The patient has a history of well-controlled hypertension and hyperlipidemia. His medications include atorvastatin and hydrochlorothiazide. He has no known drug allergies. Family history is notable for diabetes and hypertension. He drinks 4 to 5 alcoholic drinks a week and he is a former smoker. He quit smoking in his 30s and only smoked intermittently prior to quitting. He denies any illicit drug use. He works as a high school principal. Currently, he feels well. His review of systems is otherwise noncontributory.

Physical Examination

On physical exam, he is afebrile with a blood pressure of 132/75 mm Hg, respiratory rate of 10 breaths/min, and oxygen saturation of 99% on room air. He is a well appearing, overweight male. His head and neck exam is unremarkable. Lung exam reveals clear breath sounds, and cardiac exam reveals a regular rate and rhythm. His abdomen is obese, soft, and without hepatosplenomegaly. There is a large, fixed mass on the anterior lateral aspect of his right thigh. He has no appreciable lymphadenopathy. His neurological exam is unremarkable.

• What are risk factors for sarcoma?

There are few known risk factors for sarcoma. Established risks factors include prior radiation therapy, chronic lymphedema, viruses, and genetic cancer syndromes including Li-Fraumeni syndrome, hereditary retinoblastoma, and NF-1. Other environmental exposures include phenoxyacetic acids and chlorophenols.¹⁴ The majority of cases are sporadic, with only a minority of patients having one of these known risk factors.¹⁵ Up to one third of sarcomas have a specific translocation and are driven by fusion oncogenes (Table 1).

• What is the typical presentation for sarcomas?

A painless mass is the most typical presenting symptom. Size at presentation varies based on location, with extremity and head and neck locations typically presenting at smaller sizes than retroperitoneal tumors.¹⁴ Patients may experience pain and numbness as the mass enlarges and impinges on surrounding structures including nerves and vasculature. The vast majority of patients are without systemic symptoms.

• How is sarcoma staged?

The American Joint Committee on Cancer (AJCC) staging system is the most widely used staging system in the United States. The latest AJCC manual was updated in 2010 to include a 3-tiered grading system where the tumor is classified according to tumor size, lymph node involvement, metastases, and grade at time of diagnosis (Table 2 and Table 3). Additionally, tumor depth in relation to deep fascia is also taken into account, with superficial tumors being assigned a designation of “a” and deep tumors a designation of “b.”

Previously, 2 of the most widely used grading systems were the National Cancer Institute (NCI) and French Federation of Cancer Centers Sarcoma Group (FNCLCC) systems, both 3-tier grading systems. The main components that determine the NCI grade are the tumor’s histologic type and location and the amount of tumor necrosis. The FNCLCC system evaluation focuses on tumor differentiation, mitotic rate, and amount of tumor necrosis. A study that compared the NCI and FNCLCC grading systems found that FNCLCC was a better predictor of mortality and distant metastasis.¹⁶ Previously, the AJCC was a 4-tier grading system, but the 2010 version was updated to the 3-tier FNCLCC grading system. Additionally, the AJCC system has reclassified single lymph node disease as stage III as it confers better survival than metastatic disease.¹⁷ It is important that pathology be evaluated by a sarcoma specialist as disagreements with regard to histologic subtype and grade are common.^18,19

• What are the most important prognostic factors?

Prognostic factors include grade, size, and presence of metastases at presentation. Best survival is associated with low-grade, small tumors with no metastases at time of diagnosis.¹⁴

• What imaging should be considered?

Imaging should be undertaken to help differentiate between benign and malignant lesions. Ideally, it should be undertaken before a biopsy is planned as the imaging can be used to plan biopsy as well as provide invaluable prognostic information. There are several imaging modalities that should be considered during the preliminary work-up and staging of STSs. Conventional imaging includes magnetic resonance imaging (MRI) of the original tumor site; computed tomography (CT) to evaluate for pulmonary metastases and, depending on location, liver metastases; and in the case of small, low-grade tumors, chest radiography. MRI is considered the test of choice for soft tissue masses and can help delineate benign masses such as hematomas, lipomas, and hemangiomas from sarcomas.²⁰ It is difficult to compare the accuracy of positron emission tomography (PET)/CT to CT and MRI because most studies have evaluated PET/CT in parallel with CT and MRI.²¹ Tateishi et al compared the accuracy of conventional imaging, PET/CT, and PET/CT combined with conventional imaging at determining the TNM staging for 117 patients. They found that conventional imaging correctly classified 77% of patients, PET alone correctly classified 70%, PET/CT correctly classified 83%, and PET/CT combined with conventional imaging correctly staged 87%.²²

• Which subtypes are most likely to metastasize?

Although the vast majority of sarcomas spread hematogenously, 3 have a propensity to spread lymphogenously: epithelioid sarcoma, rhabdomyosarcoma, and clear-cell sarcoma. Additionally, certain subtypes are more likely to metastasize: leiomyosarcomas, synovial sarcomas, neurogenic sarcomas, rhabdomyosarcomas, and epithelioid sarcomas.²³ Sarcomas metastasize to the lungs more frequently than to the liver. The metastatic pattern is defined primarily by sarcoma subtype and site of primary tumor. Sarcomas rarely metastasize to the brain (~1%).

Management

›  Case Continued

The patient undergoes an ultrasound to better visualize the mass. Given the heterogeneous character of the mass, he is referred for an MRI to evaluate the mass and a CT scan of the chest, abdomen, and pelvis to evaluate for distant metastases. MRI reveals a 5.1 cm × 4.6 cm heterogeneous mass invading the superficial fascia of the rectus femoris muscle. No suspicious lymph nodes or other masses are identified on imaging. The patient next undergoes an image-guided core needle biopsy. Pathology from that procedure is consistent with a stage III, T2bNxMx, grade 3, dedifferentiated liposarcoma.

• What is the best management approach for this patient?

Surgery

Surgery is the mainstay of treatment for STS. Patients with the best prognosis are those who undergo complete resection with negative surgical margins.^24,25 Goal tumor-free margin is 1 to 3 cm.²⁶ Complete resection confers the best long-term survival. Both local and metastatic recurrence is higher in patients with incomplete resection and positive margins.^24,25 In a study that analyzed 2084 localized primary STSs, patients with negative margins had a local recurrence rate of 15% versus a rate of 28% in patients with positive margins. This translated into higher 5-year local recurrence-free survival for patients with negative surgical margins (82%) compared to patients with positive margins (65%).²⁷ Another study similarly found that patients with negative margins at referral to their institution who underwent postoperative radiation had high local control rates of 93% (95% confidence interval [CI] 87% to 97%) at 5, 10, and 15 years.²⁶ Although radiation improves local control, neither preoperative or postoperative radiation has been shown to improve progression-free or overall survival.²⁸ Other factors that are associated with risk of recurrence are tumor location, history of previous recurrence, age of patient, histopathology, tumor grade, and tumor size. Approximately 40% to 50% of patients with high-grade tumors (defined as size > 5 cm, deep location, and high grade) will develop distant metastases.²⁹

Zagars et al found that positive or uncertain resection margin had a relative risk of local recurrence of 2.0 (95% CI 1.3 to 3.1; P = 0.002), and presentation with locally recurrent disease (vs new tumor) had a relative risk of local recurrence of 2.0 (95% CI 1.2 to 3.4; P = 0.013).²⁶ Patients with STS of head and neck and deep trunk have higher recurrence rates than those with superficial trunk and extremity STS. A single-institution retrospective review demonstrated that patients with completely resectable retroperitoneal sarcomas have longer median survival (103 months) compared to patients with incompletely resected abdominal sarcomas (18 months).²⁵Rosenberg and colleagues compared amputation to limb-sparing surgery and radiation.²⁴ Their prospective analysis of 65 patients found no difference in disease-free and overall survival between the 2 treatment groups.The limb-sparing treatment group had higher rates of local recurrence, which was highly correlated with positive surgical margins on pathology.²⁴ Evidence from this and similar studies has resulted in radical amputations being replaced by conservative limb-sparing procedures and radiation therapy. In those found to have positive margins, re-resection is an option for some. Patients who undergo re-resection have higher local control rates than patients with positive margins who do not undergo re-resection. The 5-year control rate for patients who undergo re-resection is 85% (95% CI 80% to 89%) compared to 78% (95% CI 71% to 83%) for those who do not undergo re-resection. Similarly, patients who undergo re-resection have lower rates of metastases at 5, 10, and 15 years as well as higher 5-, 10-, and 15-year disease-free survival rates.²⁶

›  Case Continued

The patient is referred for limb-sparing surgery after presentation at a multidisciplinary tumor board. Prior to undergoing resection of the tumor, he is also referred to radiation-oncology to discuss the risks and benefits of combination radiotherapy and surgery as opposed to surgical resection alone.

• What is the evidence for radiation therapy?

Radiation THERAPY

Radiation therapy is used in the preoperative, intraoperative, and postoperative settings to reduce the risk of local recurrence. There are several options for radiation, including external beam radiation therapy (EBRT), intraoperative radiation, and brachytherapy. A newer strategy, intensity-modulated radiation therapy (IMRT), utilizes 3-dimensional modeling to reduce radiation dosages. Overall there are no differences in overall survival or local recurrence rates between preoperative and postoperative radiation in STS.²⁸

The rationale behind preoperative radiation is that it reduces seeding of tumor cells, especially at the time of surgery.³⁰ Additionally, for EBRT, preoperative radiation has smaller field sizes and lower radiation doses. It can also help to reduce the size of the tumor prior to resection. Intraoperative radiation is often paired with preoperative radiation as a boost dose given only to the area of residual tumor.

Suit et al reviewed patients treated at a single institution with limb-sparing surgery and different radiation strategies. Local control rates between preoperative and postoperative radiation groups were not statistically significant. Local recurrence was linked to grade and size of the tumor in both groups. The authors did note, however, that the preoperative radiation group tended to have larger tumor sizes at baseline compared to the patients who received postoperative radiation.³⁰ A study that compared 190 patients who received preoperative and postoperative EBRT or brachytherapy (primary end point was wound complications, and local control was a secondary end point) showed a trend towards greater local control with preoperative radiation; however, the preoperative radiation group had significantly more wound complications compared to the postoperative radiation group.³¹

Yang et al found that postoperative EBRT decreases rates of local recurrence compared to surgery alone in high-grade extremity sarcomas.³² However, there were no differences in rates of distant metastases and overall survival between the 2 treatment groups. Similarly, in patients with low-grade sarcoma, there were fewer local recurrences in those who received EBRT and surgery as compared to surgery alone.³² Another study that evaluated 164 patients who received either adjuvant brachytherapy or no further therapy after complete resection found that brachytherapy reduced local recurrence in high-grade sarcomas. No difference in local recurrence rates was found in patients with low-grade sarcomas, nor was a significant difference found in the rates of distant metastases and overall survival between the 2 treatment groups.³³ With regards to IMRT, a single institution cohort experience with 41 patients who received IMRT following limb-sparing surgery had similar local control rates when compared to historical controls.³⁴

›  Case Continued

After discussion of the risks and benefits of radiation therapy, the patient opts for preoperative radiation prior to resection of his liposarcoma. He receives 50 Gy of EBRT prior to undergoing resection. Resection results in R1 margin consistent with microscopic disease. He receives 16 Gy of EBRT as a boost after recovery from his resection.²

• What is the evidence for neoadjuvant and adjuvant chemotherapy for stage I tumors?

Chemotherapy

Localized Sarcoma

For localized sarcoma, limb-sparing resection with or without radiation forms the backbone of treatment. Studies have evaluated chemotherapy in both the neoadjuvant and adjuvant settings, with the vast majority of studies evaluating doxorubicin-based chemotherapy regimens in the adjuvant settings. Due to the rare nature of sarcomas, most studies are not sufficiently powered to detect significant benefit from chemotherapy. Several trials evaluating chemotherapy regimens in the neoadjuvant and adjuvant settings needed to be terminated prematurely due to inadequate enrollment into the study.^35,36

For stage IA (T1a-Tb, N0, M0, low grade) tumors, no additional therapy is recommended after limb-sparing surgery with appropriate surgical margins. For stage IB (T2a-2b, N0, M0, low grade) tumors with insufficient margins, re-resection and radiation therapy should be considered, while for stage IIA (T1a-1b, N0, M0, G2-3) tumors preoperative or postoperative radiation therapy is recommended.² Studies have not found benefit of adjuvant chemotherapy in these low-grade, stage I tumors in terms of progression-free survival and overall survival.³⁷

• At what stage should chemotherapy be considered?

For stage IIb and stage III tumors, surgery and radiation therapy again form the backbone of therapy; however, neoadjuvant and adjuvant chemotherapy are also recommended as considerations. Anthracycline-based chemotherapy with either single-agent doxorubicin or doxorubicin and ifosfamide in combination are considered first-line chemotherapy agents in locally advanced STS.^2,29,37

Evidence regarding the efficacy of both neoadjuvant and adjuvant chemotherapy regimens in the setting of locally advanced high-grade STS has been mixed. The Sarcoma Meta-analysis Collaboration evaluated 14 trials of doxorubicin-based adjuvant chemotherapy and found a trend towards overall survival in the treatment groups that received chemotherapy.³⁷ All trials included in the meta-analysis compared patients with localized resectable soft-tissue sarcomas who were randomized to either adjuvant chemotherapy or no adjuvant chemotherapy after limb-sparing surgery with or without radiation therapy. None of the individual trials showed a significant benefit, and all trials had large confidence intervals; however, the meta-analysis showed significant benefit in the chemotherapy treatment groups with regard to local recurrence, distant recurrence, and progression-free survival. No significant difference in overall survival was found.³⁷ Pervais et al updated the Sarcoma Meta-analysis Collaboration’s 1997 meta-analysis with the inclusion of 4 new trials that evaluated doxorubicin combined with ifosfamide and found that both patients who received doxorubicin-based regimens or doxorubicin with ifosfamide had significant decreases in distant and overall recurrences. Only the trials that utilized doxorubicin and ifosfamide had an improved overall survival that was statistically significant (hazard ratio 0.56 [95% CI 0.36 to 0.85]; P = 0.01).²⁹ Although no significant heterogeneity was found among the trials included in either meta-analysis, a variety of sarcomas were included in each clinical trial evaluated. Given the extremely small number of each sarcoma subtype present in each trial, subgroup analysis is difficult and prone to inaccuracies. As a result, it is not known if certain histological subtypes are more or less responsive to chemotherapy.^37–39

One randomized controlled trial evaluated neoadjuvant chemotherapy in high-risk sarcomas defined as tumors greater than 8 cm or grade II/III tumors. This study evaluated doxorubicin and ifosfamide and found no significant difference in disease-free and overall survival in the neoadjuvant therapy group compared to the control group.³⁵ There remains controversy in the literature with regards to adjuvant chemotherapy. Many oncologists offer adjuvant chemotherapy to patients with certain stage III subtypes. Examples of subtypes that may be offered adjuvant therapy include myxoid liposarcomas, synovial sarcomas, and leiomyosarcomas.² With regards to how many cycles of chemotherapy should be considered, a noninferiority study compared 3 cycles of epirubicin and ifosfamide to 5 cycles of epirubicin and ifosfamide in patients with high-risk locally advanced adult STSs. Three cycles of preoperative epirubicin and ifosfamide was found to be noninferior to 5 cycles with regards to overall survival.³⁸

• What is this patient’s risk for recurrence?

The patient is at intermediate risk for recurrence. Numerous studies have demonstrated that tumor size, grade, and location are the most important factors to determine risk of recurrence, with larger size, higher grades, and deeper locations being associated with higher risk of recurrence. In an analysis of 1041 patients with STS of the extremities, high grade was the most important risk factor for distant metastases.³⁹ The highest risk of recurrence is within the first 2 years. Given that the patient’s initial tumor was located in the extremity, he is more likely to have a distant metastasis as his site of recurrence; individuals with retroperitoneal tumors and visceral tumors are more likely to recur locally.⁴⁰ For STSs of the extremity, distant metastases determine overall survival, whereas patients with retroperitoneal sarcomas can die from complications of local metastases.⁴¹ Once a patient develops distant metastases, the most important prognostic factor is the size of the tumor, with tumors larger than 10 cm having a relative risk of 1.5 (95% CI 1.0 to 2.0).³⁹

• What are the recommendations for surveillance?

Surveillance recommendations are based on the stage of the sarcoma. Stage I tumors are the least likely to recur either locally or distally. As a result, it is recommended that stage I tumors be followed with history and physical exam every 3 to 6 months for the first 2 to 3 years, and then annually after the first 2 to 3 years. Chest x-rays should be considered every 6 to 12 months.² For stage II–IV tumors, history and physical exam is recommended every 3 to 6 months for the first 2 to 3 years. Chest and distant metastases imaging should also be performed every 3 to 6 months during this time frame. For the next 2 years, history and physical exam and imaging are recommended every 6 months. After the first 4 to 5 years, annual follow-up is recommended.²

A study that followed 141 patients with primary extremity STSs for a median interval of 49 months found that high-grade tumors were most likely to recur during the first 2 years, with 20% of their patients recurring locally and 40% recurring distally. Chest x-rays performed during surveillance follow-up found distant lung metastases in 36 asymptomatic patients and had a positive predictive value of 92%, a negative predictive value of 97%, and a quality-adjusted life-year of $30,000.^40,41 No laboratory testing was found to aid in detection of recurrence.

›  Case Continued

The patient does well for 1 year. With physical therapy, he regains most of the strength and coordination of the lower extremity. He is followed every 3 months with chest x-rays and a MRI of the thigh for the first year. On his fourth follow-up clinic visit, he describes increased dysp-nea on exertion over the previous few weeks and is found to have multiple lung metastases in both lungs on chest x-ray. He undergoes further evaluation for metastases and is not found to have any other metastatic lesions. Bronchoscopy and biopsy of 1 of the lung nodules confirms recurrent dedifferentiated liposarcoma.

• Should this patient undergo metastectomy?

An analysis of 3149 patients with STS treated at Memorial Sloan-Kettering who developed lung metastases found that patients with pulmonary metastases have survival rates of 25%. The most important prognostic factor for survival was complete resection of all metastases.⁴² For stage IV disease, surgery is used only in certain instances. In instances where tumor is more localized or limited, removal of metastases or metastectomy can play a role in management.²

›  Case Continued

Because the patient’s metastases are limited to the lungs, he is referred for metastectomy. He undergoes wedge resection for definitive diagnosis but it is not possible to completely resect all of the metastases. He is thus referred to a medical oncologist to discuss his treatment options.

• What are treatment options for unresectable or metastatic disease?

Metastatic Disease

Unlike local and locally advanced disease, chemotherapy forms the backbone of treatment in stage IV disease. Doxorubicin and olaratumab or doxorubicin and ifosfamide in combination are considered first line in metastatic disease. Response rates for single-agent doxorubicin range from 16% to 27%, while phase 2 and phase 3 studies of doxorubicin and ifosfamide have found response rates ranging from 18% to 36%.⁴³ In addition, the effectiveness of doxorubicin and ifosfamide phase 2 and 3 trials varied. Edmonson et al found a tumor regression rate of 34% for doxorubicin and ifosfamide as compared to 20% for doxorubicin alone.⁴⁴ In comparison, Santoro et al found a response rate of 21.3% for doxorubicin alone and 25.2% for doxorubicin and ifosfamide.⁴⁵ Neither study found increased survival benefit for doxorubicin and ifosfamide when compared to doxorubicin alone. In a Cochrane review evaluating randomized trials that compared doxorubicin and combination chemotherapy regimens, response rates varied from 14% for doxorubicin in combination with streptomycin to 34% for doxorubicin and ifosfamide. Most trials did not show a significant benefit for combination therapies when compared to doxorubicin alone.⁴³ Mean survival with doxorubicin or doxorubicin and ifosfamide is 12 months. High rates of recurrence highlight the need for additional chemotherapy regimens.

The newest approved agent is olaratumab, a monoclonal antibody that binds platelet-derived growth factor receptor alpha and prevents receptor activation. A phase 1-b and phase 2 trial evaluated patients with locally advanced and metastatic STS and randomly assigned them to either olaratumab and doxorubicin or doxorubicin alone.⁴⁶ Progression-free survival for olaratumab/doxorubicin was 6.6 months (95% CI 4.1 to 8.3) compared to 4.1 months (95% CI 2.8 to 5.4) for doxorubicin alone. The objective response rate was 18.2% (95% CI 9.8 to 29.6) for olaratumab/doxorubicin compared to 7.5% (95% CI 2.5 to 6.6) for doxorubicin alone. Furthermore, the median overall survival for olaratumab plus doxorubicin was 26.5 months (95% CI 20.9 to 31.7) compared to 14.7 months for doxorubicin alone (95% CI 5.5 to 26.0). Impressively, this improved response was notable across histological types. Furthermore, patients who had previously been treated with more than 1 regimen and those who were treatment naïve had similar response rates.⁴⁶

• What are second-line treatment options?

Doxorubicin has been used in combination with several other agents including dacarbazine (DTIC) as well as DTIC and ifosfamide (MAID). Borden et al evaluated patients with metastatic STS and randomly assigned the patients to either doxorubicin or doxorubicin and DTIC. Combination therapy demonstrated better tumor response than doxorubicin alone: 30% complete or partial response for combination therapy and 18% for doxorubicin alone.⁴⁷ However, Omura et al found similar rates of efficacy between doxorubicin and combination doxorubicin and DTIC in women with recurrent or nonresectable uterine sarcomas.⁴⁸ MAID has never been directly compared in a randomized trial to doxorubicin alone. In a study that compared MAID to doxorubicin and DTIC (AD) in patients with unresectable or metastatic sarcomas, MAID had superior response rates (32% versus 17%), but there was no difference with regards to overall survival (mean survival of 12.5 months).⁴⁹

Several additional regimens have undergone evaluation in metastatic and recurrent STSs. Gemcitabine has been used both as a single agent and as part of combination therapy in many studies. Studies with gemcitabine in combination with either docetaxel or DTIC have been the most efficacious. In a phase 2 trial, patients with metastatic STS were randomly assigned to either gemcitabine alone or gemcitabine and docetaxel. Combination therapy had a higher response rate (16% versus 8%) and longer overall survival (17.9 months versus 11.5 months) than gemcitabine alone.⁵⁰ Furthermore, a phase 2 trial of gemcitabine and docetaxel in patients with unresectable leiomyosarcoma showed an overall response rate of 56%, with 3 complete and 15 partial responses among the 34 patients enrolled in the study.⁵¹ A phase 2 trial randomly assigned patients with unresectable or metastatic STS to either DTIC or combination gemcitabine and DTIC.⁵² Gemcitabine-DTIC had a superior progression-free survival at 3 months (56% [95% CI 43% to 69%]) as compared to DTIC alone (37% [95% CI 23.5% to 50%]). Furthermore, mean progression-free survival and overall survival were improved in the gemcitabine-DTIC group (4.2 months and 16.8 months) as compared to the DTIC group (2.0 months and 8.2 months).⁵² DTIC has a single-agent response rate of 16%, but has been shown to be particularly effective in the setting of leiomyosarcomas.⁴⁹

• Does response to treatment regimens differ by histologic subtype?

The majority of STS trials include many different histologic subtypes. Given the rarity of sarcomas as a whole, many trials have had difficulty recruiting adequate numbers of patients to have sufficient power to definitely determine if the treatment under investigation has clinical benefit. Furthermore, the patients recruited have been heterogeneous with regard to subtype. Many older studies hypothesized that the efficacy of chemotherapeutic agents vary based on histologic subtype; however, for most subtypes the number of individuals included in those trials was too low to evaluate efficacy based on subtype.

Some exceptions exist, however. For example, both gemcitabine-DTIC and gemcitabine-docetaxel have been found to be particularly effective in the treatment of leiomyosarcomas.^50,52 Additionally, a retrospective study found a 51% overall response rate for patients with myxoid liposarcomas treated with trabectedin.⁵³ Studies of patients with angiosarcoma treated with paclitaxel have demonstrated response rates of 43% and 53%.^54,55

• What are the newest approved and investigational agents?

A recently approved agent is trabectedin, a tris tetrahydroisoquinoline alkaloid isolated from ascidians that binds to the minor groove of DNA and causes disruptions in the cell cycle. Samuels et al reported data from a single-arm, open-label expanded access trial that evaluated patients with advanced metastatic sarcomas.⁵⁶ In this study, patients with liposarcomas and leiomyosarcomas had an objective response rate of 6.9% (95% CI 4.8 to 9.6) as compared to a rate of 5.9% (95% CI 4.4 to 7.8) for all assessable patients. Median survival was 11.9 months for all patients, with improved median survivals for liposarcoma and leiomyosarcomas of 16.2 months (95% CI 14.1 to 19.5) compared to 8.4 months (95% CI 7.1 to 10.7 months) for other subtypes.⁵⁶

Schöffski et al evaluated eribulin, a chemotherapeutic agent that affects microtubule dynamics, in a phase 2 trial of patients with progressive or high-grade STS with progression on previous chemotherapy. They found a median progression-free survival of 2.6 months (95% CI 1.7 to 6.2) for adipocytic sarcoma, 2.9 months (95% CI 2.4 to 4.6) for leiomyosarcoma, 2.6 months (95% CI 2.3 to 4.3) for synovial sarcoma, and 2.1 months (95% CI 1.4 to 2.9) for other sarcomas.⁵⁷

Van der Graaf and colleagues randomly assigned patients with metastatic nonadipocytic STS to pazopanib or placebo in a phase 3 trial. Pazopanib is a small-molecule endothelial growth factor inhibitor with activity against vascular endothelial growth factors 1, 2, and 3 as well as platelet-derived growth factors. Median progression-free survival was 4.6 months (95% CI 3.7 to 4.8) with pazopanib compared to 1.6 months (95% CI 0.9 to 1.8) with placebo.⁵⁸ Adipocytic sarcomas (liposarcomas) were excluded from the trial because phase 2 trials had found a lower rate of progression-free survival (26%) for them compared to other subtypes.

• What are the most common toxicities associated with the approved and investigational chemotherapeutic agents?

Toxicities were seen with each of the regimens studied and were common in the randomized trials, with higher rates of toxicities in the combination chemotherapy regimens. The most common toxicities are myelosuppression, nausea, and vomiting. In the doxorubicin trials, the most common toxicities were myelosuppression, nausea, and vomiting.⁴⁴

Ifosfamide both as an individual agent and in combination with doxorubicin has higher rates and higher grades of toxicity than doxorubicin alone. Myelosuppression is the most common toxicity associated with ifosfamide, and the most commonly affected cell line is leukocytes.⁴⁴ Combination doxorubicin and ifosfamide also had high rates of nausea and vomiting (95%) and alopecia (100%).³⁵Neutropenia is the most common toxicity associated with gemcitabine and dacarbazine, while their most common nonhematologic toxicities are fatigue and nausea.^52,59 Trabectedin’s most common toxicities are nausea (29%), neutropenia (24%), and fatigue (23%). It has also been shown to cause increased alkaline phosphatase (20%) and alanine aminotransferase (19%) levels.⁵⁶ In a phase 2 study of eribulin, 50% of patients had neutropenia, and other toxicities included fatigue, alopecia, nausea, sensory neuropathy, and thrombocytopenia.⁵⁷ Pazopanib is generally well tolerated; the most common toxicities are fatigue (65%), diarrhea (58%), nausea (54%), and hypertension (41%).⁵⁸ Higher rates of neutropenia, mucositis, nausea, vomiting, diarrhea, and transfusion reactions were seen with olaratumab and doxorubicin compared to doxorubicin alone in phase 1b and 2 studies.⁴⁶

›  Case Continued

Given his poor prognosis with unresectable metastatic undifferentiated liposarcoma, the patient considers a clinical trial prior to undergoing combined therapy with doxorubicin and ifosfamide. He tolerates therapy well with stable disease at 6 months.

Conclusion

STSs are a heterogeneous collection of rare tumors. Low-grade, localized tumors have the best prognosis, and patients who undergo complete resection have the best long-term survival. Due to the rarity of STSs, trials often have limited enrollment, and little progress has been made with regards to treatment and survival rates for metastatic and unresectable disease. All patients should be evaluated and treated at specialized sarcoma centers. This case highlights the need for continued research and clinical trials to improve overall survival of patients with sarcoma. TSJ

CORRESPONDENCE

Ashley Pariser, MD, Resident, Department of Medicine, Northwestern University Feinberg School of Medicine Chicago, IL. Accepted for publication Jan/Feb 2017; Hosp Phys; Vol. 12, Part1

The Food and Drug Administration approved a new genetic sequencing test that detects mutations across 324 genes in tumor biopsy specimens with an accuracy of 94.6%.

The FoundationOne CDx (F1CDx) test from Foundation Medicine “can identify which patients with any of five tumor types” – non–small-cell lung cancer, melanoma, breast cancer, colorectal cancer, or ovarian cancer – “may benefit from 15 different FDA-approved targeted treatment options,” as well as clinical trial eligibility, “with one test report, avoiding duplicative biopsies,” the agency said in a statement.

[email protected]

The Food and Drug Administration approved a new genetic sequencing test that detects mutations across 324 genes in tumor biopsy specimens with an accuracy of 94.6%.

The FoundationOne CDx (F1CDx) test from Foundation Medicine “can identify which patients with any of five tumor types” – non–small-cell lung cancer, melanoma, breast cancer, colorectal cancer, or ovarian cancer – “may benefit from 15 different FDA-approved targeted treatment options,” as well as clinical trial eligibility, “with one test report, avoiding duplicative biopsies,” the agency said in a statement.

[email protected]

The Food and Drug Administration approved a new genetic sequencing test that detects mutations across 324 genes in tumor biopsy specimens with an accuracy of 94.6%.

The FoundationOne CDx (F1CDx) test from Foundation Medicine “can identify which patients with any of five tumor types” – non–small-cell lung cancer, melanoma, breast cancer, colorectal cancer, or ovarian cancer – “may benefit from 15 different FDA-approved targeted treatment options,” as well as clinical trial eligibility, “with one test report, avoiding duplicative biopsies,” the agency said in a statement.

[email protected]

The Diagnosis: Microcystic Adnexal Carcinoma

Microcystic adnexal carcinoma (MAC) is a rare, low-grade adnexal carcinoma consisting of both ductal and pilar differentiation.¹ It typically presents in young to middle-aged adults as a flesh-colored or yellow indurated plaque on the upper lip, medial cheek, or chin. Histologically, MACs exhibit a biphasic pattern consisting of epithelial islands of cords and lumina creating tadpolelike ducts intermixed with basaloid nests (quiz image). Keratin horn cysts are common superficially. A dense red sclerotic stroma is seen interspersed between the ducts and epithelial islands creating a "paisley tie" appearance. The lesion displays an infiltrative pattern and can be deeply invasive, extending down to the fat and muscle (quiz image, inset). Perineural invasion is common. Atypia, when present, is minimal or mild and mitoses are rare. Although this tumor's histologic pattern appears aggressive in nature, it lacks immunohistochemical staining such as p53, Ki-67, bcl-2, and c-erbB-2 that correlate with malignant behavior.² A common diagnostic pitfall is examination of a superficial biopsy in which an MAC may be mistakenly identified as another entity.

Syringomas are benign adnexal neoplasms with ductal differentiation.³ They are more common in women, especially those of Asian descent, and in patients with Down syndrome. They typically present as multiple small, firm, flesh-colored papules in the periorbital area or upper trunk. Histologically, syringomas also display comma-shaped tubules and ducts with a tadpolelike appearance and a dense red stroma creating a paisley tie-like pattern. Ductal cells have an abundant pink cytoplasm. Syringomas are well-circumscribed and more superficial than MACs without an infiltrative pattern. They lack mitotic activity or perineural invasion (Figure 1).

Desmoplastic trichoepithelioma (DTE) is a benign follicular neoplasm.⁴ It presents in adulthood with a female predominance. Clinically, it appears as a solitary flesh-colored to yellow annular plaque with raised borders and a depressed central area, often on the medial cheek. Histologically, DTEs are well-circumscribed with narrow branching cords lined with polygonal cells. A dense red stroma in combination with the epithelioid aggregates also creates the paisley tie-like pattern in this lesion. Retraction between collagen bundles within the stroma can be seen, helping distinguish this lesion from a morpheaform basal cell carcinoma (BCC), which has retraction between the epithelium and stroma. Immunohistochemistry also can be a useful tool to help differentiate DTEs from morpheaform BCCs in that sparse cytokeratin 20-positive Merkel cells can be seen within the basaloid islands of DTE but not BCC.⁵ Also seen with DTEs are numerous keratin horn cysts that commonly are filled with dystrophic calcifications. Cellular atypia and mitoses are not seen (Figure 2). Compared to MACs, DTEs lack abundant ductal structures and also contain papillary mesenchymal bodies and a more fibroblast-rich stroma.

Morpheaform BCC is an aggressive subtype of BCC. It presents as a scarlike plaque that gradually expands. Thin infiltrating strands of basaloid cells are seen haphazardly throughout a pink sclerotic stroma. Tadpolelike basaloid islands and rarely horn cysts can be seen scattered superficially, creating the paisley tie-like pattern. This lesion is more infiltrating than a syringoma or a DTE, and perineural invasion is common. Retraction is uncommon, but when present, it is seen between the epithelial cords and adjacent stroma (Figure 3).

Trichoadenoma is another benign neoplasm of follicular differentiation.⁶ It typically presents as a dome-shaped papule or plaque on the head or neck. Histologically it displays numerous dilated cystic spaces that reflect its origin from isthmic and infundibular differentiation. There is no attachment to the overlying epidermis. It can be distinguished from MAC, DTE, and syringoma due to a lack of basaloid aggregates and only a small number of non-cyst-forming epithelial cells (Figure 4).

The Diagnosis: Microcystic Adnexal Carcinoma

Microcystic adnexal carcinoma (MAC) is a rare, low-grade adnexal carcinoma consisting of both ductal and pilar differentiation.¹ It typically presents in young to middle-aged adults as a flesh-colored or yellow indurated plaque on the upper lip, medial cheek, or chin. Histologically, MACs exhibit a biphasic pattern consisting of epithelial islands of cords and lumina creating tadpolelike ducts intermixed with basaloid nests (quiz image). Keratin horn cysts are common superficially. A dense red sclerotic stroma is seen interspersed between the ducts and epithelial islands creating a "paisley tie" appearance. The lesion displays an infiltrative pattern and can be deeply invasive, extending down to the fat and muscle (quiz image, inset). Perineural invasion is common. Atypia, when present, is minimal or mild and mitoses are rare. Although this tumor's histologic pattern appears aggressive in nature, it lacks immunohistochemical staining such as p53, Ki-67, bcl-2, and c-erbB-2 that correlate with malignant behavior.² A common diagnostic pitfall is examination of a superficial biopsy in which an MAC may be mistakenly identified as another entity.

Syringomas are benign adnexal neoplasms with ductal differentiation.³ They are more common in women, especially those of Asian descent, and in patients with Down syndrome. They typically present as multiple small, firm, flesh-colored papules in the periorbital area or upper trunk. Histologically, syringomas also display comma-shaped tubules and ducts with a tadpolelike appearance and a dense red stroma creating a paisley tie-like pattern. Ductal cells have an abundant pink cytoplasm. Syringomas are well-circumscribed and more superficial than MACs without an infiltrative pattern. They lack mitotic activity or perineural invasion (Figure 1).

Desmoplastic trichoepithelioma (DTE) is a benign follicular neoplasm.⁴ It presents in adulthood with a female predominance. Clinically, it appears as a solitary flesh-colored to yellow annular plaque with raised borders and a depressed central area, often on the medial cheek. Histologically, DTEs are well-circumscribed with narrow branching cords lined with polygonal cells. A dense red stroma in combination with the epithelioid aggregates also creates the paisley tie-like pattern in this lesion. Retraction between collagen bundles within the stroma can be seen, helping distinguish this lesion from a morpheaform basal cell carcinoma (BCC), which has retraction between the epithelium and stroma. Immunohistochemistry also can be a useful tool to help differentiate DTEs from morpheaform BCCs in that sparse cytokeratin 20-positive Merkel cells can be seen within the basaloid islands of DTE but not BCC.⁵ Also seen with DTEs are numerous keratin horn cysts that commonly are filled with dystrophic calcifications. Cellular atypia and mitoses are not seen (Figure 2). Compared to MACs, DTEs lack abundant ductal structures and also contain papillary mesenchymal bodies and a more fibroblast-rich stroma.

Morpheaform BCC is an aggressive subtype of BCC. It presents as a scarlike plaque that gradually expands. Thin infiltrating strands of basaloid cells are seen haphazardly throughout a pink sclerotic stroma. Tadpolelike basaloid islands and rarely horn cysts can be seen scattered superficially, creating the paisley tie-like pattern. This lesion is more infiltrating than a syringoma or a DTE, and perineural invasion is common. Retraction is uncommon, but when present, it is seen between the epithelial cords and adjacent stroma (Figure 3).

Trichoadenoma is another benign neoplasm of follicular differentiation.⁶ It typically presents as a dome-shaped papule or plaque on the head or neck. Histologically it displays numerous dilated cystic spaces that reflect its origin from isthmic and infundibular differentiation. There is no attachment to the overlying epidermis. It can be distinguished from MAC, DTE, and syringoma due to a lack of basaloid aggregates and only a small number of non-cyst-forming epithelial cells (Figure 4).

The Diagnosis: Microcystic Adnexal Carcinoma

Microcystic adnexal carcinoma (MAC) is a rare, low-grade adnexal carcinoma consisting of both ductal and pilar differentiation.¹ It typically presents in young to middle-aged adults as a flesh-colored or yellow indurated plaque on the upper lip, medial cheek, or chin. Histologically, MACs exhibit a biphasic pattern consisting of epithelial islands of cords and lumina creating tadpolelike ducts intermixed with basaloid nests (quiz image). Keratin horn cysts are common superficially. A dense red sclerotic stroma is seen interspersed between the ducts and epithelial islands creating a "paisley tie" appearance. The lesion displays an infiltrative pattern and can be deeply invasive, extending down to the fat and muscle (quiz image, inset). Perineural invasion is common. Atypia, when present, is minimal or mild and mitoses are rare. Although this tumor's histologic pattern appears aggressive in nature, it lacks immunohistochemical staining such as p53, Ki-67, bcl-2, and c-erbB-2 that correlate with malignant behavior.² A common diagnostic pitfall is examination of a superficial biopsy in which an MAC may be mistakenly identified as another entity.

Syringomas are benign adnexal neoplasms with ductal differentiation.³ They are more common in women, especially those of Asian descent, and in patients with Down syndrome. They typically present as multiple small, firm, flesh-colored papules in the periorbital area or upper trunk. Histologically, syringomas also display comma-shaped tubules and ducts with a tadpolelike appearance and a dense red stroma creating a paisley tie-like pattern. Ductal cells have an abundant pink cytoplasm. Syringomas are well-circumscribed and more superficial than MACs without an infiltrative pattern. They lack mitotic activity or perineural invasion (Figure 1).

Desmoplastic trichoepithelioma (DTE) is a benign follicular neoplasm.⁴ It presents in adulthood with a female predominance. Clinically, it appears as a solitary flesh-colored to yellow annular plaque with raised borders and a depressed central area, often on the medial cheek. Histologically, DTEs are well-circumscribed with narrow branching cords lined with polygonal cells. A dense red stroma in combination with the epithelioid aggregates also creates the paisley tie-like pattern in this lesion. Retraction between collagen bundles within the stroma can be seen, helping distinguish this lesion from a morpheaform basal cell carcinoma (BCC), which has retraction between the epithelium and stroma. Immunohistochemistry also can be a useful tool to help differentiate DTEs from morpheaform BCCs in that sparse cytokeratin 20-positive Merkel cells can be seen within the basaloid islands of DTE but not BCC.⁵ Also seen with DTEs are numerous keratin horn cysts that commonly are filled with dystrophic calcifications. Cellular atypia and mitoses are not seen (Figure 2). Compared to MACs, DTEs lack abundant ductal structures and also contain papillary mesenchymal bodies and a more fibroblast-rich stroma.

Morpheaform BCC is an aggressive subtype of BCC. It presents as a scarlike plaque that gradually expands. Thin infiltrating strands of basaloid cells are seen haphazardly throughout a pink sclerotic stroma. Tadpolelike basaloid islands and rarely horn cysts can be seen scattered superficially, creating the paisley tie-like pattern. This lesion is more infiltrating than a syringoma or a DTE, and perineural invasion is common. Retraction is uncommon, but when present, it is seen between the epithelial cords and adjacent stroma (Figure 3).

Trichoadenoma is another benign neoplasm of follicular differentiation.⁶ It typically presents as a dome-shaped papule or plaque on the head or neck. Histologically it displays numerous dilated cystic spaces that reflect its origin from isthmic and infundibular differentiation. There is no attachment to the overlying epidermis. It can be distinguished from MAC, DTE, and syringoma due to a lack of basaloid aggregates and only a small number of non-cyst-forming epithelial cells (Figure 4).

Correct Answer: E

Rationale

On serial imaging, two worrisome features have developed in the pancreas cyst, i.e., an enhancing mural nodule and dilation of the main pancreatic duct. These features are high-risk stigmata, and therefore surgical resection is recommended. EUS FNA can be considered but is unlikely to change management if cytology is negative. Radiologic surveillance is not appropriate unless the patient refuses surgery.

Reference

1. Tanaka M., Fernández-del Castillo C., Adsay V., et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology. 2012;12(3):183-97.

Correct Answer: E

Rationale

On serial imaging, two worrisome features have developed in the pancreas cyst, i.e., an enhancing mural nodule and dilation of the main pancreatic duct. These features are high-risk stigmata, and therefore surgical resection is recommended. EUS FNA can be considered but is unlikely to change management if cytology is negative. Radiologic surveillance is not appropriate unless the patient refuses surgery.

Reference

1. Tanaka M., Fernández-del Castillo C., Adsay V., et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology. 2012;12(3):183-97.

Correct Answer: E

Rationale

On serial imaging, two worrisome features have developed in the pancreas cyst, i.e., an enhancing mural nodule and dilation of the main pancreatic duct. These features are high-risk stigmata, and therefore surgical resection is recommended. EUS FNA can be considered but is unlikely to change management if cytology is negative. Radiologic surveillance is not appropriate unless the patient refuses surgery.

Reference

1. Tanaka M., Fernández-del Castillo C., Adsay V., et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology. 2012;12(3):183-97.

PARIS – One of the most unexpected and intriguing new developments in the field of schizophrenia has to be the discovery that the risk of the disease is significantly increased in men who were diagnosed with inguinal hernia before they were 13 years old.

“I think this is interesting because inguinal hernia in boys has to do with fibroblasts producing abnormal collagen structure,” according to Kristina Melkersson, MD, PhD, who presented her study findings at the annual congress of the European College of Neuropsychopharmacology.

Bruce Jancin/Frontline Medical News

[email protected]
 

PARIS – One of the most unexpected and intriguing new developments in the field of schizophrenia has to be the discovery that the risk of the disease is significantly increased in men who were diagnosed with inguinal hernia before they were 13 years old.

“I think this is interesting because inguinal hernia in boys has to do with fibroblasts producing abnormal collagen structure,” according to Kristina Melkersson, MD, PhD, who presented her study findings at the annual congress of the European College of Neuropsychopharmacology.

Bruce Jancin/Frontline Medical News

[email protected]
 

PARIS – One of the most unexpected and intriguing new developments in the field of schizophrenia has to be the discovery that the risk of the disease is significantly increased in men who were diagnosed with inguinal hernia before they were 13 years old.

“I think this is interesting because inguinal hernia in boys has to do with fibroblasts producing abnormal collagen structure,” according to Kristina Melkersson, MD, PhD, who presented her study findings at the annual congress of the European College of Neuropsychopharmacology.

Bruce Jancin/Frontline Medical News

[email protected]
 

Correct Answer: C

Rationale

Mixed connective tissue disease can be associated with atrophy of the smooth muscle of the gut, like scleroderma. In the esophagus, this can manifest as a hypotensive lower esophageal sphincter and impaired esophageal smooth muscle peristalsis; in extreme cases, there is absent contractility in the esophagus. This contributes to impaired esophageal clearance of refluxed material, leading to prolonged acid residence times in the esophagus and severe reflux esophagitis. Many patients with mixed connective tissue disease have overlap Sjogren’s syndrome, reducing salivary neutralization of esophageal mucosal acidification and further contributing to esophagitis. While esophageal body motor function can be suboptimal in diabetes mellitus and Barrett’s esophagus, the mechanism of hypomotility is not smooth muscle atrophy and fibrosis. Polymyositis can affect skeletal muscle of the proximal esophagus, but not the smooth muscle. Lichen planus affects mucosa but not muscle.

Reference

1. Savarino E., Mei F., Parodi A., et al. Gastrointestinal motility disorder assessment in systemic sclerosis. Rheumatology (Oxford). 2013 Jun;52(6):1095-100.

2. Langdon P.C., Mulcahy K., Shepherd K.L., et al. Pharyngeal dysphagia in inflammatory muscle diseases resulting from impaired suprahyoid musculature. Dysphagia. 2012 Sep;27(3):408-17.

Correct Answer: C

Rationale

Mixed connective tissue disease can be associated with atrophy of the smooth muscle of the gut, like scleroderma. In the esophagus, this can manifest as a hypotensive lower esophageal sphincter and impaired esophageal smooth muscle peristalsis; in extreme cases, there is absent contractility in the esophagus. This contributes to impaired esophageal clearance of refluxed material, leading to prolonged acid residence times in the esophagus and severe reflux esophagitis. Many patients with mixed connective tissue disease have overlap Sjogren’s syndrome, reducing salivary neutralization of esophageal mucosal acidification and further contributing to esophagitis. While esophageal body motor function can be suboptimal in diabetes mellitus and Barrett’s esophagus, the mechanism of hypomotility is not smooth muscle atrophy and fibrosis. Polymyositis can affect skeletal muscle of the proximal esophagus, but not the smooth muscle. Lichen planus affects mucosa but not muscle.

Reference

1. Savarino E., Mei F., Parodi A., et al. Gastrointestinal motility disorder assessment in systemic sclerosis. Rheumatology (Oxford). 2013 Jun;52(6):1095-100.

2. Langdon P.C., Mulcahy K., Shepherd K.L., et al. Pharyngeal dysphagia in inflammatory muscle diseases resulting from impaired suprahyoid musculature. Dysphagia. 2012 Sep;27(3):408-17.

Correct Answer: C

Rationale

Mixed connective tissue disease can be associated with atrophy of the smooth muscle of the gut, like scleroderma. In the esophagus, this can manifest as a hypotensive lower esophageal sphincter and impaired esophageal smooth muscle peristalsis; in extreme cases, there is absent contractility in the esophagus. This contributes to impaired esophageal clearance of refluxed material, leading to prolonged acid residence times in the esophagus and severe reflux esophagitis. Many patients with mixed connective tissue disease have overlap Sjogren’s syndrome, reducing salivary neutralization of esophageal mucosal acidification and further contributing to esophagitis. While esophageal body motor function can be suboptimal in diabetes mellitus and Barrett’s esophagus, the mechanism of hypomotility is not smooth muscle atrophy and fibrosis. Polymyositis can affect skeletal muscle of the proximal esophagus, but not the smooth muscle. Lichen planus affects mucosa but not muscle.

Reference

1. Savarino E., Mei F., Parodi A., et al. Gastrointestinal motility disorder assessment in systemic sclerosis. Rheumatology (Oxford). 2013 Jun;52(6):1095-100.

2. Langdon P.C., Mulcahy K., Shepherd K.L., et al. Pharyngeal dysphagia in inflammatory muscle diseases resulting from impaired suprahyoid musculature. Dysphagia. 2012 Sep;27(3):408-17.

The rate of self-inflicted injuries has increased significantly among young girls since 2009, according to a study of emergency department visits for self-inflicted injuries from 2001 to 2015.

In a research letter, Melissa C. Mercado, PhD, and her associates reached that conclusion based on data from 43,138 emergency department visits for self-inflicted injury among young people aged 10-24 years, which were captured by the National Electronic Injury Surveillance System–All Injury Program (JAMA. 2017;318[19]:1931-3. doi: 10.1001/jama.2017.13317).

From 2001 to 2008, the overall weighted, age-adjusted rate of self-inflicted injury showed no statistically significant trend upward or downward, reported Dr. Mercado of the National Center for Injury Prevention and Control, Atlanta, and her associates. From 2009 to 2015, however, the rate increased by a significant 5.7% per year, reaching 303.7 per 100,000 population in 2015, compared with 201.6 in 2001.

This increase was even more pronounced among girls, rising by 8.4% per year from 2008 to 2015 in all females but by 18.8% per year in those aged 10-14 years. In adolescent females aged 15-19, the rate of self-inflicted injury rose 7.2% per year from 2008 to 2015. In young women aged 20-24 years, the rate rose 2% per year from 2001 to 2015.

Meanwhile, the rates of self-inflicted injury for males were stable across all time periods and age groups.

“Self-inflicted injury is one of the strongest risk factors for suicide – the second-leading cause of death among those aged 10 to 24 years during 2015,” Dr. Mercado and her coauthors wrote.

The most common method of self-inflicted injury for females was poisoning. As with the overall rates of injury in females, the rates of this method of harm were stable until 2007, then increased by 5.3% until 2015. Self-inflicted injuries among females using a sharp object increased by 7.1% each year from 2001 to 2015, but the rates of blunt-object injuries were stable from 2006 to 2015.

The authors wrote that the finding of an increase in self-harm among females was consistent with youth suicide data, which also show an increase after 2006, particularly among girls and female adolescents aged 10-14 years.

Dr. Mercado and her associates called for the implementation of evidence-based, comprehensive suicide and self-harm prevention strategies. “These strategies include strengthening access to and delivery of care for suicidal youth within health systems and creating protective environments, promoting youth connectedness, teaching coping and problem-solving skills, and identifying and supporting at-risk youth within communities.”

The study was conducted under the auspices of the National Center for Injury Prevention and Control, which is part of the Centers for Disease Control and Prevention. The findings, however, do not necessarily represent the views of the CDC. No conflicts of interest were declared.

[email protected]

The rate of self-inflicted injuries has increased significantly among young girls since 2009, according to a study of emergency department visits for self-inflicted injuries from 2001 to 2015.

In a research letter, Melissa C. Mercado, PhD, and her associates reached that conclusion based on data from 43,138 emergency department visits for self-inflicted injury among young people aged 10-24 years, which were captured by the National Electronic Injury Surveillance System–All Injury Program (JAMA. 2017;318[19]:1931-3. doi: 10.1001/jama.2017.13317).

From 2001 to 2008, the overall weighted, age-adjusted rate of self-inflicted injury showed no statistically significant trend upward or downward, reported Dr. Mercado of the National Center for Injury Prevention and Control, Atlanta, and her associates. From 2009 to 2015, however, the rate increased by a significant 5.7% per year, reaching 303.7 per 100,000 population in 2015, compared with 201.6 in 2001.

This increase was even more pronounced among girls, rising by 8.4% per year from 2008 to 2015 in all females but by 18.8% per year in those aged 10-14 years. In adolescent females aged 15-19, the rate of self-inflicted injury rose 7.2% per year from 2008 to 2015. In young women aged 20-24 years, the rate rose 2% per year from 2001 to 2015.

Meanwhile, the rates of self-inflicted injury for males were stable across all time periods and age groups.

“Self-inflicted injury is one of the strongest risk factors for suicide – the second-leading cause of death among those aged 10 to 24 years during 2015,” Dr. Mercado and her coauthors wrote.

The most common method of self-inflicted injury for females was poisoning. As with the overall rates of injury in females, the rates of this method of harm were stable until 2007, then increased by 5.3% until 2015. Self-inflicted injuries among females using a sharp object increased by 7.1% each year from 2001 to 2015, but the rates of blunt-object injuries were stable from 2006 to 2015.

The authors wrote that the finding of an increase in self-harm among females was consistent with youth suicide data, which also show an increase after 2006, particularly among girls and female adolescents aged 10-14 years.

Dr. Mercado and her associates called for the implementation of evidence-based, comprehensive suicide and self-harm prevention strategies. “These strategies include strengthening access to and delivery of care for suicidal youth within health systems and creating protective environments, promoting youth connectedness, teaching coping and problem-solving skills, and identifying and supporting at-risk youth within communities.”

The study was conducted under the auspices of the National Center for Injury Prevention and Control, which is part of the Centers for Disease Control and Prevention. The findings, however, do not necessarily represent the views of the CDC. No conflicts of interest were declared.

[email protected]

The rate of self-inflicted injuries has increased significantly among young girls since 2009, according to a study of emergency department visits for self-inflicted injuries from 2001 to 2015.

In a research letter, Melissa C. Mercado, PhD, and her associates reached that conclusion based on data from 43,138 emergency department visits for self-inflicted injury among young people aged 10-24 years, which were captured by the National Electronic Injury Surveillance System–All Injury Program (JAMA. 2017;318[19]:1931-3. doi: 10.1001/jama.2017.13317).

From 2001 to 2008, the overall weighted, age-adjusted rate of self-inflicted injury showed no statistically significant trend upward or downward, reported Dr. Mercado of the National Center for Injury Prevention and Control, Atlanta, and her associates. From 2009 to 2015, however, the rate increased by a significant 5.7% per year, reaching 303.7 per 100,000 population in 2015, compared with 201.6 in 2001.

This increase was even more pronounced among girls, rising by 8.4% per year from 2008 to 2015 in all females but by 18.8% per year in those aged 10-14 years. In adolescent females aged 15-19, the rate of self-inflicted injury rose 7.2% per year from 2008 to 2015. In young women aged 20-24 years, the rate rose 2% per year from 2001 to 2015.

Meanwhile, the rates of self-inflicted injury for males were stable across all time periods and age groups.

“Self-inflicted injury is one of the strongest risk factors for suicide – the second-leading cause of death among those aged 10 to 24 years during 2015,” Dr. Mercado and her coauthors wrote.

The most common method of self-inflicted injury for females was poisoning. As with the overall rates of injury in females, the rates of this method of harm were stable until 2007, then increased by 5.3% until 2015. Self-inflicted injuries among females using a sharp object increased by 7.1% each year from 2001 to 2015, but the rates of blunt-object injuries were stable from 2006 to 2015.

The authors wrote that the finding of an increase in self-harm among females was consistent with youth suicide data, which also show an increase after 2006, particularly among girls and female adolescents aged 10-14 years.

Dr. Mercado and her associates called for the implementation of evidence-based, comprehensive suicide and self-harm prevention strategies. “These strategies include strengthening access to and delivery of care for suicidal youth within health systems and creating protective environments, promoting youth connectedness, teaching coping and problem-solving skills, and identifying and supporting at-risk youth within communities.”

The study was conducted under the auspices of the National Center for Injury Prevention and Control, which is part of the Centers for Disease Control and Prevention. The findings, however, do not necessarily represent the views of the CDC. No conflicts of interest were declared.

[email protected]

Editor’s note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform health care and revolutionize patient care. The program has been expanded for the 2017-2018 year, offering two options for students to receive funding and engage in scholarly work during their first, second, and third years of medical school. As a part of the longitudinal (18-month) program, recipients are required to write about their experience on a monthly basis.

For my research project, we are looking to develop a tool that would use data from within 24 hours of a patient’s admission to the hospital to predict whether they will require post-acute care placement after discharge. While I have often been summarizing my project with this broad one-liner, in the last two weeks I have been delving more into the details of what exactly we mean by “data from within 24 hours of a patient’s admission.”

Monisha Bhatia, a native of Nashville, Tenn., is a fourth-year medical student at Vanderbilt University in Nashville. She is hoping to pursue either a residency in internal medicine or a combined internal medicine/emergency medicine program. Prior to medical school, she completed a JD/MPH program at Boston University, and she hopes to use her legal training in working with regulatory authorities to improve access to health care for all Americans.

Editor’s note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform health care and revolutionize patient care. The program has been expanded for the 2017-2018 year, offering two options for students to receive funding and engage in scholarly work during their first, second, and third years of medical school. As a part of the longitudinal (18-month) program, recipients are required to write about their experience on a monthly basis.

For my research project, we are looking to develop a tool that would use data from within 24 hours of a patient’s admission to the hospital to predict whether they will require post-acute care placement after discharge. While I have often been summarizing my project with this broad one-liner, in the last two weeks I have been delving more into the details of what exactly we mean by “data from within 24 hours of a patient’s admission.”

Monisha Bhatia, a native of Nashville, Tenn., is a fourth-year medical student at Vanderbilt University in Nashville. She is hoping to pursue either a residency in internal medicine or a combined internal medicine/emergency medicine program. Prior to medical school, she completed a JD/MPH program at Boston University, and she hopes to use her legal training in working with regulatory authorities to improve access to health care for all Americans.

Editor’s note: The Society of Hospital Medicine’s (SHM’s) Physician in Training Committee launched a scholarship program in 2015 for medical students to help transform health care and revolutionize patient care. The program has been expanded for the 2017-2018 year, offering two options for students to receive funding and engage in scholarly work during their first, second, and third years of medical school. As a part of the longitudinal (18-month) program, recipients are required to write about their experience on a monthly basis.

For my research project, we are looking to develop a tool that would use data from within 24 hours of a patient’s admission to the hospital to predict whether they will require post-acute care placement after discharge. While I have often been summarizing my project with this broad one-liner, in the last two weeks I have been delving more into the details of what exactly we mean by “data from within 24 hours of a patient’s admission.”

Monisha Bhatia, a native of Nashville, Tenn., is a fourth-year medical student at Vanderbilt University in Nashville. She is hoping to pursue either a residency in internal medicine or a combined internal medicine/emergency medicine program. Prior to medical school, she completed a JD/MPH program at Boston University, and she hopes to use her legal training in working with regulatory authorities to improve access to health care for all Americans.