Soft tissue and Bone Sarcomas
Sarcomas are malignant tumors arising from some mesenchymal cells of the skeletal or extra-skeletal connective tissue including the peripheral nervous system. These mesenchymal cells include Cartilage and Bone, Fat and Vascular structures or Hematopoietic tissues. Sarcomas may arise from any of these cells, forming many sub-types: Primary Sarcomas arising in the connective tissue and Secondary or Metastatic Sarcomas arising somewhere else in the body, like in the Breast, Lungs or Prostate.
Sarcoma derived from the Greek (Sark) which mean flesh. The American Joint Committee on Cancer (AJCC) Association has divided them in two major groups, The Bone Sarcomas and the Soft Tissue Sarcomas classified in different sub-types like Osteosarcoma, Leiomyosarcoma, Liposarcoma, Angiosarcoma, Chordoma, Rhabdomyosarcoma, Chondrosarcoma. Adamantinoma, Synovial Sarcoma and many others like Dermatofibrosarcoma, Fibrosarcoma etc.).
There is no clearly defined etiology in most of the cases of soft tissue sarcomas but some associated factors have been discovered. Genetic predisposition or gene mutations, chemotherapy and Radiation Therapy, as well as chemical carcinogens and lymphedema have been found in many studies to be associated with Sarcoma. More viral infection like HIV or the human herpes virus 8 (HHV-8) in Kaposi sarcoma and in Epstein Bar virus (EBV) have been found in immunocompromised patients to be associated with sarcoma.
Often, the children of parents with defined inherited condition like Li-Fraumeni syndrome (LFS) or Retinoblastoma have a genetic predisposition to cancer. Many other genes have been analyzed to show monogenic or polygenic variations for cancer risk. A mutation of the TP53 tumor suppressor gene in the Li-Fraumeni is more common in the pediatric sarcomas (Osteosarcoma, Rhabdomyosarcoma, and Ewing Sarcoma). In a study on 151 children with soft tissue sarcomas, 5 families (3.3 %) manifested the classic LFS familial cancer syndrome, 10 families (6.6%) had features consistent with the syndrome and 16 families (10.5) had one parent with the hereditary cancer syndrome.
LI-Fraumeni syndrome (LFS) is inherited as an autosomal dominant trait and a mutation in the TP53 tumor suppressor gene was demonstrated in bone sarcomas, breast cancer, leukemia etc. Retinoblastomas and sarcoma of soft tissue or bone like osteosarcoma have been seen later in the life of surviving patients with retinoblastoma. These individuals have inherited a mutant copy of the mutant gene predisposing to secondary cancers. Neurofibromatosis of Von Recklinghausen (NF1) can also undergo malignant changes in the peripheral nerve sheath with changes in neurofibrosarcomas or malignant schwannomas. Other autosomal recessive conditions with kin atrophy, telangiectasias have an increased risk for osteosarcoma.
The Genetics of Sarcomas can be divided in two groups: one with specific genetic alterations and one with simple karyotypes. In many cases, an aberrant protein act as an abnormal transcriptional regulator, providing the molecular basis for the oncogenesis while the pathogenesis for sarcomas with unbalanced karyotypic complexity has not been definitely proven. It seems that the TP53 pathway appears to be a striking feature between these tumors.
There is a high incidence of acquired (somatic) gene alterations and DNA ploidy by flow cytometry has identified an autosomal cell population in 84% of the tumors. Other studies on DNA sequencing for 722 protein coding genes have been implicated in cancer formation from 200 samples. Frequently mutated genes included the TP53 tumor suppressor gene in Liposarcomas (17%), Type 1 Neurofibromatosis NF1; in myxofibrosarcomas (10.5%), in pleomorphic Liposarcomas (8%) and PIK3CA myxoid/round cell Liposarcomas (18%). Retinoblastoma RB was mutated in 4% of the pleomorphic Liposarcomas. DNA chromosome 12q were observed in 90% of patients with dedifferentiated Liposarcomas. Other studies have matched mutations in the receptor tyrosine kinase, RAS in Rhabdomyosarcomas. etc.
Bone Sarcomas are rare and count for less than .001% risk in a previously healthy person while the soft tissue sarcomas rests between .0014. The American Cancer Society (ACS) reported 3599 new cases of bone sarcomas in 2019 while 12,750 new cases of soft tissue sarcomas have been discovered, representing only .2% of all types of cancer (1,762,450). Bone Sarcomas are the 30th most common type of bone cancer but soft tissue sarcomas represent .7% of all cancer, representing the 22nd most common type of cancer. Sarcomas affect people at all ages. Notably, 50% of bone sarcomas and 20% of soft tissue sarcomas are diagnosed under the age of 35. Chondrosarcoma, Leiomyosarcomas, GI stromal tumors are more common in adults than children while high grade bone sarcomas like Ewing’s or Osteosarcomas are more common in children and young adults.
Scientist in 2016 have discovered a fossil 1.6-1.8 million old with an osteosarcoma from the skeleton of an old hominin species.
The symptoms in bone sarcomas include especially night pain and swelling at the tumor site while soft tissue sarcomas present with painless lumps or nodules generally firm in consistency. Gastrointestinal stromal cells are generally painless in nature but can be seen with vague abdominal discomfort, a sensation of fullness or any sign of obstruction.
There are no known causes for most bone sarcomas but several factors have been associated with their arousal. Exposure to Ionizing radiation (previous radiation therapy) or alkylating agents (Chemotherapeutic drugs) have shown an increase in risks for bone sarcomas. We have earlier discussed the relation between some inherited genetic syndromes like the LI-Fraumeni Syndrome RB1 gene mutations and Paget disease of bones to the incidence of bone sarcomas. On the other side, soft tissue sarcomas present with more sporadic genetic mutations within an affected cell. Ionizing radiation is also found in these category as a risk factor. Vinyl Chloride (PVC) Arsenic, Thorotrast are all associated with the risk of Angiosarcoma like also complicating the lymphedema following breast cancer surgery. Other inherited genetic syndromes can be associated with soft tissue sarcoma formation including Neurofibromatosis type 1, Familial adenomatous type 1 and heritable RB1 gene mutations.
The mechanism by which certain healthy cells transform into cancer cell is not well known but certain types of sarcomas are associated with particular genetic mutations:
1- Most cases of Ewing sarcomas are associated with the translocation of chromosome 11 in which part of that chromosome fuses with part of chromosome 22 resulting in an EWS gene. Other genes can be found as well in Ewing Sarcomas like the FLI1 gene (90%) and ERG gene (5-10%). Such fusions result in the production of abnormal proteins which may result in the cancer formation.
2- In Dermato-fibromasarcoma protuberans, a translocation of the chromosome produces the fusion of COL1A1 Gene and PDGEFRB Gene. thought to promote the cell division leading to a tumor formation. I will refer you to an article in which I am a co-author describing a Dermatofibrosarcoma lesion involving the soft tissue of the hand and I urge one to lean a little more about this form of soft tissue malignancy. (Reference # 13).
3- Inflammatory myofibroblastic tumor are associated to the arrangements of the ALK Gene and the HMGA2 gene.
4- Malignant giant cell tumors of soft tissue are associated with the translocation of Chromosome 1 and Chromosome 2 in which CSF 1 Gene and COL6A3 Gene become fused increasing the SCF1 protein production, believed to be responsible of the development of the cancer cells.
5- Liposarcomas are associated with the duplication of chromosome 12, producing oncogenes such as CDK4 Gene, MDM2 Gene and HMGA2 Gene associated to the production of tumoral cells.
A history and physical examination is mandatory to evaluate a patient with bone sarcomas. Such approach will help us in finding signs and symptoms. Although at this point, laboratory studies may not be useful but we have to realize that in bone sarcomas especially osteosarcomas, there is a tendency to observe an alkaline phosphatase elevation while tumors like Ewing sarcoma will present with an erythrocyte sedimentation rate elevation which in both tumors do not show any specificity and can’t be relied upon for a diagnosis. Differently Imaging studies like plain X-rays, MRI, CT Scans Radioisotope bone scans can play an important role in obtaining a diagnosis…and can used in the staging of the tumor. In the last resort, a definite diagnosis requires a biopsy reviewed by an experimented pathologist.
The diagnosis on soft tissue sarcomas begin also with a true history and physical examination. Subsequent CT, MRI may be obtained depending on the location in the chest or abdomen or retroperitoneal area. Positive Emission tomography (PET) scan have found also a role in depicting soft tissue malignant lesions. it will be more useful when the staging of a typical lesion is involved. Finally, a biopsy is the best way to asset a definitive diagnosis. through the eyes of a trained pathologist.
An advanced cancer is evaluated by the staging of the lesion to be determined by the tumor size and the location in other parts of the body. The staging will also affect the prognosis and the types of treatment susceptible to treat the pathology. Tumor will expand to the tissue around in a local invasion or in a distant way, creating a metastasis locally or distantly to any tissue, lymph nodes, organs or bones etc.
Many imaging tools are used to assess the staging of a bone or soft tissue sarcoma. MRI and CT scans are best at evaluation of the primary tumor with or without contrast to check on the evidence of spreading or metastasis to organs like liver, lungs or bones. The same for the soft tissue lesion to determine the size and the location as well.
Cancerous tumors are also assigned a grade (Low, Intermediate or High) depending on the appearance and the way the cells are seen under the microscope. It is a way to appreciate the aggressively of the tumor and its spreading to other part of the body or to the tissues around. The lower the grade, the better is the diagnosis. One will have to determine if radiation therapy or chemotherapy can be offered for the treatment, alone or in combination with surgical treatment. The higher the grade the more you are expected to encounter metastasis locally or at distant sites. Sarcomas sensitive to chemotherapy have shown an improvement in the survival rate of the patients.
Guidelines has recommended preventive screening for different types of tumors, but it is more difficult to do it for sarcomas. The American Cancer Society (ACS) has also some guidelines for common types of cancer but not the sarcomas.
Most sarcomas confined or without too much expansion to other parts of the body, are commonly treated with a surgical treatment. Limb salvage (sparing) surgery is preferred to amputation at least in 90% of the extremities (arm or leg). Radiation therapy or chemotherapy can be administered before surgery (adjuvant Therapy) or after surgery (neo-adjuvant therapy) improving the prognosis for some patients with sarcomas. This form of treatment may last 6 months to a year.
Examples: After a Liposarcomas surgical resection, Adjuvant radiotherapy maybe used as well after the surgical excision of a Rhabdomyosarcoma. In the second group, studies have shown a survival rate 50-85%. In osteosarcoma, neoadjuvant chemotherapy is performed first after the surgical excision but radiation therapy has not always showed any improvement. Studies have presently shown promising outcome in childhood sarcomas presenting a receptor B7-H3 while Cyclophosphamide, a cytotoxic agent is used. This drug has shown good tumor efficacy.
On a prognosis point of view, the AJCC has identified several factors:
1- The size of the tumor: the larger, the worse is the prognosis.
2- The spreading to the soft tissue around locally worsens the prognosis.
3- The stage and the presence of metastasis to lymph nodes or other organs or tissues like the lungs worsens the prognosis as well
4- The higher the grade, the worse the diagnosis.
5- Tumor originating from the spine or pelvic bone carry also a poor prognosis. Compared to the one originating from the bones of the extremities.
6- Tumors that have metastasized, carry the worse prognosis.
The AJCC has recommended the use of the French Federation of Cancer Sarcoma Group (FNCLCC) Grading for soft tissue sarcomas with high grades which carry a worse prognosis compared to the low grade tumors The key factor to affect the prognosis is the mitotic rate referring to the fraction of cells that are actively dividing with high mitotic figures. The more mitotic figures, the worse the prognosis.
The National Cancer Institute (NCI) has published a 5-year survival for bone sarcomas of 66.9% based on 1660 people who died in 2019 from bone sarcomas (.3% of all Cancer rate death) with a median age of 61. Under the age of 20, 12.3% of bone sarcoma patient will die while 13.8% will show the same features in people between 20-34 increasing with age. Among the 55-65 age group and older there is a 13.5 % to 16.4% will die with bone sarcoma.
The overall 5-year survival for soft tissue sarcomas is 64.5 no matter the age. If the tumor has not spread beyond the primary site, the survival rate reaches 80%. If it spread to the lymph nodes the survival rate will decrease to 58% while if organs metastases are seen, it decreases further to 16.4%. It is estimated that 5270 people had died of soft tissue sarcoma in 2019 (.9% of all cancer death).
We have already discussed the way a spreading sarcoma which metastasized requires chemotherapy first. There are many side effects with such kind of treatment. Newer medications are being discovered with less toxicities than the actual agents to kill cancer cells. Immunotherapy anti-PDL1 or anti –CTLA4 etc. have been tried in the treatment of bone sarcomas. Other therapies like small-molecule targeted therapy, biologic agents, nanoparticle-directed therapy are being investigated also studied. Specific genetic and molecular factors causing sarcoma are also studied in the hope of helping in the prognosis. Finally, the presence of the H3-B3 immunoregulatory checkpoint receptors in the tumoral cells are also being tested in new drugs.
Time will tell with the discovery of more sophisticated drugs with less toxicity how we will be able to treat better Bone and soft tissues sarcomas.
Maxime J Coles MD (3-13-2020)
References:
1- Tobias J (2015). Cancer and its management, Seventh Edition. Chi-Chester, West Sussex, PO198SQ, UK: John Wiley & Son Ltd. P 446.
2- Amin MB (2017). AJCC Cancer Staging Manual. Eight Edition. Chicago, IL 60611 USA: Springer International Publishing AG Switzerland. pp. 471-548.
3- Vincent (2015). De Vita, Hellman and Rosenberg’s Cancer: Principles & Practices of Oncology. 19th Edition. Philadelphia, PA 19103, USA: Wolters Kluwer Health pp 1241-1313.
4- “Metastatic Cancer”. National Cancer Institute. 12 May 2015.
5- Unni KK 92010). Bone Tumors. Philadelphia, PA 19106: Lippincott William & Williams. pp. 1-8.
6- Buecker P (2005). “Sarcoma: A Diagnosis of Patience”. ESUN. 2(5). 15 April 2009.
7- Longhi A, Errani C, De Paolis M, Mercuri M, Bacci G. “Primary bone Osteosarcoma in the pediatric age: state of the art”. Cancer Treatment Reviews. 32 (6): 423-436.
8- “Rhabdomyosarcoma”. Boston Children’s Hospital.
9- Osteosarcoma Treatment & Management-Treatment at e-Medicine.
10- “Soft Tissue Cancer- Cancer Stat Facts”. SEER (March 2019).
11- AJ Willingham. “Scientists find cancer in million-year-old fossil. CNN 27 March 2019.
12- Thanindretam, Pichaya (2019). “advances in immune checkpoint inhibitors for bone sarcoma therapy”. Journal of Bone Oncology. 13.
13- Coles M, Smith M, Rankin E; “An Unusual Case of Dermatofibrosarcoma Protuberans”: Journal of Hand Surgery, January 1989; 14A, pp.135-138.