by

John M. Goldberg, MD and Karen Albritton, MD

Dana-Farber Cancer Institute

Children’s Hospital, Boston

Introduction

This article discusses two very rare soft tissue sarcomas, clear cell sarcoma and alveolar soft part sarcoma. Although distinct and unrelated subtypes of sarcoma, they have several characteristics that lead us to consider them in tandem. They each are very rare and often defy classification with other soft tissue sarcomas. They each have a characteristic chromosomal translocation that is felt to be critical to its cancerous growth. They each have a high rate of metastasis and a propensity to recur years after the initial diagnosis. Beyond discussing their distinct clinical presentation, treatment, prognosis and the genetic events thought to be important to each tumor, this article will then explore why some investigators propose that they may have a molecular similarity that could serve as a target for treatment. A vaccine trial under development for tumors having these genetic changes is described.

What is Clear Cell Sarcoma?

Clear cell sarcoma (CCS), also known as melanoma of soft parts or melanoma of tendons and aponeuroses, is a very rare malignant soft tissue tumor that affects all age ranges, including young adults and children. Tendons and aponeuroses connect muscles to bones, and this tumor often arises in those structures. It tends to present as a mass in the lower extremities, usually occurs in the limbs, particularly around the ankles. There are usually few symptoms until the lesion becomes large enough to cause localized pain. At times, the presenting lesion is close enough to the surface of the skin for patients to notice it early on, but generally it is not (Weis and Goldblum 2001).

CCS is at times pigmented, like melanoma, and under the microscope has an appearance that is similar to melanoma (Weis and Goldblum 2001). While melanoma is a tumor derived from pigmented cells, CCS seems to “copy” the appearance of melanoma because of a specific genetic change that makes it a melanoma-mimic. CCS does not usually start in the skin like melanoma, either, so it can often be distinguished from melanoma based on clinical presentation and by the test for the translocation associated with the diagnosis, described below.

CCS can metastasize (spread) throughout the body; like other soft tissue sarcomas (STS), it commonly spreads to the lungs. More so than other STS, it sometimes spreads to the lymph nodes surrounding the original site of the tumor. Like other sarcomas, the best chance to cure CCS is by cutting it all out surgically, although local or distant recurrences may still occur. CCS does grow more slowly than some other cancers, despite the fact that it is malignant and will spread if untreated (Weis and Goldblum 2001).

What is Alveolar Soft Part Sarcoma?

Alveolar soft part sarcoma (ASPS) is a very rare, slow growing, highly angiogenic (vessel-forming) tumor that can occur in any age group. It is most frequently found in young adults and teenagers and often begins in the lower extremities (Lieberman, Brennan et al, 1989). A recent analysis of the MD Anderson Cancer Center’s institutional database, which may over represent incidence as a tertiary care center for rare tumors, estimated 90 total new cases of ASPS in the United States in 2004; it predicted that about half of the patients would fall between the ages of 15 and 29 years (Herzog 2005). A query of the SEER database shows 42 cases diagnosed in the 11 SEER registries (representing approximately 15% of the US population) between 1992 and 1999, or a rate of 0.134 cases per million per year, which would estimate about 41 cases per year in the U.S. Likewise, about half of SEER cases were in patients 15 to 29 years old.

Most patients with ASPS probably have had the cancer for some time before they come to medical attention. The reason is that the tumor grows so slowly that it at first causes few symptoms and does not form a large mass. By the time the tumor is big enough that the patient feels a lump from the primary lesion and seeks out a physician for help, the tumor has frequently spread, establishing small metastatic colonies throughout the body, frequently found in the lungs and even the brain. It grows even more slowly than CCS, but is definitely a malignant tumor that tends to spread inexorably if not completely removed by surgery. Many patients can live with disease for years and even decades (Pappo, Parham et al. 1996). Although most patients with ASPS can never be rid of their cancer completely, many can undergo repeated surgery over the years to keep it somewhat at bay (Weis and Goldblum 2001).

Pathology—What do CCS and ASPS Look Like under the Microscope?

CCS tends to look similar to melanoma under the microscope. Described by Enzinger in 1965, CCS gets its name from an abundant material (glycogen) found within the cells that does not stain with conventional pathological tests and hence appears to leave “clear” spaces within the cells (Enzinger 1965; Weis and Goldblum 2001). At times, the defining translocation between chromosomes 12 and 22 can be detected based on routine cytogenetic evaluation, a technique whereby the pathologist can look at the individual chromosomes to determine if there is translocation between them.

ASPS gets the “alveolar” part of its name from the arrangement of cells seen under the microscope by the pathologist (Weis and Goldblum 2001). Alveoli are a small air sacks deep within the lung where oxygen is absorbed into the body, and this cancer has an appearance similar to these air sacks. On gross pathological inspection, meaning on visual inspection without the aid of a microscope, of the tumor after it has been cut out, ASPS has numerous blood vessels, reflecting its angiogenic nature. The increased blood flow can even cause an audible noise from blood rushing through the tumor—known in medical terms as a bruit (Pappo, Parham et al. 1996). They must be distinguished from vascular malformations (collections of blood vessels that have grown out of control but they are generally not malignant and will not spread like ASPS).

Radiology—What do CSS and ASPS Look Like on Scans?

Both CCS and ASPS appear to be solid, soft tissue masses on radiological exam.If there is erosion of underlying bone (as sometimes occurs with ASPS) or a rare bony metastasis a nuclear medicine bone scan might be positive. They generally do not have extensive calcifications in them.. The extensive blood supply of ASPS can sometimes be appreciated on CT scan as well, since most CT scans done to find cancer use radiological intravenous dye that will light up the blood vessels feeding the tumor as it passes through them (Pang, Roebuck et al. 2001), Lung metastases for both diseases tend to appear similar to the lung metastases of other sarcomas-they are small, round opacities easily seen on chest CT. In Figure 3, we see some of the lung metastases associated with ASPS. These lesions have remained stable despite being followed for more than a year and despite therapy.

Figure 1: ASPS demonstrating polygonal cells with clear or finely stipples eosinophilic cytoplasm. We see that ASPS has lobular architecture wiht pseudo-membrane surrounding nests of cell, reminiscent of the structure of the alveolus of the lung.

Figure 2: We see that ASPS cells are filled with a PAS positive material. This reflects glycogen, just as the clear appearance of CCS on routine histology does. While essentially all samples of this cancer stained with PAS show this material, investigators still do not completely understand what the role of this material in cancer might be.

Figure 3:  We see the lung metastases associated with a case of ASPS. The lesions have grown very little over time, and yet have not responded to therapy.

Initial Work Up

The initial staging for any sarcoma should include adequate evaluation of the site of disease – in other words, usually a CT scan or MRI of the body part where the tumor originated. This should be followed by thorough evaluation of the lungs for evidence of disease spread there. Generally a CT of the lungs will suffice. Nuclear medicine scans such as bone scans or PET scans may be positive at sites of disease that would otherwise go undetected, and are probably a good idea to perform at initial work up, although their utility as screening for otherwise undetected disease has not been proven. A brain MRI or CT should be considered in patients diagnosed with ASPS to rule out brain metastases; selective use is important in patients with neurologic symptoms or other systemic metastases

Treatment and Prognosis

CCS typically presents with involvement of the extremities and has a poor long-term prognosis if not fully surgically resected at diagnosis, with a 54% 5 year survival rate for all patients, 33% for patients with metastatic disease at diagnosis(Deenik, Mooi et al. 1999), despite a variety of treatments. Currently, for patients with metastases at diagnosis, the ability to completely cure patients of this slow moving cancer is poor. However, patients who are able to undergo surgical removal of their disease tend to do well, and one series by surgeons in the Netherlands described excellent outcomes in a group of patients who were able to undergo full resection at diagnosis (Kuiper, Hoekstra et al. 2003). Radiation may have a role in palliation of local disease when CCS cannot be fully resected, but is generally not an effective cure for soft tissue sarcomas (Spunt, Poquette et al. 1999; Paulino, Ritchie et al. 2004). Chemotherapy used for other STS (such as Ifosfamide and Doxorubicin) is relatively ineffective against CCS; some oncologists advocate using melanoma-type chemotherapy (such drugs as dacarbazine, cisplatin, carmustine and taxanes)

The prognosis of ASPS is most influenced by its stage. For patients with tumors that are localized at diagnosis, 87% will remain alive five years later; only 20% of those with metastases at diagnosis will live five years (Portera, Pisters, et al, 2001). However, even patients with metastases can have indolent courses, and are likely to have a longer life expectancy than a patient with comparable extent of another soft tissue sarcoma.

Most series reported also suggest that ASPS does not respond to chemotherapy, and that surgical therapy should be the mainstay of therapy and is associated with a chance for a long term survival (Pappo, Parham et al. 1996; van Ruth, van Coevorden et al. 2002). Surgical resection of progressive metastases—even scores of lung metastases—should be considered on a case by case basis. Some studies suggest that, particularly in adults, for tumors that cannot be completely resected but do not have evidence of spread beyond the local area where they have occurred, radiation therapy to the tumor bed may be associated with a lower chance for recurrence (Sherman, Vavilala et al. 1994). As children may have a better chance for cure with aggressive surgery and are more likely to suffer from growth disturbance or second malignancies after radiation therapy, the indications for radiation therapy in the child with locally unresectable but non-metastatic disease are not so clear (Pappo, Parham et al. 1996). While there have been no formal studies regarding the use of anti-angiogenic agents in the treatment of patients with ASPS, the well characterized ability of this slow growing tumor to both mimic vascular malformations on clinical exam and control blood flow pathologically suggest that blocking the blood supply of this tumor may result in tumor shrinkage.

As stated above, many oncologists have tried standard sarcoma therapies to treat CCS and ASPS without consistent success (Auerbach and Brooks 1987). There are occasional reports of a response to interferon in ASPS patients. Interferon is a cytokine that may act to inhibit blood vessel formation in tumors but may also act to recruit the immune system to attack the tumor (Kuriyama, Todo et al. 2001; Roozendaal, de Valk et al. 2003). Another possible approach to therapy for these tumors is to block angiogenesis, or new blood vessel formation.

Follow Up

Patients treated for CCS and for ASPS should be followed for many years by an experienced oncologist, both for the risk of recurrence and for the risk of side effects from therapy. Even many years out from diagnosis and even in the cases where surgery has rendered the patient apparently “disease free”, these indolent cancers can recur or grow for decades, distinctly longer than the risk period of most other soft tissue sarcomas. This is particularly true for ASPS. Because late recurrences can occur, and recurrences can be treated with further benefit, long term follow-up including evaluation of the original sites of disease and the lungs is advisable. The individual recommendations for the schedule and type of surveillance scans will vary according to the patient and should consider the small but not negligible risks of repeated exposure to radiation. While there are few treatments that are curative for these tumors if they come back, it is possible that future recurrences will be amenable to surgery and it is also possible that research will uncover new therapies in the future to treat a recurrence.

Laboratory Research and Potential Therapies

Several researchers are pursuing specific therapies based on translocations, following the premise that sarcomas are addicted to their translocations because they do not seem to have the great number of second genetic mutations that carcinomas have. One group showed that they could make the EWS-ATF1 translocation of CCS into an immune stimulant (Worley, van den Broeke et al. 2001).

As described above in “What is Clear Cell Sarcoma”, expression profiling for CCS reveals that it has many activated genes in common with melanoma, regardless of whether or not MITF activity, ATF1 activity, or the activity of another transcription factor called SOX10 is more important in driving the growth of the actual cancer (Segal, Pavlidis et al. 2003). Unfortunately, melanoma is a cancer that is also somewhat resistant to treatment, so there are no melanoma-specific weaknesses to exploit in CCS yet aside from immunotherapy or biochemotherapy, which are described for melanoma below. It is possible that what will help someday to cure melanoma may also work to cure CCS. The microarray analysis conducted by Segal et al compared CCS, melanoma and other soft tissue sarcomas, and found that CCS was more like melanoma than it was like other sarcomas.

One interesting new finding demonstrated upon a second microarray analysis performed on CCS is the increased activity of the tyrosine kinase ERBB3 in CCS (Schaefer, Brachwitz et al. 2004). Tyrosine kinases are molecular switches in cells that can be used by cancer cells to turn on inappropriately. EGFR, also known as ERBB1, is a tyrosine kinase that is similar to ERBB3 and has been shown to be the target of successful therapy with gefitinib in certain cases of lung cancer (Lynch, Bell et al. 2004). It is possible that a way will be found to inhibit ERBB3 in CCS in the future. The increased activity of the gene for ERBB3 was found by analyzing microarrays of CCS samples – this is a method for looking at tens of thousands of genes at a time to see if any unexpected ones appear to be very important to the cancer. Treating this tumor by the inhibition of ERBB3 might be very non-toxic, but it is still a ways away.

No cell lines (tumor cells taken out of the body that continue to grow in a laboratory) currently exist for ASPS, making research with this tumor quite difficult to perform. Investigators must deduce important biology of the tumor through pathology staining, microarray analysis that cannot be confirmed in a live system (i.e. it can only be done on dead tumor tissue carefully frozen after surgery) and other methods based more on observation than experimentation.

What are MITF and TFE3 and Why Might They Control Useful Targets in Treating CCS AND ASPS?

MITF and TFE3 are two related genes that are found to be abnormal in CCS and ASPS. MITF stands for Microphthalmia (small eye) Associated Transcription Factor, so named since mice missing this gene have very small eyes. It is a transcription factor that controls pigmentation, proliferation and differentiation of normal melanocytes. Melanocytes are the pigmented cells that give color to skin by secreting different kinds of melanin, the pigment found in human skin. The function of transcription factors like MITF is to turn on other genes by allowing their genetic code to be read by the cell to make a specific protein. Thus, the MITF gene causes other genes to become active and make other proteins; in melanocytes, these other genes lead to the creation of melanin. MITF is also thought to be essential to the survival of melanoma cells (Widlund and Fisher 2003). In one study, all melanoma samples tested have some level of MITF, which likely reflects the fact that MITF is a normal gene for melanocytes, the cells from which melanoma originates (Granter, Weilbaecher et al. 2002). However, MITF and TFE3 are not normal genes in CCS and ASPS, or at least, they do not function normally.

These cancers have “dysregulation” of genes through translocation. Translocations occur when one piece of a chromosome breaks off and becomes stuck to another chromosome. This disrupts genes, turning off important “anti-growth” or tumor suppressor genes in some cases and turning on important “pro-growth” genes, also called oncogenes, in other cases. All genes have “promoters” and other regulatory elements that allow the cell to switch them “on” and “off” at the appropriate time. Translocations are probably important in the early development of these tumors because they can disrupt the regulatory elements that the cell normally uses to control genes. They are an important class of genetic events that can lead to cancer (Hanahan and Weinberg 2000). In ASPS, the ASPL gene from chromosome 17 is stuck to the TFE3 gene on the X chromosome and interrupts the part of the genetic code that controls TFE3 (Ladanyi, Lui et al. 2001). Some feel that this will lead TFE3 to be dysregulated. This is similar to the dysregulation of c-Myc in Burkitt’s lymphoma, in which a cell that is supposed to make antibodies for the immune system instead tells itself to make more Myc, which leads to cancer by turning on too many genes.

In CCS, a translocation in a different gene turns on MITF inappropriately, probably disrupting its regulation, leading the cells of the tumor to look somewhat like melanoma. While MITF is quite normal in melanocytes, cancer cells may be able to take advantage of its important role in making pigment and turning it instead towards making more cancer cells. Because MITF also causes pigment cells to produce melanin, its activity in CCS sometimes can even cause it to make melanin itself. CCS may be using MITF to be stronger, but it is entirely possible that the translocation of CCS, described above, turns on MITF and that this has little importance for the growth of the cancer other than to make the tumor appear similar to a melanoma under the microscope. Investigators who think that MITF is critical to the growth of CCS are exploring ways to attack MITF pathways in the cancer cells to treat the tumor.

Some of the pigment related proteins driven by MITF in melanoma cells can become targets for the immune system after patients are given vaccination or other treatments to stimulate an attack on their cancer (Du, Miller et al. 2003; Miller, Du et al. 2004). These genes, thought of as “differentiation antigens” or proteins associated specifically with melanocytes, include tyrp-1, tryp-2, MART-1, are all genes either proven or hypothesized to be controlled by MITF. Thus, the activity of MITF to upregulate these genes could lead to the upregulation of genes in other tumor types that will be susceptible to immune attack. While these genes make proteins that are not abnormal in melanocytes, something about the context of these genes in melanoma causes them to be seen by the immune system as abnormal and causes some destruction of the melanoma cells. Obviously, this is not enough to make malignant melanoma disappear, as very little seems to stop melanoma once it takes over, but there are clearly rare melanoma patients in whom stimulation of the immune system has led to disease shrinkage (Rosenberg, Yang et al. 2004). In fact, the response rate on this large review of immunotherapy trials was quite low over all.

It is hoped that the slow growing nature of both CCS and ASPS suggest that the immune system may be able to destroy these cancers since it is often thought that most cancers grow too fast for the immune system to mount an effective attack against them. While it is a hypothesis to say that patients with CCS and ASPS will respond to a vaccine strategy that was designed for melanoma, we believe that immune therapy may offer a new type of treatment for these patients. This treatment strategy has been associated with low toxicity for the melanoma patients to whom it has been administered in the past.

Biochemotherapy and Immunotherapy in Melanoma and CCS

There is convincing evidence that malignant melanoma frequently stimulates the immune system to respond to it—both by making new antibodies or anti-tumor proteins and by making T-cells that hunt down and recognize the tumor cells, bringing the rest of the immune system with them when they find their target (Sahin, Tureci et al. 1995; Chen, Gure et al. 1998; Old and Chen 1998). This works because cancer cells may have the wrong kind of proteins on the outside surface of their membranes—sometimes these are proteins that are actually mutated, and sometimes they are just not appropriate proteins to have on the cell. T-cells and antibodies directed against the melanoma can be detected in the blood of many patients (Anichini, Mortarini et al. 1996; Boon and van der Bruggen 1996; Romero, Dunbar et al. 1998; Jäger, Nagata et al. 2000; Zeng, Wang et al. 2001). Patients found to have T-cells attacking their melanoma do better and are less likely to have their cancer come back after surgery (Clark, Elder et al. 1989; Clemente, Mihm et al. 1996). However, most patients with melanoma that has spread still do poorly, despite all the evidence that the immune system is working in melanoma. The understanding that tumor cells stimulate poor antigen presentation—i.e. the abnormal proteins are not targeted effectively by the immune system - despite the naturally occurring phenomenon of anti-melanoma immunity, has motivated the design of several new strategies to increase anti-tumor immunity. Such strategies, reviewed in the three references cited below, include giving the patient immune cells designed to attack their tumor, vaccination with proteins derived from the melanoma, high-dose chemotherapy administered at the same time as immune stimulators, various combinations of these therapies, and whole tumor cell vaccines manipulated to become good vaccines after resection. While objective response rates have been low in Stage IV melanoma, there have been some surprising responses associated with some of these therapies, and some patients have had unexpectedly long survival when treated with tumor cell vaccines, despite the fact that their tumors did not shrink (Mach and Dranoff 2000; Jäger, Jäger et al. 2002; Rosenberg, Yang et al. 2004). Whole tumor vaccines are the kind of immunotherapy described in the next section that is being explored for CCS and ASPS now.

There is also evidence that CCS can be modulated therapeutically by the immune system, or at least treated in a manner that is similar to melanoma. An adult patient who had CCS with lymph node metastases was treated with intralesional injections of interferon to her primary tumor in her ankle. Interferon is a naturally occurring cytokine; cytokines are small hormones that stimulate the immune system and cause other responses that destroy tumors and pathogens. This patient went into an apparent remission for 17 months. Interferon may have acted to recruit the immune system to her major sites of disease, namely the ankle and the lymph node in her groin (Steger, Wrba et al. 1991). A 57 year old man obtained a 17 month remission after subcutaneous interferon was given co-temporaneously with cytotoxic chemotherapy (Lauro, Bordin et al. 1999). This is similar to “biochemotherapy”, a strategy in which patients with metastatic melanoma are given high doses of chemotherapy along with a cytokine, such as interleukin-2, that stimulates the immune system. These therapies do seem to make melanoma shrink in many patients, but generally do not seem to result in greater overall survival for patients with melanoma (Eigentler, Caroli et al. 2003). The discovery of tumor specific immune cells from a sample taken from a 14-year-old girl with CCS has also been reported (Liao, Perng et al. 1996). This natural phenomenon supports the notion that manipulation of the immune response for CCS may have therapeutic potential because it is quite similar to melanoma, in which tumor specific immune cells are frequently found inside the tumors.

GM-CSF Secreting Autologous Tumor Cell Vaccines

In an effort to harness the immune response against melanoma for therapeutic purposes, investigators at the Dana-Farber Cancer Institute have been developing GM-CSF secreting autologous tumor cell vaccines. These vaccines are created by taking a piece of tumor removed during surgery, breaking the tumor up into single cells in a special laboratory and then treating the cells to make a vaccine that will stimulate the immune system to attack other tumors when the vaccine is given back to the patient. The treatment of the cells in the laboratory includes using adenoviral mediated gene transfer, which adds a new gene to the cancer cells. Adenoviruses are common respiratory pathogens and can cause illnesses similar to a cold in normal people. In the laboratory, researchers can trick adenovirus into carrying a helpful gene while losing its ability to cause an illness. The gene that is transferred to make the vaccine is GM-CSF, a powerful cytokine that stimulates the immune system. The cells are then given enough radiation so that they will never grow when given back to the patient, but not enough to completely destroy them. They are then injected into the patient on a regular schedule. The actual injections are like childhood vaccinations that go under the skin or into the muscle. It is hoped that the cancer cells that have been made to secrete the hormone GM-CSF will cause the immune system to attack the cancer in other parts of the body.

This vaccine will be used to treat patients with CCS, ASPS, pediatric renal carcinoma and children with melanoma in the near future at the Dana-Farber Cancer Institute, but it is not yet available. Children with melanoma have been studied with interferon, as two pediatric oncology groups recently published experiences using interferon, but few trials include Stage IV pediatric patients (Chao, Schwartz et al. 2004; Navid, Furman et al. 2005). While GM-CSF secreting vaccines are not proven to cure patients with advanced melanoma, they tend to have little toxicity and may be safe in patients with CCS and ASPS. An additional hurdle in treating patients with this vaccine strategy is that they must go to the treatment center where the vaccine is being offered to undergo surgery, and then remain there to receive their vaccinations. This hurdle is comparable to that for most pediatric oncology protocols and protocols for rare sarcomas, which are not widely available and generally require patients to go to large cancer centers for treatment.

Conclusion

CCS and ASPS are two odd, slow growing soft tissue cancers for which there are few effective therapies besides surgical resection. They both have genetic aberrations involving related transcription factors, and thus may share the same strengths and, hopefully, vulnerabilities to therapy. This may include shared biology with melanoma, as they share with melanoma the activity of MITF and MITF related genes. It is possible that new strategies to treat these tumors will include immunotherapy designed originally to treat melanoma. For more information on ASPS, please refer to the website for The Alliance Against Alveolar Soft Part Sarcoma (TAAASPS). TAAASPS will also maintain updated information about any trials related to alveolar soft part sarcoma, including the vaccine protocol under development at the Dana-Farber Cancer Institute and other novel treatment strategies elsewhere.

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