Soft tissue sarcoma

What a sarcoma is, and why it is not a carcinoma

Almost every cancer you know is a carcinoma: it arises from the lining of an organ, the layer of cells that covers the breast, the colon, the lung or the skin. A sarcoma arises from the other tissue, the supporting tissue — in a building, the beams rather than the walls. They are two different families, and they behave differently.

The first difference is how they travel. A carcinoma spreads mainly through the lymph nodes. A sarcoma almost never does: when it spreads, it goes through the blood, and the place it reaches most often is the lung. That is why lymph nodes are not removed routinely in a sarcoma, and why the chest is always imaged.

The second difference lies at the edge. A sarcoma appears to have a capsule, a wrapping that separates it from healthy tissue. It is not a capsule: it is healthy tissue flattened by the tumour, and it is infiltrated. A surgeon who follows that edge, “shelling out” the tumour, removes the wrapping and leaves cells behind. Almost everything that follows stems from that.

As for frequency, it is a rare cancer. In Europe between four and five cases are diagnosed per 100,000 people each year, around 1% of adult malignancies. And it is not one disease but many: the World Health Organization classification distinguishes more than seventy subtypes, each with its own behaviour. The commonest in adults are liposarcoma, leiomyosarcoma, undifferentiated pleomorphic sarcoma, myxofibrosarcoma and synovial sarcoma.

That variety has a practical consequence: the diagnosis under the microscope is difficult. In a European study of centralised sarcoma review, the initial diagnosis matched the expert pathologist's completely in little more than half of cases. That is why guidelines ask for the biopsy to be read, or reviewed, by a reference sarcoma pathologist.

Incidence and share of adult tumours: ESMO-EURACAN-GENTURIS soft tissue sarcoma guidelines (Gronchi et al., Annals of Oncology, 2021). Subtypes: WHO Classification of Soft Tissue and Bone Tumours, 5th edition (2020). Diagnostic concordance on centralised review: Ray-Coquard et al., Annals of Oncology, 2012.

The warning signs of a lump

The vast majority of lumps that appear under the skin are lipomas, cysts or other benign lesions. A typical lipoma is soft, sits just beneath the skin, moves under the fingers and has been the same for years. That lump is not the problem. The problem is the one that does not look like it.

UK guidance sums up the warning signs in a rule that is easy to remember, the golf ball rule: any soft tissue lump with one of these features should be imaged before anyone touches it.

• It measures more than five centimetres — the size of a golf ball.
• It is deep: it lies beneath the fascia, the sheet that wraps the muscle, and does not move with the skin.
• It is growing, however slowly.
• It is painful, or has started to hurt with no injury to explain it.
• It has come back in the same place after being removed.

Golf ball referral rule: UK guidelines for the management of soft tissue sarcomas (Grimer et al., Sarcoma, 2010) and NICE urgent referral recommendations (NG12).

How it is diagnosed: imaging first, needle second, scalpel never

The order matters, and it is always the same. Imaging first: contrast-enhanced MRI for lumps in the arms, legs and trunk, and CT when the tumour sits in the abdominal wall or the pelvis. The same CT extends to the chest, because that is where distant disease has to be looked for before anything is decided.

Then the biopsy, and here is the rule that is hardest to keep: it is an image-guided core needle biopsy, taking several cores, through a track chosen by the surgeon who will operate. The reason is physical: the needle leaves a path containing tumour cells, and that path is removed later together with the tumour, in the same specimen. If the needle goes in where it should not, the path falls outside the plan.

What is not done is to open up and remove the lump to see what it is. An open biopsy, or excision “to have it analysed”, of a deep mass or one over five centimetres breaks the edge, contaminates the neighbouring planes and turns a clean operation into a large re-operation. Nor is fine needle aspiration enough: it yields loose cells, and a sarcoma is diagnosed by the architecture of the tissue and its genetics, not by the isolated cell.

With the biopsy in hand, the report will say two more things worth understanding. The grade, from 1 to 3, measures how aggressive the tumour is under the microscope, adding up how closely it resembles normal tissue, how many cells are dividing and how much necrosis there is; it is the factor that weighs most in predicting metastasis. The stage, under the current international classification, is based above all on size: up to five centimetres, five to ten, ten to fifteen and over fifteen, combined with the grade and with whether or not there is distant disease.

Diagnostic sequence, core needle biopsy and expert pathology review: ESMO-EURACAN-GENTURIS guidelines (2021) and NCCN soft tissue sarcoma guidelines. Grading system: Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC). Staging: AJCC Cancer Staging Manual, 8th edition (2017).

The operation: wide margins and a preserved limb

Surgery is the treatment that cures a localised sarcoma, and its principle comes down to two words: en bloc. The tumour is removed whole, unopened, with a cuff of healthy tissue around it or an intact anatomical barrier — the fascia or the periosteum — between the tumour and the edge of the specimen. That is called an R0 resection: the pathologist finds no tumour cells at the margin.

What is not done is what seems most logical: following the edge of the tumour and lifting it cleanly out of its surroundings. That edge, as said above, is infiltrated. An operation that respects it leaves microscopic disease behind and multiplies the chance of the tumour coming back in the same place.

In the arms and legs, the question everyone dreads now has a clear answer: in more than 90% of cases the limb is preserved. Limb-sparing surgery combined with radiotherapy gives the same survival as amputation, something shown in a randomised trial more than forty years ago, and since then amputation has been reserved for cases where the tumour encases the vessels, the nerves and the bone at once, or where the limb that remained would be of no use.

Preserving the limb often means reconstructing what is removed. That is why reconstruction is planned from the start, together with the resection rather than after it, and why for sarcomas of the abdominal wall, the trunk and the pelvis it is worth being operated on by a surgical oncologist used to resecting the wall in its full thickness, to working in the pelvis alongside the vessels and viscera, and to reconstructing with mesh and flaps what has been taken.

En-bloc resection and R0 margin principles: ESMO-EURACAN-GENTURIS guidelines (2021). Survival equivalence of limb-sparing surgery with radiotherapy and amputation: National Cancer Institute randomised trial (Rosenberg et al., Annals of Surgery, 1982). Proportion of limb-sparing surgery: NCCN soft tissue sarcoma guidelines.

Radiotherapy and chemotherapy: for whom

Radiotherapy accompanies surgery in most sarcomas that are high grade, deep or larger than five centimetres, because it reduces local recurrence. The question left open for years was when to give it, before or after the operation, and a Canadian trial that compared the two answered it.

The result was that local control is the same with either strategy, and that what changes is the kind of problem each causes. Giving it before the operation increases wound complications, which occurred in 35% of patients compared with 17% with postoperative radiotherapy; giving it afterwards means irradiating a larger volume at a higher dose, and leaves more fibrosis, more joint stiffness and more swelling in the long term. Many sarcoma units prefer preoperative radiotherapy when the function of the limb is at stake, and the decision is made case by case at the board.

Chemotherapy is not part of standard treatment for most localised sarcomas. It is considered in selected patients with high-risk tumours — large, deep and high grade — and in subtypes that respond to the drugs. The Italian trial that tried to tailor the regimen to each subtype did not manage to beat the standard anthracycline and ifosfamide regimen, and that remains the one used when chemotherapy is used at all. The benefit is real but modest, which is why it is discussed one case at a time at the board rather than offered to everyone.

Preoperative versus postoperative radiotherapy: NCIC SR2 trial (O'Sullivan et al., Lancet, 2002; 190 patients), with long-term functional follow-up in Davis et al. (Radiotherapy and Oncology, 2005). Histotype-tailored neoadjuvant chemotherapy: ISG-STS 1001 (Gronchi et al., Lancet Oncology, 2017). Indications: ESMO-EURACAN-GENTURIS guidelines (2021).

“Whoops surgery”: when the lump was removed without knowing what it was

It is the commonest situation in a sarcoma clinic, and it has a name of its own in the medical literature: whoops surgery, after the exclamation of whoever receives the report. A lump that looked like a lipoma or a cyst was removed, without prior imaging and without a biopsy, and the pathologist says sarcoma.

There are two things worth knowing. The first is that, even when the report says the lump came out whole, in most cases it did not: when the bed of one of these excisions is re-operated and what is removed is examined, residual tumour is found in a high proportion of specimens — in many series around half. What was removed was the wrapping with the tumour inside; the cells that remain are at the edge, along the drain track and in the scar.

The second is that it can be put right, and that putting it right is a planned operation: an MRI of the surgical bed, review of the pathology by a sarcoma pathologist, imaging of the chest, and then an en-bloc re-excision of the whole bed, scar and drain sites included, almost always with radiotherapy. Done that way, in a reference centre, re-excision recovers results close to those of surgery planned properly from the start. The cost is a bigger operation, often with reconstruction, that an ultrasound and a needle would have avoided.

Management of unplanned excision and residual tumour at re-excision: ESMO-EURACAN-GENTURIS guidelines (2021) and institutional series summarised in the NCCN soft tissue sarcoma guidelines.

Why where you are treated changes the outcome

In a common cancer the hospital matters little: the pathways are built and everyone has walked them hundreds of times. In a sarcoma it is the other way round. A general surgeon sees a handful in a whole career; a sarcoma unit sees them every week. That difference can be measured, and it has been.

From 2010 France organised a national network of sarcoma reference centres, NETSARC, and registered every patient in the country. Those presented to a multidisciplinary sarcoma board before their first treatment were more likely to receive the treatment guidelines recommend, had fewer re-operations and had better relapse-free survival. And those operated on in one of those centres, compared with those operated on outside the network, had fewer local recurrences and better overall survival.

That is why European guidelines ask for every sarcoma to be treated, from the biopsy onwards, in a reference centre, and why networks exist for it: CSUR in Spain and EURACAN across Europe. At Hospital General Universitario Gregorio Marañón sarcomas are treated within that programme and by a multidisciplinary sarcoma board, with surgical oncology, medical oncology, radiation oncology, radiology and pathology.

Effect of a multidisciplinary board before first treatment: NETSARC network (Blay et al., Annals of Oncology, 2017). Effect of surgery in a reference centre on local recurrence and survival: Blay et al., Annals of Oncology, 2019. Reference-centre treatment recommendation: ESMO-EURACAN-GENTURIS guidelines (2021).

GIST and desmoid tumours: two relatives with rules of their own

GIST, the gastrointestinal stromal tumour, is the commonest sarcoma of the digestive tract. It arises from the cells that set the rhythm of the stomach's and bowel's movements, and in most cases it does so through a mutation in a specific gene, KIT or PDGFRA. That made it the first sarcoma with a targeted treatment: imatinib, which blocks that mutation and transformed the prognosis of advanced disease.

Its surgery has three rules of its own. Lymph nodes are not removed, because GIST almost never spreads through them. It is taken out whole, with its wrapping intact, because rupturing it during the operation seeds the abdomen and automatically places the patient in the high-risk group. And after surgery, in tumours at high risk of relapse, imatinib is given for three years, which is what was shown to prolong survival compared with one year. Small gastric GISTs, under two centimetres, can be watched without surgery.

A desmoid tumour is something else. It is not a cancer: it does not metastasise and does not kill by spreading. But it infiltrates locally, sometimes grows quickly and can come back again and again after surgery. It appears in the abdominal wall, often after a pregnancy, in the limbs and in the mesentery, and in that last case familial polyposis should be ruled out.

Its treatment has turned around in ten years. For decades it was operated on straight away, and watched come back. Today international consensus recommends starting with active surveillance: observing with imaging, because a considerable share of desmoids stops or shrinks on its own. Only if the tumour progresses or causes symptoms does treatment begin, which may be medical, with oral drugs, or surgical in favourable sites such as the abdominal wall. Surgery is no longer the first step.

GIST: ESMO-EURACAN-GENTURIS GIST guidelines (Casali et al., Annals of Oncology, 2022); three years versus one year of adjuvant imatinib: SSG XVIII trial (Joensuu et al., JAMA, 2012). Desmoid tumour: Desmoid Tumor Working Group global consensus (European Journal of Cancer, 2020).

Follow-up, and when a second opinion changes decisions

A sarcoma comes back in two ways: in the same place, or in the lung. Follow-up is organised to look for both, with an examination and imaging of the operated site when needed, and with a periodic chest X-ray or CT. In high-grade tumours visits are every three to four months for the first two to three years, then every six months to year five, then once a year; in low-grade tumours, every four to six months for the first years and then annually.

Metastases appearing in the lung do not close the door. When they are few and slow-growing, they are operated on, and a share of those patients lives for many years. A local recurrence is also re-operated in most cases.

As for a second opinion, there are four moments when it changes most. Before the first operation, when everything can still be planned. When a lump has already been removed and the report says sarcoma. When an amputation is proposed. And when you have been told there is nothing to be done about a recurrence or lung metastases. To ask for one you need the imaging in digital form — the full study, not the report — the pathology, and the operative note from any previous surgery.

None of the above replaces a consultation. Subtype, grade, size, location and your general condition decide the plan, and none of the five can be read off a screen. If the tumour is in the retroperitoneum, behind the abdomen, the rules change enough for it to have its own page, linked below.

Follow-up schedule and management of recurrence: ESMO-EURACAN-GENTURIS soft tissue sarcoma guidelines (2021).