Value of radiotherapy for tumour on the bronchial stump after resection for bronchial carcinoma.

Two groups have been selected from 1000 patients who had lobectomy or pneumonectomy for bronchial carcinoma. The first group was of 26 patients with tumour affecting the mucosa of the resected bronchial margin reported histologically at the time of surgery. Twelve of these were given postoperative radiotherapy but with no apparent benefit, either in the incidence of recurrence of tumour at the bronchial stump or in five-year survival. The second group was of 17 patients who developed recurrence of tumour at the bronchial stump, bronchoscopically confirmed, some time after surgery. In six of these cases the recurrence was detected while it was confined to the bronchial stump region, and these patients were then given radiotherapy. Five of the six survived five years after radiotherapy, with complete eradication of the tumour recurrence confirmed by repeat bronchoscopy. In 11 cases the tumour recurrence was not detected until it had become more extensive. Radiotherapy may also have prolonged survival in some of these patients, although none survived five years.     

Vertebral metastasis from malignant degeneration of urethro-perineal fistula. A case report

Adenocarcinoma mucinusum of the anal canal is a rare tumour, which may appear as a fistula. The fistula has an effect on quality of life and besides it may lead to tumour formation. Early recognition and regular check-up are important, and early operation is recommended. Early surgical excision combined with chemo- and radiotherapy may be effective, with 5 year recurrence rate lower than 37%. The prognosis of late treatment is poor with 1 year average survival. Our case report presents evidence that the key to successful therapy and improved quality of life is early diagnosis and combined surgical-oncological treatment.     

Desmoid tumor of rectus muscle of abdomen in a woman of childbearing age: what can we do?

The desmoid tumor (DT) is a soft tissue neoplasm most frequently localized in the anterior abdominal wall typically in females of childbearing age. Because its particular incidence in women who had recently been pregnant, it was correlated with delivery's trauma stimulating proliferation of muscolo-aponeurotic tissues. Complete surgical resection is the recommended treatment approach to prevent recurrence. Many authors emphasize the role of radiotherapy in regression of DT and in controlling local recurrence in patient who had incomplete resection. Many others emphasize the role of chemotherapy or antiestrogenic compounds, even though tumour does not express estrogen receptors. DT, otherwise, is neoplasm with high rates of recurrence after surgery but it never develops distant metastases, so that function and structure-sparing surgery may be a reasonable choice in young women when possible without leaving macroscopic residual disease. Furthermore literature data suggest that the presence of incomplete histological surgical resection does not correlate with local recurrence and that pregnancy does not represent a risk factor. In women of childbearing age, even after non radical histological DT primary resection, adjunctive radiotherapy, chemotherapy or antiestrogen therapy could be avoided and clinical observation alone may be considered.     

Treatment of medulloblastoma in children: Long-term results following surgery,radiotherapy and chemotherapy

Summary Forty-seven children with histologically confirmed medulloblastoma are considered. Forty-five cases were surgically treated by direct approach to the tumour, while two cases were treated only with a shunt. A shunt was inserted preoperatively in 14 cases, postoperatively in 4 cases. Surgical resection was total or subtotal in 52% of cases, partial in 35%, and limited to a biopsy in 13%. Radiation treatment to the entire neuraxis was done in 37 cases: 10 of these cases received additional chemotherapy—mostly with CCNU—as primary treatment for medulloblastoma.Ten patients died within 30 days after surgery. Twenty-two patients died months after treatment, mainly from tumour recurrence (19 cases). One patient was lost to follow-up. Thirteen patients are survivors from 10 months to 20 years after treatment. As a whole, the one year survival rate has been 67%, 3 year survival 43%, and 5 year survival 27%. Complications affecting prognosis have been presented by tumour recurrence and metastases. CSF shunting and lack of prophylactic irradiation to the cerebral hemispheres have been considered responsible for the high incidence of supratentorial metastases in our series.Factors influencing prognosis have been the extent of tumour resection and association of primary chemotherapy with radiotherapy. Within 3 years after surgery survival has been 52% in cases with total resection against 31% in cases with partial resection of tumour. As regards chemotherapy, 3 year survival has been 60% for patients with combined treatment (chemo- and radiotherapy) against 37% in patients with radiotherapy alone. It is concluded that the best results in children with medulloblastoma are achieved by a radical resection, associated with a combined primary treatment of radiotherapy and chemotherapy.     

Treatment of advanced and inaccessible sarcomas with continuous intra-arterial chemotherapy prior to definitive surgery or radiotherapy--a possible alternative to amputation or disabling radical surgery

Four patients with advanced and inaccessible soft tissue sarcomas were treated with a regimen of intra-arterial chemotherapy followed by radiotherapy and/or surgical excision. Two of the patients had advanced sarcomas in the buttock and thigh regions which would otherwise have required hindquarter amputation in one case or disarticulation of the hip in the other case. These sarcomas responded significantly to intra-arterial chemotherapy to the extent that subsequent local surgery was effective in eradicating the residual tumours. No viable tumour cells were found in the resected specimens. In both patients amputation was avoided and local tumour eradication was achieved. In the other two patients, advanced and non-resectable sarcomas in the head were first treated with a similar regimen of intra-arterial chemotherapy. In both cases the tumours regressed in size prior to administration of local radiotherapy. After completion of chemotherapy and radiotherapy no viable tumour cells were detected in either lesion. In one case (originally a very extensive sarcoma of the jaw in a 5 year old child) a residual lump was resected but no viable tumour was detected in the resected specimen. These four patients represent our total experience with this plan of management. All responded well and there has been no evidence of local disease recurrence in any of the four patients. One patient (Case 2) did develop pulmonary and bone metastases from which she died 2 years later but the other three patients remain well with no evidence of residual disease, 11 years, 4 years and 20 months after presentation.     

TREATMENT OF ADVANCED AND INACCESSIBLE SARCOMAS WITH CONTINUOUS INTRA-ARTERIAL CHEMOTHERAPY PRIOR TO DEFINITIVE SURGERY OR RADIOTHERAPY—A POSSIBLE ALTERNATIVE TO AMPUTATION OR DISABLING RADICAL SURGERY

Four patients with advanced and inaccessible soft tissue sarcomas were treated with a regimen of intra-arterial chemotherapy followed by radiotherapy and/or surgical excision. Two of the patients had advanced sarcomas in the buttock and thigh regions which would otherwise have required hindquarter amputation in one case or disarticulation of the hip in the other case. These sarcomas responded significantly to intra-arterial chemotherapy to the extent that subsequent local surgery was effective in eradicating the residual tumours. No viable tumour cells were found in the resected specimens. In both patients amputation was avoided and local tumour eradication was achieved. In the other two patients, advanced and non-resectable sarcomas in the head were first treated with a similar regimen of intra-arterial chemotherapy. In both cases the tumours regressed in size prior to administration of local radiotherapy. After completion of chemotherapy and radiotherapy no viable tumour cells were detected in either lesion. In one case (originally a very extensive sarcoma of the jaw in a 5 year old child) a residual lump was resected but no viable tumour was detected in the resected specimen. These four patients represent our total experience with this plan of management. All responded well and there has been no evidence of local disease recurrence in any of the four patients. One patient (case 2) did develop pulmonary and bone metastases from which she died 2 years later but the other three patients remain well with no evidence of residual disease, 11 years, 4 years and 20 months after presentation.     

Desmoplastic melanoma: the role of radiotherapy in improving local control

Background: Desmoplastic melanoma (DM) is a rare subtype of cutaneous malignant melanoma reported to have a high local recurrence rate with surgical excision alone. The incidence of regional and distant metastasis is considered to be lower than traditional cutaneous melanoma, warranting more aggressive treatment of local disease. We conducted a retrospective analysis of patients with DM treated through the Princess Alexandra Hospital Melanoma Clinic to address the role of radiotherapy in the local control of this tumour. Methods: A review of a clinical database identified 24 patients between January 1997 and March 2006 with histopathologically confirmed DM who had received surgical excision as initial treatment followed by postoperative radiotherapy. All histopathology reports and radiotherapy treatment plans were reviewed. The primary outcome measure was 3‐year in‐field relapse‐free survival. Results: There were 24 patients with 22 having a DM in the head and neck region. The median tumour thickness was 5.2 mm. The histopathological margin was less than 10 mm in 17 (71%) of patients. The 3‐year in‐field relapse‐free survival was 91% (95% confidence interval 68.1–97.6%), the 3‐year relapse‐free survival was 86% (95% confidence interval 63.2–95.4%) with a 3‐year overall survival of 83% (95% confidence interval 54.9–94.3%). Conclusion: In a selected series of patients with DM with a high risk of local recurrence, adjuvant radiotherapy may have been effective in reducing the rate of local recurrence after surgical resection. A randomized trial is currently being developed to confirm this possible benefit.     

Desmoid tumour. The risk of recurrent or new disease with subsequent pregnancy: a case report.

Desmoid tumours are rare, benign tumours arising from fibrous tissue in muscle fascia or aponeurosis. They are most common in women of child-bearing age and most often appear during or after pregnancy in this age group. The recommended treatment is wide surgical excision, if possible, but unresectable tumours may be treated with radiotherapy, anticancer drugs, nonsteroidal anti-inflammatory agents or antiestrogenic compounds. The recurrence rate is high and seems to be related to the achievement of resection margins free of tumour. The literature is not specific about how to counsel women who have had a desmoid tumour and subsequently wish to have a child. Patients should be advised that these tumours may be estrogen sensitive but subsequent pregnancy is not necessarily a risk factor for recurrence or development of new disease.     

The results of concurrent chemo‐radiotherapy for recurrence after treatment with bacillus Calmette‐Guérin for non‐muscle‐invasive bladder cancer: is immediate cystectomy always necessary?

OBJECTIVES

To report our original experience in patients in whom bacille Calmette‐Guérin (BCG) therapy has failed for T1 bladder cancer with subsequent progression to T2 disease treated with chemo‐radiotherapy, as the management of recurrent high‐grade T1 bladder cancer after failed BCG therapy is challenging, and radical cystectomy is the standard treatment because there are no well established second‐line bladder‐preserving therapies.

PATIENTS AND METHODS

From 1988 to 2002, 18 patients with T2 recurrence after failure of BCG therapy for T1 bladder cancer were treated with chemo‐radiotherapy at the authors’ institution. Patients received a visibly complete transurethral resection of the bladder tumour (TURBT) and concurrent chemo‐radiotherapy with a mid‐treatment evaluation after 40 Gy. Patients with less than a complete response had a prompt cystectomy; the others completed radiotherapy to 64–65 Gy. The primary treatment outcome was freedom from cystectomy due to recurrence not treatable by conservative measures; secondary outcomes included disease‐specific (DSS) and overall survival (OS).

RESULTS

With a median follow‐up of 7.0 years, only one patient had persistent tumour at re‐staging TURBT and had an immediate cystectomy. Of the remaining 17 patients, 10 (59%) were free of any bladder recurrence. The actuarial 7‐year DSS and OS were 70% and 58%, respectively. At 7 years, 54% of patients were alive with intact bladders and free of invasive recurrence.

CONCLUSIONS

In this study we specifically evaluated patients with apparently small muscle‐invasive recurrences after BCG treatment for T1 bladder cancer. Selective bladder preservation with chemo‐radiotherapy is possible, with low morbidity and a high chance of long‐term bladder control. If successful in treating T2 recurrences after BCG therapy, it now seems timely to critically evaluate chemo‐radiotherapy as an alternative to immediate cystectomy in the management of patients with T1 recurrences after BCG.     

Intraventricular glioblastoma: a paediatric case report

The authors report the case of a nine-year-old boy admitted with raised intracranial pressure in relation with a tumour of the right lateral ventricle. Complete removal of the lesion was achieved and pathological diagnosis was glioblastoma multiform. Adjuvant radio and chemotherapy was given, but the child died from a recurrence of the disease one year after diagnosis. In addition, last MRI demonstrated, distant from the initial tumor site, an extra-cerebral lesion that is supposed to be a glioma metastasis rather than a radio-induced tumour.     

Evaluation of recurrent metastatic brain tumor of lung cancer origin

The authors examined numerous clinical features in 15 patients in whom brain metastases from lung cancer recurred after total or subtotal removal. The incidence of recurrence after initial removal of brain nodules was 46.9% (15 of 32 cases). There was no significant correlation between the incidence of recurrence and the histology of the lung cancer, the site of brain nodules, or age. Recurrent brain nodules were the cause of or contributed to death in 60% of recurrent cases. Recurrence was within 3 months of initial removal of brain nodules in 10 of the 15 patients. Brain metastasis recurred only at the initial site in 11 cases (73.3%). Three patients developed carcinomatous meningitis and one had multiple metastases in addition to recurrence or regrowth at the original site. The primary lung cancer was relatively stable at the time of recurrence of brain nodules in 60% of the patients. Tumor removal and radiotherapy are highly recommended for prevention of early recurrence following initial removal of brain metastases. Removal of metastatic tumor is advised in the event of recurrence after 1 year from initial surgery, since the outcome after second surgery tends to be fair. However, tumor removal and radiotherapy are sometimes capable of inducing recurrence of brain nodules. Therefore, it is hoped that more effective cancer chemotherapy will be developed in the near future.     

Complete remission of primary retroperitoneal transitional cell carcinoma after radiotherapy and oral chemotherapy: a case report

Primary retroperitoneal transitional cell carcinomas (TCCs) are extremely rare neoplasms for which prognosis is very poor. We present a case that underwent complete remission after radiotherapy and concurrent oral chemotherapy. A 68-year-old woman presented with acute onset of bloody stool. Urgent colonoscopy only detected haemorrhoids. Subsequent abdominal ultrasonography revealed a mass of 7cm in maximal diameter in the left iliac fossa. Laparotomy disclosed a retroperitoneal mass that could not be dissected and therefore only incision biopsy was performed. After a final diagnosis of primary retroperitoneal TCC, chemotherapy with tegafur-uracil (UFT) was initiated but was not effective. Subsequently, radiotherapy was initiated concurrently with UFT at a total dose of 50Gy in 25 fractions. At 20 months after radiotherapy, the tumour seemed to have completely remitted. At the last follow-up, ten years from radiotherapy, computed tomography revealed no recurrence.We identified only three single case reports regarding primary retroperitoneal TCC over the last five decades. All patients died from the tumour 8−24 months after diagnosis or treatment. Based on the success of our case, radiotherapy with concurrent oral chemotherapy should be considered as an option for unresected cases.     

Diagnostic criteria in pituitary tumour recurrence—Combined modality of surgery and radiotherapy

Summary The tumour recurrence rate of 210 patients with operated hypophysomas were investigated. Depending on the surgicaal approach, total or subtotal extirpation of the adenomas, the recurrence rates varied from 10,4 to 35%. 33 patients with pituitary tumour recurrences were followed up over a period of 20 years. Clinical symptoms CT-results at relapse are represented. Serum prolactin level (PRL) was determined before and after surgical and radiotherapy of PRL-producing adenomas. In these cases PRL can be accepted as a tumour marker. 13 patients with relapsed hypophysomas received local irradiation (5.7 MeV linear accelerator) after recurrence operation. An individual comparison in the same patient between surgical therapy alone and combined surgical and radiotherapy was possible. Based on the obtained experience with this combined treatment a therapy scheme using combined surgery and radiotherapy in pituitary tumours is suggested.     

Intracranial hemangiopericytoma: study of 12 cases

Summary  Most hemangiopericytomas (HPCs) are located in the musculoskeletal system and the skin, while the intracranial location is rare. They represent 2 to 4% in large series of meningeal tumours, thus accounting for less than 1% of all intracranial tumours. Many authors have argued about the true origin of this tumour. The current World Health Organization classification of Central Nervous System tumours distinguishes HPC as an entity of its own, and classified it into the group of “mesenchymal, non-meningothelial tumours”. Radical surgery is the treatment of choice, but must be completed with postoperative radiotherapy, which has proved to be the therapy most strongly related to the final prognosis. HPCs have a relentless tendency for local recurrence and metastases outside the central nervous system which can appear even many years after diagnosis and adequate treatment of the primary tumour.  Twelve patients with intracranial HPC were treated at our Unit between 1978 and 1999. There were 10 women and 2 men. Ten tumours were supratentorial and most located at frontoparietal parasagittal level. The most common manner of presentation was a focal motor deficit. All tumours were hyperdense in the basal Computed Tomography scans and most enhanced homogeneously following intravenous contrast injection. In 50% of cases, tumour margins were irregular or lobulated. Seven tumours were studied with Magnetic Resonance Imaging, being six of them iso-intense with the cortical gray matter on T1-weighted and T2-weighted images. Twenty operations were performed in the 12 patients. In 10 cases radical excision could be achieved with no operative mortality. Total recurrence rate was 33.3%. Eight patients were treated with external radiotherapy at some time through the course of their disease. Eight out of the 12 patients in this series are disease-free (Glasgow Outcome Scale categories 1 and 2) after a mean follow up of 52 months.     

Midterm results after treatment of liposarcoma in the extremities

PURPOSE: In this retrospective analysis, survival time, local recurrence and rate of metastasis were appraised in patients with primary liposarcoma of the extremities depending upon the applied primary and adjuvant therapy procedures. Furthermore, we compared the representativity of histological results of the biopsy with the final histology of the resected tumour. MATERIAL AND METHOD: Between 1990 and 1998, 27 patients were surgically treated who suffered from a primary liposarcoma of the extremities. At the mean follow-up time of 62.4 months (39-141 months) postoperative survival rate, rate of metastasis and local recurrence were determined. The results were analysed with regard to intraoperative resection distance, tumour size and localisation as well as histological classification of previous biopsy and finally resected tumour. The influence of radiotherapy on the results was also determined. RESULTS: In 5 patients (18.5%) the amputation and in 22 cases (81.5%) the limb sparing resection of the liposarcoma was performed. 6 patients underwent a marginal resection and one patient an intralesional resection. At follow-up we observed a local recurrence rate of 22.2% (n = 6) and a survival rate of 74.1%. 18.5% of the patients had metastases. After adjuvant radiotherapy three patients (50%) showed local recurrence after marginal resection. In only 8 cases (29.6%) the results of primary biopsy and final tumour classification (entity, subtype and grading) were identical. CONCLUSION: The development of metastases (often pulmonary) and local recurrences even after long tumour-free interval makes adequate follow-up investigations mandatory in liposarcoma patients. With regard to the problems in assessing liposarcoma biopsies, MRI-orientated biopsies from several tumour areas via one biopsy approach are recommended.     

The role of radiation therapy after surgical resection of nonfunctional pituitary macroadenomas

OBJECTIVE: Radiotherapy after aggressive surgical resection of nonfunctional macroadenoma (NFA) of the pituitary remains controversial. Historically, immediate postoperative radiotherapy has been recommended to decrease risk of recurrence. With the availability of high-resolution imaging, most neurosurgeons now withhold radiation until recurrence. There is relatively little evidence to support this practice, however. This study reviews postoperative results in a large number of patients with NFA, the majority of whom did not undergo prophylactic radiation. METHODS: Of the 258 patients who underwent surgery from 1979 to 1999 for NFA, medical records were available for 176. Forty-four patients were treated with immediate postoperative radiotherapy after tumor resection, and the remaining 132 patients were followed up with serial imaging studies and treated with radiotherapy only when a recurrence was documented by follow-up imaging. RESULTS: Patients in the group that received immediate postoperative radiotherapy at time of initial diagnosis and surgery did not differ significantly with respect to age or sex from those in the group that was observed. Five- and 10-year recurrence rates were 2.3 and 2.3%, respectively, for patients who received immediate postoperative radiotherapy, as compared with 15.2 and 50.5%, respectively, for patients who were followed up and did not receive radiotherapy unless there was evidence of recurrence or progression. No patient had symptomatic recurrence in the group that was observed if consistent follow-up was performed. Of the 26 patients who received radiotherapy at time of tumor recurrence or progression, 18 had adequate follow-up, and in all cases, the tumors either remained stable or regressed. CONCLUSION: Withholding radiotherapy after a high-percentage resection of NFA leads to a higher recurrence rate, but it avoids exposing all patients to the risks of radiation. Deferring radiotherapy for patients with complete or near-complete resection seems to be a safe and prudent approach, as our data suggest that recurrences may be detected early with high-resolution imaging and treated effectively with radiation at time of recurrence. Therefore, immediate postoperative radiotherapy may be eliminated for patients with complete or near complete resection of NFA and who agree to undergo close follow-up for a long period.     

Lymphoma of the small intestine

In a group of 179 patients with small bowel tumours presenting over a 10 year period, lymphomas (20%) were the second most common group. The tumour was usually a white mass and was usually resectable. Eighty-one per cent of patients had regional invasion or metastasis at the time of surgery. Treatment was by surgery and radiotherapy for regional disease. If patients survived 2 years they were usually cured. The overall survival rate was 57%. Fresh tissue for expert histology is essential. Histological review by an experienced panel revealed many tumours previously classified as undifferentiated and several anaplastic carcinomata to be lymphoma. It has been recommended that the criteria for intestinal lymphoma be revised.     

Pancoast tumours: clinical assessment and long-term results of combined radiosurgical treatment

BACKGROUND: Many oncologists have now accepted a combined radiosurgical approach as the treatment of choice in patients with Pancoast tumour but most reports show an incorrect assessment of the disease. METHODS: Stage III lung cancer was classified as Pancoast tumour if the pulmonary extent was limited to the upper apical segment and if at least one of the features of Pancoast syndrome, indicating tumour spread to the para-apical structures, was present. Between 1984 and 1988 15 consecutive patients were treated with primary radiotherapy followed by surgery or with primary excision and subsequent radiotherapy in the absence of an initial histological diagnosis. RESULTS: The mortality of patients given the combined treatment was 6.6% (one death due to pulmonary embolism), and the five year survival rate was 26.6% for all patients and 57% for those who underwent complete resection without N2 disease. Long-term survival was 0% for those cases with incomplete resection, N2 disease, or malignant invasion of the first rib. CONCLUSIONS: Stage III lung cancer, classified as Pancoast tumour according to strict, consistent criteria, is best treated by primary radiotherapy; combined treatment should be used only for patients with potentially resectable cancer without N2 disease and/or malignant invasion of the first rib.


     

Surgical treatment for invasive lobular carcinoma of the breast

The management and outcome of 131 women with infiltrating lobular carcinoma treated in the Belfast City Hospital between October 1987 and February 1999 were reviewed. Two patients had primary hormonal treatment and were excluded from the statistical analysis, and 129 patients were followed up. Fifty-four patients (41%) had initial breast conservation surgery, which was followed by re-excision of margins in eight patients (14.8%) and completion total mastectomy in 26 patients (48.1%). The breast conservation surgery group, 28 patients (21.7%), was compared with the total mastectomy group, 101 patients (78.2%), after a median follow-up period of 90 months (range 24-160 months). The overall survival was 68.7%. Survival analysis was performed using Kaplan-Meier and Cox regression which showed that lymph node involvement and tumour grade were the only variables affecting survival (P<0.0001, and 0.01, respectively). The type of surgery performed did not affect survival (P=0.42). The total number of patients who developed local recurrence was 17 patients (13.1%, 12 patients in the breast conservation surgery group and five patients in the total mastectomy group, P<0.0001). Kaplan-Meier analysis of local recurrence showed that the type of surgery (P<0.0001), patient age (P=0.02), tumour grade (P=0.002), adjuvant radiotherapy (P=0.013), chemotherapy (P=0.031) and hormonal treatment (P=0.003) significantly affected local recurrence. Cox regression analysis showed that the only factor significantly affecting local recurrence was the type of surgery performed (P=0.02). Patients who underwent mastectomy had less local recurrence than those who had breast conservation surgery. Local recurrence after breast conservation surgery is high, even with clear surgical margins and post-operative radiotherapy. The authors believe that total mastectomy for infiltrating lobular carcinoma is a safer option to control local disease, especially in younger patients and those with high-grade tumours. Overall survival is not affected by the type of surgical treatment. Local recurrence can be a late event and a long-term follow-up is recommended.     

Predicting local recurrence of carcinoma of the rectum after preoperative radiotherapy and surgery

A prospective study of prognostic factors has been carried out in a group of 186 patients with tethered rectal carcinomas. Of these, 97 were randomized to surgery alone and 89 to receive preoperative radiotherapy (20 Gy in four fractions). DNA ploidy was determined by flow cytometry. DNA aneuploidy was detected in 60 patients (62 per cent) in the surgery only group, but in only 33 patients (37 per cent) after radiotherapy (P less than 0.01). There was a significant reduction in local recurrence in irradiated patients (P less than 0.0001). DNA diploid tumours were less likely to recur locally. This was more marked in the radiotherapy group (P = 0.01) than in the surgery only group (P = 0.06). After radiotherapy, only the surgeons' assessments of a 'curative' resection and DNA ploidy were independent predictors of local recurrence in multivariate regression analysis, whilst Dukes' classification was not. In conclusion, DNA ploidy may indicate response to radiotherapy and is an important predictor of subsequent local tumour progression.