Thankamma Ajithkumar
Case history
A 55-year-old man presented with a week’s history of melaena. There were no associated symptoms. He had never smoked and was not taking any medications. Further investigations with a barium enema and endoscopies were normal, and his symptom subsided without any intervention.
The patient presented again 8 months later with melaena. His haemoglobin level was 5.1g/dl. He received 10 units of blood transfusion over a period of 3 days. Endoscopies and imaging were normal and he underwent an exploratory laparotomy. At laparotomy, he was found to have an exophytic tumour just distal to the duodeno-jejunal flexure with no other abnormalities in the abdomen.
The tumour was resected. Histopathology showed a 6cm × 4cm × 4cm extramural tumour composed of interlacing fascicles of spindle cells and collagen. The average mitotic rate was 2 per 50 HPF. There was no necrosis. The resection margins were free of tumour. The tumour cells were positive for CD34 and CD117, focally positive for actin, and negative for desmin and cytokeratin.
Questions
1. What is the histopathological diagnosis?
2. How do you estimate the prognosis?
3. Outline your further management.
Answers
1. What is the histopathological diagnosis?
The histopathological appearance is that of a mesenchymal tumour, and the differential diagnoses are gastrointestinal stromal tumour (GIST), leiomyosarcoma, and leimyoma.
GISTs comprise >85% of all sarcomas arising from the GI tract. Around 95% of GISTs express CD117 (a KIT receptor tyrosine kinase), while other malignant mesenchymal tumours are CD117 negative. Before the discovery of CD117, CD34 (a haematopoietic stem cell marker) was the best available diagnostic marker for GIST (60–70% positivity). However, CD34 expression varies according to the location of the primary, with the highest positivity for gastric GISTs (85%) and only 50% positivity for small intestinal GISTs. Some GISTs may show positivity for smooth muscle markers such as actin and desmin. Cytokeratin, an epithelial marker, is usually negative in GIST. Therefore the final pathological diagnosis is a GIST of the proximal jejunum.
GISTs most commonly originate in the walls of the stomach and the small intestine from the interstitial Cajal cells. The presenting features of jejunal GISTs include non-specific abdominal pain, obstruction, or haemorrhage. A pre-operative diagnosis of jejunal GIST is often difficult due to non-specific and variable clinical symptoms.
2. How do you estimate the prognosis?
In 2002, the known prognostic factors were the location of tumour (stomach tumours have the most favourable outcome), size (>5cm was considered malignant), and mitotic rate. Tumours with 0–1 mitoses per 10–50HPF were considered at low risk for metastases and those with >5 mitoses per 50HPF as malignant. The median survival of GIST in the pre-imatinib era was 5 years for resectable disease and 10–20 months for recurrent and metastatic disease.
There a number of tools for estimating the risk of recurrence of GIST such as the National Institutes of Health (NIH) consensus risk criteria, the Armed Forces Institute of Pathology criteria, the modified NIH criteria and the Memorial Sloan-Kettering Cancer Centre (MSKCC) GIST nomogram.
Using the MSKCC GIST nomogram, the 5-year recurrence-free survival of this patient would be 67%.
3. Outline your further management.
This patient had complete resection of a non-metastatic GIST. There was no proven role for any adjuvant treatment and regular follow-up was advised.
During a routine follow-up 4 years later, his liver function tests showed a raised serum ALT and alkaline phosphatase, but he was asymptomatic. An ultrasound of the abdomen showed multiple liver lesions. The CT scan images are shown in Fig. 29.1.
Fig. 29.1
Questions
4. What does the scan in Fig. 29.1 show?
5. If his primary diagnosis of GIST was made only recently, would you advise any adjuvant treatment?
6. Outline your further management.
Answers
4. What does the scan in Fig. 29.1 show?
The scan shows multiple low-attenuation lesions throughout both lobes of the liver. One of the lesions has an enhancing rim (a). No biliary dilatation is seen. There are at least two omental nodules (b). Other images (not shown) showed similar masses in the liver, omentum, and mesentery with no ascites or lymph node mass. The chest was clear. The appearance is suggestive of multiple liver, omental, and mesenteric metastases.
5. If his primary diagnosis of GIST was made only recently, would you advise any adjuvant treatment?
Only 50% of patients with completely resected localized GIST remain recurrence free at 5 years. According to the modified NIH criteria, patients with at least one of the following features are considered as high risk (>15–20% risk of recurrence) and may benefit from adjuvant imatinib:
♦ tumour of >10cm
♦ mitotic index of >10/50HPF
♦ tumour of >5cm with mitotic index of >5/50HPF
♦ tumour rupture
♦ any non-gastric tumour of 2–5cm with a mitotic index of >5/50HPF or 5–10cm with a mitotic index of ≤5/50HPF.
The ACOSOG Z9001 study has reported an improved PFS with 1 year of adjuvant imatinib in patients with GIST of ≥3cm (Dematteo et al. 2009). The recently reported Scandinavian Sarcoma Group (SSG) XVIII trial, which compared 36 versus 12 months of imatinib in high-risk resected GIST, showed that 36 months of adjuvant imatinib resulted in an improved 5-year OS (92% versus 81.7%) and recurrence-free survival (65.6% versus 47.9%) (Joensuu et al. 2012).
According to the modified NIH criteria, this patient has a high-risk resected GIST. However, in the UK, imatinib is not currently approved for adjuvant therapy, though it is recommended according to the National Comprehensive Cancer Network (NCCN) guidelines.
6. Outline your further management.
Since this patient has metastatic recurrence of CD117-positive GIST, the treatment of choice is imatinib 400 mg daily (a TKI). Non-randomized studies of imatinib report a 2-year survival of 78% with a partial response rate of 66% in locally advanced or metastatic GIST. The most common side-effects of imatinib include diarrhoea, fluid retention, nausea, fatigue, abdominal pain, muscle cramps, and rash.
A follow-up CT scan 3 months after starting imatinib at a daily dose of 400mg showed shrinkage of liver, omental, and mesenteric metastases with a marked reduction in the density of liver lesions, and loss of hypervascular rims in some liver lesions (Fig. 29.2). There was no new disease.
Fig. 29.2
Question
7. What is the significance of the appearance of the scans in Fig. 29.2?
Answer
7. What is the significance of the appearance of the scans in Fig. 29.2?
On the CT scan, among the earliest evidence of treatment response is a decrease in the tumour density (the lesion becoming hypodense). It may take 4–6 months for the tumour to show any shrinkage, and after initial shrinkage the size of the tumour may stabilize. All patients need a scan at 2–3 months after the start of imatinib to rule out any progression.
Three years and 10 months after his follow-up CT scan the patient presented with abdominal cramps. A CT scan showed no change in the size or number of the metastatic lesions in the liver, mesentery, or omentum. There were no new lesions. Some of the liver lesions contained a new soft-tissue component. Figure 29.3 shows that the soft-tissue component in the hypodense lesion has increased from 1.8cm (A) to 2.2 cm (B), and the average attenuation value has increased from 40 to 55 Hounsfield units (HU).
A histopathology review confirmed the previous findings, and also reported DOG1 (Discovered on Gist-1) positivity in the tumour cells. Genetic testing with sequencing of exon 11 of the C-KIT gene has shown a 9 base pair deletion starting at nucleotide 1668.
Fig. 29.3
Questions
8. How do you interpret the findings of the scan in Fig. 29.3?
9. What is the significance of DOG1 positivity and the genetic mutation?
10. Outline your further management.
Answers
8. How do you interpret the findings of the scan in Fig. 29.3?
There is a progressive soft-tissue mass in a previously hypodense lesion with an increase in density from 40 to 55HU, an increase of 30%. There is no increase in the overall size of the metastases. According to the RECIST (response evaluation criteria in solid tumours) criteria, which are based on the size of tumour, the disease is stable; however, progression in GIST can manifest as a partial or complete filling of a previously hypodense lesion (Fig. 29.3) or as a hyperdense ‘nodule within a mass’, without any apparent increase in the size of the pre-existing lesion. These features need to be taken into consideration when assessing disease status in GIST.
Choi et al. (2007) described alternative criteria for evaluating response in GIST and these criteria have been shown to correlate better with survival than RECIST. According to these criteria a 15% reduction in tumour density or 10% unidimensional reduction in tumour size is a better predictor of response.
9. What is the significance of DOG1 positivity and the genetic mutation?
DOG1 is a monoclonal antibody against a chloride channel protein expressed by 95% of GISTs. It has a high sensitivity and specificity, and is also useful in the diagnosis of CD117-negative GIST.
The type of KIT mutation correlates with response to imatinib and survival in patients with GIST. Those with exon 11 mutations have a better objective response (74% versus 44%), and a longer median survival (60 versus 38 months) compared with exon 9 mutations. A meta-analysis has shown that in patients with exon 9 mutations a high dose of imatinib (800mg daily) results in a better PFS and overall response rate (47% versus 21%).
10. Outline your further management.
Though there is some evidence that dose escalation may be an option during progression, particularly in those with an exon 9 mutation, it is not recommended by NICE.
The recommended treatment for this patient is the multi-targeted TKI sunitinib, 50mg daily for 4 of every 6 weeks. The side-effects include fatigue, reaction of the skin on the hands and feet, discoloration of the skin and hair, sore mouth, vomiting, abdominal pain, diarrhoea, mucositis, and hypothyroidism. In imatinib-refractory patients, sunitinib improves PFS compared with placebo (27 versus 6 weeks).
Follow-up and progress
The patient was started on sunitinib and remained well with stable disease after 2 years.
Further reading
Casali PG, Blay JY and the ESMO/CONTICANET/EUROBONET Consensus Panel of Experts. Gastrointestinal stromal tumours: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Annals of Oncology2010; 21: v98–v102.
Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. Journal of Clinical Oncology 2007; 25: 1753–1759.
Demetri GD, Garrett CR, Schöffski P, et al. Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure. Clinical Cancer Research 2012; 18: 3170–3179.
Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. The Lancet2009; 373: 1097–1104.
Joensuu H. Risk stratification of patients diagnosed with gastrointestinal stromal tumor. Human Pathology 2008; 39: 1411–1419.
Joensuu H, Eriksson M, Sundby Hall K, et al. One vs three years of adjuvant imatinib for operable gastrointestinal stromal tumor: a randomized trial. Journal of the American Medical Association 2012; 307: 1265–1272.
Memorial Sloan-Kettering Cancer Centre. GIST nomogram: