Tom Treasure Weblog

Reading the most enjoyable, varied and stimulating blogs from Dr Bob Replogle I realise that I have again taken a rather dry surgical subject. But seeing the calendar at November 2005 I wanted to catch the fiftieth anniversary to tell this story. To lighten the tone I will close with a poem by Hilaire Belloc. If you read nothing else, read that.

Fifty years ago this month, in November 1955, the thoracic surgeon Geoffrey Flavell performed a remarkable clinical experiment. He asked a patient with lung cancer if he would consent to a thoractomy during which Flavell would only divide the vagus; he proposed re-opening the chest incision a week later to perform the lobectomy (Lancet 1956; 270:260-262 ). In May this year I gave the inaugural Geoffrey Flavell Lecture at the Society of Apothecaries in London and that prompted me get out the original Lancet paper. The man had severe hypertrophic osteoarthropathy (HPOA) Flavell wanted to test the hypothesis that the vagus nerve was the afferent pathway of a mechanism that caused clubbing and the more severe changes of HPOA. The man had first developed painful swelling of the ankles in August and over the next couple of months the knees, then the wrists, elbows and fingers also became stiff and painful. “Radiography showed typical hypertrophic osteoarthropathy of all the long bones”. Remember that this was about 20 years before the first CT images and Flavell relied for assessment of operability on simple radiology and his rigid bronchoscope. There was a small opacity in the upper lobe of the left lung which was diagnosed as lung cancer on sputum cytology. “The patient agreed to a two-stage operation”.



Dr. Geoffrey Flavell

At the first operation on 23rd November 1955 Flavell disturbed nothing but the vagus nerve and divided it just distal to the recurrent laryngeal nerve. The following morning the patient was asked if he felt any different. “Goodness me, yes” Flavell quotes “all my pains are gone; and look – I can bend my knees for the first time in weeks!”. The swelling went in 48 hours and the pain never recurred. A week later Flavell removed what proved to be a squamous carcinoma without lymph node metastases.

The background as Flavell wrote was this: “It has long been known that resection of the growth is followed instantly by cessation of all pain …” This is accepted whenever I have discussed it with colleagues; it is a striking and consistent observation. Flavell made the further observation that pain is also relieved in patients in whom resection had failed, but a preparatory dissection around the hilum had been performed. He describes two such cases in this paper. In another two cases, both on the right, he divided the vagus above the azygos vein, the last through a minimal thoracotomy. In all cases, the patients’ pain was completely abolished. In his conclusion Flavell proposed division of the vagus nerve in inoperable cases with the objective of relieving pain.

As a resident at the London Chest Hospital in 1978, I was studying the teaching collection of x-rays in the radiology department. I chanced upon the films an inoperable right sided lung cancer and a pathology laboratory report of a confirmatory biopsy of the vagus nerve obtained through a mediastinoscope. It was impressed upon my memory. Reaching and dividing the vagus – and sending a bit to the lab – seemed to me not something that would have been attempted by the faint hearted or unskilled. The surgeon was a resident called Magdy Yacoub. It was this chance discovery of the story that prompted my interest in HPOA and my curiosity remains. The young Yacoub reported this and another case (Br J Dis Chest 1965; 59:28-31, Br J Dis Chest 1966; 60:144-147). One was a man who was admitted to hospital in 1962 with left sided cancer which had already destroyed the recurrent laryngeal nerve. The pain from HPOA was so severe that he could not sleep. Division of the vagus in the neck gave dramatic relief. In the second case in 1964 the patient had lost the use of his hands due to the severity of HPOA. This was the man in whom Magdy passed a mediastinoscope through the usual neck incision divided the vagus nerve in the tracheo-oesophageal groove. “The joint and bone pains subsided immediately, and five days later he could close his fists easily”.

Flavell and Yacoub reviewed the evidence for proposed mechanisms. On the basis of these cases and their review of the experimental and clinical evidence they believed that the ipsilateral vagus nerve was the key afferent pathway. While the observation that pain is consistently relieved by resection is generally agreed, standard clinical texts on lung cancer shy away from this vagal hypothesis, stating that the mechanism is unknown. The possibility of a vagal mechanism is mentioned in some texts but usually no source is cited. Little credence is given to the vagal contribution and various humoral mechanisms are postulated. Since 2000 there are fewer than 100 references to HPOA in PubMed, predominately case reports of rare associations and strange phenomena. Lung tumours cause a wide range of paraneoplastic syndromes due to the release of proven or postulated substances and a neural and humoral mechanisms could co-exist. However, the vagal mechanism is not favoured. It appears to be largely discounted. Why?

Is there a question about the reliability of these surgical reports? This seems to me unlikely. Cardiothoracic surgery was then and remains a very public specialty. The London Hospital and the London Chest Hospital were both major contributors to teaching, training and clinical reports in the 1950s and 1960s. Flavell named each referring physician in his Lancet paper. Yacoub acknowledged his senior colleague Jack Belcher when he wrote in the British Journal of Diseases of the Chest (a journal which one of my mentors in the 1970s used to refer to as the Brompton Hospital “school mag”). Erroneous or over enthusiastic assertions could hardly have gone unremarked.

There is the possibility that the dramatic relief reported by Flavell and Yacoub was a placebo effect - a result of suggestion. There are good reasons to consider that possibility. When we see lung cancer patients with HPOA at least one doctor, and probably several, will tell them “That pain will go away when we take the cancer out”. A thoracotomy would surely qualify as an intervention sufficient to prompt a placebo effect. And yet the effect is consistently reproducible and the physical and radiological changes regress, along with the pain. A placebo effect seems unlikely.

HPOA is generally regarded as at the severe end of the clinical spectrum of the physical changes that are seen under the general heading of finger clubbing. Clubbing is said to have been described by Hippocrates in his account of empyema and is seen in about a third of cases of lung cancer. The incidence of HPOA in lung cancer was about 3% (9 out of 280) in a consecutive series seen between about 1970 and 1975. The occurrence of “Hypertrophic pulmonary osteoarthropathy without clubbing of the digits” (Skeletal Radiol 2001; 30:652-655) is so rare as to be published only in as few as four case reports.

In many discussions of the subject which I have had with very well informed physicians, Flavell’s evidence is played down and it is because the mechanism seems to them to be implausible. The preferred theory is that there is some form of tumour derived growth factor which is responsible. Although the surgical “experiments” of Flavell and the clinical application by Yacoub provide strong empirical evidence for a central role for the vagus, the theory is not liked because it does not fit with any known physiological mechanism or that appears plausible in the light of current accepted scientific knowledge. There is a danger there. In the 1840s Semmelweiss provided evidence that hand washing with chlorinated water between the post mortem room and the labour ward dramatically reduced the death rate from puerperal sepsis but his contemporaries were able to discredit him because the microbes had “never yet been seen”. I would accept that any parallel between the discrediting of Semmelweis and the forgetting of Flavell would be far too strong but the more gentle message from Belloc is worth recalling: “Oh! Let us never never doubt what nobody is sure about”.

If anyone has more evidence about HPOA and the vagus I would be interested to know. With modern minimal access approaches, perhaps we should consider offering this form of palliation in inoperable lung cancer.

THE MICROBE
by: Hilaire Belloc (1870-1953)
HE MICROBE is so very small
You cannot make him out at all,
But many sanguine people hope
To see him through a microscope.
His jointed tongue that lies beneath
A hundred curious rows of teeth;
His seven tufted tails with lots
Of lovely pink and purple spots,
On each of which a pattern stands,
Composed of forty separate bands;
His eyebrows of a tender green;
All these have never yet been seen--
But Scientists, who ought to know,
Assure us that is must be so...
Oh! let us never, never doubt
What nobody is sure about!

"The Microbe" is reprinted from More Beasts for Worse Children. Hilaire Belloc. Duckworth, 1912.