Journal ofNeurology, Neurosurgery, and Psychiatry, 1978, 41, 283-289

Conservative removal of small pituitary tumours:is it justified by the pathological findings?PHILIP WRIGHTSON

From the Department of Neurology and Neurosurgery, Auckland Hospital and The Department ofSurgery, University of Auckland, Auckland, New Zealand

S U M M A R Y Operation by the trans-sphenoidal route allows removal of small pituitary adenomatawith conservation of normal gland. Histological examination of tissue obtained at operation andnecropsy in 73 cases showed that surgical methods at present in use are likely to leave tumourbehind in the pituitary gland and in the dura mater of the pituitary fossa. The clinical significanceof these findings will only become evident after following patients for an extended period, butthere appears to be a strong indication for routine postoperative radiotherapy.

The development of the trans-nasal operation forpituitary adenomas has made it possible in suitablecases to remove the tumour and preserve normalgland. The ability to diagnose small secretingtumours has provided such cases, and the earlyresults have been good, with remission of symp-toms of oversecretion and retention of pituitaryfunction in many cases (Williams et al., 1975,Hardy et al., 1976). However, close examinationof what is done at operation and of the criteriaof endocrine assessment postoperatively raisesdoubt whether the long-term results will be assatisfactory. The growth of pituitary tumours isslow and the situation will not be clear for someyears; in the meantime management policy needsconstant review and it is important to look forways of anticipating the final judgement.The critical issues are whether conservative re-

moval of adenomas is complete enough to abolishabnormal secretion and to prevent recurrence; andwhether radiotherapy should be given post-operatively as a routine, or only when there arespecific signs that operation has been incomplete.The question whether the remaining normal gland,subject to the continuing influence of the hypo-thalamus, is liable to produce further tumours willnot be considered here.Complete removal of the tumour has been

claimed if there is clinical remission and if hor-

Address for reprint requests: Auckland Hospital, Private Bag,Atuckland 1, New Zealand.Accepted 14 October 1977

mone levels return to normal. However, thoughthe reduction of clinical signs after operation isoften dramatic, it may be difficult to be sure thatthey have disappeared completely, especially ifthere are residual tissue changes such as occur inacromegaly. Postoperative hormone levels aresubject to a similar uncertainty. In judging theirsignificance it is. necessary to allow for the con-tribution from the remaining normal gland, whichmay entirely mask the continuing autonomoussecretion from a small amount of residual tumour.Faced with these doubts, a histological assess-

ment of the adequacy of conservative removalwould be useful. The opportunity for a completeassessment postoperatively is, fortunately, rare,but useful conclusions can be drawn from materialremoved at both conservative and radical opera-tions, and from necropsy of patients with pituitarytumours. From the examination of this material,some answers may be given to the questions thesurgeon asks when he attempts the conservativeremoval of an adenoma. Firstly, which is tumourand which is gland? Tumour is usually paler thangland, but the important difference is that of con-sistency, tumour being soft and gland firm. Thehistologist will see this as a difference of cellularityand the amount of a connective tissue stroma.The second question is whether there is a plane

of cleavage between tumour and gland, andwhether dissection along this plane is likely toresult in complete removal of the tumour. To thehistologist, a definite plane of cleavage will showas a sharp transition of cellularity and stroma

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content on passing from tumour to gland. Thechange of consistency which guides the surgeonmay be exaggerated by increase of connectivetissue in the gland at the junction, partly due tocompression of its stroma and partly to the forma-tion of new connective tissue. If removal is to becomplete, there must be no tumour on the glandside of this plane of dissection.

Lastly, having removed the adenoma, does thebed in which it lay contain tumour cells? Theremaining normal gland will be examined fortumour cells, but dura mater also is often in con-tact with tumour, and it too must be searched forinvasion (Shaffi and Wrightson, 1975).

If these three questions can be answered, judge-ment of the effectiveness of conservative removalof a pituitary adenoma may be possible.

Materials and methods

Histological material was examined from 73patients presenting from 1967 onwards withclinical features of pituitary adenoma. Forty-fourpatients had acromegaly, four had Cushing'sdisease (three with Nelson's syndrome), two pre-sented with amenorrhoea and galactorrhoea, and23 had no clinical evidence of increased hormonesecretion. In 64 cases the specimens were obtainedat operation and in nine at necropsy.

Biopsy material consisted of tumour, fragmentsof normal gland, and, where possible, pieces ofthe diaphragma sellae or dura mater from theanterior wall of the fossa. It was usually fixed informalin, embedded in paraffin, and cut at severallevels.Necropsy material was fixed in formalin. In

eight cases the sphenoid and sella turcica wereremoved entirely, decalcified, and serial or step-serial sections cut in the coronal plane.

All sections were stained with haematoxylin andeosin (H & E) and with periodic acid-Schiff-haematoxylin-Orange G (PAS/Hx/OG). Massontrichrome, Heidenhain-Azan, and PAS/Hx/OG/Light green stains were used on some sections.

Black and white prints were made from photo-graphs on Ilford Pan F film: with H & E staininga light green filter was used, and with other stainsusually no filter.

Restilts

In 24 of the 73 cases enough normal gland waspresent to allow comparison of the amount ofstroma in the normal gland with that in thetumour. In all cases most of the tumour washighly cellular and contained very little stroma.

In four cases there were areas of tumour, measur-ing 0.5 mm to 1 mm across on the slide, withabout the same amount of stroma as the gland,and in four further cases some areas showed agood deal more stroma than normal gland (Figs. 1and 2). It is reasonable to conclude, therefore, thatsoft areas encountered at operation are tumour,but that tumour may be present in areas which areindistinguishable by their consistency from normalgland.

In 13 of the 24 cases in which normal glandwas present, there were areas in which theboundary between tumour and gland could beseen without artefact for a reasonable distance,usually between 0.5 mm and 1 mm on the slide.Passing from tumour to normal gland, theboundary was usually marked by a diminution ofcellularity and an increase in stroma (Fig. 1). Thetissue of the gland was often somewhat compressedat the junction, with the cells ranged in rowsparallel to it. In two of the 13 cases there was aconsiderable accumulation of connective tissue inthe gland at the boundary. In one of these therewas further tumour on the far, or gland, side ofthe connective tissue (Figs. 3 and 4). The changein cell morphology at the apparent boundary wasexamined. In two of the 13 cases the change wassharp throughout and coincided with the boundary(Fig. 1). In eight cases the general line of theboundary was apparent, but there was considerablecellular interchange across it (Fig. 5). In threecases there was no real boundary to be seen, cellsof tumour and gland mingling over a wide area(Fig. 6). It is again reasonable to say that, thoughin most cases the plane of surgical dissection willcoincide with the boundary of the tumour, insome cases tumour cells will be present in thenormal gland beyond this plane, and that in othersthe distinction between tumour and gland will belost and no plane will be detectable.

In 41 cases parts of the dura mater from thetumour bed were examined. In 23 cases there wasdefinite invasion by tumour, six of these beingclassed as gross (Fig. 7).Four of the nine necropsies were upon patients

who had been diagnosed in life as having smallsecreting tumours and who had died from causesother than their pituitary tumour. In one case, theadenoma was uniform in structure, sharply cir-cumscribed, and without invasion of normal glandor dura mater, as in Fig. 1. In one, the boundarybetween tumour and gland was diffuse (Fig. 6). Intwo cases there was tumour tissue outside thesellar dura mater, in one in the cavernous sinusand in the other in the bone of the posteriorclinoid process.

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Fig. I Acromegaly PH. Operative specimen-adenoma above, normal gland below.PAS/Hx/OG X250.

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Fig. 2 Acromegaly PH. Same slide as Fig. 1. Area of adenoma showing marked increase ofstroma. PAS/Hx/OG X250.

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Fig. 3 Acromegaly AK. Operative specimen-adenoma on right, normal gland on left,separated by zone of collagenous tissue. No tumour cells seen in gland tissue. Masson trichromeX250.

Fig. 4 Acromegaly AK. Same patient as Fig. 3, different level of section. Adenoma above,normal gland below, separated by collagenous tissue. Tumour present on the gland side ofcollagenous tissue. Masson trichrome X250

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Fig. 5 A cromegaly AP. Operative specimen- adenoma on right occupying one-third offigure, normal gland on left. The position of boundary can be estimated, but there is nodefinite line. PAS/Hx/OG X250.

AP# A, s }*Fig. 6 Cushing's disease CT. Necropsy specimen, death five days after adrenalectomy. Tumourcells have small darkly staining nuclei. Main mass of tumour to the right of the areaphotographed. Note absence of boundary with normal gland and free infiltration. H and E X250.

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Fig. 7 Non-secreting adenoma BH. Operative specimen of diaphragma sellae. Theconnective tissue has been infiltrated by spindles of tumour cells. H and E X500.

It is reasonable to conclude, therefore, that inover 50% of cases tumour will have spread fromits bed into the dura mater of the pituitary fossaand that, even in the case of small and slowlygrowing tumours, the bone of the sella turcica orthe cavernous sinus may be involved.

Discussion

These findings have given definite answers to thethree questions posed in the introduction. Theyshow that to make sure of removing the source ofabnormal secretion and to prevent regrowth, thesurgeon must excise as widely as he can the bedin which the tumour lay, as well as the tumouritself. In doing this he will be constrained by twofactors, the need to preserve normal gland, andthe difficulty of removing the dura mater whichhas been in contact with the tumour.The need to preserve normal gland will vary

from patient to patient. In a middle-aged man withacromegaly who already shows some pituitarydeficiency, the advantage of retaining normalgland tissue will be outweighed by that of com-plete clearance of the sellar contents. Replace-ment therapy for the postoperative hypopituitarismshould present no problems. On the other hand, in

the case of a young woman who complains of in-fertility, with amenorrhoea and galactorrhoea, it isobligatory in removing her prolactin secretingadenoma to preserve pituitary function, even at theexpense of leaving some tumour.The ability to preserve the gland depends on

making the distinction between it and tumour. Atoperation, the first step is to remove the soft partof the tumour. This will expose some areas of ap-parently clean separation from normal gland. Therewill be others where there is tissue which appearsabnormal, and this must be removed piecemeal,remembering that parts of the tumour may havethe same consistency as gland. We have seen thatthe resulting surface, even in the areas where theseparation appeared clean, cannot be taken to befree of tumour, and there is reason to use an agentsuch as Zenker's fluid in the hope of destroyingthe superficial half millimetre of tissue. If thereis condensation of connective tissue at theboundary, it will be easier to separate tumourtissue from within it. Bergland (1975) has illus-trated from Hardy's necropsy material a micro-adenoma with a "capsule" presumably of thissort. However, tumour may have penetrated thiscapsule (cf Fig. 4) and the plane of excisionshould be outside it and not within, as Bergland

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suggests. Where wide excision seems likely tocompromise normal gland, biopsy and frozensection may help to distinguish normal from ab-normal tissue (Hardy, 1973). However, with a

small fragment of tissue whose structure is dis-torted by removal it is difficult for the pathologistto be sure that tumour is not present, and thenumber of areas which can be sampled is limited,so that the manoeuvre may not be of great benefit.The other element of the tumour bed, the dura

mater, lines the bone of the sella turcica and isfolded to form the diaphragma sellae and thewalls of the cavernous sinus. Any adenoma whichgrows to involve the surface of the gland will comeinto contact with dura mater, and large tumourswill remain invested by it as they arise out of thefossa or expand into the sphenoidal sinus. AsHardy (1975) points out, this was referred to inolder literature as the "capsule" of the tumour,and it was sometimes recommended that it shouldbe removed. As it forms the wall of the cavernous

sinus and merges with the adventitia of the in-ternal carotid arteries, this is plainly impracticable.Thus, though it has been shown that the duramater is invaded by tumour in at least 50% ofcases, no practical surgical measure is availablefor removing it.

It is necessary then for the surgeon to acceptthe anatomical limits to the tissue that he may

remove, and the endocrine dictates of what hemust leave, and that some tumour is likely toremain after the widest excision that these limitsallow. The effects of such persistent tumour willdepend on its mass, its biological behaviour, andits sensitivity to radiotherapy. Decisions on fur-ther treatment are relatively straightforward if themass of the tumour is sufficient for it to bedetected by persistence of abnormal hormonesecretion. There appears to be a consensus thatunless there should be a special reason for re-

operation, radiotherapy should be given. This islikely to prevent regrowth of tumour, and there isa reasonable chance that, with time, abnormalhormone secretion will decrease. If blood hormonelevels are normal, however, there is no proof avail-able of persisting tumour; the consensus appears

to be to withhold radiation until such proof ap-

pears (Hardy, 1975; Williams et al., 1975). Thepresent findings suggest, however, that though thesurgical clearance may appear to have been good,some tumour is likely to remain, though there maynot be sufficient for its hormone output to bereadily detected. Since the results of radiotherapyshould be best when the tumour mass is smallest,

routine postoperative radiation seems indicated. Ifit is withheld until abnormal hormone levels pro-vide evidence of regrowth, the wheel has turnedfull circle and the patient is in the same situationas when he first presented with his illness; radio-therapy would not have been expected to curehim then.Though the histological observations here are

definite, conclusions about their clinical relevancecan only be tentative. Only careful observation ofseveral series of patients over a number of yearswill show whether conservative removal of smallpituitary tumours is a safe and adequate pro-cedure. Until this time, the pathological limita-tions must be kept in mind and precautions, suchas careful attention to surgical detail and the useof adjuvant radiotherapy, should be taken tocircumvent them.

I am grateful to Associate Professor J. F. Arthurfor allowing me access to the material of theDepartment of Pathology, Auckland Hospital; toProfessor E. M. Nanson for laboratory facilities;and to Mr R. Paterson, Mrs K. Speak, and MissA. Richards for their histological preparations.The work has been done in collaboration with theDepartment of Endocrinology, Auckland Hospital,and was supported by a grant from the HackettMemorial Trust.

References

Bergland, R. M. (1975). Pathological considerations inpituitary tumours. Progress in Neurological Surgery,6, 62-94.

Hardy, J. (1973). Transsphenoidal surgery of hyper-secreting pituitary tumours. In Diagnosis and Treat-ment of Pituitary Tumours. Edited by P. 0. Kohlerand G. T. Ross. Excerpta Medica: Amsterdam.

Hardy, J. (1975). Trans-sphenoidal microsurgicalremoval of pituitary micro-adenoma. Progress inNeurological Surgery. 6, 200-216.

Hardy, J., Somma, M., and Vezina. J. L. (1976).Treatment of acromegaly: radiation or surgery?In Current Controversies in Neurosurgery. Editedby T. P. Morley. W. B. Saunders: Philadelphia.

Shaffi, 0. M., and Wrightson, P. (1975). Dural in-vasion by pituitary tumours. New Zealand MedicalJournal, 81, 386-390.

Williams. R. A., Jacobs, H. S., Kurtz, A. B.. Millar,J. G. B., Oakley. N. W., Spathis, G. S., Sulway,M. J., and Nabarro. J. D. N. (1975). The treatmentof acromegaly with special reference to trans-sphenoidal hypophysectomy. Quarterly Journal ofMedicine, New Series, 44, 79-98.

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