FP1444 : Association of Ophthalmic Features with Hormonal and Immunohistological Type of Pituitary Adenoma

Dr.Punita Kumari Sodhi, S06682, Dr.Anita Jagetia, Dr.Arvind Kumar Srivasatava, Dr.Prashank Goel

Aim- To find association of ophthalmic features with hormonal and immune-histological type of pituitary adenoma

Methods- Fifty patients (18 to 67 years) including 31 (62%) males and 19 (38%) females having pituitary adenomas were enrolled.

Results- The age range was similar in secretory and non-secretory groups while secretory adenomas had a longer duration of symptoms (21.24±26.21 months). In secretory adenomas, serum prolactin, growth hormone, insulin growth factor, adeno-corticotrophic hormone and thyroid stimulating hormone were raised; and diminution of vision (94.6%), headache (89.2%), squint (10.8%), amenorrhea (28.6%), acromegaly (21.6%) vomiting (2.7%) and field defects (29.7%) were more common. There was a SS correlation (p<0.001) between raised serum hormonal levels w.r.t. immuno-histologically detected hormones in resected tumors.

Conclusion- The secretory adenomas have greater ophthalmic impact and resection of tumors can cause regression of symptoms.

Keywords:Pituitary adenoma and ophthalmic features; non-functioning pituitary adenoma and eye;functioning pituitary adenoma and eye; pituitary adenoma and eye: secretory and non-secretory adenomas

INTRODUCTION

 Pituitary adenomas are associated with significant morbidity. The usual symptoms on presentation are visual and neurological symptoms including headache, impairment of consciousness, diminution of vision or complete loss of vision, optic nerve dysfunction, binocular diplopia, oculomotor palsies and field defects; of endocrine dysfunction including acromegalic features like coarse facial features, enlarged hands and feet, restrictive extraocular myopathy; and hormonal manifestations including irregular menstruation; and mass effects. Visual dysfunction is one of the most common symptom of pituitary adenoma which is caused by direct compression to the optic chiasma or disturbance in the optic chiasma’s blood supply system.^[1],[2]

The pituitary adenoma is the most common tumor that impairs the visual pathway structures followed by craniopharyngioma, posterior fossa tumour & meningioma and the common neuro-ophthalmic features should be carefully examined for early detection of intracranial tumors.^[3]

Ventura et al have stated that secreting pituitary tumorsexert both secretional and pressure effectsand often cause hormonal imbalance and a variety of non-visual symptoms.^[4],[5] Non-secreting pituitary tumors have pressure effect on chiasmal fibres causing mechanical and ischemic damage leading to visual symptoms. These are often asymptomatic until relatively moderate stages when visual field defects typically appear, as the tumors become large enough to compress and elevate the chiasma.^[6]

A number of studies on secretory and non-secretory tumors have been done in literature but comparison between ocular manifestations of these two types of pituitary tumors has rarely been done before.In this study we found association of ophthalmic features with hormonal and immune-histological type of pituitary adenoma

MATERIALS AND METHODS

 Fifty patients in age range of 18 to 67 years including 31 males (62%) and 19 females (38%) having pituitary adenomas were enrolled into this prospective study. The subjects who were previously operated cases with recurrence of adenoma; and subjects with other causes of vision deterioration like cataract, corneal opacity, glaucoma, retinal or optic nerve pathology other than compressive pathology were excluded from the study. The study was approved by Institutional ethical committee. Informed consent was obtained from all the participants.

The study outcome parameters included adenoma type from immunohistology, serum hormonal levels and vision assessment (visual acuity, visual field, fundus).

 A detailed history to rule out significant ocular disease, retinal disease, other central nervous system disease or systemic diseases like diabetes, hypertension, etc. was taken. History was also taken for symptoms like diminution of vision, headache, squint, field defects, vomiting, amenorrhea (in females) and loss of libido. They were subjected to detailed examination including for visual acuity, refraction for best corrected visual acuity (BCVA), fundus examination for optic nerve head changes,visual field defects on the Humphrey’s Field Analyzer using the 24-2 testing protocol/appropriate protocol by SITA-Standard strategy, wherever possible;and features of excess secretion of growth hormones (acromegaly) like enlarged hand, coarse voiceand broad forehead.

The serum hormonal levels ofgrowth hormone (GH), insulin growth factor (IGF), prolactin (PRL), adeno-corticotrophic hormone (ACTH), thyroid stimulating hormone (TSH), follicle stimulating hormone (FSH), luteinizing hormone (LH) and cortisol wereassessed.For immunohistochemistry, resected tissue specimen was fixed in 10% buffered formalin for 48 hours and paraffin embedded. Paraffin section of each tumor was immune-stained using the primary antibodies against the following pituitary hormones: GH, PRL, ACTH, TSH, FSH, LH (DAKO, Carpinteria, California, USA). The presence of more than 10% of hormone immunopositive cells was considered secretory tumor.

The subjects were divided into secretory (if any of the serum hormone level was raised) and non-secretory category (if none of the serum hormone level was raised).

The patients underwent standard treatment procedure for pituitary adenomas. Post-operatively, the serum hormonal level, visual outcome was measured to find the influence of treatment.

 Data collection

All the data was collected by the investigator on a pre-designed proforma.

 Statistical evaluation: Statistical Product and Service Solutions (SPSS) 17 software (SPSS Inc, USA) was used for the statistical analyses. Quantitative data was expressed in mean and standard deviation. Chi-square test was used for qualitative data and ANNOVA, TUKEYS test, and Student t test for quantitative data.

 RESULTS

Fifty patients in age range of 18 to 67 years including 31 males (62%) and 19 females (38%) having pituitary adenomas were enrolled into this study. The subjects presented with symptoms like diminution of vision (n=47, 94%), headache (n=44, 88%), squint (n=4, 8%), field defects (n=14, 28%), vomiting (n=1, 2%), amenorrhea (in females) (n=5,25.2%), loss of libido (n=2, 4%) and features of excess secretion of growth hormones (acromegaly) like enlarged hand, coarse voice, broad forehead (n=10, 20%).

There were n=37 (74%) secretory adenomas and n=13 (26%) non-secretory adenomas. The number of males having secretory adenomas were n=19 (51.4%) and the number of males having non-secretory adenomas were n=12(92.3%). There was statistically significant difference between the two groups of males; (p value <0.01; Fisher exact test). The number of females having secretory adenomas were n=18 (48.6%) and number of females having non-secretory adenomas were n=1 (7.7%).

The age range was similar in secretory and non-secretory groups while secretory adenomas had a longer duration of symptoms (21.24±26.21 months). The age range for secretory adenomas was 18-67 years (38.14 ±10.89) and the age range for non-secretory adenomas was20-62 years (40.85 ±14.26). The duration of symptoms ranged from 0 months to 144 months in secretory adenomas (21.24 ±26.21) and the duration of symptoms ranged from 2 months to 36 months in non-secretory adenomas (12.08 ±11.75).

In secretory adenomas, serum prolactin, growth hormone, insulin growth factor, adeno-corticotrophic hormone and thyroid stimulating hormone were raised; and diminution of vision (94.6%), headache (89.2%), squint (10.8%), amenorrhea (28.6%), acromegaly (21.6%) vomiting (2.7%) and field defects (29.7%) were more common. The subjects of secretory adenomas had symptoms like diminution of vision (n=35, 94.6%), headache (n=33, 89.2%), squint (n=4, 10.8%), field defects (n=11, 29.7%), vomiting (n=1, 2.7%), amenorrhea (in females) (n=5, 28.6%), loss of libido (n=0, 0.0%) and features of excess secretion of growth hormones (acromegaly) like enlarged hand, coarse voice, broad forehead (n=8, 21.6%). The subjects of non-secretory adenomas had symptoms like diminution of vision (n=12, 92.3%), headache (n=11, 84.6%), squint (n=0, 0.0%), field defects (n=3, 23.1%), vomiting (n=0, 0.0%), amenorrhea (in females) (n=0, 0.0%), loss of libido (n=2, 15.4%) and features of excess secretion of growth hormones (acromegaly) like enlarged hand, coarse voice, broad forehead (n=3, 23.1%).

For the secretory tumors, the number of subjects had raised serum levels of pituitary hormones like prolactin (n=17, 45.9%), [Rise varying from 0.24% to 435% increase]; growth hormone (n=8, 21.6%), [Rise varying from 0.01% to 6.75% increase]; insulin growth factor (n=9, 24.3%), [Rise varying from 0.44% to 3.86% increase]; luteinizing hormone (n=0, 0.0%), [Rise varying from 0.01% to 0.68% increase]; follicle stimulating factor hormone (n=1, 2.7%), [Rise varying from 0.01% to 2.25% increase]; adeno-corticotrophic hormone (n=1, 2/7%) [Rise varying from 0.15% to 1.38% increase]; and thyroid stimulating hormone (n=2, 5.4%), [Rise varying from 0.14% to 1.74% increase]. There was also found a decrease in serum levels of cortisol in some patients (n=20, 54.1%).

For the non-secretory tumors, the number of subjects had raised serum levels of pituitary hormones like prolactin (n=0, 0.0%), [Rise varying from 0.17% to3.33 % increase]; growth hormone (n=0, 0.0%), [Rise varying from 0.0% to 1.0% increase]; insulin growth factor (n=0, 0.0%), [Rise varying from 0.58% to 1.0% increase]; luteinizing hormone (n=0, 0/0%), [Rise varying from 0.0% to 0.39% increase]; follicle stimulating factor hormone (n=0, 0.0%), [Rise varying from 0.0% to 0.83% increase]; adeno-corticotrophic hormone (n=0, 0.0%) [Rise varying from 0.15% to 0.15 % increase]; and thyroid stimulating hormone (n=0, 0.0%), [Rise varying from 0.0% to 0.60% increase]. There was also found a decrease in serum levels of cortisol in some patients (n=0, 0.0%).

The pituitary adenomas were resected and adenoma types were determined from immunohistology.The tumors were subjected to immune-histochemistry after resection and hormonal levels including prolactin, growth hormone, luteinizing hormone, follicle stimulating hormone, adeno-cortico-trophic hormone and thyroid stimulating hormone were studied in these specimens. The correlation/association between raised hormone level w.r.t. one particular hormone were studied with presence of that particular hormone in tumor specimen and it was that there was a statistically significant correlation/association between presence of raised serum hormone w.r.t. immune-histochemistry detected hormone for all hormones studied.

S. No.		Statistically significant correlation/association between presence of raised serum hormone w.r.t. immune-histochemistry detected hormone	P value
1.	Raised Serum Prolactin	0.55	<0.001
2.	Raised Serum Growth Hormone	0.61	<0.001
3.	Raised Serum Insulin growth factor	0.79	<0.001
4.	Raised Serum luteinizing hormone	–	–
5.	Raised Serum follicle stimulating hormone	0.10	0.47
6.	Raised Serum adeno-corticotropic hormone	0.32	0.02
7	Raised Serum thyroid stimulating hormone	0.21	0.13

 

Table 1 shows the statistical association/correlation between serum and immune-histochemistry detected hormone in the tumor

From the table it is visible that serum levels of hormone can be used to predict immune-histo-chemistry test results in a tumor.

The patients underwent standard treatment procedure for pituitary adenomas. Post-operatively, the serum hormonal levels fell down and visual symptoms got reduced.

 DISCUSSION

Abouaf et al found that incidence of non-functioning pituitary adenomas was 28-33.2% in pituitary adenoma population and stated that non-functioning pituitary adenomas may lead to blindness and cause visual impairment in 58% cases and more rarely ocular motor disorder. Patients are however slow to become aware of their visual dysfunction despite bitemporal hemianopia, vision in one eye compensating the deficit in the other. These authors emphasized that assessment of visual function, comprising visual acuity, visual field evaluation and fundus examination should be performed regularly in these patients. Visual impairment is associated in 75% of cases.^[7]Diplopia most often involves decompensation of heterophoria, visual field fusion being hampered by the visual field defect; such diplopia without ocular motor deficit is known as “hemifield slide”. Diplopia associated with ocular motor palsy is caused by tumoral invasion of the cavernous sinus (third, fourth or sixthnerve palsy); in large impairment, restricted eye movement is easily observed; milder palsies require neuro-ophthalmologic assessment and/or Lancaster test.^[7]Even non-secretory tumors have an acute presentation if there is pituitary apoplexy wherein there israpid enlargement of a pituitary adenoma because of haemorrhage or infarction and it isa potentially life-threatening clinical condition. Then the patients may present with sudden onset of headache, ptosis and ophthalmoplegia with diminution of vision.^[8]Then degree of neuro-ophthalmologic impairment is one of the main criterion guiding treatments and follow-up. Otherwise, non-functioning adenomas (non-secretory) are diagnosed later than secretory tumors and often with larger tumor volume.^[7]

The visual impairment, caused by compression of anterior visual pathways (optic nerves, chiasma, optic tracts) by the adenoma is variable due to variable location of anterior visual pathways with respect to pituitary gland.^[7]Even in chiasmal compression, one or both optic nerves anteriorly or optic tracts posteriorly may be compressed.^[7]Though the Humphrey visual field analysis of 24-2 and 30-2 assesses only central visual fields, it detects vast majority of defects induced by pituitary adenoma.^[7]

Damage to visual pathways includes retrograde degeneration of retinal ganglion cell (RGC) axons resulting reduction in retinal nerve fibre layer thickness while RGC activity is restored by tumor reduction.^[4] In glaucoma, the presumed insult (elevated IOP and other factors) act at retina and optic nerve head whereas with pituitary tumors, the presumed insult acts at a retrobulbar location.^[4]

Optical coherence tomography is a non-invasive imaging technique without contact, based on infrared light (820 nm) enabling in vivo assessment of eye tissue structure. The RNFL (retinal nerve fibre layer) module quantitatively estimates number of ganglion cell axons constituting the optic nerve and this is used to quantify optic nerve atrophy though subjective evaluation of fundus optic nerve head is non-quantifiable. Optic nerve optical coherence tomography (OCT) can quantify optic atrophy reproducibly, and is of prognostic value for postoperative visual recovery.^[7]Jacob et al stated the most reliable prognostic factor for visual recovery was RNFL on OCT and the thinner the RNFL the greater is the optic atrophy and greater is the expected visual defect after treatment. The thinner RNFL has worst prognosis. The inferior RNFL showed very strong prognostic value.^[9]Zhang et al concluded that both parameters including — visual field analysis and OCT parameters (ganglion cell complex thickness and RNFL thickness) as macular GCC thickness could rather increase due to swelling while simultaneously papillary RNFL could be thinner, thus visual field analysis will show the actual picture.^[10]

The secretory tumors are more aggressive in course as seen in ACTH secreting pituitary adenomas which show orbital invasion.^[11] Young et al studied 100 patients of secretory adenomas secreting gonadotrophs (follicle stimulating hormone and luteinizing hormone) and serum levels of prolactin were increased (maximum, 110 ng/mL). The patients had visual loss (43%), symptoms of hypopituitarism (22%), headache (8%), or a combination of these findings (10%); visual field defects (68%) and 17% of the patients were asymptomatic and complete or partial anterior pituitary failure was present in 77%. After a median follow-up of 4.3 years, 69% of the patients who had had visual field defects noted normalization or improvement. Persistent or clinically recurrent pituitary tumor tissue was present in 42%. A second pituitary surgical procedure was required in eight patients.^[12]

In our subjects, in secretory adenomas, serum prolactin, growth hormone, insulin growth factor, adeno-corticotrophic hormone and thyroid stimulating hormone were raised; and diminution of vision (94.6%), headache (89.2%), squint (10.8%), amenorrhea (28.6%), acromegaly (21.6%) vomiting (2.7%) and field defects (29.7%) were more common than the non-secretory tumors.

Dekkers et al stated that improvement of visual field defects continues even years after the initial surgical treatment. Visual acuity improves progressively after surgical treatmentfor non-functioning pituitarymacroadenomas, at least within the first year after transsphenoidal surgery. Visual acuity improved significantly within 3 months after transsphenoidal surgery. The mean visual acuity increased from 0.65 +/- 0.37 to 0.75 +/- 0.36 (P < 0.01) (right eye), and from 0.60 +/- 0.32 to 0.82 +/- 0.30 (P < 0.01) (left eye). Visual acuity was improved 1 year after transsphenoidal surgery compared to the 3 months postoperative values. The mean visual acuity increased from 0.75 +/- 0.36 to 0.82 +/- 0.34 (P < 0.05) (right eye), and from 0.82 +/- 0.30 to 0.88 +/- 0.27 (P < 0.05) (left eye).^[13]

Thomas et al studied 93 patients of non-secretory field defects and found that eighty-eight (94.6%) of the 93 patients had a field defect. Typical field defects were seen in 69 (74.2%) patients and atypical in 19 (20.4%). A severe typical defect involving at least 3 quadrants in one or both eyes was the most common (24 patients or 25.80%). All 31 patients (33.3%) with a tumour size greater than 20 cc had field defects. Severity of field defect increased with tumour volume (Chi-square test for trends significant p = 0.0096).^[14]

Schaardenburget al stated that non-functioning pituitary adenomas were treated medically, that is with bromocriptine, if they are without alarming eye symptoms, In their series, 25 patents were treated medically while 18 other patients with this condition underwent surgery as the first therapeutic modality.^[15]

The post-surgical visual recovery period consists of three phases according to Kerrison et al.^[16]The phase upto one month postoperatively, corresponds patho-physiologically to release of conduction block caused by compression. The phase between 1 and 4 months is phase of remyelinization. The phase between 4 months and 3 years improvement continues due to neuronal plasticity effects within anterior visual pathways.Gnanalingham et al followed up 41 patients for 5 years with very precise quantitative study of visual field defect and found that more than 50% of the improvement takes place within 6 months.^[17]

In a study of12 children with giant pituitary adenomas, Sinha et al found that functioning adenomas were found in 83% patients, with prolactinomas being most common and visual deterioration (73%) was most common presentation.These12 children underwent 16 microsurgical tumor excision procedures, with two surgeries in 4/12 patients (25%). Despite a near total excision (>90% tumor removal) in six (50%) patients, visual improvement was observed less than 50% patients (in 44% patients) and no improvement was possible when the eye was negative to perception of light prior to surgery.^[18]

In study by Sinha et al, post-surgical follow-up of secretory versus non-secretory tumors show that finally all the patients with functioning adenomas achieve hormonal remission, and in all the patients with non-functioning adenomas, there was no residual/recurrent tumor.^[18] The authors additionally stated that functional tumors are more aggressive.

Kalini et al studied changes in visual functions in 427 patients with pituitary adenomas after endoscopicendonasaltranssphenoidaltumor removal and found that not only the specific features of tumor growth and size and the baseline function, but also the efficacy of surgery and a patient’s age affect postoperative changes in visual impairments.^[19]

Wolf et al did endoscopic resection of pituitary adenomas and they reported improvement in vision function in up to 80%-90% of patients with visual impairment due to these adenomas. The authors prospectively collected data from 50 patients who underwent endoscopic resection of pituitaryadenomas.This cohort included 32 patients (64%) with visual impairment preoperatively. Twenty-seven patients (54%) had pituitary dysfunction, including 17 (34%) with secretory adenomas. After endoscopic resection of adenomas, both secretory and non-secretory adenoma patients reported improvement across all these categories 6 weeks postoperatively, and this improvement was maintained by 6 months postoperatively.But 27 patients with preoperative pituitary dysfunction (including secretory adenomas) perceived their general health and physical function as poorer, with some of these patients reporting improvement in perceived general health after the endoscopic surgery. All patients noted that their ability to work or perform activities of daily living was transiently reduced 6 weeks postoperatively, followed by significant improvement by 6 months after the surgery.^[20]

Müslümananalyzed functioning and nonfunctioning pituitary adenomas (PAs)>3 cm, with special emphasis on preoperative and postoperative visual functions in 49 women and 54 men with mean age of 43.2 years (range 19-66 years). They adopted transsphenoidal approach in 117 procedures, and the transcranial approach in 8 procedures, achieving radical tumor excision in 50 of 103 patients. Preoperative and postoperative visual acuity, visual field, and ocular fundi and their relationship with the pattern and duration of the symptoms and the size of the tumor were evaluated. Normalization of visual acuity was obtained in 71.5% of patients, improvement occurred in 13.6%, symptoms persisted in 13.6%, and symptoms worsened in 1%. Postoperative improvement of visual field defects (VFDs) was observed in 74.1% of patients, and visual impairment score improved postoperatively in 92% of patients. Patients operated on <6 months before the onset of vision loss had better and more sustained visual improvement. One patient died, and 15.5% of patients experienced surgery-related complications. This study shows that patients with severe visual impairment may have remarkable improvement if surgical decompression is done early. The transsphenoidal approach should be performed to correct the patient’s visual impairment and to relieve the pressure on the optic apparatus caused by macroadenoma of any size.^[21]

In our subjects also, resection of tumors can cause regression of symptoms in both secretory and non-secretory tumors.

Abnormal ophthalmological manifestation was the first diagnostic symptom in 26.2%, of pituitary tumors and by fully understanding clinical features in the eye with pituitary tumor, it is helpful in early diagnosis and timely treatment of tumor.^[22]The secretory adenomas have greater ophthalmic impact and resection of tumors can cause regression of symptoms.While long-term tumor control is outstanding for nonsecretorytumors (96% at 10 years); there is a major drop in the control rate of secretory tumors: 10-year clinical and biochemical control was 62% (SS diff; P<0.0001 vs. 96%); overadded with this is dual impact from secretory tumors.^[23] Early detection of chiasmal dysfunction is under investigation to facilitate timely treatment of the condition and to prevent irreversible visual loss.

FINANCIAL SUPPORT AND SPONSORSHIP

Nil

CONFLICTS

There are no conflicts of interest

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