case 25 prolactinom

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Vol. 333 No. 7 CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL 441

CASE RECORDS

OF THE

MASSACHUSETTS GENERAL HOSPITAL

Weekly Clinicopathological Exercises

FOUNDED BY RICHARD C. CABOT

R

OBERT

E. S

CULLY

, M.D.,

Editor

E

UGENE

J. M

ARK

, M.D.,

Associate Editor

W

ILLIAM

F. M

C

N

EELY

, M.D.,

Associate Editor

B

ETTY

U. M

C

N

EELY

,

Assistant Editor

CASE 25-1995

P

RESENTATION

OF

C

ASE

A 44-year-old woman was admitted to the hospitalbecause of headache, blurred vision, and an intrasel-lar mass.

She had been well until nine months earlier, whena vaginal hysterectomy was performed because of uter-ine prolapse; no oophorectomy was performed. Threemonths before admission occipital headaches devel-

Figure 1. Axial CT Image through the Sella Turcica, Obtained with-

out Contrast Material.The pituitary gland is slightly enlarged. There is no evidence of

acute hemorrhage or calcification.

*Minutes in parentheses denote the interval after the intravenous injection of thyrotropin-

releasing hormone and cosyntropin. To convert values for thyroxine to nanomoles per liter,

multiply by 12.87. To convert values for total triiodothyronine to nanomoles per liter, multiply

by 0.01536. To convert values for cortisol to nanomoles per liter, multiply by 27.59.

Table 1. Results of Hormonal Studies.

*

V

ARIABLE

7 W

EEKS

BEFORE

A

DMISSION

5

1

/

2 W

EEKS

BEFORE

A

DMISSION

O

N

A

DMISSION

N

ORMAL

R

ANGE

Follicle-stimulatinghormone (U/liter)

7.6 10.3 0.613.3

Luteinizing hormone

(U/liter)

5.2 9.5 0.128

Thyroid-stimulating

hormone (

m

U/ml)

0.17 0.19

0.86 (20 min)1.26 (30 min)

1.60 (60 min)

0.55

Thyroxine (

m

g/dl) 2 4.711.1Free thyroxine index 1.5

Total triiodothyronine (ng/dl) 157 75195

Thyroid hormonebindingindex

0.76 0.771.23

Human growth hormone

(ng/ml)

3 25

Somatomedin C (ng/ml) 192.3 141389

Prolactin (ng/ml)

Alpha subunit

16.5 6.6

14.6 (10 min)

22.6 (20 min)25.8 (60 min)

0.5

015

0.52.5Cortisol (random level)

(

m

g/dl)0.5 1.4

5.3 (30 min)

6.1 (60 min)

oped and persisted for five weeks. Seven weeks beforeadmission a computed tomographic (CT) scan of thecranium (Fig. 1) disclosed a slightly enlarged, homoge-neously enhanced pituitary gland (height, 12 mm). Thepatient began to have nocturnal hot flashes and insom-

nia. Hormonal studies were performed (Table 1).Five and a half weeks before admission the patient

Figure 2. Coronal T

1

-Weighted MRI Scan through the Sella Tur-

cica Obtained before the Administration of Gadolinium.

A homogeneous mass with a smooth contour fills the sella andextends upward from it, causing a slight mass effect on the optic

chiasm. There is no evidence of hemorrhage.

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442 THE NEW ENGLAND JOURNAL OF MEDICINE Aug. 17, 1995

told her gynecologist that she continued to have hotflashes and insomnia, along with fatigue, diffuse boneaches, and anorexia. Gynecologic examination wasnormal. Hormonal studies were performed (Table 1).Two weeks before admission magnetic resonance imag-

ing (MRI) of the cranium, performed before and afterthe administration of gadolinium (Fig. 2 and 3), showeda smooth mass, 13 mm by 20 mm by 14 mm, that filledthe sella turcica and extended superiorly, with a masseffect on the central portion of the optic chiasm. Theinfundibulum was buckled and displaced slightly to-

ward the right and upward, without thickening or ab-normal enhancement. The carotid arteries, cavernoussinus, and sphenoid sinus appeared normal. The mass

was isotense with gray matter on T

1

-weighted andT

2

-weighted images before the administration of gado-linium and had homogeneous enhancement after theadministration of gadolinium. Prominent VirchowRob-in spaces were noted. The ventricular system appearednormal.

Nine days before admission an endocrinologist ex-amined the patient and reported that she constantlyfelt exhausted and cold, had occasional blurred visionin the right eye, and was anorectic, with a loss of 9.1kg in weight. She had had three successful pregnanciesand had lactated but had not breast-fed. She rarelydrank alcohol and did not smoke. She had mild asthmathat was treated with an albuterol inhaler. There wasno history of galactorrhea, polydipsia, polyuria, loss ofaxillary or pubic hair, easy bruising, changed facial ap-pearance, or increased shoe or glove size. Her motherhad diabetes mellitus; her children, siblings, and father

were well.Physical examination showed that the pulse was 90

and the respirations were 16. The blood pressure was140/90 mm Hg. There was a questionable defect of theright superior temporal visual field.

Hormonal studies were performed (Table 1).The results of routine laboratory studies, which com-

prised a urinalysis, a complete blood count with a dif-ferential count, prothrombin and partial-thromboplas-tin times, and measurement of urea nitrogen, creatinine,glucose, and electrolyte levels, were normal. An electro-cardiogram and radiographs of the chest were normal.

An ophthalmologic consultant found no abnormalityexcept for a very subtle bilateral defect of the superiortemporal visual field, which was more prominent in theright eye. A transsphenoidal surgical exploration showedthat the pituitary gland was enlarged, tough, fibrous,and yellowish; no separate mass was seen.

A diagnostic procedure was performed.

D

IFFERENTIAL

D

IAGNOSIS

D

R

. J

EFFREY

R. G

ARBER

*: May we review the radio-logic studies?

D

R

. S

HARON

S

ELTZER

: The initial CT scan of thehead (Fig. 1), obtained without contrast material, showshomogeneous intrasellar tissue at least 10 mm in height,

without calcification or acute hemorrhage. After en-hancement with contrast material, slightly thinner sec-tions reveal that this tissue is 12 mm in height and ho-mogeneously enhanced. An MRI scan, obtained seven

weeks later, shows a homogeneous soft-tissue masstouching the optic nerves at the region of the chiasm

Figure 3. Coronal (Left) and Sagittal (Right) T

1

-Weighted MRI Scans through the Sella Turcica Obtained after the Administration ofGadolinium.

A homogeneously enhancing soft-tissue mass that is inseparable from normal pituitary tissue fills the sella and extends upward, caus-ing a slight mass effect on the central portion of the optic chiasm and buckling of the infundibulum. No abnormal enhancement of the

infundibulum, hypothalamus, or basal meninges is evident.

*Chief, Endocrine Division, Health Centers Division, Harvard CommunityHealth Plan; associate physician, Beth Israel Hospital and Brigham and Womens

Hospital; instructor in medicine, Harvard Medical School.




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on the coronal T

1

-weighted image before the adminis-tration of gadolinium (Fig. 2). There is no abnormallyhigh or low signal within this tissue and no evidence ofhemorrhage. The maximal height is 13 mm, the widthis 20 mm, and the anteroposterior diameter is 14 mm.On the T

2

-weighted image there is no low signal sug-

gestive of hemosiderin. The intrasellar tissue appearsminimally hypointense, as compared with normal sellartissue. On the T

1

-weighted coronal scan obtained be-fore the administration of gadolinium, the sellar massis smoothly contoured, homogeneous, and isodense

with gray matter and causes a very slight tenting of thechiasm. On images obtained after the administration ofgadolinium (Fig. 3), there is homogeneous enhance-ment of the intrasellar tissue. There is no tissue withdifferent enhancement suggestive of pituitary tissueseparate from the mass. The infundibulum is buckledand slightly deviated to the right and upward, withoutabnormal thickening or enhancement. There is a mass

effect on the central optic chiasm. On the sagittal sec-tion there is no abnormal enhancement of the hypo-thalamus, dura, or infundibulum after the administra-tion of gadolinium.

D

R

. G

ARBER

: This 44-year-old woman had partialhypopituitarism. I shall first review the evidence forthat conclusion and the extent of the deficiency in herpituitary function. Her headaches commenced threemonths before admission, persisted for five weeks, andbecame temporally associated with nocturnal hot flash-es, which presumably caused the insomnia and suggestestrogen withdrawal. Since this patient had undergonea hysterectomy, a menstrual disturbance is not avail-

able as a clue. Menopause or primary ovarian failure isdocumented by elevated gonadotropin levels and lowestrogen levels. Since early menopause is associated

with normal as well as elevated gonadotropin levels,random low levels may not be sufficient to documentmenopause. In this case, without measurement of thepatients estrogen level, the gonadotropin levels are nothelpful.

Headaches suggest a structural basis for the gonad-otropin deficiency and secondary estrogen deficiency,and the CT scan obtained seven weeks before admis-sion suggests a pituitary lesion as the cause. The previ-ously held belief that hot flashes do not occur with a go-

nadotropin deficiency has been abandoned. Estrogenwithdrawal itself has been shown to be the basis of thevasomotor lability that accounts for hot flashes.

1

It ispossible that the measurable gonadotropin levels re-flected residual immunoreactive gonadotropin secre-tion that was biologically inactive, as seen with glyco-protein-secreting tumors, but the normal value for thealpha subunit of prolactin is evidence against that pos-sibility.

2

The absence of evidence of an estrogen defi-ciency on gynecologic examination leaves open thepossibility that gonadotropin secretion and ovarianfunction were wholly or partially intact, suggesting analternative basis for the hot flashes.

The free thyroxine index, an estimate of circulatingfree thyroxine, was quite low, which is consistent withhypothyroidism, and the thyroid-stimulating hormone

level was subnormal, suggesting a pituitaryhypotha-lamic basis for the hypothyroidism. The value for totaltriiodothyronine was at the high end of the normalrange. Normal levels may be seen with either primaryor secondary hypothyroidism. Preservation of normallevels in secondary hypothyroidism is associated with

alterations in the peripheral metabolism of thyroxinedesigned to preserve the more potent form of thyroidhormone.

3

This patients fatigue, aches, and subsequentsensation of being cold could have reflected hypothy-roidism. An alternative hypothesis for the relativelyhigh total triiodothyronine level, the low thyroxine lev-el, and the low free thyroxine index in conjunction witha low value for thyroid-stimulating hormone is inges-tion of thyroid hormone, leading to the suppression ofthyroid-stimulating hormone dependent on the secre-tion of thyroid hormone, but nothing in the case recordsuggests the surreptitious use of thyroid hormone.

The low random value for cortisol suggests hypoa-

drenalism, which might have caused the patients fa-tigue, achiness, and anorexia. Although secondary hy-poadrenalism that develops gradually is not usuallyassociated with weight loss, profound acute or subacutehypoadrenalisn with anorexia can result in weight loss.The history, physical examination, and laboratory test-ing showed no evidence of hypersecretion of growthhormone or diabetes insipidus. There is no history ofpostpartum hemorrhage or shock or of failure to lac-tate. The preservation of axillary and pubic hair sug-gests that the patients adrenal insufficiency was notlong-standing, because adrenal androgens are neces-sary for the maintenance of axillary and pubic hair in

females. Physical examination revealed minimal bilat-eral defects of the superior temporal field. The consis-tently normal prolactin levels, with normal prolactin re-lease after a thyrotropin-releasing hormone stimulationtest, rule out excessive or deficient secretion of prolac-tin. The subnormal response of thyroid-stimulating hor-mone to thyrotropin-releasing hormone and the sub-normal response of cortisol to synthetic corticotropinare consistent with secondary hypothyroidism and pri-mary or secondary hypoadrenalism. The growth hor-mone and somatomedin C levels suggest normal secre-tion of growth hormone.

In summary, this woman had hypopituitarism, with

hypothyroidism, hypoadrenalism, and possibly hypogo-nadism, without evidence of hypersecretion of prolac-tin, growth hormone, corticotropin, thyroid-stimulatinghormone, or gonadotropins. The absence of diabetes in-sipidus suggests that the hypothalamus and posteriorpituitary gland were at least partially intact. Moreover,the headaches associated with temporal visual-field de-fects point to a structural lesion in the hypothalamicpituitary region.

Pituitary enlargement was documented by the CTscan obtained seven weeks before admission. Althoughthe MRI scan obtained two weeks before admissionconfirmed the enlargement of the pituitary gland, we

cannot conclude that there had been much growth dur-ing the five weeks between the two imaging studies.In addition, the enlargement was mild to moderate,




4/7


diffuse, and symmetric, with minimal suprasellar ex-tension, and was not associated with any evidence ofhemorrhage, cysts, calcification, the formation of ananeurysm, meningeal involvement, or other brain le-sions. Furthermore, the posterior pituitary gland ap-peared intact, without definite evidence of infundibular

thickening, although the pituitary stalk may have beenslightly compressed. There was no evidence of a bonyabnormality or involvement of the sphenoid or cavern-ous sinus. Finally, the neurosurgeons description of thepituitary gland strongly suggests fibrosis.

I shall now review intrasellar processes that typicallycause symmetric, solid enlargement of the pituitarygland and hypopituitarism. Pituitary adenomas accountfor approximately 10 percent of all diagnosed intracra-nial tumors.

4

Prospective studies of normal personsand postmortem examinations reveal pituitary adeno-mas in approximately 10 percent of adults.

5

These tu-mors are almost always small. The case record suggests

initially the diagnosis of a pituitary adenoma. The CTand MRI findings of pituitary enlargement with en-hancement with contrast material and the hormonaldeficiencies are consistent with this diagnosis. Whenhypopituitarism is present, however, pituitary tumorsare usually substantially enlarged, with a considerableextrasellar component. A discrete adenoma separatefrom other pituitary tissue is often noted. With an acuteor subacute presentation that includes headache, visualcompromise, and hypopituitarism, one must considerhemorrhage into a preexistent pituitary adenoma (re-ferred to as apoplexy). Furthermore, when pituitarytumors reach the size that is usually associated with hy-

popituitarism and apoplexy, they typically do not ap-pear uniform or symmetric, and a preserved diaphrag-ma sellae accounts for the dumbbell or figure-eightshape of many of these masses. Evidence of subacutebleeding is usually seen on serial MRI scans. Remotebleeding and adenoma degeneration are often reflectedby the presence of intratumoral cysts and fluid levels.The typical sequence of hormonal deficiencies associat-ed with a large pituitary adenoma is early loss ofgrowth hormone and gonadotropin secretion, with laterloss of thyrotropin and corticotropin secretion. More-over, many pituitary adenomas are hypersecretory. Pro-lactinomas account for most of these tumors. Tumors

secreting growth hormone, corticotropin, glycoproteins,and least commonly, thyroid-stimulating hormone ac-count for the remaining tumors.

The patient under discussion did not have a marked-ly enlarged, asymmetric, semicystic sellar mass with ev-idence of recent hemorrhage. There is no evidence ofpituitary hormone hypersecretion. The preservation ofgrowth hormone secretion and possibly gonadotropinsecretion, together with the loss of thyroid and adrenalfunction, would be atypical in a patient with a mac-roadenoma causing hypopituitarism. The yellow, tough,fibrotic pituitary tissue observed during surgery differsfrom the typically softer, brown-red appearance of a pi-

tuitary adenoma.

Primary or secondary pituitary hyperplasia can causesymmetric, diffuse, solid pituitary enlargement but isnot, at least in its early stages, associated with hypopi-tuitarism. Lactotroph hyperplasia has been proposed asa cause of hyperprolactinemia with pituitary enlarge-ment. Thyrotroph hyperplasia can result from profound

primary hypothyroidism, with the sellar volume corre-lated with the increase in the level of thyroid-stimulat-ing hormone.

6

Gonadotroph hyperplasia is seen with allforms of primary gonadal failure, but the extent to

which it is associated with substantial pituitary enlarge-ment is unclear.

7

Corticotroph hyperplasia, caused byprimary adrenal insufficiency, rarely progresses to theformation of an adenoma. Corticotroph hyperplasia,

when seen with ectopic production of corticotropin-releasing hormone, causes concomitant hypersecretionof cortisol. Similarly, somatotroph hyperplasia with ec-topic production of growth hormonereleasing hor-mone causes excessive secretion of growth hormone. In

the absence of elevations in the prolactin, thyroid-stim-ulating hormone, follicle-stimulating hormone, luteiniz-ing hormone, and growth hormone levels, only corti-cotroph hyperplasia should be considered, but it seemsunlikely without evidence of primary adrenal diseasebeyond a glucocorticoid deficiency namely, hypoten-sion, hyperpigmentation, loss of axillary and pubic hair,or suggestive electrolyte abnormalities.

The most common neoplasm in the hypothalamicpituitary region in children is a craniopharyngioma, butit can develop at any age. It arises in a remnant of Rath-kes pouch, which can also be the site of nontumorouslesions, especially cysts. The intrasellar center of the le-

sion, without cyst formation or calcification, seen on CTscanning in this patient, in combination with her age,makes a craniopharyngioma very unlikely.

Metastasis to the pituitary gland, a potential causeof pituitary enlargement, is seen most commonly withbreast and gastrointestinal cancers and is associated

with substantial enhancement with contrast materialand adjacent brain edema. Metastatic disease is typi-cally accompanied by multiple lesions within the brainand evidence of tumor elsewhere. Pituitary carcinomais very rare and is characterized by rapid growth, inva-siveness, and extrapituitary involvement.

8

Meningio-mas can be intrasellar, but normal pituitary tissue is

usually evident radiologically. Also, bony involvement isdemonstrable on CT scans, and a dural tail is seen onMRI scans; neither was observed in this case. Other tu-mors that involve the sella include germ-cell tumors,

which usually involve the pineal region, and melano-mas, for which we have no evidence. There is nothingto suggest hemochromatosis, which in its late stagesshould appear as a small, dark pituitary gland. Amyloi-dosis presenting as an isolated pituitary mass withoutsystemic abnormalities or structural pituitary abnor-malities in a young woman seems a remote possibility.

Rare destructive inflammatory diseases of the pitu-itary gland can cause hypopituitarism that is dispro-

portionate to the degree of pituitary enlargement, as




5/7


seen in this case, and would explain the pattern of hor-monal loss better than a pituitary adenoma. Moreover,the development of fibrosis without evidence of previ-ous hemorrhage or infarction, as seen in Sheehans syn-drome,

9

and without evidence of degeneration in anadenoma caused by hemorrhage or radiation or bromo-

criptine therapy is consistent with previous diffuse in-flammation.

Lymphocytic hypophysitis, which is rare, with ap-proximately 60 reported cases, predominantly affectsfemales and usually presents during late pregnancy orthe first 14 months thereafter. Early reports empha-sized a high frequency of associated autoimmune dis-ease, particularly Hashimotos thyroiditis. Because ofthe occasional presence of antipituitary antibodies, alymphoid infiltration similar to that seen in autoim-mune thyroiditis, and the presence of activated lym-phocytes interdigitated with pituicytes, the concept oflymphocytic hypophysitis as an autoimmune disease

became firmly established relatively early. Subsequentexperimental models of lymphocytic hypophysitis pro-duced by the injection of pituicytes with Freunds adju-

vant into rabbits and mice

10,11

supported this concept.More recently, rubella virus membrane-associated E1and E2 glycoproteins were shown to induce hypophys-itis in hamsters

11

; neonatal thymectomy prevented thedevelopment of hypophysitis. Although autoantibodiesagainst the pituitary gland developed, passive transferof the antibodies failed to induce hypophysitis in otherhamsters. The authors concluded that the hypophysitis

was both antigen-specific and mediated by T cells.Authors of subsequent reviews

12,13

reported that the

loss of pituitary function was often out of proportion tothe degree of pituitary enlargement; depending on thephase of the disease, the pituitary gland could be en-larged, normal in size, or small. An isolated deficiencyof a hormone, especially corticotropin, could occur. So-matotroph function and gonadotroph function weremore likely to be preserved than corticotroph or thy-rotroph function, unlike the findings in hypopituitarismdue to a sizable pituitary adenoma. The posterior pitu-itary gland and pituitary stalk were typically spared, sothat diabetes insipidus was not part of the characteris-tic picture. The presentation often included weight loss,

weakness, anemia, a change in vision, and a low glu-

cose level. The presence of a change in vision was asso-ciated with a better outcome, probably because of anearlier diagnosis. Prolactin levels were elevated in up to40 percent of the cases, probably as a result of stalkcompression. An unusually firm and tough pituitarygland was evident in approximately 30 percent of thecases. Radiologic studies, the majority of which wereCT scans, could not distinguish the lesion from a mac-roadenoma that had not bled.

Although the diagnosis can be suspected preopera-tively, the definitive diagnosis relies on a biopsy. The re-sponse to steroid therapy has not been consistent, andpituitary function, as well as pituitary size, may ulti-

mately return to normal in any case. Because of the po-

tential for the recovery of pituitary function, surgicalintervention should be avoided whenever possible.

Lymphocytic hypophysitis is probably greatly un-derdiagnosed because of the number of cases withspontaneous resolution, the potential confusion withSheehans syndrome (which is decreasing in frequency

because of improved obstetrical techniques but is oftendiagnosed in parous women with hypopituitarism ofunknown cause if they have small pituitary glands,even without a clear-cut history of postpartum shock orhemorrhage), and confusion with other cases of idio-pathic hypopituitarism (particularly isolated cortico-tropin deficiency). In addition, in some cases of theempty-sella syndrome, there is evidence of the resolu-tion of pituitary enlargement caused by previously un-recognized hypophysitis.

The second form of hypophysitis that I shall discussis granulomatous hypophysitis. In 1954 Rickards andHarvey

14

reported 113 cases of the disorder, mostly in

young women; 23 cases were idiopathic. Pamir et al.

15

pointed out that the diagnosis of idiopathic giant-cellgranulomatous hypophysitis was made by biopsy inonly 10 of 30 cases reported by 1993, with the diagnosismade at autopsy in the remainder. The pathologicalfindings in granulomatous hypophysitis were first de-scribed in 1911 by Gougerot and Gy

16

and in 1917 bySimmonds,

17

whose name has become the eponym forhypopituitarism on the basis of his description of hypo-pituitarism related to sepsis (an uncommon cause ofthe disorder today), as well as other causes. In both re-ports the authors pointed out that the pathologicalfindings probably reflected the stage of the process,

with the early stages characterized by purulence andthe late stages by fibrosis.Granulomatous hypophysitis should be suspected

when evidence of pituitary enlargement is associatedwith hypopituitarism and diabetes insipidus. Some gran-ulomatous diseases, such as sarcoidosis and Langer-hans cell histiocytosis, have a predilection for the pos-terior pituitary gland and hypothalamus. The key tothe diagnosis of granulomatous hypophysitis resultingfrom generalized granulomatous diseases is documen-tation of the systemic manifestations of these disor-ders, including evidence of sarcoidosis in the lungs,liver, or skin; positive serologic tests and gumma for-

mation in patients with syphilis; and positive tests foracid-fast bacilli in patients with tuberculosis. Langer-hans cell histiocytosis is typically associated with dis-tinctive skull lesions, proptosis, and diabetes insipidus.Wegeners granulomatosis would be characterized byophthalmic, sinus, pulmonary, and renal findings. Testsfor fungi, mycobacteria, and spirochetes should be partof the evaluation of granulomatous inflammation of thepituitary gland. Preoperatively, however, without evi-dence of granulomatous disease elsewhere, there areno well-established methods (CT or MRI scanning orother methods) to distinguish granulomatous hypo-physitis from lymphocytic hypophysitis or either disor-

der from pituitary adenoma. However, there are some




6/7


clues to the diagnosis. The presence of diabetes insipi-dus and infundibular thickening is evidence in favor ofgranulomatous rather than lymphocytic hypophysitis.Sarcoidosis involving the sella is more common thanlymphocytic hypophysitis. Idiopathic granulomatous hy-pophysitis has no known relation to pregnancy and

tends to be seen in patients over 40 years of age,whereas patients with lymphocytic hypophysitis aregenerally younger.

Idiopathic granulomatous hypophysitis and lympho-cytic hypophysitis may be different stages of the samedisorder. Viral meningitis has been reported in associ-ation with both diseases, as has Rathkes cleft cyst. Acraniopharyngioma and a prolactinoma have been re-ported in association with lymphocytic hypophysitis.Sarcoidosis after an episode of lymphocytic hypophysi-tis has also been reported. Furthermore, ultrastructuralstudies by McKeel

18 raise the possibility that the twodisorders are related.

In conclusion, I believe that this patient had hypo-physitis of either the lymphocytic or the granuloma-tous type.

D

R

. E. T

ESSA

H

EDLEY

-W

HYTE

: Dr. Ross will com-ment on the preoperative considerations.

D

R

. D

OUGLAS

S. R

OSS

: We thought that a pituitarymacroadenoma was the most likely diagnosis.

C

LINICAL

D

IAGNOSIS

Pituitary macroadenoma, nonfunctioning.

D

R

. J

EFFREY

R. G

ARBER

S

D

IAGNOSIS

Hypophysitis, either lymphocytic or granuloma-

tous type.

P

ATHOLOGICAL

D

ISCUSSION

D

R

. H

EDLEY

-W

HYTE

: Dr. Swearingen performed thepituitary exploration.

D

R

. B

ROOKE

S

WEARINGEN

: After examination of afrozen-section biopsy specimen yielded a diagnosis oflymphocytic hypophysitis, we removed the lower por-tion of the gland to decompress the chiasm but left re-sidual tissue in the hope of maximizing the recovery ofpituitary function. The visual symptoms resolved post-operatively, but the pituitary function has not returnedto normal, despite high-dose corticosteroid therapy.

D

R

. H

EDLEY

-W

HYTE

: Microscopical examination ofthe specimen revealed a diffuse infiltration of lympho-cytes (Fig. 4 and 5), with a few plasma cells and eosin-ophils, as well as residual pituitary cells. Immunohisto-chemical staining for prolactin confirmed the presenceof pituitary glandular tissue (Fig. 6). We found no mi-croorganisms on special staining. We therefore madethe diagnosis of lymphocytic hypophysitis.

At least 50 cases of this disease have been reportedin the English and French literature.

19

Cases have alsobeen reported in the Japanese and Italian literature,and presumably elsewhere as well.

Although early reports emphasized an association

with pregnancy, six cases of this disorder have been re-

ported in men and at least four in nulliparous and fourin postmenopausal women.

20

In 1994 alone, six patientswith the disease were described in the literature; onewas a nulliparous woman, and three were men.

19,20

Inrare cases the disorder is accompanied by sarcoidosisin another organ.

21

In the differential diagnosis of a lymphocytic infil-trate in the pituitary gland, the choice is between lym-phocytic and granulomatous hypophysitis. In this case

no granulomas or multinucleated giant cells were found.These entities probably overlap, however, and the ab-

Figure 4. Frozen Section Showing Sheet of Lymphoid Cells with-

out Recognizable Pituitary Architecture (Hematoxylin andEosin,

60).

Figure 5. Lymphocytes Infiltrating Pituitary Tissue (Hematoxylinand Eosin,

220).

Larger, paler pituicytes are visible in the background.




7/7


sence of granulomas does not prove that this disorderis not part of a granulomatous process. The immediaterisk for this woman was permanent loss of vision, which

was averted by the decompression.Dr. Ross, will you describe the patients subsequentcourse?

D

R

. R

OSS

: She was given a two-week empiricalcourse of high-dose corticosteroids. Her visual fieldsand vision returned to normal, and her headaches re-solved, but the function of her pituitaryadrenal axishas not returned to normal. Cosyntropin stimulationtests performed three weeks ago showed that the basalcortisol level was 0.2 m

g per deciliter (5.5 nmol per li-ter), and it rose to 2.2 m

g per deciliter (61 nmol per li-ter) 60 minutes after the injection. She has continuedto take levothyroxine (0.1 mg a day) and prednisone

(5 mg a day), and we have not yet reevaluated her pi-tuitarygonadal axis.D

R

. R

OBERT

B. C

OLVIN

: In view of the assumedautoimmune nature of this disease, is it worthwhile tolook for autoantibodies in the circulation?

D

R

. G

ARBER

: The usefulness of looking for pituitaryautoantibodies is unclear. In a study by Yoon et al.

22

an-tipituitary antibodies developed in hamsters with hypo-physitis, but passive transfer of these antibodies failedto induce hypophysitis in other hamsters. The reviewby Cosman et al.

12

points out that antipituitary anti-bodies were detected in only two of five patients withdocumented hypophysitis in whom antibody testing

was performed. Moreover, antipituitary antibodies havebeen detected in normal women in the postpartum pe-riod in whom hypophysitis did not subsequently devel-op.

23

These observations suggest that autoantibodiesmay be associated with the development of lymphocytichypophysitis but do not cause it. Therefore, the pres-ence of antibodies supports but does not confirm the di-

agnosis of lymphocytic hypophysitis, whereas their ab-sence does not rule out the diagnosis.

A

NATOMICAL

D

IAGNOSIS

Lymphocytic hypophysitis.

R

EFERENCES

1. Bider D, Mashiach S, Serr DM, Ben-Rafael Z. Endocrinological basis of hotflushes. Obstet Gynecol Surv 1989;44:495-9.

2. Kourides IA, Weintraub BD, Rosen SW, Ridgway EC, Kliman B, Maloof F.Secretion of alpha subunit of glycoprotein hormones by pituitary adenomas.

J Clin Endocrinol Metab 1976;43:97-106.

3. Lum SM, Nicoloff JT, Spencer CA, Kaptein EM. Peripheral tissue mecha-nism for maintenance of serum triiodothyronine values in a thyroxine-defi-

cient state in man. J Clin Invest 1984;73:570-5.

4. Kohler PO. Diseases of the hypothalamus and anterior pituitary. In: Peters-dorf RG, Adams RD, Braunwald E, Isselbacher KJ, Martin JB, Wilson JD,

eds. Harrisons principles of internal medicine. 10th ed. Vol. 1. New York:

McGraw-Hill, 1983:587-604.5. Hall WA, Luciano MG, Doppman JL, Patronas NJ, Oldfield EH. Pituitary

magnetic resonance imaging in normal human volunteers: occult adenomasin the general population. Ann Intern Med 1994;120:817-20.

6. Yamada T, Tsukui T, Ikejiri K, Yukimura Y, Kotani M. Volume of sella tur-

cica in normal subjects and in patients with primary hypothyroidism and hy-perthyroidism. J Clin Endocrinol Metab 1976;42:817-22.

7. Samaan NA, Stepanas AV, Danziger J, Trujillo J. Reactive pituitary abnor-

malities in patients with Klinefelters and Turners syndromes. Arch InternMed 1979;139:198-201.

8. Mixson AJ, Friedman TC, Katz DA, et al. Thyrotropin-secreting pituitary

carcinoma. J Clin Endocrinol Metab 1993;76:529-33.9. Sheehan HL. Simmondss disease due to post-partum necrosis of the ante-

rior pituitary. Q J Med 1939;32:277-309.

10. Levine S. Allergic adenohypophysitis: new experimental disease of the pitu-itary gland. Science 1967;158:1190-1.

11. Klein I, Kraus KE, Martines AJ, Weber S. Evidence for cellular mediatedimmunity in an animal model of autoimmune pituitary disease. Endocr Res

1982;9:145-53.

12. Cosman F, Post KD, Holub DA, Wardlaw SL. Lymphocytic hypophysitis:report of 3 new cases and review of the literature. Medicine (Baltimore)

1989;68:240-56.

13. Parent AD. Lymphoid hypophysitis. In: Wilkins RH, Rengachary SS, eds.

Neurosurgery update II: vascular, spinal, pediatric, and functional neurosur-gery. New York: McGraw-Hill, 1991:3-8.

14. Rickards AG, Harvey PW. Giant-cell granuloma and the other pituitarygranulomata. Q J Med 1954;23:425-39.

15. Pamir MN, Zirh TL, Ozek MM, Sav A, Erzen C, Erbengi T. Magnetic res-

onance imaging in the diagnosis of idiopathic giant-cell granulomatous hy-pophysitis: a rare cause of hyperprolactinemia. Neurochirurgia (Stuttg)

1993;36:20-5.16. Gougerot H, Gy A. Insuffisance pluriglandulaire interne thyro-testiculo-sur-

renale. Nouv Iconog Salpetriere 1911;24:449-62.

17. Simmonds M. Uber das Vorkommen von Reisenzellen in der Hypophyse.Virchows Arch Pathol Anat 1917;223:281-90.

18. Primary hypothyroidism and hypopituitarism in a young woman. Am J Med

1984;77:319-30.19. Paja M, Estrada J, Ojeda A, Ramon y Cajal S, Garcia-Uria J, Lucas T. Lym-

phocytic hypophysitis causing hypopituitarism and diabetes insipidus, and

associated with autoimmune thyroiditis in a non-pregnant woman. PostgradMed J 1994;70:220-4.

20. Lee J-H, Laws ER Jr, Guthrie BL, Dina TS, Nochomovitz LE. Lymphocytichypophysitis: occurrence in two men. Neurosurgery 1994;34:159-63.

21. Hayashi H, Yamada Y, Kuroki T, et al. Lymphocytic hypophysitis and

pulmonary sarcoidosis: report of a case. Am J Clin Pathol 1991;95:506-11.

22. Yoon JW, Choi DS, Liang HC, et al. Induction of an organ-specific autoim-

mune disease, lymphocytic hypophysitis, in hamsters by recombinant rubel-la virus glycoprotein and prevention of disease by neonatal thymectomy.

J Virol 1992;66:1210-4.

Figure 6. Prolactin-Positive Cells (Brown), Confirming the Pres-ence of Anterior Pituitary-Gland Tissue (Immunoperoxidase Stain

for Prolactin,

220).

The Massachusetts General Hospital wishes to acknowledge the generous support ofGlaxo, Inc.,

whose sponsorship makes possible the continued preparation of the Case Records.

The New England Journal of MedicineDownloaded from nejm org by LOKESH VUYYURU on March 24 2012 For personal use only No other uses without permission

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