primary hypophysitis: idiopathic inflammatory...

Primary Hypophysitis: Idiopathic Inflammatory Disordersof the Pituitary Gland

M. Necmettin Pami.r and Koray Ozduman

Department of Neurosurgery, Marmara University Faculty of Medicine, Istanbul, Turkey

Summary: Primary hypophysitis is a rare but significant cause of sellar space-occupying lesions. Three forms have been described: granulomatous, lymphocytic, andxanthomatous hypophysitis. Current methods cannot diagnose or distinguish theseentities before surgery with sufficient certainty. The disease most commonly presentswith sellar space-occupying symptoms as a result of pituitary enlargement and hor-monal abnormalities such as potentially lethal pituitary insufficiency or hyperprolac-tinemia. Pituitary insufficiency almost always ensues, with progressive inflammatorydestruction of the pituitary tissue. All three disorders clinically and radiologicallymimic pituitary adenomas, and the diagnosis is usually made after surgery. Idiopathicgiant cell granulomatous hypophysitis is a cryptogenic inflammatory lesion. The di-agnosis rests on eliminating secondary causes. Lymphocytic hypophysitis is a chronicautoimmune disorder of the anterior and, rarely, posterior pituitary. Although it is mostcommonly seen in peripartum women, it may be encountered in either sex and may beassociated with other autoimmune diseases. Surgical removal, biopsy, and medicaltherapy are the three options of therapy. Response to medical therapy is unpredictable,but remissions are reported with steroids. A consensus regarding drug choice timing,duration, and dosage of therapy is lacking, but in preoperatively suspected cases, atherapeutic trial is justified. Surgery results in cure at the expense of potentially viablepituitary tissue. The natural course of these rare disorders is currently unknown, theprognosis is unpredictable, and the choice of effective therapy is yet to be established.Key Words: Granulomatous hypophysitis—Lymphocytic hypophysitis—Xanthomatous hypophysitis—Giant cell hypophysitis—Pituitary surgery—Pituitaryadenoma.

Inflammatory processes compose a small but signifi-cant proportion of sellar pathologic findings.1,2 Since thepopularization of pituitary surgery at the beginning of the20th century, these rare entities have become more com-monly recognized, and their management has challengedeven skillful neurosurgeons.3 After the description ofgranulomatous hypophysitis in 19114 and lymphocytichypophysitis in 1962,5 only a limited number of caseshave been reported. Although their causes are still ob-scure, the epidemiology and characteristics of these raredisorders are roughly established.1

Three forms of primary hypophysitis have been de-scribed: granulomatous, lymphocytic, and xanthomatoushypophysitis.6 All three are considered in the differentialdiagnosis of sellar space-occupying lesions, and theirdistinction from pituitary adenomas poses great diagnos-tic difficulties.6–8 Currently, a noninvasive means of dis-tinguishing these entities before surgery is nonexis-tent.6,9,10

All cases of biopsy-verified idiopathic giant cellgranulomatous hypophysitis reported in the literature arelisted in Table 1. The first report of giant cell granulo-matous hypophysitis was in 1911 by Geurgeot and Gy,4

followed by a report by Simmonds in 1917.11 In 1949,Sheehan and Summers12 hypothesized that this lesionmay be the presentation of a distinct specific disease of

Address correspondence and reprint requests to M. Necmettin Pami.r,

MD, Department of Neurosurgery, Marmara University Hospital, To-phanelioglu caddesi, No. 13/15 Altunizade, Istanbul, 81190 Turkey.E-mail: [email protected]

Neurosurgery Quarterly12(3):197–215 © 2002 Lippincott Williams & Wilkins, Inc., Philadelphia

197 DOI: 10.1097/01.WNQ.0000023274.57247.F9

TABLE 1. Biopsy-verified idiopathic giant cell granulomatous hypophysitis

Reference(year)

Patient age(years)/gender Presentation

Endocrinestatus Radiologic findings

Steroid therapy/response

Operation performed/intraoperative findings

Taylon andDuff78 (1980)

50/M H/A, CN III palsy No detailsgiven

No MRI available; intrasellar mass andright cavernous sinus involvement on CT

None Transsphenoidal surgery/edematous gland

Del Pozo etal.79 (1980)

28/F H/A, amenorrhea PH No MRI available; enlargement of the sellaon radiography; upward displacement ofthe sella on pneumoencephalography

None Transsphenoidal surgery/close resemblance to afibrous adenoma

Hassoun et al.55

(1985)65/F N/V, weight loss PH No MRI available; intrasellar mass and no

increase in volume of the sella on CTNone Transsphenoidal surgery/

firm massScanarini et

al.14 (1989)20/F H/A, galactorrhea PRL, DI, PH No MRI available; ring-enhancing

low-density intrasellar mass on CTNone Transsphenoidal surgery/

cyst containing thickwhitish fluid

19/F Galactorrhea,amenorrhea

PRL No MRI available; ring-enhancinglow-density intrasellar mass on CT

None Transsphenoidal surgery/cyst containing creamygrayish yellow fluid

57/M H/A, CN III palsy,impotence

PH No MRI available; slightly enhancingintrasellar mass expanding into the rightparasellar area and sphenoid sinus on CT

None Transsphenoidal surgery/solid with a firmcapsule

58/M PH PH No preoperative MRI available; uniformlyenhancing isodense mass enlarging thesella on CT

None Transsphenoidal surgery/fibrous encapsulatedmass

Siquieiria etal.80 (1989)

37/M H/A, CN III palsy,CN VI palsy

PH No MRI available; intrasellar mass andsuprasellar extension with hyperdenseareas on CT; no abnormalities oncerebral angiography

Before surgery,reversed CNpalsies

Transsphenoidal surgery/firm mass

Yoshioka etal.65 (1992)

76/F Visual symptoms,sterile meningitis

PH Intrasellar mass and suprasellar extensionon MRI

Only replacementtherapy


Higuchi et al.81

(1993)46/F Visual symptoms PRL, PH No MRI available; intrasellar mass an

suprasellar extension with thickenedinfundibulum on CT

None Transsphenoidal surgery/calcified mass

55/F DI DI Intrasellar mass, suprasellar extension, andhomogeneous enhancement withthickened infundibulum on MRI

None Transsphenoidal surgery/fibrous mass

55/M Visual symptoms PH Intrasellar mass, suprasellar extension, andhomogeneous enhancement withthickened infundibulum on MRI

None Transsphenoidal surgery/fibrous mass

Pamir et al.54

(1993)41/F PRL Intrasellar mass, suprasellar extension, and

homogeneous enhancement withirregular hyperintensities on MRI;calcifications on CT

None Transsphenoidal surgery/encapsulated grayishyellow firm mass

36/F PRL Intrasellar mass, suprasellar extension, andhomogeneous enhancement on MRI

None Transsphenoidal surgery/encapsulated grayishyellow firm mass

Brisman et al.17

(1996)72/F H/A, vomiting,

visualsymptoms,adrenalinsufficiency

PH Intrasellar mass, suprasellar extension,homogeneous enhancement, and enlargedstalk on MRI


Transsphenoidal surgery/yellow firm massadherent to arachnoidand cavernous sinus

Honegger etal.24 (1997)

16/F Sterile meningitis PH, DI, PRL Intrasellar mass, homoenous contrastenhancement, nonenhancing center,suprasellar extension, and thickened stalkon MRI

None Transcranial surgery(frontotemporalapproach)/firm capsulewith creamy content

48/F H/A PH, DI, PRL Intrasellar mass, suprasellar extension, andthickened stalk with sphenoid mucosalthickening on MRI

None Transcranial surgery(frontotemporalapproach)/firm mass

Vasile et al.8

(1997)40/F H/A, sterile

meningitis,DI

DI, PH Intrasellar mass, suprasellar extension,heterogenous enhancement, and duralenhancement with no posterior glandsignal, sphenoid mucosal thickening, orabnormal sphenoid bone marrow on MRI

None Transsphenoidal surgery/firm whitish massadherent to dura mater

Kristof et al.53

(1999)16/F DI, hypogonadism,

dwarfismGH, LH/

FSH, DIAtrophic pituitary and enlarged stalk

on MRIMethylprednisone

pulse, noresponse

Transcranial stalk biopsy(subfrontal approach)/thickened but otherwisenormalappearing stalk

Gazioglu et al.80

(2000)32/F DI, visual

symptoms,menstrualirregularity

Mild hypo-cortisolemia

Intrasellar mass, dumbbell suprasellarextension, chiasmal compression,sphenoid mucosal thickening, andstalk unidentifiable on MRI



33/F H/A, N/V PRL Intrasellar mass, suprasellar extension,isointense on T1, heterogenous on T2,and nonenhancing center on MRI



M. PAMIR AND K. OZDUMAN198

Neurosurgery Quarterly, Vol. 12, No. 3, 2002

unknown origin. In 1954, Rickards and Harvey13 re-ported 115 cases of granulomatous hypophysitis andidentified a group of 23 idiopathic cases in which evi-dence of systemic granulomatous disease was lacking.Since its first description, several other causes leading tosecondary granulomatous hypophysitis have been de-scribed, but idiopathic giant cell granulomatous hy-pophysitis has emerged as a separate entity.14 It is char-acterized by varying degrees of lymphocytic infiltrationin the pituitary parenchyma and by the presence of non-caseating granulomas with epithelioid histiocytes andmultinucleated giant cells.14,15 In secondary granuloma-tous hypophysitis, anterior pituitary tissue is primarilyaffected, but the neurohypophysis, the pituitary stalk, andeven the hypothalamus may also be involved.6 Patientsmay present with headache, nausea, vomiting, visualsymptoms, hypopituitarism, hyperprolactinemia, diabe-tes insipidus (DI), or cranial nerve palsies.16,17

All cases of biopsy-verified lymphocytic hypophysitisreported in the literature are listed in Table 2. Lympho-cytic hypophysitis was first described by Goudie andPinkerton in 1962.5 The first report was that of the post-mortem examination of a young postpartum woman whohad pituitary lymphoid infiltration, adrenal atrophy, andHashimoto thyroiditis. Initial reports were mainly fo-cused on peripartum women, but the range has beenbroadened to encompass a diverse population, includingmen and postmenopausal women, and the disease’s cau-sal relation with pregnancy has been questioned.6,9,18,19

Autoimmunity is the most plausible pathogenetic mecha-

nism for the selective inflammation of the pituitary glandin lymphocytic hypophysitis.6,20,21

Recently, a third form of primary hypophysitis hasbeen introduced to the literature by Folkerth et al.22 Xan-thomatous hypophysitis, first described in 1998, is theleast common form of primary hypophysitis. The processhistopathologically resembles that of xanthomatous in-flammations encountered in other parts of the body suchas the genitourinary and biliary tracts in response tochronic bacterial infection.6,22

PATHOGENESIS

It has been suggested that the three forms of primaryhypophysitis, namely, granulomatous, lymphocytic, andxanthomatous hypophysitis, may be different stages orvarious presentations of a single disease.6,10,23,24 Evi-dence supporting this hypothesis is currently lacking.6,22

Preoperative diagnostic methods usually cannot differen-tiate between these three entities in spite of the fact thatthere are considerable differences in the epidemiology ofthese three conditions.6,7,10 Whether they are related hasyet to be investigated.6

Giant Cell Granulomatous Hypophysitis

Occurrence of granulomatous hypophysitis is attribut-able to systemic granulomatous diseases and infectionssuch as tuberculosis,14,25–27 syphilis,14 sarcoidosis,14 his-tiocytosis X,14 Wegener granulomatosis,28 pyoderma

TABLE 1.—(Continued)

Reference(year)

Patient age(years)/gender Presentation

Endocrinestatus Radiologic findings

Steroid therapy/response

Operation performed/intraoperative findings

50/M H/A PH but normalPRL

Intrasellar mass, suprasellar extension,isotense on T1, heterogenous on T2, andnonenhancing center on MRI



Cheung et al.6

(2001)39/F H/A, N/V, weight

loss, hot andcold flashes

PRL, hypo-cortisolism

Intrasellar mass and suprasellar extensionon MRI

At recurrence,yes


Buxton andRobertson58

(2000)

32/F H/A, amenorrhea,visual symptoms

PH Pituitary mass, no details given No details given Transsphenoidal surgery/firm mass

38/F PH, visualsymptoms

PH, DI Pituitary mass, no details given No details given Transsphenoidal surgery/firm mass

45/F Diplopia, bilateralCN VI palsy,visual symptoms

PH Pituitary mass, no details given No details given Transsphenoidal surgery/firm mass

46/F H/A, amenorrhea PH Intrasellar mass and suprasellar extensionon MRI

No details given Transsphenoidalsurgery/firm mass

Arsava et al.59

(2001)53/F Amenorrhea,

ptosis, diplopiaPH Intrasellar mass on MRI Associated optic

neuritis respon-sive to methyl-prednisolone

Transsphenoidal surgery/firm fibrotic yellowishmass

PH, panhypopituitarism; PRL, hyperprolactinemia; H/A, headache; N/V, nausea-vomiting; CN, cranial nerve; DI, diabetes insipidus; MRI, magnetic resonance imaging;GH, growth hormone; LH/FSH, luteinizing hormone/follicle-stimulating hormone; CT, computed tomography.

PRIMARY HYPOPHYSITIS 199


TABLE 2. Biopsy-verified lymphocytic hypophysitis cases

Reference(year)

Age(years)/gender

Associationwith

pregnancy Presentation Radiologic findingsImmunosuppressive

therapy/response

Mode ofdiagnosis/intraoperative

findingsAssociated

autoimmune disease

Goudie andPinkerton5

(1962)

22 F No Hypopituitarism,amenorrhea

N/A No Necropsy/atrophic Hashimoto thyroiditis

Hume andRoberts83

(1967)

74/F No Hypopitutarism N/A No Necropsy/atrophic Pernicious anemia

Egloff et al.84

(1969)29/F Postpartum Hypopituitarism,

amenorrheaN/A No Necropsy/enlarged None

Kiaer andNorgaard85

(1969)

74/F No Hypopituitarism,H/A

N/A No Necropsy/N/A None

Lack86 (1975) 42/F No Hypopituitarism N/A No Necropsy/not enlarged Parathyroiditis,adrenalitis

Gleason et al.87

(1978)60/F No Hypopituitarism N/A No Necropsy/enlarged None

Quencer88

(1980)25/F Postpartum Amenorrhea,

galactorrheaEnhancing intrasellar

mass on CTNo Transsphenoidal

surgery/enlargedNone

Richtsmeieret al.38(1980)

32/F Postpartum Adrenal insufficiency N/A No Necropsy/thickenedcapsule

Hashimoto thyroiditis,adrenalitis,pancreatitis

Mayfield et al.47

(1980)23/F Postpartum Hypopituitarism, H/A,

fever, CN VI palsyEnlarged sella and

intrasellar masson CT

50 mg/d prednisone/CN VI palsyresolved

Transsphenoidalsurgery/grittynonencapsulatedmass

None

Asa et al.58

(1981)28/F Antepartum Amenorrhea, visual

symptoms,hypopituitarism

Lobulated intrasellarmass with asymmetricsuprasellar extensionon CT

No Transsphenoidalsurgery/enlarged

None

29/F Postpartum Amenorrhea,hypopituitarism

Intrasellar mass on CT No Transsphenoidalsurgery/enlarged

None

Portocarrero etal.62 (1981)

25/F Postpartum Amenorrhea, H/A,galactorrhea

Diffuse enhancement ofthe pituitary, but nosuprasellar extensionon CT


None

Cebelin et al.89

(1981)22/F No H/A, galactorrhea N/A No Necropsy None

Hungerford etal.90 (1982)

27/F Antepartum Visual symptoms,hypopituitarism

Uniformly enhancingintrasellar mass andsuprasellar extensionon CT


None

Baskin et al.3

(1982)33/F Antepartum Visual symptoms,

hypopituitarismUniformly enhancing

intrasellar mass,suprasellar extension,and bone erosion onCT


Transsphenoidalsurgery/firm whitemass

None

28/F Postpartum Visual symptoms Uniformly enhancingintrasellar mass,suprasellar extension,and bone erosion onCT


Transsphenoidalsurgery/firm yellowmass

None

McKeel91

(1983)30/F No Hypopituitarism N/A No Necropsy None

Mazzone et al.56

(1983)37/F Postpartum Hypopituitarism, H/A Sellar enlargement and

intrasellar mass onCT

No Transsphenoidalsurgery/fibrotictissue adherent tothe surroundingstructures

Pernicious anemia

Ludmerer andKissane50

(1984)

33/F No Amenorrhea, H/A,hypopituitarism

No abnormalities on CT No Transsphenoidalsurgery/atrophic

None

Madsen et al.92

(1985)29/F No Amenorrhea,

hypopituitarismN/A No Necropsy None

Sobrinho-Simoeset al.52 (1985)

24/F No Amenorrhea, H/A,hypopituitarism

Normal skull radiograph No Necropsy None

Okamoto et al.93

(1986)28/F Postpartum Visual symptoms,

H/A,hypopituitarism

Roundcontrast-enhancingintrasellar mass onCT


None

Gal et al.94

(1986)29/F No Visual symptoms,

coma, hypopitui-tarism

N/A No Necropsy/enlarged None




Reference(year)

Age(years)/gender

Associationwith


therapy/response


findingsAssociated

autoimmune disease

Moriyama etal.95 (1986)

28/F Antepartum Visual symptoms,hypopituitarism

Intrasellar mass andenlarged sella on CT


Transsphenoidalsurgery/enlarged

None

Kurisaka et al.96


hypopituitarismEnlarged sella and intra-

sellar mass on CTOnly replacement

therapyTranssphenoidal


Jensen et al.35

(1986)32/F Antepartum Amenorrhea, H/A,

PRLIntrasellar enhancing

mass on CTOnly replacement

therapyTranssphenoidal


Wild andKepley61

(1986)

31/F No Amenorrhea Enlarged sella on CT No Transsphenoidalsurgery/not enlarged

None

Meichner et al.46


H/AIntrsellar enhancing

mass and suprasellarextension on CT

No Transcranial surgery(subfrotalapproach)/enlarged

None

Guay et al.18 52/M Male Impotence, H/A,hypopituitarism

Intrasellar enhancingmass on CT


None

McGrail et al.71


H/A, N/V, Fever,hypopituitarism

Intrasellar enhancingmass and suprasellarextension on CT


None

Vanneste andKamphorst64

(1987)

29/F No PH, galactorrhea,H/A, fever

Intrasellar enhancingmass and suprasellarextension on CT


None

Parent et al.97

(1988)21/F Postpartum Amenorrhea, visual

symptoms, H/A,hypopituitarism

Enlarged sella on CT No Transsphenoidalsurgery/enlarged

None

29/F Postpartum Amenorrhea,galactorrhea, H/A,visual symptoms,hypopituitarism


None

Levine et al.66

(1988)18/F Postpartum H/A, visual


Homogeneous isointenseintrasellar mass butno suprasellarextension on MRI


None

McDermott etal.98

31/F Antepartum H/A, visualsymptoms,hypopituitarism


None

45/F No H/A, visualsymptoms, PH,amenorrhea


None

Castle et al.99 37/F Postpartum Visual symptoms,hypopituitarism

Enlarged sella on CT Only replacementtherapy


None

Cosman et al.100 29/F Postpartum Amenorrhea, visualsymptoms, H/A,hypopituitarism

Intrasellar mass,suprasellar extension,and chiasmalcompression on MRI



None

34/F Postpartum Amenorrhea, H/A,hypopituitarism

Intrasellar mass andsuprasellar extensionon CT



None

38/F Postpartum H/A, hypopituitarism Intrasellar mass,suprasellar extension,and left parietalarachnoid cyst onMRI



None

Miura et al.101 45/F No Visual symptoms,PH, DI

Diffuse pituitaryenlargement andabsent posterior glandhigh signal on MRI



None

24/F No H/A, amenorrhea,hypopituitarism

Diffuse pituitaryenlargement andabsent posterior glandhigh signal on MRI



None

Pestell et al.102


H/A, PRLEnlarged sella on CT Yes/positive

responseTranssphenoidal


61/M Male Hypopituitarism Enlarged sella on CT Yes/positiveresponse


None

McConnon etal.30 (1991)

22/F No Amenorrhea, H/A,galactorrhea, PRL

Coincidental intrasellaradenoma on MRI


None

Bitton et al.103

(1991)22/F Antepartum H/A, visual

symptoms,hypothyroidism

Enlarged sella on CT Only replacementtherapy


None

Hashimoto etal.104 (1991)

39/F Postpartum Visual symptoms,hypopituitarism, DI

Intrasellar mass andsuprasellar extensionon MRI



None




Reference(year)

Age(years)/gender

Associationwith


therapy/response


findingsAssociated

autoimmune disease

Hayashi et al.105


H/A, hypopitui-tarism

Intrasellar mass on CT Only replacementtherapy


Pulmonary and eyesarcoidosis

Nussbaum etal.24 (1991)

40/M Male Bilateral CN VIpalsy,hypopituitarism, DI

Mildly enlargedpituitary withhomogeneousenhancement on CT,isotense mass andcavernous sinusinvolvement on MRI


Transsphenoidalsurgery/avasculargray fibrous tissue

None

34/F Postpartum H/A, amenorrhea, DI Intrasellar mass on MRI No Transsphenoidalsurgery/enlarged

None

McCutcheon andOldfield106

(1991)

29/F No H/A, PRL Enlarged pituitary onCT


None

Stelmach andO’Day107

(1991)

21/F No H/A, visualsymptoms, PRL


Dexamethasonepositive response


None

Prasad et al.108 44/F No H/A, visualsymptoms,hypopituitarism

Intrasellar mass on CT Yes/positiveresponse


None

Feigenbaum etal.109 (1991)

26/F No H/A, fever,hypopituitarism

Intrasellar mass on CT Only replacementtherapy


None

Supler andMickle110

(1992)

56/M Male H/A, hypopituitarism Intrasellar mass andcavernous sinusinvolvement on MRI



None

Reusch et al.72

(1992)29/F Antepartum Visual symptoms Intrasellar mass,

suprasellar extension,and chiasmalcompression on MRI

Dexamethasone/noeffect


None

Ahmed et al.42

(1993033/M Male DI, HP Enlarged pituitary and

strong homogeneousenhancement in MRI

60 mg/dprednisolone/clinical andradiologicresponse

Transsphenoidalsurgery/grittycapsule, creamycontent,panhypophysitis

None

39/M Male DI Enlarged pituitary andstrong homogeneousenhancement on MRI

No Transsphenoidalsurgery/necrotictissue

None

Nishioka etal.111

33/F Postpartum H/A, visualsymptoms,hypopituitarism

Homogeneouslyenhancing intrasellarmass and suprasellarextension on MRI


Transsphenoidalsurgery/firm whitemass

None

Koshiyama etal.112 (1994)

50/F No H/A, DI Homogeneouslyenlarged pituitary,loss of posteriorgland high signal, andthickened stalk on MRI



None

Yamagushi etal.113 (1994)

44/F No H/A, fever,hypopituitarism, DI

Homogeneouslyenhancing isointenseintrasellar mass,suprasellar extension,and loss of posteriorpituitary signal no MRI



Pustulosis palmaris etplantaris witheosinophilia

Lee et al.9 (1994) 47/M Male H/A, decreased libido Intrasellar mass,suprasellar extension,and chiasmalcompression on MRI



None

27/M Male H/A, impotence Intrasellar mas, suprasellarextension, and chiasmalcompression on mRI



None

Paja et al.114

(1994)25/F No Amenorrhea, fever,

hypopituitarism, DIIntrasellar mass,

suprasellar extension,and thickened stalk onMRI


None

Magner andWest115 (1994)

30/F Postpartum H/A, visual symptoms Enhancing intrasellarmass, suprasellarextension, and chiasmalcompression on MRI



None




Reference(year)

Age(years)/gender

Associationwith


therapy/response


findingsAssociated

autoimmune disease

Beressi et al.44

(1994)27/F No H/A, visual

symptoms,amenorrhea,,galactorrhea, PRL

Diffusely enhancingintrasellar mass withsuprasellar extension,and thickened stalkon MRI

60 mg/d predniso-lone/positiveresponse


None

Naik et al.75

(1994)34/F Postpartum H/A, N/V,

amenorrhea,hypopituitarism

Pure intrasellarhomogeneouslyenhancing mass onCT



None

Ahmadi et al.7

(1995)40/M Male H/A, visual


Intrasellar slightlyhyperintense mass,diffuse enhancementand suprasellarextension on MRI

N/A Transsphenoidalsurgery/enlarged

None

15/F No H/A, diplopia Intrasellar slightlyhyperintense mass,diffuse enhancement,suprasellar extension,cavernous sinusinvolvement, anddural enhancement onMRI


None

33/F No H/A, hypopituitarism Intrasellar slightlyhyperintense mass,diffuse enhancement,suprasellar extension,and duralenhancementon MRI


None

38/F No H/A, visualsymptoms,hypopituitarism

Pure intrasellar massand duralenhancement on MRI

N/A Transsphenoidalsurgery/not enlarged

None

Abe et al.116

(1995)52/M Male Impotence,

hypopituitarism, DIIntrasellar mass,

suprasellar extension,loss of posteriorgland high signal, andehickened stalk onMRI



None

McDonald etal.117 (1995)

34/F Postpartum H/A, hypopituitarism,PRL

Cystic heterogenousintrasellar mass andsuprasellar extensionon MRI


None

Thodou et al.15

(1995)52/M N/A H/A, DI Intrasellar lesion on CT No Transsphenoidal


27/F No Visual symptoms,PRL, DI

Normal sella and stalklesion on CT


Transsphenoidalsurgery/stalk lesion

None

?/F Postpartum Hyperthyroidism N/A Only replacementtherapy


Thyroiditis

38/F No PH N/A Only replacementtherapy

Necropsy None

34/F Postpartum PH N/A Only replacementtherapy

Necropsy None

32/M Male Hypopituitarism Intrasellar mass andsuprasellar andcavernous sinusinvolvement on CT



None

31/F Antepartum H/A, visual loss Intrasellar mass,suprasellar extension,and cysticdegeneration on CT


None

41/F Postpartum H/A Intrasellar mass,suprasellar extension,and cavernous sinusinvolvement on MRI

Dexamethasone/noresponse


None

24/F No Amenorrhea N/A No Transsphenoidalsurgery/enlarged

None

29/F Antepartum PRL, visualsymptoms



None

29/F No Visual loss, PRL, DI Stalk lesion, suprasellarextension, and opticatrophy on MRI

High-dosesteroids/noresponse


None




Reference(year)

Age(years)/gender

Associationwith


therapy/response


findingsAssociated

autoimmune disease

Hughes et al.118

(1995)33/F No PH Intrasellar mass,

suprasellar extension,and homogeneousenhancement on MRI



None

Nishioka et al.73

(1997)53/F No DI Intrasellar poorly

enhancing mass andloss of posteriorgland high signal onMRI


None

Jabre et al.16

(1997)25/M Male H/A, N/V Ring-enhancing mass

and suprasellarextension withchiasmal compressionon MRI

Yes/resolution ofsymptoms


None

Honeggeret al.23 (1997)

35/M Male H/A, PRL Enlarged pituitary andthickened stalk onMRI

No Transsphenoidalsurgery/stalk lesion

None

42/F No DI, PRL Enlarged pituitary andthickened stalk onMRI


None

18/F No DI, PRL Enlarged pituitary,suprasellar extension,thickened stalk, andsphenoid sinusmucosal swelling onMRI


None

28/F No PRL Intrasellar mass on MRI No Transsphenoidalsurgery/enlarged

None

38/F No PH, PRI, DI Intrasellar ringsenhancing mass andthickened stalk onMRI

Desamethasone/positive response


None

40/M Male Hypopituitarism, PRL Intrasellartriangular-shapedenhancing lesion,thickened stalk, andsphenoid mucosalthickening on MRI

Desamethasone/positive responsewith recurrence


None

52/F No PH, PRL Intasellar ring-enhancingmass, thickened stalk,and sphenoid mucosalthickening on MRI


None

Tsujii et al.39

(1997)56/M Male DI Mass in the posterior

pituitary and loss ofposterior pituitaryhigh signal on MRI

No Transsphenoidalsurgery/soft mass inthe neurohypophysis

None

Sato et al.40

(1998)31/M N/A PH, DI Enlarged pituitary and

loss of posteriorpituitary high signalon mRI



None

53/M Male Decreased libido Enlarged pituitary andloss of posteriorpituitary high signalon MRI



None

Crock21 (1998) 57/F No Apoplexy, PH Enlarged pituitary andsuprasellar extensionon MRI


None

43/F No Hypopituitarism Enlarged pituitary andsuprasellar extensionon MRI


IDDM, Gravesdisease, psoriasis

51/M Male PH Enlarged pituitary onMRI

No Transsphenoidalsurgery

None

25/F No Hypopituitarism Enlarged pituitary andsuprasellar extensionon MRI


None

52/F No PH Enlarged pituitary andsuprasellar extensionon MRI


IDDM, perniciousanemia

32/F No Meningoencephalitis Enlarged pituitary andring enhancement onMRI


None



gangrenosum,29 or Crohn disease.6 Foreign body reac-tions to adenomas,30,31 ruptured Rathke cleft cysts,32–34

mucoceles,14 and even previous surgery (personal expe-rience) have all been reported to cause granulomatoushypophysitis. After exclusion of all systemic disorders,there remains a small but distinct group with a crypto-genic etiology,14 commonly known as giant cell granu-lomatous hypophysitis. Some authors claim that pituitarygranulomas attributable to systemic granulomatous dis-eases have become exceedingly rare in the postantibioticera.23 No associations with any known autoimmune dis-

ease have been reported, except for cases secondary topyoderma gangrenosum29 or Crohn disease.6

There are three reports of granulomatous hypophysitiscaused by ruptured intrasellar Rathke cleft cysts.32–34

All reported patients were women who presented withheadache and amenorrhea. On magnetic resonance im-aging (MRI), all patients had masses with suprasellarextension, each with a cystic area. None of these caseswas associated with pregnancy, and in none of thesecases was a preoperative diagnosis of hypophysitis sus-pected. The histologic examination was identical to that


Reference(year)

Age(years)/gender

Associationwith


therapy/response


findingsAssociated

autoimmune disease

60/M Male PH, DI Stalk mass on MRI No Transsphenoidalsurgery

None

Kristof et al.10

(1999)23/M Male PH Enlarged pituitary,

suprasellar extension,thickened stalk, andenhancing diaphragmon MRI

Methylprednisolonepulse/none

Transsphenoidalsurgery/whitish firmmass

None

29/F Antepartum H/A, visualsymptoms, PH

Enlarged pituitary,suprasellar extension,and enhancing stalkon MRI

Methylprednisolonepulse/completeresponse,shrinkage toempty sella

Transphenoidalsurgery/whitish firmmass

None

36/F No Oligomenorrhea, PH Enlarged pituitary,suprasellar extension,and enhancing butnormal-sized stalk onMRI

Methylprednisolonepulse/none

Transsphenoidalsurgery/reddish firmmass

None

Li et al.48

(1999)73/M Male Sjogren syndrome, DI Mildly enlarged

pituitary, extensioninto hypothalamusand cavernous sinus,thickened stalk,enhancing tentoriumand adjacent dura,and loss of posteriorpituitary high signalon MRI

Methylprednisolonepulse/completeresponse

Transsphenoidalsurgery/firm mass

Sjogren syndrome,hypertrophiccranialpachymeningitis

Alexiadou-Rudolph etal.119 (2000)

24/F Antepartum H/A, visualdisturbances

Intrasellarhomogeneouslyenhancing mass andsuprasellar extensionon MRI

No Transsphenoidalsurgery/firm mass

None

Cheung et al.6

(2001)24/F Postpartum H/A, galactorrhae,

oligomenorrhaeNo MRI available;

diffuse sellarenlargement on CT

No Transsphenoidalsurgery/stickyyellowish

None

Buxton andRobertson51

(2001)

26/F Antepartum H/A, visualsymptoms,oligomenorrhea

Pituitary mass but nofurther information onMRI


Transsphenoidalsurgery

None

Fujiwara et al.63

(2001)47/F No PH, DI, PRL Suprasellar mass and

empty sella on MRINone Transcranial

surgery/panhypophysitisempty sella

None

72/F No PH Enlarged pituitary andthickenedinfundibulum on mRI


Not reported None

Tubridy et al.67

(2001)46/M Male DI, PH, unilateral CN

IV palsyThickened enhancing

stalk and leftcavernous sinus masson MRI

Prednisolone +methotrexate/completeresponse

Transsphenoidalbiopsy/posteriorhypophysitis

None

PH, panhypopituitarism; PRI, hyperprolactinemia; DI, diabetes insipidus; H/A, headache; N/V, nausea-vomiting; CN, cranial nerve; N/A, data not available;MRI, magnetic resonance imaging; IDDM, insulin-dependent diabetes mellitus.



of idiopathic cases, except for the demonstration of aRathke cleft cyst. Mucin staining identified the cyst ma-terial as the cause of the sterile granulomatous reaction inone of the reports.33 A granulomatous foreign body re-action to leakage of cyst contents was proposed as thecause of hypophysitis in these patients.32,33 Because oftheir close resemblance to giant cell granulomatous hy-pophysitis, Roncaroli et al.33 hypothesized that at leastsome of the cases of idiopathic granulomatous hypophy-sitis were caused by nondemonstrated ruptured Rathkecleft cysts, but this has never been proven.

Lymphocytic Hypophysitis

Autoimmunity was suspected from the first case re-ported,5 and this hypothesis still continues to be the mostplausible pathogenetic mechanism.6 The presence oflymphoid follicles and activated immune cells,1,35 inter-digitation of lymphocytes with pituitary cells on electronmicroscopy,1,35 presence of antipituitary antibod-ies20,36,37 in several cases, and association with severalother autoimmune pathologic findings15 support this no-tion. The immunologic picture, however, is quite non-specific, and it is not known whether the humoral orcell-mediated arm is primarily active.35

In most cases, only the adenohypophysis is affected.6

This inflammation is assumed to be caused by antibodiesdirected at pituitary cells.6,21 Autoimmunity against asingle population of hormone-producing cells has beenreported.35,38

The disease process less frequently affects the neuro-hypophysis, but disease restricted to the neurohypophy-sis and pituitary stalk may still be seen.24,39–41 Immura etal.41 suggested that at least some cases of idiopathic DImight be caused by lymphocytic hypophysitis. Some au-thors claimed that infundibuloneurohypophysitis was adistinct entity but that the coexistence of inflammatoryinfiltrates in both the adenohypophysis and neurohy-pophysis favors a common etiology.39 The disease pro-cess is reported to be self-limiting, and remissions suchas those seen in lymphocytic hypophysitis may occur.1

Selective inflammation of the neurohypophysis withoutany change in hormone production in the anterior pitu-itary may occur. A necrotizing form of infundibuloneu-rohypophysitis is reported to be associated with DI.42

Experimental autoimmune hypophysitis models inmice and rabbits were created by injecting laboratoryanimals with autologous or homologous pituitary tissuehomogenates in combination with Freund adjuvant.18,43

Interestingly, in the rat model of hypophysitis, inflam-mation was found to be more severe in pregnant or lac-tating rats.4

Antipituitary antibodies were present in several cases,although none were detectable in others.20,36,37 Bottazzoet al.20 were the first to describe autoantibodies directedtoward prolactin-producing pituitary cells. Several otherstudies have investigated antipituitary antibodies with in-cidences reaching 18% in postpartum women.44–46 Nospecificity could be shown, and it was hypothesized thattheir presence might be a result of nonspecific pituitarydamage.37 Bottazzo et al.20 reported that corticotrophiccells of the pituitary exhibited a nonspecific affinity forthe human immunoglobulin Fc site in immunofluores-cence assays. Earlier reports on pituitary antibodies thusshould be cautiously interpreted.21 Newer tests such asimmunoblotting are not hampered by this phenom-enon.21 Nishiki et al.36 detected serum antibodies to 68-,49-, and 43-kd anterior pituitary antigens by immuneelectrophoresis in 5 of 13 cases with lymphocytic hy-pophysitis, 1 of 12 cases of infundibuloneurohypophysi-tis, and 0 of 4 cases with isolated adrenocorticotropichormone (corticotropin) deficiency. The authors’ conclu-sion was that these antigens were specific but infrequent.Crock21 speculated that the 49-kd autoantigen might berelated to selective corticotrophin loss occurring in asso-ciation with lymphocytic hypophysitis or in isolation, buthis findings were not supported by Nishiki et al.36 Theabsence of any detectable antipituitary antibody does notexclude an immune pathogenesis that may take placeearly in the pathologic process, and the lack of antibodiesin the rat and rabbit models supports this notion.18,24,43

Guay et al.18 reported the disappearance of pituitary an-tibodies in a case treated by transsphenoidal surgery.Pituitary antibodies are also found in empty sella syn-drome,36 Sheehan syndrome,37 idiopathic growth hor-mone deficiency,15 Cushing syndrome,45 and severalother endocrinopathies without hypophysitis.15 Theirsignificance is debatable.15

Only a few investigators reported an association withhuman leukocyte antigens (HLAs).1,39,47–49 In one ofthese cases, the patient carried HLA-B8, which the au-thors reported to be associated with immunologic hyper-responsiveness in normal persons and several autoim-mune diseases.18 An association with several HLAs wasreported in hypophysitis cases, but none was common toall.1,39,47–49 It has been suggested that aberrant expres-sion of HLA–D-related antigens and the capacity of ep-ithelial cells to present autoantigens to T lymphocytesmay be of importance in the formation of endocrine au-toimmunity.15 It is most likely that the HLAs are notresponsible, per se, but only closely related.1 McCutch-eon et al.49 failed to demonstrate major histocompatibil-ity complex class II antigens on pituitary cells from pa-tients with hypophysitis.



An association has been reported with several autoim-mune diseases in as many as 30% of cases.6,10,23 Primarythyroiditis is the most common associated endocrinopa-thy. Others include Graves disease,35,50 dacroadenitis,51

idiopathic retroperitoneal fibrosis,51,52 adrenalitis,38 atro-phic gastritis and pernicious anemia,21,52 diabetes melli-tus,21 pancreatitis,38,51 Sjögren syndrome,48 and lympho-cytic parathyroiditis.52

Xanthomatous Hypophysitis

Only a few cases of xanthomatous hypophysitis havebeen reported. Because of its close histopathologic re-semblance to other infectious xanthomatous findingselsewhere in the body, an infectious etiology is suspectedbut remains unproven.22

PATHOLOGIC FINDINGS

Histopathologic findings in both diseases vary accord-ing to the stage of the inflammation. The acute inflam-matory process is followed by progressive scarring,eventually leading to complete replacement of the pitu-itary tissue by a fibrous scar.12,31,53,54

Macroscopically, hypophysitis may be solid3,8,10,23,47,55

or cystic,14,23,42 and it may appear whitish,3,8,10,14, yel-lowish,3,14,54 or reddish tan.10,61 Its consistency mayrange from soft6,39 to fibrous and gritty.3,10,47,56 Cystsare often surrounded by a thick capsule. Ultrastructur-ally, giant cell granulomatous hypophysitis and lympho-cytic hypophysitis resemble each other.55 The adenohy-pophysis is primarily affected.23 Extension within theposterior pituitary or stalk may be seen.39 Giant cellgranulomatous hypophysitis is characterized by nonca-

seating granulomas of epithelioid histiocytes and multi-nucleated giant cells.53,54 Lymphocyte collections ofvarying degree also may be noted.54 Schaumann andasteroid bodies characteristic of sarcoidosis as well ascaseating necrosis, which is a hallmark of tuberculosis,are lacking.54

Lymphocytic hypophysitis is thought to start as anacute inflammation with symmetric and diffuse enlarge-ment of the gland.15 The severity of the infiltrate variesfrom minimal and focal to diffuse and destructive.35,38

Interstitial fibrosis may be noted and becomes mostprominent with prolonged disease.9 The disease processeventually leads to total replacement of the pituitary tis-sue by fibrosis and the development of empty sella syn-drome.57

Lymphoplasmacytic infiltration of the anterior pitu-itary with occasional lymphoid follicles with pale ger-minal centers is the hallmark of the disease.1 Varyingnumbers of neutrophils, eosinophils, and macrophagesmay be demonstrated.1 The pituitary parenchyma is dif-fusely damaged.1 Selective loss of pituitary cell popula-tions is also reported.15,35 This selective loss is claimedto be a result of immune attack. In cases presenting withisolated corticotropin deficiency,21,47,52 no corticotro-phic cells were demonstrated by immunohistochemistryor electron microscopy.42 Occasional islands of pre-served cells are seen and may be demonstrated by im-munohistochemistry for cytokeratins and hormones.1

Neurohypophyseal tissue may be demonstrated by vaso-pressin, neurophysins, neurofilaments, S-100, and glialfibrillary acidic protein.1

As shown by immunohistochemistry, the infiltrateconsists of a mixed population of T and B cells, with Tcells being more common.17 The T4-to-T8 ratio is re-ported to be 2:1.35 The B cells tend to form follicles.35

FIG. 1. Granulomatous hypophysitis. (A) Diffuse, symmetrical enlargement of the pituitary is noted on T1W nonenhanced coronal MRI. Note thegranular enhancement of the gland and the symmetrical sellar floor. (B)The enlarged pituitary gland appears hypointense on T2W MR images. (C)Thickening of the pituitary stalk is noted with contrast enhancement of the sellar diagphram.



Electron microscopic examination reveals that the in-filtrating cells are mainly plasma cells and lympho-cytes.1,35,58 Degenerative changes are noted in pituitarycells, and the number is reduced.35 A scant numberof secretory granules are noted.1 Oncocytic changes insecretory cells and crinophagy may be noted.1 Interdigi-tation of activated “cytotoxic” lymphocytes with pitu-itary cells is reported, which favors an autoimmune eti-ology.23 No immune complex deposits have beennoted.58

Mixed forms of lymphocytic and granulomatous hy-pophysitis are reported.23

Xanthomatous hypophysitis is characterized by vari-able degrees of lymphocyte infiltration as well by lipid-

laden foamy histiocytes in a well-preserved pituitarygland.20 The lesions tend to be cystic on both MRI andsurgery.6

INCIDENCE

Granulomatous hypophysitis is rare, accounting forless than 1% of all pituitary lesions approached via thetranssphenoidal route,14,54 but rates up to 1.4% havebeen reported. An annual incidence of 1 in 1 million hasbeen reported.6 According to Cheung et al.,6 the meanage at diagnosis is 21.5 years for women and 50 years formen, but patient age ranges from 16 years to 76 years.

Lymphocytic hypophysitis makes up 0.38% to 1.1%

FIG. 2. Lymphocytic hypophysitis. (A) Diffuse, symmetrical, triangle-shaped enlargement of the pituitary gland with suprasellar extension andcompression of the optic apparatus is noted on T1W nonenhanced coronal MRI. The gland appears heterogeneous and slightly hypointense. (B)Diffuse, rather homogeneous enhancement is noted after intravenous gadolinium injection. Note the enhancing sellar diaphragm and sphenoid mucosa.No asymmetry on the sellar floor is seen. (C) T2W coronal image showing the enlarged and hyperintense pituitary gland. (D) Sellar plain x-rayshowing ballooning of the sella, erosion of the dorsum, and posterior clinoids. (E) Enlarged pituitary with suprasellar extension is noted in the sagitalcontrast enhance image. Note the loss of posterior gland high signal and the thickened sphenoid mucosa.



of all cases operated on for sellar pathologic findings.1 Astrong female predilection with a ratio of as much as8.5:1 was reported1; however, the disease has been re-ported in a diverse patient population, including men andpostmenopausal women.6,9,18,19 It is now widely ac-cepted that hypophysitis unrelated to pregnancy is morefrequent than previously thought.6 The typical patient isa young woman during late pregnancy or in the postpar-tum period.6 Forty-seven percent to 62% of patients pres-ent in the peripartum period.10 Despite the strong asso-ciation of lymphocytic hypophysitis with pregnancy anddelivery, no such association is reported with granulo-matous hypophysitis.1 The mean age of presentation inwomen is 34.5 years. In male patients, the entity presentsa decade later, with a mean age of 44.7 years.10

CLINICAL MANIFESTATIONS

As many as 60% of patients present with mass effect.6

Unlike pituitary adenoma, headache is usually accompa-nied by nausea and vomiting and is a common symp-tom.23 Headache and decreased libido are the most com-mon symptoms in male patients.16 Chiasmal compres-sion is common.10 Diplopia has been reported in 6% ofthe cases and is attributed to cavernous sinus involve-ment.10,24,59 Other ocular palsies caused by cavernoussinus involvement have been reported.24 Ocular palsiesin hypophysitis have been shown to be responsive tosteroids.47

Seventy percent of patients present with endocrine ab-normalities.10 Most commonly, a partial or total adeno-hypophyseal insufficiency is noted, and unlike pituitaryadenoma, corticotrophic and thyrotrophic functions aremore commonly affected.10,35,38,60 Most of the earlycases were diagnosed after death in patients who werelost as a result of unrecognized adrenal insuffi-ciency.5,15,38,52 Suggestive cases must be approachedwith a great deal of suspicion, because if unrecognizedand untreated, the disease may result in death as a resultof pituitary insufficiency.6

In pituitary tumors, the size of the tumor is the majordeterminant of the degree of hypopituitarism. In patientswith lymphocytic hypophysitis, the degree of insuffi-ciency is out of proportion to the size of the mass, how-ever.10,23

Even though isolated corticotropin deficiency is rare,it is the most commonly encountered single hormonedeficiency in lymphocytic hypophysitis.15 Isolated thy-roid-stimulating hormone deficiency or selective absenceof gonadotropins has also been reported.15

Giant cell granulomatous hypophysitis most fre-quently presents with pituitary dysfunction. This may

range from single hormonal abnormalities, such as hy-perprolactinemia, to panhypopituitarism.14 Hyperprolac-tinemia is usually of moderate degree and may clinicallypresent as the syndrome of amenorrhea and galactor-rhea.14,54 Markedly elevated levels also may be encoun-tered.14 Hyperprolactinemia is a frequent finding in lym-phocytic hypophysitis and is encountered in 38% ofcases.10,61 It is more common in lymphocytic hypophy-sitis than in idiopathic giant cell granulomatous hy-pophysitis.54 Thodou et al.,31 having documented lacto-trophic hyperactivity and hyperplasia with electron mi-croscopy, reported that this may be a normal finding inpregnancy and the postpartum period. Nevertheless, thistheory fails to explain the hyperprolactinemia in men andpostmenopausal women. Hyperprolactinemia has beenattributed to four mechanisms, including stalk compres-sion by the suprasellar mass,14 direct alteration of dopa-mine receptors by immune attack,1 increased hormoneproduction by stimulating antibodies similar to the onesobserved in Graves disease,62 and destruction of thegland and escape of produced hormone to the circula-tion.1 Lactation failure as a result of reduced prolactinlevels may be seen in the postpartum period and may beeasily confused with Sheehan syndrome.57

Diabetes insipidus with involvement of the neurohy-pophysis, which is most commonly reported in neurosar-coidosis, is an uncommon feature in hypophysitis but isreported in both granulomatous and lymphocytic hy-pophysitis.15,24,63,64 It is reported that as many as 31% ofthe patients with lymphocytic hypophysitis may presentwith a sudden onset of DI.10 Neurohypophyseal dysfunc-tion is reported to result from compression of the poste-rior pituitary or stalk or by direct invasion of the inflam-matory infiltrate.40 In such cases, granulomatous hy-pophysitis or infundibuloneurohypophysitis should bestrongly suspected.

Both lymphocytic and giant cell granulomatous hy-pophysitis have been reported to cause pleocytosis andmeningitis.23,64,65 Patients may present with classic signsand symptoms of meningitis. Cerebrospinal fluid cul-tures are always sterile.23,64,65 A cerebrospinal fluid ex-amination is not reported in every patient in the litera-ture.23 Increased cerebrospinal fluid cells counts withoutassociated aseptic meningitis may be noted in occasionalpatients with lymphocytic hypophysitis.23 Whether pleo-cytosis is secondary to spillage of inflammatory cellsfrom the inflamed pituitary or whether it is a result of thespread of the immune reaction to the cerebrospinal fluidspaces has not been ascertained. An increased erythro-cyte sedimentation rate may also be noted in patientswith hypophysitis.23



DIAGNOSIS

Preoperative diagnosis of primary hypophysitis ischallenging. There are no serologic or biochemical mark-ers.16 Several cases of lymphocytic hypophysitis with apreoperative MRI diagnosis and steroid managementhave been reported.10 In none of the reported cases ofprimary granulomatous hypophysitis was the diagnosismade before surgery.7 The diagnosis of giant cell granu-lomatous hypophysitis is one of exclusion.53

Imaging

Routine radiographic imaging reveals a normal-sizedor symmetrically enlarged sella.23 Erosion of the dorsumor thinning of the sellar floor may be seen.54

Computed tomography only demonstrates an intrasel-lar space-occupying lesion and falls short of distinguish-ing neoplastic disease from inflammation.9,54 Lesionshave been shown to express one of various contrast en-hancement patterns, including homogeneous, patchy, andring-formed patterns, and the degree ranged from sparseto heavy.8,9,14,54

With its superb soft tissue resolution, MRI is themethod of choice for imaging of hypophysitis.23 Preop-erative use of MRI was first reported by Levine at al.66

for lymphocytic hypophysitis and by Pamir et al.54 forgiant cell granulomatous hypophysitis. A diffusely en-larged pituitary gland as seen on MRI is encountered in83% of cases.15 Suprasellar extension is a frequent find-ing.15 The mass is frequently iso- or hypointense to thebrain parenchyma on T1-weighted images and hyperin-tense on T2-weighted images, and it enhances stronglywith contrast, mimicking macroadenomas.7,23 The pat-tern of enhancement is granular, however.54 Lesions maybe cystic, and xanthomatous hypophysitis is more likelyto be cystic than other forms of hypophysitis.22 A nor-mal-sized or even shrunken pituitary may also be seen.10

An empty sella was seen in 7% of cases of granuloma-tous hypophysitis and in 9% of cases of lymphocytichypophysitis. In roughly 9% of cases, imaging was un-remarkable.10

Several findings have been shown to be suggestive ofhypophysitis. A symmetric enlargement of the sellar con-tent was seen in 66% of cases.10 Asymmetric enlarge-ment was seen in only 18% of patients.10 Unlike pituitaryadenomas, which cause an early asymmetric depression,the sellar floor is usually plain in hypophysitis.23 Loss ofposterior gland high signal is frequent.15 Enlargement ofthe neurohypophysis may be noted.15 Radiologic in-

volvement of the posterior pituitary is not always corre-lated with the presence of DI, however.15 Thickening ofthe pituitary stalk or infundibulum is a frequent findingin hypophysitis.8,15,23 Because the pituitary stalk is anextremely rare site for a pituitary adenoma, this finding ishighly suggestive of hypophysitis. It may be seen ingranulomatous or lymphocytic hypophysitis, primarily orin combination with findings suggestive of anterior hy-pophysitis. Thickening was noted in 56% of lymphocytichypophysitis cases and in 66% of granulomatous hy-pophysitis cases.10 Usually, both the stalk and enlargedpituitary tissue enhance homogeneously with contrast.8

A granular pattern may be seen.54 Grossly, heteroge-neous enhancement was seen in 20% and 12% of cases ofgranulomatous and lymphocytic hypophysitis, respec-tively.10 Enhancement of the diaphragma sella and/oradjacent dura7,8 or tongue-like extensions along the basalhypothalamus7,10 are suggestive of hypophysitis. Cav-ernous sinus or hypothalamic involvement was seen inroughly 12% and 8% of lymphocytic and granulomatoushypophysitis cases, respectively.7,10,23,24,67 Ahmadi etal.7 reported that cavernous involvement might result inunilateral or bilateral narrowing of the carotid, mimick-ing the Tolosa-Hunt syndrome.

The presence of enhancing nodular aggregates of epi-thelioid histiocytes in the subarachnoid space is a rarefinding.7

Hypertrophy of the sphenoid sinus mucosa andchanges in the sphenoid bone marrow are frequent find-ings in hypophysitis.8,23 Submucosal contrast enhance-ment on MRI may be noted.7 Whether these changes arerelated to hypophysitis itself or whether they are a coin-cidence is yet to be determined.23

The radiologic appearance closely resembles that of apituitary adenoma; reportedly, most cases were operatedon with a misdiagnosis of pituitary adenoma.3,15,47,54

When combined with clinical suspicion, the presence ofsuggestive findings may be highly suggestive of hy-pophysitis.10 In such cases, a more conservative ap-proach may be favored in comparison to aggressive sur-gery in the absence of any thread to the visual sys-tem.7,10,23

All the aforementioned findings may be encounteredin granulomatous, lymphocytic, and secondary hypophy-sitis and cannot distinguish between these pathologic en-tities.8,53 Honegger et al.23 reported that an isointenseand diffusely enlarged gland with a triangular suprasellarextension and diffuse and homogeneous enhancementaccompanied by enhancement of the diaphragma sella isa rare but pathognomonic feature of lymphocytic hy-pophysitis.



Differential Diagnosis

The most common pituitary mass is adenoma.6 Withfew exceptions, most cases of inflammatory pituitary dis-orders were operated on with a preoperative diagnosis ofpituitary adenoma.7 Other neoplastic pathologic entitiessuch as germinoma, craniopharyngioma, dermoid tumor,and metastasis must also be included in the differentialdiagnosis.6,50

Inflammatory pathologic findings of the pituitary arerare.1,23 Despite their rarity, these entities are of greatdiagnostic importance, because conservative manage-ment may be more rewarding than aggressive surgery.6

A wide variety of causes may result in hypophysitis.Secondary hypophysitis may be caused by bacte-rial,2,6,25–27 fungal, or viral pathogens50 as well as bysystemic inflammatory diseases such as sarcoidosis68–70

and histiocytosis X.5 Systemic diseases such as Wegenergranulomatosis,28 Takayasu disease,6 pyoderma gangra-nosum,29 and Crohn disease6 have rarely been shown toresult in secondary granulomatous hypophysitis in singlecase reports.

Hypophyseal involvement is an exceedingly rare com-plication of tuberculosis.27 It is shown to induce hy-pophysitis either primarily or secondarily from extensionof diffuse basal meningitis.27 The disease mainly causescaseating granulomas, but as in miliary tuberculosis, ca-seation necrosis and the demonstration of acid-fast ba-cilli may not always be possible.26 The radiologic ap-pearance is usually indistinguishable from that of othercauses of hypophysitis with an intrasellar mass andthickened pituitary stalk.27 Other systemic foci are usu-ally lacking in 71% of these patients, but systemic mark-ers of tuberculosis such as an increased erythrocyte sedi-mentation rate and a positive purified protein derivativetest may be found.27

Pituitary apoplexy caused by hypophysitis may befalsely interpreted as Sheehan syndrome.1 In patientswith Sheehan syndrome who lack a clear history of post-partum hemorrhage or sepsis, lymphocytic hypophysitisshould be suspected.57,71 Empty sella, a common findingin Sheehan syndrome, is reported to be rare in inflam-matory hypophysitis.53,57 Diabetes insipidus is an un-common finding in Sheehan syndrome.57

TREATMENT

Medical Therapy

Because of possible lethal consequences, hormone re-placement should be promptly instituted as indicated.1,10

Adrenal and thyroid functions are the main concerns. An

early morning serum cortisol level below 5 �g/dL sug-gests secondary adrenal insufficiency and a level above11 �g/dL excludes it.60 A cosyntropin test should beperformed if the level is 5 �g/dL to 11 �g/dL. A lowserum free thyroxin level suggests secondary hypothy-roidism.60 Replacement should be started by correctingadrenal insufficiency, because levothyroxine therapymay exacerbate adrenal insufficiency.60 Therapy shouldbe continued as long as the insufficiency lasts.

Although the disease is largely accepted to be of au-toimmune origin, anti-inflammatory therapies are notcommonly reported.10 Use of corticosteroids is reported,with variable therapeutic regimens and results to date.10

According to Kristof et al.,10 lasting improvements oc-curred in 15% of cases and transient improvements oc-curred in 62% of cases. Patients should be maintained onsteroid therapy over a long period.23 Relapses were seendays to months after discontinuation of therapy,10 andcases unresponsive to steroid therapy have been re-ported.69

Probably because of the rarity of the entity and thelack of reliable diagnostic parameters, no prospectivecontrolled trials have been reported. Kristof et al.10 re-ported the only trial of high-dose methylprednisolonepulse therapy. A pulse therapy was chosen to reducelong-term sequelae caused by steroid therapy and to dif-ferentiate therapeutic effect from the natural course. Theauthors reported a normalization or improvement of MRIfindings in 88% of their cases. The results appearedwithin 6 weeks in 7 of 15 patients and within 6 monthsin 8 of 15 patients. Improvement in adenohypophysealfunction was seen in 44% of these patients. No relapsesor spontaneous recoveries were detected in the series.Total recovery of hypophyseal function occurred in noneof these patients. Despite its encouraging results, thestudy lacks long-term follow-up, and definitive conclu-sions cannot be made.

Reusch et al.72 reported a 5-day trial of 4 mg/d dexa-methasone in a pregnant woman without any response.The patient underwent decompressive surgery at 27weeks. The authors stressed the fact that steroids do crossthe placental barrier to result in earlier lung maturation.

Tubridy et al.67 reported the successful use of a com-bination of prednisolone and methotrexate after histo-logic confirmation of lymphocytic hypophysitis. The pa-tient had complete symptomatic and radiologic resolu-tion as confirmed by MRI 9 months after therapy.

Steroid therapy has been used in giant cell granulo-matous hypophysitis as well. Kristof et al.53 reported acase unresponsive to a trial of 4 days of 120 mg/kgprednisolone tapered over the next 7 weeks. Neverthe-less, the authors noted that the fibrosis of the entire



gland, proven by histopathology, might be responsiblefor the unresponsiveness of the patient to therapy andthat the giant cell granulomatous hypophysitis should notbe regarded as unresponsive to steroid therapy on thebasis of a single case.17 Only a few reports exist stressingthe importance of timing when initiating steroidtherapy.16,17,46

A trial of steroid therapy seems justified in patientswith a presentation highly suggestive of lymphocytic hy-pophysitis.1,10 Possible causes that may mimic lympho-cytic hypophysitis should be excluded by laboratory in-vestigations.1,6,10,54 In patients with progressive symp-toms, however, surgery should not be withheld.6,15 Thedose, duration, and efficacy of therapy are yet to bedetermined.10,23

Bromocriptine therapy has been shown to reduce thevisual field deficits and lower prolactin levels,1,15 but theeffect on tumor volume has not been documented.1,6,15 Incases where no tumor shrinkage is observed after bro-mocriptine therapy, lymphocytic hypophysitis should besuspected.1

Surgery

Most patients with lymphocytic or granulomatous hy-pophysitis are diagnosed after having been operated onfor suspected pituitary adenoma.7 Preoperative diagnosisis unlikely, except for cases that present during the peri-partum period.15,23,54 Intraoperative pathologic diagnosismay be of value in limiting the surgery to pure biopsyinstead of aggressive removal of potentially salvageablepituitary tissue.15,23

The indications for surgery are intolerable side effectsof steroid therapy, progressive compressive symptoms,uncertainty of diagnosis, and radiologic progres-sion.6,10,15 Transsphenoidal surgery is the method ofchoice and is reported to be both diagnostic and thera-peutic.71

Resolution of symptoms is reported after surgery evenif the removal is incomplete or the lesion is only biop-sied.15,23,71 Incompletely removed lesions should be fol-lowed for recurrence.23. The only case with documentedrecurrence was reported by Nishioka et al.73 after transs-phenoidal biopsy. Instant relief of visual symptoms17 aswell as relief of hyperprolactinemia15,54 and DI73 occursafter surgery but usually without endocrinologic recov-ery.10,53 McGrail et al.71 reported a patient managed bytranssphenoidal biopsy, who showed total hormonal re-covery 1 year after the operation.

Complications such as worsening of the visual fielddeficits or worsening hypopituitarism are reported to oc-cur.6 Honegger et al.23 stressed that manipulations above

the sellar entrance must be avoided because they carrythe risk of damage to suprasellar structures.

PROGNOSIS

The natural course of lymphocytic hypophysitis ishighly variable and poorly understood.73 Long-term fol-low-up has rarely been reported. Spontaneous resolutionof both the mass effect and hypopituitarism has beenreported1,6,71,74 as well as late relapse after documentedregression.73 Naik et al.75 reported persistent pituitaryenlargement after 10 years. The overall prognosis isgood, however, with complications. Despite effectivetherapy and clinical response, most patients fail to re-cover endocrinologically because of the destructive na-ture of the disease process.10,53 Thodou et al.15 reportedthat 19% of their patients suffered fatal complications asa result of severe and permanent hypopituitarism. Prompthormone replacement is needed in such cases.1

The impact of subsequent pregnancies on the course oflymphocytic hypophysitis is not well established.76 Sixcases of spontaneous pregnancies in patients with previ-ous lymphocytic hypophysitis were reported.76 Hayesand McKenna76 reported a patient with presumed post-partum lymphocytic hypophysitis, who was managed bysteroids alone with complete radiologic response. Theirpatient did not have tissue confirmation of lymphocytichypophysitis, but her first radiologic presentation wasconsistent with lymphocytic hypophysitis. This patientreportedly gave birth to a healthy infant and had no re-currence as confirmed by computed tomographic imag-ing. Five additional cases were reported in the literaturewith hypopituitarism as a result of lymphocytic hy-pophysitis.77 All these patients received human meno-pausal gonadotropin/human chorionic gonadotropintherapy for ovulation induction in addition to hormonereplacement therapy. Neither the new pregnancies northe uncomplicated deliveries resulted in disease re-lapse.76,77

Nishioka et al.73 reported a postmenopausal womanwho presented with central DI, was successfully man-aged by transsphenoidal biopsy with radiologic and clini-cal remission, and had a recurrence 28 months after theinitial biopsy. The relapse resulted in optic compressionbut was successfully managed by steroid therapy withradiologically documented volume reduction.

CONCLUSION

Inflammatory disorders of the pituitary are rare disor-ders. Three forms of primary hypophysitis are described:granulomatous, lymphocytic, and xanthomatous hy-



pophysitis. Current knowledge does not allow us to dis-tinguish between these entities before surgery.

Primary idiopathic granulomatous hypophysitis is acryptogenic inflammatory lesion of the pituitary clini-cally resembling lymphocytic hypophysitis, but it is epi-demiologically distinct. The diagnosis rests on elimina-tion of causes that may result in secondary granuloma-tous hypophysitis. Lymphocytic hypophysitis is achronic autoimmune disorder of the anterior and, rarely,posterior pituitary that clinically and radiologically mim-ics pituitary adenomas. The disease most commonlypresents with compressive symptoms caused by pituitaryenlargement and with potentially lethal pituitary insuffi-ciency. Although it is most commonly seen in peripartumwomen, it may be encountered in either sex and may beassociated with other autoimmune diseases. Xanthoma-tous hypophysitis is the least common form of primaryhypophysitis and is characterized by its tendency to becystic. An infectious etiology is suspected. However, theentity has been described fairly recently and only a fewcases have been reported, precluding sufficient data for aclear description.

Transsphenoidal surgery with removal of the inflamedtissue induces an instant response, with disappearance ofneurologic symptoms, including hyperprolactinemia andDI. Potentially viable pituitary tissue is lost, however. Asimple diagnostic biopsy may be considered for tissuepreservation, but pituitary insufficiency almost alwayspersists after the operation whether the surgery is aggres-sive or conservative.

Response to medical therapy is unpredictable; how-ever, a total response is not uncommonly reported andjustifies a therapeutic trial. If a preoperative diagnosiscan be made with considerable certainty, a trial of ste-roids is justified and may allow for preservation of po-tentially functional pituitary tissue. Consensus regardingdrug choice, timing, duration, and dosage of therapy islacking.

The natural course of these rare disorders is currentlyunknown, and the prognosis is unpredictable.

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