ACTH-Producing Pituitary Cancer: Experience at theKing Faisal Specialist Hospital & Research Centre Corticotropin-Producing Pituitary Carcinoma

Ahmed et al.

Mohammed Ahmed1, Imaddudin Kanaan2,Abdullah Alari~1, Ebtessam Ba-Essa1,Muhammad Saleem3, Asma Tulbah4,Peter McArthur3, and Richard Hessler4

1Departments of Medicine, 2Neurosciences, 3Surgery, and4Pathology & Laboratory4, King Faisal Specialist Hospital &Research Centre, Riyadh, Kingdom of Saudi Arabia

Abstract. Pituitary gland is an uncommon site of a primary

cancer. Of more than 600 cases of pituitary tumors seen at

the KFSH&RC between 1975 to 1998 only 3 patients had

primary pituitary cancer. We have previously reported a

case of pituitary ~brosarcoma arising as a rare compli-

cation of external radiotherapy (ERT) for GH-secreting

pituitary adenoma (PA) [1]. We report now 2 cases of

ACTH-producing primary pituitary carcinoma (ACTH-PPC);

their follow-up data provide information on the natural

history of this cancer. Patient #1; a 46 year old lady with

Cushing’s disease (CD) presented with an enlarged right

cervical lymph node (LN) 2 years after having undergone a

partial hypophysectomy through transsphenoidal surgery

(PHYPX/TSS) and ERT for an invasive pituitary tumor. Pa-

tient #2; a 26 year old man presented with CD and under-

went bilateral adrenalectomy (ADx) and pituitary ERT.

Thirty-nine months later he developed Nelson’s syndrome

and a PHYPX/TSS was performed. Incidentally discovered

hepatic metastases in this patient and an excisional biopsy

of the LN in patient #1 showed histological features very

similar to the pituitary tumor, and they stained strongly

positive for ACTH. Perinuclear spherical hyalinized cyto-

plasmic inclusions were seen in the LN biopsy that corre-

sponded to bundles of type 1 micro~laments (speci~c for

pituitary ACTH-producing cells) seen by electron micros-

copy. A whole body 18-Fluoro-2-Deoxy-D-Glucose positron

emission (FDG-PET) scanning, showed an intense uptake in

the neck mass. A trial of octreotide did not change the

exceedingly high levels of ACTH in patient #2, further sup-

porting the diagnosis of ACTH-PPC. The clinical course of

102 months prior to his demise showed continued progres-

sion of the primary and the metastatic tumor. Patient #1, is

alive at 15 months follow-up; hypercortisolemia is control-

led using ketoconazole. ACTH-PPC should be entertained

in a patient with CD presenting with persistent cervical

lymphadenopathy. The clinical course in our patients sug-

gests that the emergence of PC may involve a proliferative

continuum from a pre-existing PA to an invasive tumor,

culminating in a carcinoma. Adjunctive events such as

ERT/ADx may predispose to the evolution of PC in geneti-

cally susceptible individuals. Because ERT is an effective

treatment for PA its use will continue; it is important to be

aware of the possible complication of primary pituitary

carcinoma.

Keywords. pituitary cancer, corticotropin-producing pitui-

tary carcinoma

Introduction

Primary pituitary cancer (PPC) is an uncommon clini-cal encounter [1–6]. Many aspects of the natural his-tory of this tumor have remained unanswered. Gather-ing clinical and follow-up data in all such cases is crucialto improve the diagnosis and management of pituitarymalignancies.

We report two cases of ACTH-producing PPC caus-ing Cushing’s disease (CD); it had metastasized to thecervical lymph node in one case and to the liver in theother. These cases underscore the vagaries confrontedin clinical presentation of ACTH-PPC, and a need foran awareness in the diagnosis. They also elucidate im-portant events in the pathogenesis of pituitary cancerwhich have implications in patient management. As-pects of management including improvement in thequality of life are also discussed.

Case ReportsCase #1

A 46-year-old married lady presented to the Head andNeck Clinic at King Faisal Specialist Hospital and Re-search Centre with a six-month history of a painlessprogressively enlarging swelling of the right neck. Shealso complained of a generalized increasing pigmenta-tion, an increase in facial and body hair, amenorrhea,easy bruising, fatigue, and dif~culty in climbing stairs.She was diagnosed as a Type II diabetic six years agoand had been treated initially using Glibenclamide andsubsequently, switched to insulin because of deterio-rating glycemic control with blood glucose values in-

Pituitary 2000;3:105–112

© Kluwer Academic Publishers. Boston. Printed in U.S.A.

105

Presented as an Abstract (P1-132) at the 81st Annual Meeting ofthe Endocrine Society, San Diego, California, June 1999.

Address correspondence to: Mohammed Ahmed, M.D., FACP,FACE, Consultant Endocrinologist, Department of Medicine(MBC-46), King Faisal Specialist Hospital and Research CentreP.O. Box 3354, Riyadh 11211, Saudi Arabia. Fax: (966-1) 442-7499; E-mail: ahmed@kfshrc.edu.sa

creasing to 23 mmol/L. There was no history of headache, deterioration of vision, or galactorrhea. She de-nied smoking or use of alcohol, and denied use of ster-oids in any form. Two years ago, she had undergone atranssphenoidal partial hypophysectomy, followed byexternal radiation treatment (speci~cs could not be as-certained) at a hospital at another country, for a largeinvasive pituitary tumor. We were able to obtain thepreoperative MRI ~lms to con~rm this diagnosis andalso con~rmed the histological diagnosis of a pituitarytumor. Following immunohistochemical staining of thehistological material obtained from the other hospital,we found the tumor to be diffusely and strongly posi-tive for ACTH.

On examination, she had features of CD consistingof a buffalo hump over the back of the neck, centralobesity, thin extremities, thin ecchymotic skin, in-creased pigmentation especially over the exposed ar-eas, and hirsutism. She weighed 66 kg., stood 156 cm.tall, BP was 150/75 mmHg. She had a 435 cm ~rm,non-tender right neck mass and proximal myopathy.The rest of the examination including ear, nose, throat,thyroid, breasts, visual ~elds, fundi, and nervous sys-tem were within all normal limits.

Methods: A ~ne needle aspiration biopsy (FNAB) ofthe neck mass showed clusters of neoplastic cells witheccentric nuclei and prominent nucleoli, consistentwith a neuroendocrine tumor. On immunohistochemi-cal staining these cells were strongly positive forsynaptophysin. These ~ndings indicated a metastaticneuroendocrine tumor to the cervical lymph node.

Imaging studies: CT scanning of the neck massshowed a 2.5 3 3 cm homogenous lymph node mass(Fig. 1). MRI imaging of the pituitary fossa revealed an

intrasellar mass with infrasellar extension. A wholebody positron emission tomography (PET) scanning,using 10 mCi (370 MBq) 18-_uoro-2-Deoxy-D-Glucose(FDG), showed a very intense uptake of the FDG in theright neck mass, indicative of a metabolically activelesion (Fig. 2). However, no activity of the pituitarylesion could be detected on the PET scanning. CT scan-ning of the chest, abdomen and pelvis and a whole bodyscanning using I123-metaiodobenzyleguanidine (MIBG)were done to detect a potential extrapituitary neuro-endocrine tumor; these showed no abnormal ~ndings.

Hormonal studies: serum cortisol values were ab-normally high and showed a loss of diurnal variation.Morning cortisol sample, 699 (reference range 120–620nmol/L) and a late afternoon sample, 841 (85–460nmol/L), 24-hour urinary free cortisol, 1500 (50–350nmol/L), morning plasma ACTH, 96 and 207 (0–70pg/L). There was only a partial (20%) suppression ofserum cortisol (from 841 to 671 nmol/L) following anovernight 1 mg dexamethasone and only a 30% sup-pression of serum cortisol (from 699 to 484 nmol/L),following administration of a high dose overnight 8 mgdexamethasone. The following hormonal studies werewithin normal limits: Serum free T4 15.4 (11–23pmol/L), T3 1.1 (1.0–2.5 nmol/L), TSH 5.4 (0.35–5.5mu/L), serum estradiol 466 (90–680 pmol/L), LH 8(1.9–33.4 IU/L), FSH 10 (1.9–33.4 IU/L), Prolactin 14(2.8–29.2 lg/L), serum calcitonin (,2 pg/ml).

Other investigations: Serum alphafetoprotein, 3(0–15 Ug/L), CEA 2.6 (0–5 lg/L), urinary 5 hydroxyin-doleacetic acid screen was negative. Fasting blood glu-cose ranged 10.3–20.9 mmol/L (3.0–6.9 mmol/L),HbAIC 0.139 (0.048–0.078), creatinine 77(45–100

Fig. 1. CT scan of neck, axial view, with contrast enhancementshows a 2.5 3 3 cm homogenous lymph node mass (T) repre-senting metastases from ACTH-producing pituitary cancer.

Fig. 2. A whole body positron emission tomography scan us-ing 18-_uoro-2-Deoxy-D-Glucose (FDG), shows an intense up-take of FDG in the right neck mass of metastatic ACTH-pro-ducing pituitary tumor.

106 Ahmed et al.

umol/L), creatinine clearance 0.9 (1.3–2.1 ml/Sec), se-rum sodium, 138 (135–147 mmol/L), potassium 4.2(3.5–5.0 mmol/L). Liver function tests, consisting ofALT 16 (10–50IU/L), AST 11 (10–45 IU/L), total biliru-bin 7 (0–21 umol/L), total proteins 67 (65–81 G/L), werenormal; total cholesterol 6.6 (3.0–5.2 mmol/L), completeblood picture: Hemoglobin 111 (118–148 G/L), redblood cell count 4.1 (4.5–5.2 3 10312/L); total whiteand differential white cell counts were normal.

An excisional biopsy of the right neck mass wascarried out. It was histologically con~rmed as a neuro-endocrine tumor in a cervical lymph node with histo-logical features very similar to the pituitary tumor. Bylight microscopy, both the primary tumor in the sellaand the lymph node metastases (Fig. 3A) were com-posed of a solid growth of chromophobe cells withprominent nucleoli and abundant cytoplasma. In manycells, perinuclear spherical hyalinized cytoplasmic in-clusions were seen that corresponded to bundles ofType 1 micro~laments seen by electron microscopy.These micro~laments are considered to be speci~c forpituitary ACTH-producing cells. Mitoses were presentbut infrequent. Foci of micronecrosis were present inthe metastatic lesion. On immunohistochemical stain-ing, the tumor cells were strongly positive for ACTH(Fig. 3B), chromogranin, synaptophysin (not shown)and showed negative staining for calcitonin.

Ultrastructural studies of the FNAB demonstratedepitheloid cells with scant neurosecretory granulesand central spherical bundles of ~laments (Fig. 4);higher magni~cation demonstrated the ~laments to beconsistent with type I micro~laments (Fig. 4 [insert]).

Clinical course: Postoperatively, patient was startedon ketaconazole 200 mg BID (to control hypercorti-solemia), in conjunction with hydrocortisone 20 mg inthe morning and 10 mg in the evening. The morningserum cortisol returned to normal limits (125–291nmol/L) with plasma ACTH of 67 pg/L. Her blood glu-cose values normalized with the use of combination ofregular and NPH insulin used twice daily. She did notwish to receive further treatment for the pituitary tu-mor. The patient is currently alive with remission inclinical signs of CD.

Case #2

A 26-year-old Saudi male was admitted with classicalclinical features of Cushing’s syndrome (CS). Evalu-ation had revealed hypercortisolism with loss of diur-nal rhythm. At 0700 hours serum cortisol value was1413 (reference range 138–690 nmol/L) and at 1900hours it was 1236 (reference range 69–348 nmol/L).There was a failure of suppression of serum cortisolfollowing administration of 8 mg Dexamethasone at2300 hours (baseline serum cortisol 1258 nmol/L andpost Dexamethasone value remained unchanged), anda 24-hour urinary free cortisol value was elevated at12559 (30–300 nmol/d). Plasma ACTH value at 0700

hours remained unsuppressed at 7.7 (reference up2.2–17.6 pmol/L). Serum electrolytes were repeatedlywithin normal limits as also the chest x-rays. A CT scanof the adrenal glands revealed bilateral hyperplasia,with the rest of the intra-abdominal organs including

Fig. 3. (A) H & E section of the neck mass demonstrates amonomorphic population of epitheliod tumor cells with promi-nent nucleoli and abundant, chromophobic cytoplasm. Manycells contained spherical, hyalinized cytoplasmia inclusions (ar-rowhead) corresponding to Type 1 micro~laments seen by elec-tron microscopy (not shown) (Hemotoxylin and Eosin 3400).(B) Immunohistochemical staining for ACTH demonstratesstrong cytoplasmic staining in the majority of cells within the tu-mor nodules (arrow) in contrast to the adjacent unstained con-nective tissue. (ACTH immunohistochemistry 3400).

Corticotropin-Producing Pituitary Carcinoma 107

liver appearing normal; CT of the pituitary glandshowed a macroadenoma measuring 20 mm with su-prasellar and parasellar extension into the right cav-ernous sinus (Fig. 5). The patient became acutely sickwith salmonella sepsis which responded to the admini-stration of IV ampicillin and gentamycin. A trial of

octreotide 200 micrograms every 8 hours s.c. for 3 daysfailed to induce a change in plasma ACTH value at 11pmol/L. Interim treatment consisting of metyraponeadministration 750 mg every 6 hours resulted in a de-crease in AM serum cortisol value to 267 and the PMvalue to 243 nmol/L. The patient declined pituitarysurgery and a bilateral adrenalectomy was done 6weeks following the initial presentation; histologicalexamination con~rmed bilateral adrenal cortical hy-perplasia. External radiotherapy by linear accelerator(6 MV) was used to administer 5040 cGy over 49 daysin 28 fractions to the right and left lateral pituitaryfossa in a parallel pair in an attempt to prevent furtherenlargement of the pituitary tumor following adrenal-ectomy.

Follow-up course

Twelve months later, the pituitary tumor remained un-changed on CT scan; however, the plasma ACTH levelhad increased to 32.6 pmol/L with a serum cortisolvalue of 551.8 nmol/L (on replacement hydrocortisone).Twenty-four months post adrenalectomy, CT scan re-vealed a signi~cant decrease in size of the tumor whichwas now intrasellar and remained so for a year (Figurenot shown). However, 39 months following adrenalec-tomy, a major increase in the size (15 mm) with su-

Fig. 4. Ultrastructural studies on the ~ne needle aspirate material demonstrates epitheloid cells with scant neurosecretory granulesand central, spherical bundles of ~laments (bar 5 2 micrometers). Higher magni~cation (insert) demonstrates the ~laments to be con-sistent with type 1 micro~laments. (bar 5 1 micrometer).

Fig. 5. CT scan (coronal view, contrast enhancement) showsan enhancing tumor of the pituitary gland, measuring 20 mm,extending into the suprasellar cistern (arrow), and the rightcavernous sinus (arrow head).

108 Ahmed et al.

prasellar extension was seen; plasma ACTH level in-creased to values ranging from 346–881 pmol/L with amarked increased in skin pigmentation.

A month later, the patient agreed and underwenttranssphenoidal surgery with partial removal of thetumor; histopathological ~ndings are shown in Figure6. The tumor was strongly and diffusely positive forACTH on immunoperoxidase staining. The postopera-tive course was complicated by diabetes insipidus andcerebrospinal _uid leak. Postoperatively, panhypo-pituitarism was documented as follows: serum free T4, 6 (NR 11–25 pmol/L), TSH , 0.1 (NR 0.2–5 mu/L),testosterone , 0.4 (NR 10–40 nmol/L) LH and FSH ,1 IU/L each and prolactin , 3 ug/L (NR 1.1–21). Thepatient received hormonal replacement therapy con-sisting of L-thyroxine, Depo-Testosterone, andDDAVP for central diabetes insipidus; hydrocortisone20 mg every morning and 10 mg every evening, andFlorinef 0.1 mg everyday were continued.

Following detection of an abnormal serum creat-inine (133–156: Ref 40–105 lmolL), an ultrasound (US)of the abdomen was done which showed normal sizedkidneys but incidental ~ndings of multiple hyperechoichepatic lesions varying from 7 mm to 35 mm in sizewere noted (Figure not shown).

Further clinical course

Five months later, plasma ACTH had increased to12772 pmol/L and 10 months later CT scan showed anincrease in the size of the tumor with extension into thesuprasella, laterally into the cavernous sinus and in-feriorly into the sphenoid sinus (Figure not shown). Afollow-up U/S study showed that the lesion in the leftlobe of liver had increased to 4.2 3 3.6 3 4 cm andCT-guided tru-cut needle biopsy of the lesion showedit to be a neuroendocrine carcinoma, cytologically re-sembling the pituitary tumor (Figure not shown);

many liver tumor cells stained very densely positivefor ACTH. Further investigations were directed atuncovering another potential primary tumor produc-ing ACTH and metastasizing to the liver. Computedtomography scans of chest, abdomen, and pelvis werenormal. A total body MIBG I123 scan was negative anda bone scan ~ndings were consistent with aseptic ne-crosis of femoral heads with no evidence of metastaticlesions. The 24-hour urinary 5-hydroxyindoleaceticacid was 53 (NR 53–209 lmol/d). Plasma ACTH levelsremained elevated at 1629.5 pmol/L.

Terminal course

A follow-up US study done 20 months later showed aninterval increase in the number (about 14) and size (upto 5.6 cm in the left lobe) of liver nodules with cysticdegeneration of a nodule in the right lobe. A CT scan ofthe pituitary done at this time (75 months followingadrenalectomy) showed a new tumor nodule in the rightchiasmal area with tumor extension into right cavern-ous sinus; 2 months later there was a further increase inthe supra-, infra-, and parasellar components of the tu-mor (Figure not shown). The patient remained asymp-tomatic for the next 8 months, except for anorexia andweight loss of 8 kg and he continued to work as a secu-rity guard at a bank for 8 hours a day until 90 monthsfrom the initial presentation. Investigations done amonth later for personality changes and confused men-tal status included absence of clinical or biochemicalstigmata of liver decompensation, a negative toxicologyscreening, and no further change in size of the pituitarytumor on CT scan. The possibility of hypothalamic com-pression was entertained but remained unproved. Thepatient was last seen 6 months later; he remained con-fused, emaciated, anorexic, and weighed only 35 kg. Afollow-up CT scan showed signi~cant tumor progres-sion (Fig. 7). The patient died ~ve months later (102months following the initial presentation).

Fig. 6. Microscopic examination of the pituitary neoplasm(hematoxylin and eosin; 3200 magni~cation); cells arrangedin a diffuse pattern. They are polygonal with round nuclei andvariable amounts of acidophilic and amphophilic cytoplasm.There is mild nuclear pleomorphism. Rare mitoses are seen.

Fig. 7. CT scan (coronal view, contrast enhancement) shows amarked interval increase in the size of the pituitary tumorobliterating the third ventricle and in~ltrating the base of theskull.

Corticotropin-Producing Pituitary Carcinoma 109

Discussion

Two patients described here had Cushing’s disease(CD) secondary to an ACTH-producing invasive pitui-tary tumor that had metastasized to the cervical lymphnode in one case and to the liver in the other case withNelson’s syndrome. The histological features of the me-tastatic lesions resembled the pituitary tumors in bothpatients. On immunohistochemical staining the metas-tatic tumors were also strongly positive for ACTH. Anextensive search revealed no evidence of any otherprimary tumor. These criteria ful~ll eminently, an equi-vocal diagnosis of an ACTH-producing PPC in bothcases.

Pituitary carcinoma (PC) ful~lling the strict criteriaof metastases to the extracranial region or the cerebro-spinal space are rare and account for less than 1% of allpituitary tumors [2–6]. It represented six of the 3000pituitary tumors (0.2%) resected between 1955 to 1994at the Mayo Clinic [3]. Ninety-~ve cases of PC had beenreported in the English literature up to April 1998,inclusive of the 15 cases collectively reported betweenfour major tertiary care centers (Mayo Clinic, St.Michael’s Hospital, Toronto, University of Alabama,and Brigham and Women’s Hospital, Boston) [2–14]. Ofthese 30 (31.6%) were considered as “clinically silent,”and 65 (68.4%) as hormone-producing [4]. Since manyof the former were described prior to the routine useof serum prolactin or immunochemistry, it is likely thatthe true frequency of the hormone-producing tumorshas been underestimated. Of the reported hormonallyactive tumors, prolactin-producing carcinomas accountfor the commonest subtype (25; 26%), followed byACTH producing (24; 25%), GH-producing (13; 14%),and one each of the TSH-secreting and gonadotropin-producing types [2–14]. With the inclusion of our casesthe total number of PC becomes 97 of which theACTH-producing subtype accounts for 26. Of the pre-viously reported cases at least 5 (19%) occurred in thecontext of Nelson’s syndrome [3–10].

It is generally agreed that distant metastasesshould be documented as a prerequisite to establishthe diagnosis of a pituitary carcinoma. Excluding in-tracranial metastases, the liver is the frequent site ofmetastases from PC [10,11]. Other sites of systemicmetastases include lungs, bones, lymph nodes, kidney,heart and tonsils [10–14]. In 75% cases, metastatic le-sions were diagnosed only at postmortem examination[10–12]. This suggests that the true frequency of ma-lignant pituitary neoplasms may be greater than hasbeen realized. Lymph node metastases (LNM) havebeen previously reported in at least 14 other cases[3,5,10,13,14]. The duration of illness, as also the chro-nologies of extracranial metastases in these cases werehighly variable, ranging between 7 weeks to 17 years[3,5,10,13,14]. Of these, LNM only, such as in our case#1, was documented in six cases with additional extra-nodal lesions occurring in the other eight cases re-ported previously [3,5,10,13,14]. The primary tumor

was reported as “chromophobe” in 6, “undifferenti-ated” in 2, prolactinomas in 2, growth hormone-produc-ing in 1, ACTH-producing in 1, “non-functioning” in 1,“acidophilic stem cell adenoma” in 1 [3,5,10,13,14].FNAB was undertaken for diagnosis of cervical LNMin two previous cases [5], as was the case in our patient.These cases illustrate the important role of the FNABin the investigation of enlarged lymph nodes in pa-tients with known/ suspected underlying neuroendo-crine malignancies. Nevertheless, the distinction be-tween PPC metastatic to the cervical LN and othertumors has been challenging [5].

Following bilateral adrenalectomy, patients withCD may develop rapidly growing pituitary adenoma orexperience expansion of a previous tumor. This is asso-ciated with production of large quantities of ACTH;serum ACTH rises to abnormal levels and the patientbecomes hyperpigmented. This was ~rst described byNelson [15]. It was considered that our patient #2 haddeveloped Nelson’s syndrome despite pituitary irra-diation. External irradiation of pituitary prior to orfollowing adrenalectomy is thought to help preventNelson’s syndrome in some patients [16,17], however,others disagree [18]. Most pituitary tumors in Cush-ing’s disease are benign adenomas. A few are invasiveand a very few are malignant [17]. Patients remain atrisk inde~nitely of developing Nelson’s syndrome afteradrenalectomy. Pituitary tumors may manifest afterintervals ranging from 6 months to 16 years (mean 7.4years) [17]. Complete removal of such invasive tumorsis often dif~cult, and recurrence is common.

It is noteworthy that patient #2 had very high levelsof urinary cortisol and demonstrated failure of serumcortisol suppression following the overnight 8 mg dex-amethasone administration, features that are unusualfor Cushing’s disease. The possibility of PC was enter-tained initially when a major increase in the size ofpituitary tumor and plasma ACTH occurred, some 39months postadrenactomy. Although metastatic diseasewas diagnosed at least 54 months prior to his demise,the possibility of PC at initial presentation cannot beruled out.

Ante-mortem diagnosis of metastases was made inonly 25% of ACTH-secreting carcinomas [17]. Therehave been at least fourteen de~nitely identi~able casesof Cushing’s disease secondary to ACTH-PPC re-ported previously [10]. None had evident metastasesinitially and patients survived for 4 to 6 years followingthe diagnosis [10,11]. The majority of these patientshad macroadenomas diagnosed at presentation render-ing the outcome to be unsuccessful either by surgicaland/or irradiational intervention [10]. Pituitary sur-gery is the primary therapeutic modality for PC inorder to relieve compressive symptoms and to provideaccurate diagnosis. Pituitary surgical procedures arecurative only very rarely, do not necessarily in_uencethe possibility of metastatic spread and incomplete re-section may result in recurrent disease. Despite theselimitations the preferred treatment remains surgical

110 Ahmed et al.

removal of the PC. However, patient #2 had declinedthis option.

Although many patients have survived for up toseveral years following the diagnosis, their quality oflife (QOL) has been compromised. The QOL can beimproved using ketoconazole, as in our patient #1. Thisdrug has been effective in the treatment of patientswith CD who either refuse surgery or in whom surgeryor external treatment irradiation have proved unsuc-cessful [19]. Ketoconazole is an antimycotic agent thatdecreases serum cortisol by inhibiting cholesterol syn-thesis through blockade of the 14-demethylation oflanosterol [19]. This drug may also inhibit 11-hydroxy-lation, and may decrease the binding of glucocorticoidto its receptor [19].

The challenge in the diagnosis of PPC is com-pounded by the dif~culties in distinguishing clinicallyor histologically alone, a primary pituitary carcinomafrom one metastasizing to the pituitary gland, evenfollowing the resection of the lesion [5,6]. Metastases tothe pituitary gland has been confused with a primarypituitary cancer [5,20].

A de~nitive diagnosis of PC is made using investiga-tive modalities consisting of immunohistochemicalstaining, gel ~ltration chromatography for ACTH/CRHor northern blot analysis for detection of mRNA forACTH/CRH in both the primary pituitary tumor, andthe metastases [12].

PPC are clonal in origin [12]. The pathogenesis ofpituitary tumors may involve a proliferative contin-uum originating as benign adenoma, to invasive tumoreventuating in carcinoma. Alternatively, benign ade-noma and invasive adenoma/carcinoma may representdistinct clinical entities arising de novo. Factors sup-portive of the concept of an evolution of a carcinomafrom an adenoma include the following: most aremacroadenoma/invasive tumor at initial diagnosis, along latency period (mean duration 6.5 years betweenthe diagnosis of adenoma and the occurrence of metas-tases) and more frequent and abundant occurrence ofmitotic activity in PC which is an uncommon ~nding innoninvasive and invasive adenoma [3]. An expressionof Ki-67 antigen, a proliferating marker selectively ex-pressed during G1, S1, and M phases of the cell cycle(MIB-1) and proliferating cell nuclear antigen (PCNA;an auxiliary protein of DNA polymerase synthesized inthe late G1 and S1 phases of the cell cycle) labelingindices were reported to be higher in the majority ofPC compared with the adenoma, and were detected inall metastases examined [3]. These indices of cell pro-liferation are generally associated with tumor inva-siveness or recurrence.

Allelic loss of the retinoblastoma tumor suppressorgene has been identi~ed in malignant and invasive pi-tuitary tumors, but not in the benign adenomas [20].Additionally, activation and over-expression of rasgenes may play a role in the acquisition of invasive andmetastatic potentials by a tumor. In vivo, ras activationmay be an early event in cellular transformation sug-

gesting that additional events are necessary for metas-tatic behavior [20]. ERT and/or adrenalectomy havebeen suggested as possible factors for malignant trans-formation of a pituitary tumor [1,2,10,11] and may rep-resent such adjunct events. It is noteworthy that pitui-tary cancer had emerged in several patients who wereadministered ERT to the pituitary tumor and had un-dergone adrenalectomy as well [3,10]. It is evident thatmultiple molecular events are responsible in the evolu-tion of PPC. Our patients had received ERT to thepituitary and such an intervention may carry the riskof malignant transformation of a preexisting macro/in-vasive pituitary tumor. Because irradiation is an effec-tive treatment for pituitary tumors and the occurrenceof malignancy could only be a rare potential complica-tion, its use will continue. It is nevertheless importantto be aware of such an occurrence. Early diagnosis andappropriate interventional measures are necessary inan attempt to improve the QOL.

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