Pituitary Fibrosarcoma and Prolactinoma with Neuronal Metaplasia 149Case Report

149

Department of Pathology(MM, CG, BWS, RVL),Mayo Clinic, Rochester, MN,Departments of Pathology (PR),Endocrinology (CE),and Neurosurgery (AJL),Auckland Hospital, Auckland,New Zealand and St. Michael’sHospital (KK), University ofToronto, Toronto, ON, Canada

Address correspondence toDr. Bernd W. Scheithauer,Department of Pathologyand Laboratory Medicine,200 First Street, SW,Rochester, MN 55905, USA.E-mail: scheithauer.bernd@mayo.edu

Endocrine Pathology, vol. 15,no. 2, 149–158, Summer 2004© Copyright 2004 by HumanaPress Inc. All rights of anynature whatsoever reserved.1046–3976/04/15:149–158/$25.00

Combined Sellar Fibrosarcoma and Prolactinomawith Neuronal Metaplasia:Report of a Case Unassociated with Radiotherapy

Mario Moro, Caterina Giannini, Bernd W. Scheithauer,Ricardo V. Lloyd, Paul Restall, Carl Eagleton, Andrew J. Law,and Kalman Kovacs

AbstractWe report the occurrence of a primary pituitary fibrosarcoma causally unrelated toradiotherapy, admixed in association with a prolactin cell pituitary adenoma showingneuronal metaplasia. These unique findings were associated with multiple endocrineneoplasia type 1 (MEN 1).Primary fibrosarcoma involving the sella is a very rare tumor. The majority of cases havebeen associated with prior irradiation of either a pituitary adenoma or a craniopharyn-gioma. Pituitary adenoma with neuronal metaplasia is also rare and usually occurs in thesetting of acromegaly. Despite the intimate association of both elements in our lesion,no transition of adenoma to sarcoma was demonstrable by immunohistochemistry orin situ hybridization studies.Key Words: Pituitary fibrosarcoma; prolactin cell adenoma with neuronal metaplasia;pituitary adenoma/neuronal choristoma (PANCH).

these lesions has been variably referred toas intrasellar gangliocytoma, ganglioglioma,neuronal hamartoma, and choristoma.Recent morphologic evidence suggests thatthe neuronal component accompanyingpituitary adenomas has its origin in neu-ronal metaplasia of the neoplastic adenomacells [15,17,50]. Such tumors are very rare:fewer than 60 adenomas and only onepituitary carcinoma [52] with neuronalmetaplasia have been reported. The mostcommonly associated endocrine disorderis acromegaly, but examples with Cushing’sdisease or hyperprolactinemia have alsobeen described. Two patients having apituitary adenoma with neuronal metapla-sia were affected by multiple endocrine neo-plasia type 1 (MEN 1) [30,50]. Pituitary

Introduction

Primary pituitary sarcomas, mainlyfibrosarcoma and osteogenic sarcoma, arevery uncommon. The majority are post-irradiation sarcomas that occur after treat-ment of sellar region neoplasms, mainlypituitary adenomas and craniopharyngio-mas [2,40,42,43,45,56,61,66]. Fibrosarco-mas unrelated to previous radiotherapy arerare [31,37,68].

Although with rare exceptions [18], thepituitary gland does not contain neurons.However, pituitary tumors composedpartly or entirely of neuronal cells havebeen reported [1,4–11,14,15,17,19–22,27,29,30,33–36,38,44,46,48,49,51–55,58,59,63,65]. The neuronal element of

150 Endocrine Pathology Volume 15, Number 2 Summer 2004

adenomas are a part of MEN 1, a syndromethat also includes parathyroid and pancre-atic endocrine tumors. Among the pitu-itary adenoma subtypes seen associatedwith MEN 1, prolactinomas are the mostfrequent, followed by GH-secreting,ACTH, producing, and non-functioningtumors [13,30,32,39,50].

Herein, we report a unique example ofan MEN 1-associated pituitary prolactincell adenoma exhibiting neuronal metapla-sia and intimately associated with fibrosa-rcoma to form a “composite tumor.”

Case Report

The patient, a 33-yr-old male, first cameto medical attention in 1991 when he pre-sented with a perforated duodenal ulcer.His serum gastrin level was 5240 pmol/L(N<75 pmol/L). Although a CT scan ofthe abdomen was negative, angiographydisclosed several highly vascular pancreaticlesions, consistent with multiple gastrinomas(Zollinger–Ellison syndrome). Omeprazoletreatment (80 mg/d) alleviated his pepticulcer symptoms and stabilized gastrin lev-els. In 1996, a large (11 cm) anteriormediastinal mass was incidentally found.The lesion, a thymic carcinoid tumor withlymph node metastases, was resected, aswas a single parathyroid adenoma. Thepatient received four cycles of cisplatin andetoposide as well as external beam radio-therapy (45 Gy) to the mediastinum. Thetumor did not recur. Postoperatively,primary hyperparathyroidism persisted(serum calcium level 2.6–2.7 mmol/L) andwas treated conservatively. At that time,mild hyperprolactinemia (165 ng/mL;N<25 mg/mL) prompted a CT scan,which disclosed a 2.3 × 1.7 cm sellar mass.A diagnosis of sporadic MEN 1 seemedlikely although no family history of thedisorder was elicited, nor was there evi-

dence of hypercalcemia in his parents, twosiblings, or other second degree relatives.Bromocriptine therapy (2.5 mg bid) sup-pressed the hyperprolactinemia, but causedno significant tumor shrinkage. At age 41,the patient presented with a short historyof headache and diplopia. Neurologicexamination disclosed a left third nervepalsy. Visual fields were normal. The serumprolactin level on bromocriptine was55 ng/mL. No clinical or biochemical fea-tures of acromegaly or Cushing’s syndromewere noted. A urine 5HIAA level was nor-mal. An MRI scan disclosed a large pitu-itary mass extending into the left cavernoussinus and the suprasellar region (Fig. 1).

At transsphenoidal hypophysectomy, afirm tumor was partially debulked resultingin transient resolution of the left third nervepalsy. Two months later, the third nerve palsyreturned. A repeat MRI scan showed furthercavernous sinus invasion. The patient diedat home in 2001. He experienced recurrenceof the tumor with intracranial extension.The patient was treated with radiotherapybut not chemotherapy.

Pathology Findings

Histologic examination revealed thepresence of two intimately associatedprocesses, a pituitary adenoma and a fib-rosarcoma (Fig. 2). Little normal adeno-hypophyseal tissue was noted. Of the twoprincipal elements, the adenoma was leastabundant. It consisted of uniform, oftenclustered cells showing immunoreactivityfor synaptophysin, chromogranin, and,to a lesser extent, prolactin (Fig. 3). Thelatter showed a Golgi pattern of staining.No other pituitary hormones (GH,ACTH, LH, FSH, TSH, α-subunit) werenoted. Immunoreactivity for keratin, CK 7,and CK 20 was seen in a minority ofadenoma cells. Stains for thyroid transcrip-

Pituitary Fibrosarcoma and Prolactinoma with Neuronal Metaplasia 151

tion factor (TTF), EMA, and S-100 pro-tein were negative. Sources of these anti-bodies, specifics of the staining method,

and control procedures have been pub-lished previously [25,26]. No mitoses werepresent in the adenoma component, and

Fig. 1. MRI with contrast showing large tumor extending into the left cavernous sinus and suprasellar region.

Fig. 2. Histologic appearance of the pituitary adenoma on H&E stain (left). Portions of the tumor wereintimately admixed with anaplastic mesenchymal cells (right).

152 Endocrine Pathology Volume 15, Number 2 Summer 2004

Fig. 3. The adenoma cells were strongly immunoreactivity for chromogranin (left) and to a lesser extent forprolactin (right).

Fig. 4. Neurons within the adenoma were large with Nissl-substance-containing amphophilic cyto-plasm and open chromatin with prominent nucleoli (left). Occasional examples were binucleate (center).Neuronal cell processes were strongly immunopositive for neurofilament protein (right).

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Pituitary Fibrosarcoma and Prolactinoma with Neuronal Metaplasia 153

its MIB1 labeling index was low. Nuclearp53 staining was minimal.

Of particular note was the presence offar larger, full-bodied cells with the featuresof neurons, including ample amphophiliccytoplasm, large open nuclei, and promi-nent nucleoli (Fig. 4). These, too, werereactive for synaptophysin and chromo-granin but not for prolactin. Interveningtissue was seen to contain cell processesstrongly immunoreactive for neurofilamentprotein (Fig. 4). No glial element was seenon glial fibrillary acidic protein (GFAP) stain.

The intimately associated sarcoma com-ponent consisted of nondescript spindlecells with frequent mitotic figures (7/10 HPF)and a high Ki-67 labeling index (60%)(Fig. 5). A reticulin preparation demon-strated the typical pericellular staining pat-tern of sarcoma. On immunohistochemicalstains, these spindle cells were reactive forvimentin but showed no reaction for

smooth muscle actin, keratins, EMA,synaptophysin, chromogranin, GFAP, orpituitary hormones. Lastly, in situ hybrid-ization for chromogranin was positive inthe adenoma cells and neurons, but nega-tive in the sarcoma.

Discussion

Sarcomas of the sellar region are rare.Most occur following irradiation of pitu-itary adenomas or craniopharyngiomas[2,40,42,43,45,56,61,66]. By definition,the tumors occur in the irradiated region,typically after a latency period of 2.5 tomore than 20 yr. Fibrosarcomas predomi-nate over osteosarcomas at a ratio of 4:1[56]. Microscopically, as in the present case,most specimens show an intimate admix-ture of the sarcoma with the adenoma cell.As in our case, no convincing transition of

Fig. 5. The fibrosarcoma element consisted of nondescript spindle cells showing brisk mitotic activity (left)and a high MIB-1 labeling index (right).

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adenoma to sarcoma has ever beendocumented.

Only a few cases of primary sarcoma ofthe sellar region unrelated to prior irradia-tion have been reported. These includefibrosarcomas [31,37,68], osteosarcomas[24,45], and single examples of leiomyo-sarcoma [3] and alveolar soft part sarcoma[16]. The essential clinicopathologic fea-tures of these cases and of our own are sum-marized in Table 1.

Of particular interest is the report ofNagasaka et al. of prolactin cell pituitaryadenoma in which a fibrosarcoma super-vened [37]. The patient was a 21-yr-oldwoman whose adenoma had been oper-ated 5 yr prior. The adenoma has beentreated solely with bromocriptine, adopamine agonist. Reoperation was under-taken for a presumed recurrence. Histologi-cally, the tumor consisted of an intimateadmixture of pituitary adenoma and fib-rosarcoma. The authors suggested that thiscase represented the first example of sarco-matous transformation of a pituitary

adenoma and implicated bromocriptinetherapy in the genesis of the sarcoma.No objective evidence was provided foreither a transition of adenoma to sarcomaor for a role for bromocriptine.

Our case is similar to this reportedexample in that the fibrosarcoma arose inintimate association with the pituitaryadenoma, which had been treated withbromocriptine (BCP) alone for a pro-tracted period. Treatment with BCP isrecommended for management of pro-lactinomas and is known to induce bothatrophy of prolactin cells and tumoralfibrosis [28]. In such cases the fibrous pro-liferation is entirely benign. It has been sug-gested that such marked fibrosis maycompromise the adenoma’s eventual resec-tion [28]. There are presently no firm data,clinical or experimental, linking the devel-opment of a pituitary sarcoma to BCPtherapy. One further consideration arisesin our case. The patients’ thymic carcinoidtumor was treated by chemotherapy.The target of one of the agents, etoposide,

Table 1. Summary of Primary Sarcomas of the Sellar Region, Unrelated to Previous Radiation Therapy

Case Author Age/Sex Site Tumor type Treatmenta Outcome

1 Willis, 1938 67/M Pharynx roof, sphenoid Fibrosarcoma None DOD, 3 moand ethmoid, with metastasesleft orbit and frontal lobes to lung and skull vault

2 Kleinsasser, 1957 [24] 48/F Sphenoid sinus, Osteosarcoma Partial resection Postoperative deathsellar and parasellar mass

3 Anderson et al., 1980 [3] 35/M Large sellar/suprasellar mass Leiomyosarcoma STR and RT (5000 rads) Stable at 32 mo

4 Reichenthal et al., 1981 [68] 22/M Region of the tuberculum sellae Osteosarcoma Biopsy, RT (5500 rads), Alive at 19 moanterior portion chemotherapy with enlargingof sphenoid sinus parasellar mass

5 Bots et al., 1988 [16] 9/M Sellar/suprasellar mass Alveolar soft part STR, RT (4500 rads) Recurrence at 39 moRt lateral ventricle, GTR,A&W 29 mo later

6 Lopes et al., 1998 [31] 51/F Sellar/suprasellar mass 1.6 cm Fibrosarcoma GTR and radiosurgery Recurrence at 7 mo, STR,no further follow-up

7 Nagasaka et al., 1998 [37] 21/F Large sellar/suprasellar mass Fibrosarcoma, Surgery (× 3) Recurred twice in 8 mo,prior adenoma RT started,

no further follow-up

8 Present case 42/M L cavernous sinus, Fibrosarcoma, STR At 2 mo continuous growthsellar/suprasellar mass prior adenoma into cavernous sinus

aSTR, subtotal resection; RT, radiotherapy.

Pituitary Fibrosarcoma and Prolactinoma with Neuronal Metaplasia 155

is topoisomerase 2α, a substance expressedin several pituitary tumor types One canspeculate that etoposide treatment, bydamaging the adenoma cells, facilitatedtheir transformation to fibrosarcoma cells.Again, there is no support for this concept.

On clinical grounds, our tumor wasconsidered a prolactinoma despite therelatively mild degree of hyperprolactinemia(165 ng/mL) in the presence of whatappeared to be a macroadenoma. Thepresentation was also in keeping withprolactin elevation due to pituitary stalkcompression effect. This was indirectly sup-ported by lack of significant tumor shrink-age during bromocriptine treatment.Nonetheless, immunostains demonstratedreactivity for prolactin.

The coexistence of pituitary adenomawith neurons is a rare event. A wide vari-ety of terms has been applied to thisassociation, including intrasellar ganglio-cytoma, ganglioglioma, neuronal hamar-toma, and pituitary adenoma/neuronalchoristoma. Convincing data indicate thatpituitary adenoma cells can undergo neu-ronal metaplasia [17,51]. At the immuno-histochemical level the neurons are oftenseen to contain the same hormone as theassociated adenomas [17,51]. The presenceof neuronal differentiation is confirmed bythe finding of neurofilament proteinimmunoreactivity within the processes ofneuronal cells. This intermediate filamentprotein is not expressed in the normaladenohypophysis [64]. Lastly, ultrastruc-tural studies have shown not only the pres-ence of mature neurons, but of cells withmorphologic features intermediate betweenadenoma cells and neurons [17]. Thatthe neuronal component establishes anautocrine relationship with the adenomacells is suggested by the presence ofhypothalamic releasing hormones, e.g.,GH-releasing hormone, in the neurons ofsome examples [7]. Interestingly, a subset

of GH adenomas has been shown to manu-facture this hypothalamic-releasing hor-mone [62], an arrangement that maypermit autocrine stimulation. The actualmechanism underlying neuronal differen-tiation of pituitary adenoma cells remainsunexplained.

Overall, our patient’s clinical coursefits well with sporadic MEN1, causingZollinger–Ellison syndrome, hyperpar-athyroidism, pituitary adenoma, and a thy-mic carcinoid tumor. The subject ofendocrine neoplasia and oncogenes/tumorsuppressor genes has recently been reviewedrelative to germline mutations and loss ofheterozygosity (LOH) in familial and spo-radic MEN1 [32]. Thymic carcinoidtumors occur in less than 2% of MEN1cases and show a male gender predilectionpossibly associated with additional modi-fying genes. Teh et al. found LOH of aputative tumor suppressor gene in two ofseven thymic carcinoid tumors studied [60].

In summary, it appears that the presentexample of sellar fibrosarcoma arose in agenetically predisposed pituitary cell popu-lation. Whether its genesis, as in sporadicand familial endocrine neoplasms occur-ring in MEN-1, involved activating muta-tions of the menin gene is unclear. Perhapsanalysis of our patient’s specific MEN1mutation and of tumor-related mutationsin his thymic carcinoid tumor, pituitaryadenoma, and sarcoma would provideinsight into the nature of his genetic pre-disposition and the process of tumorigen-esis involved.

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