The Differential Diagnosis of Lesions Involving the Sella Turcica
Kalman Kovacs, MD, PHD and Eva Horvath, PHD
Abstract
The sella turcica and the surrounding area contain several different tissues varying in morphology and cytogenesis. Thus, it is not surprising that a large number of diverse lesions may arise in the sellar region. The most frequent abnormalities are the pituitary adenomas, which based on histology, immunocytochemistry, and transmission electron microscopy can be classified into several distinct entities. Pituitary adenomas originate in and consist of adenohypophysial cells. They are usually slowly growing benign epithelial tumors, which may be associated with increased hormone secretion or may be endocrinologically nonfunctioning. Pituitary carcinomas also arise in adenohypophysial cells. They are rare and can be diagnosed only when cerebrospinal and/or systemic metastases are documented. To illustrate the diversity, practical importance, and diag- nostic difficulties, four cases were selected for presentation: lymphocytic hypophysitis, thyrotroph hyperplasia, growth hormone-producing pituitary adenoma with neuronal transformation, and composite tumor consisting of adenomatous periodic acid Schiff- positive as well as adrenocorticotropic hormone-immunoreactive adenohypophysial cells and adrenocortical cells. The first two cases are important from a practical point of view because the proper diagnosis can easily be missed, and appropriate interpretation of the findings is essential to prognosis and treatment. The latter two cases are odd, unusual entities; their histogenesis is unresolved. Study of these and many other cases convinced us that careful and detailed morphologic investigation of lesions involving the sella tur- cica is of fundamental significance. Histology, immunocytochemistry, transmission elec- tron microscopy, and, in some cases, molecular methods are essential to reach a correct diagnosis and to draw conclusions on histogenesis, growth potential, biologic behavior, prognosis, and therapeutic responsiveness.
Key Words: Histology; immunocytochemistry; pathology; pituitary; pituitary neoplasm; ultrastructure.
Division of Pathology, Department of Laboratory Medicine, St. Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada.
Address correspondence to Dr. Kalman Kovacs, St. Michael’s Hospital, Division of Pathology, Department of Laboratory Medicine, 30 Bond Street, Toronto, Ontario, Canada, M5B 1W8.
Endocrine Pathology, vol. 12, no. 4, 389-395, Winter 2001 @ Copyright 2001 by Humana Press Inc. All rights of any nature whatsoever reserved. 1046-3976/01/12:389-395 $11.75
Introduction
The sella turcica is the home of the pituitary gland and is in close proximity to several vital structures such as the hypo- thalamus, nerves, vessels, bone, and con- nective tissue. Thus, it is not surprising that many diverse lesions may occur in the sellar region. The lesions represent a wide range of abnormalities: malformation; inflamma- tion; infection; necrosis; hyperplasia; and a great variety of benign and malignant,
primary and secondary tumors. Pituitary adenomas arising in adenohypophysial cells are the most common lesions. There are several types of pituitary adenoma that by immunocytochemistry, transmission elec- tron microscopy, and, in some cases, molecular methods can be properly classified into distinct entities [1-3]. Large numbers of morphologically different lesions arise outside the pituitary from adjacent structures or reach the sella turcica by hematogenous route. Table 1 lists the
| Table 1. Tumors and Nontumorous Lesions Involving Sella Turcica | |
| Abscess | Hamartoma |
| Acute hypophysitis | Hemangioblastoma |
| Adenoma (pituitary) | Hemangioma |
| Amyloidosis | Hemangiopericytoma |
| Aneurysm | Hemosiderosis |
| Angioma, angiosarcoma | Infections (bacterial, viral, fungal, parasitic) |
| Arachnoid cyst | Internal carotid artery |
| Carcinoma (pituitary) | Langerhans cell histiocytosis |
| Carcinoma (sphenoid sinus, nasopharynx) | Leukemia |
| Cholesteatoma | Lipoma |
| Chondroma, chondrosarcoma | Lymphocytic hypophysitis |
| Chordoma | Lymphoma |
| Choristoma | Malformations |
| Craniopharyngioma | Melanoma |
| Dermoid cyst | Meningioma |
| Empty sella syndrome | Metastatic tumors (carcinoma, sarcoma) |
| Epidermoid cyst | Mucocele |
| Esthesioneuroblastoma | Mucopolysaccharidosis |
| Fibroma, fibrosarcoma | Osteoma, osteosarcoma |
| Fibrous dysplasia | Paraganglioma |
| Gangliocytoma | Plasmacytoma |
| Ganglioglioma | Postirradiation sarcoma |
| Ganglioneuroma | Rathke cleft cyst |
| Germ cell tumors (germinoma) | Sarcoidosis |
| Giant cell granuloma | Schwannoma |
| Giant cell tumor of bone | Syphilis |
| Glioma (optic nerve, hypothalamus, stalk, neurohypophysis) | Teratoma |
| Glomangioma | Tuberculosis |
| Granular cell tumor | Xanthomatous hypophysitis |
| Granulomatous hypophysitis | |
various tumors and nontumorous lesions involving the sella turcica.
It would be impossible in this brief sum- mary to describe the morphologic features of all the sellar lesions and to discuss their cellular origin, differential diagnosis, pathogenesis, and biologic behavior. For this reason, only four representative cases were selected for presentation. The first two have considerable practical significance. They pose difficult diagnostic problems for the pathologist. It is of great importance to make the proper diagnosis of these abnormalities because prognosis and treatment depend on the evaluation of morphologic changes. The remaining two cases are rare and unusual entities. Their histogenesis is still questionable, and more
cases have to be investigated to understand their development and draw meaningful conclusions about their prognosis.
Case Reports Case 1
A 30-yr-old woman presented with visual disturbance during the third trimes- ter of her pregnancy. Her blood prolactin (PRL) levels were elevated, and magnetic resonance imaging (MRI) demonstrated an enlarged pituitary. The diagnosis of PRL-producing pituitary adenoma was made. By transsphenoidal surgery, a portion of the enlarged pituitary was removed. Histologic examination revealed no adenoma. The PRL-producing cells
were increased in number but the acinar architecture of the gland was preserved. The adenohypophysis was extensively infiltrated with B- and T-lymphocytes, plasma cells, and macrophages. Based on the morphologic findings, a diagnosis of lymphocytic hypophysitis was made. The presence of inflammatory response and injury of adenohypophysial cells was con- firmed by ultrastructural investigation (Figs. 1 and 2).
Lymphocytic hypophysitis is a rare dis- order that occurs most frequently in young women and is often associated with preg- nancy. The lesion is regarded as autoim- mune in origin. The diagnosis should be suspected on clinical ground and on imaging findings. If the disease progresses, partial or total hypopituitarism may develop [4-9].
Case 2
A 50-yr-old woman complained of fatigue, decreased energy level, and visual disturbance. MRI revealed an enlarged pituitary gland. Endocrine testing was not performed. Clinically nonfunctioning pituitary adenoma was diagnosed, and the patient was operated on by transsphenoidal approach. Histologic examination of the removed portion of the pituitary revealed no adenoma. The acinar architecture was expanded but preserved. The most strik- ing finding was the accumulation of enlarged thyrotrophs. These cells are poly- hedral with eccentric nucleus and abun- dant, vacuolated cytoplasm containing
periodic acid-Schiff (PAS)-positive glob- ules. Immunocytochemistry demonstrated thyroid-stimulating hormone (TSH) immunoreactivity in these cells, and elec- tron microscopy confirmed that they represented hyperactive thyrotrophs called thyroid deficiency or thyroidectomy cells (Figs. 3 and 4). These cells are characteristic features of protracted primary hypothy- roidism. Based on the morphologic findings, a diagnosis of pituitary thyro- troph hyperplasia was made. Patients with primary hypothyroidism and consecutive thyro-troph hyperplasia who undergo pituitary surgery are most commonly young (less than 40 yr of age) and have mild hyperprolactinemia. After the mor- phologic diagnosis, endocrine tests were performed in our patient. Blood levels
of levorotatory thyroxine and triiodothyro- nine were low and those of TSH were markedly elevated.
In several patients with thyrotroph hyperplasia, the clinical diagnosis of primary hypothyroidism was not made and the morphologic findings clarified the endocrine abnormality. The pathologist should be aware of this condition and be able to exclude the diagnosis of adenoma and other abnormalities. Thyrotroph hyperplasia is a reversible lesion, and with thyroid hormone replacement therapy, a patient’s condition improves and the enlarged pituitary regresses to normal size [10-15].
Case 3
The third case patient, a 45-yr-old woman, had the characteristic clinical fea- tures and laboratory results of acromegaly. Blood growth hormone (GH) levels were elevated and were not suppressed by glu- cose. MRI revealed a large pituitary tumor, which was removed by transsphenoidal adenomectomy. Histologic examination revealed a partly acidophilic, partly chromophobic, PAS-negative pituitary adenoma. Many tumor cells were immunopositive for GH, few for a-sub- unit, but not for the other adenohypo- physial hormones. In a few areas, several groups of large cells were apparent. They resembled nerve cells and were interspersed with neuropil. Several large cells showed immunoreactivity for GH and/or a-sub- unit; their cytoplasmic processes were immunopositive for neurofilament protein antigen. In several fields, transitional cells were seen between adenohypophysial cells and nerve cells, providing evidence that the adenohypophysial cells were capable of transforming to nerve cells. Electron microscopy confirmed the light micro- scopic findings (Fig. 5). The tumor was diagnosed as a sparsely granulated GH cell adenoma of the pituitary with neuronal transformation [16-19].
There is increasing evidence that under certain conditions, GH cells can transform to PRL- and TSH-producing cells [20]. This plasticity of adenohypophysial cells is an exciting new finding, and it is in con- tradiction with previously held dogmas claiming that the adenohypophysial cells are irreversibly committed to their origi- nal phenotype. The concept of the one cell, one hormone theory, which assured that one cell can produce only one hormone, is no longer acceptable because there is con- clusive proof that endocrine cells can pro-
duce more than one hormone and change their phenotype. The mechanism and the causative factors accounting for the trans- formation are obscure; thus, this intrigu- ing area of endocrine pathology requires further studies.
Case 4
An 18-yr-old female complained of amenorrhea, and MRI revealed a mass in the sella turcica. She had no additional endocrine abnormality and her blood hor- mone levels were within the normal range. Transsphenoidal adenomectomy was per- formed. Histology revealed an adenoma
composed of two different cell types. Groups of small cells were PAS positive and immunoreactive for adrenocorticotropic hormone (ACTH). The large cells pos- sessed abundant, slightly vacuolated acido- philic cytoplasm; they were negative for PAS and ACTH. By electron microscopy, the small cells showed the characteristic features of pituitary corticotrophs, whereas the large cells were typical steroid-produc- ing cells resembling those of the adrenal cortex (Fig. 6). Additional immunocy- tochemical studies documented the pres- ence of steroidogenic dehydrogenases and hydroxylases in the large cells and their absence in the small cells. Based on the morphologic studies, the tumor was diag- nosed as a composite silent corticotroph adenoma of the pituitary interspersed with adrenocortical cells [21-24].
We have seen three cases of this very rare and odd type of tumor. All three cases occurred in teenagers, were clinically nonfunctioning, and showed identical morphologic features. The histogenesis of this composite type of tumor is obscure. It may be that the adrenocortical cells were misplaced and settled in the pituitaries during embryonic development. Alterna- tively, it is possible that the pituitary tumor originated in a multipotential stem cell that differentiated into two different phenotypes: corticotrophs and adrenocor- tical cells.
Discussion
These four cases clearly illustrate the diversity of lesions involving the region of the sella turcica. They also show the con- siderable difficulties facing the pathologist. Finally, they conclusively prove the impor- tance of careful morphologic investigation, a prerequisite to reaching the proper diag- nosis. Application of immunocytochemis-
try as well as electron microscopy and, in certain cases, molecular biology methods is essential.
Acknowledgments
We gratefully acknowledge the support of Stephen and Gail Jarislowski and the Lloyd Carr-Harris Foundation.
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