Primary Lymphoma of the Pituitary: An Emerging Clinical Entity

Pituitary masses are diagnosed with increasing frequency due to the progressive refinement of endocrine tests and imaging procedures. Pituitary adenomas are the most common cause of a mass in the sella, accounting for up to 10–15% of intracranial neoplasms (1). However, when dealing with abnormal intrasellar masses, a number of different etiologies are possible: germ cell tumor, gliomas, meningiomas, metastatic tumors, vascular lesions, granulomatous, and infectious and inflammatory processes (2). Lymphomas originating in the parasellar region have been anedoctically reported to be among the most unusual causes of sellar masses. However, during the last decade there have been an increasing number of isolated reports describing new cases of pituitary lymphomas, including a Clinical Case Seminar recently published in JCEM (3). The aim of this report is to put in a clinical perspective all the available data on primary pituitary lymphomas (i.e. without other localization of the disease) described so far, including the features of a recent and unpublished case observed by us. Here, we show that pituitary lymphomas are not a simple clinical curiosity but a precise, and emerging, entity likely heterogeneous in origin with possible specific risk and pathogenetic factors and distinct clinical features. We also provide elements for the clinician for the differential diagnosis and treatment of pituitary lymphomas. Finally, prognostic and outcome data on affected patients are given in this article. All these elements are put in perspective in the attempt to help endocrinologists in the understanding of pituitary lymphomas and in being prepared to deal with what we think is an emerging clinical entity. Intracranial tumors. The frequency of tumors of the central nervous system (CNS) ranges between 3.8 and 5.1 per 100,000 subjects. In the United States, CNS tumors constitute the fourth cause of death in males aged 35–54 yr. In Europe, those tumors account for only 2% of all deaths due to cancer (4). On the other hand, pituitary tumors account for about 10% of intracranial neoplasms and have an annual incidence in the general population of about 25 per million (5). Primary CNS lymphoma (PCNSL) is now thought to constitute 3% of all intracranial neoplasms (6). Intracranial lymphomas. Non-Hodgkin’s lymphoma (NHL) may involve the CNS either as a primary tumor or after spreading from an established systemic lymphoma. This occurs in 5–29% of patients with systemic lymphoma during the natural history of the disease and is usually associated with progressive widespread systemic disease (7). PCNSL is a less commonly encountered clinical entity and is defined as lymphoma limited to the cranial-spinal axis without systemic disease. In the past, PCNSL was considered a rare disorder, accounting for 1–2% of all cases of NHL and fewer than 5% of all cases of primary intracranial neoplasm (7). This frequency has largely increased because of the increasing number of patients with congenital and iatrogenic immunosuppression and acquired immunodeficiency syndrome (AIDS) (8). However, recent data also show an increase in the incidence of primary intracranial malignant lymphomas in immunocompetent individuals (6). Lymphomas of the pituitary. As far as this last localization is concerned, 38 cases of hypophyseal lymphoma were found in an autopsy series of 165 patients (about 23%) who died of hematological malignancies, although there was no mention of hypopituitarism during life (9). Recently, some authors have carried out a clinicopathological examination of brain tissue taken postmortem from patients with PCNSL to determine the topographic involvement of the CNS. The pituitary gland was involved in 5 of 22 cases (about 25%) and particularly the posterior but not anterior lobe (10). In a recently reported series of 1120 patients undergoing transphenoidal surgery for sellar masses from January 1981 through May 1998 only a single lymphoma was diagnosed (less than 1‰) (2). Recently, several cases of PCNSL, presenting as pituitary tumor, have been described. The total number of cases reported in some detail in the literature is now 24, specifically 14 cases of apparently primary pituitary lymphoma (2, 3, 11–22) and 10 cases of secondary localization or infiltration of the sella turcica (10, 23–31). Our analysis of the main clinical features of primary pituitary lymphomas is based on the detailed description available in the literature (Medline search, proceedings of international meetings) of 13 cases [11 available as full papers (2, 3, 11, 13, 14–19, 22) and 2 as abstracts (12, 20)]. In fact, for one case (21) there is no possibility to obtain from the literature an adequate characterization, which was not the scope of the original publication reporting the case. Conversely, for the case observed by us, and reported so far only in abstract form (20), some details have been added to the present analysis. Age- and sex-linked incidence. The annual incidence of malignant lymphomas ranges from 8–9 per 100,000, with about 75% due to NHL. The male to female ratio is greater than 1.1–1.3:1 for NHL. The slightly higher number of males with NHL is constant at any age and for all histological kinds. For NHL there is a first incidence peak at the age of 10, a decrease at about 20 yr of age, and a progressive increase until the age of 70 (32). PCNSL can appear at all ages, with peak incidence between the 6th and 7th decade in nonimmunodepressed subjects (33). In these subjects the male to female ratio is 3:2, whereas more than 90% of AIDS patients are males and of younger age (32). Pituitary tumors are generally benign tumors, although they may show histological evidence of invasion of the capsule or into the surrounding structures. The peak incidence occurs between the ages of 30 and 60 yr, being somewhat earlier in women than men because of the greater frequency of prolactinomas in young women (5). Lymphocytic hypophysitis has been reported to be predominantly a disease of females, frequently associated with pregnancy or presenting during the postpartum period (in the literature, this association was found in 63% of female patients) (34). The mean age of presentation in females is 35 yr whereas in males it is one decade later (35, 36). Primary pituitary lymphomas have been predominantly observed in males (male of female ratio is 2:1) (Fig. 1). The peak incidence of the disease occurs around the 6th decade of age (Fig. 1). The mean age of the patients described so far is 59.46 ± 17.16 yr (mean ± sd). The age of higher incidence of NHL of the pituitary is similar to cerebral lymphomas in general as it is the male prevalence. In the only patients with AIDS reported so far (Table 1 and Ref. 11), the pituitary lymphoma appeared at a younger age than in the remaining population, reflecting a similar decrease in the age range of cerebral NHL in immunodepressed subjects. Age and sex distribution of primary pituitary lymphomas. Endocrine characteristics of 13 patients with primary pituitary lymphomas Endocrine characteristics of 13 patients with primary pituitary lymphomas Among the established or hypothetical risk factors for pituitary lymphomas are AIDS, pituitary adenomas, and lymphocytic hypophysitis. AIDS and other immunodeficiency states. The main reason for the increase in cases of PCNSL in immunodeficient subjects is the AIDS epidemic, and it is probably due to the improved survival of AIDS patients. Two and one half percent of AIDS patients develop PCNSL (37). In autopsy studies involvement of the pituitary has been reported as a result of direct spread from adjacent structures or metastasis from extra neural sites. The tendency of primary central nervous lymphomas to grow in the brain may be explained by the decreased immune surveillance normally found within the CNS. Thus, PCNSL in the patients with AIDS may be the result of a process of uncontrolled Epstein-Barr virus (EBV)-induced B lymphocyte proliferation with possible subsequent neoplastic transformation in an immunologically privileged site in a patient with baseline impaired immune surveillance (7). Lymphocytic hypophysitis. There has been one previous report suggesting lymphocytic hypophysitis to be a likely risk factor for the development of pituitary lymphoma (22). This possibility is also suggested by the case observed by us (20). Therefore, even with the caution suggested by the limited clinical evidence so far, it can be hypothesized, by analogy with other endocrine gland lymphomas (38), that lymphocytic hypophysitis (17) may be potentially a risk factor for pituitary lymphomas. Prospective studies on the outcome of patients with hypophysitis are needed to possibly confirm this hypothesis. Pituitary adenomas. Patients with pituitary adenomas were reported to have an increased risk of second malignancies, including lymphoma (39). Furthermore, lymphoma cells possess endocrine hormone receptors, and growth of both T and B lymphoma cells can be stimulated by PRL and other pituitary hormones (40) (a local concentration of pituitary hormones may favor the growth of lymphoma cells). On the other hand, the breaching of the blood brain barrier by the pituitary tumor may also allow easy access of the lymphoma cells to an immunologically privileged site for rapid proliferation (19). Several cases of PCNSL as a concomitant or secondary malignancy following intracerebral or extracerebral neoplasms are on record (41). Often, the preceding tumors had been of high malignancy and treated by chemotherapy and/or radiotherapy thought to have carcinogenic effects on hematopoietic cells (42, 43), possibly associated with genetic predisposition. This explanation is also likely to apply to malignant brain tumors occurring after radiotherapy of benign tumors. However, in the cases reviewed by us and in the patient observed by us no radiotherapy was recorded in the clinical history and therefore, it cannot be implicated in the development of pituitary lymphomas. Two specific pathogenetic pathways for pituitary lymphomas may be hypothesized: Hypophysitis in immunocompromised/immunocompetent patients. A policlonal lymphocytic inflammation (mixed T- and B-cell population) may undergo monoclonal expansion with subsequent malignant transformation, possibly triggered by an infectious agent. In fact, transient “sentinel” brain lesions have been observed in immunocompetent subjects to precede PCNSL, and histologically they included inflammatory T cells (44). Because almost all PCNSLs of immunocompromised patients contain genome of the oncogenic EBV (45), it is conceivable that polyclonal inflammatory disorders due to EBV or another herpes virus may undergo monoclonal conversion. In a previous study (22) as well as in the case of pituitary lymphoma by us observed (20) there were histological signs of inflammatory lesion even if there was not previous history of hypophysitis. Moreover, subclinical, smouldering preexisting inflammation cannot be excluded in other cases. It is interesting to hypothesize that what could take place at the pituitary level is an already well described phenomenon at the thyroid level with Hashimoto’s thyroiditis (HT). Histological features of HT include, as in lymphocitic hypophysitis, diffuse infiltration of lymphoid cells usually with formation of lymphoid follicles, varying degrees of fibrosis, oxyphillic change, or squamous metaplasia in the epithelial cells (38). An etiologically important role of HT in the development of thyroid mainly B-cell lymphomas has been confirmed by epidemiological studies (46). Pituitary adenomas. The role of pituitary adenomas in the pathogenesis of pituitary lymphomas is far to be clear, and, therefore, the possible links between these two clinical entities are somewhat hypothetical and not yet proven. Possible pathogenetic pathways for intraadenomatous lymphoma development include monoclonal growth of T cell-infiltrates, expression of adenoma-specific adhesion molecules, and the mitogenic potential of some pituitary hormones. The expression of mutated adhesion molecule on adenomatous pituitary cells may act as lymphocyte “homing” signals to the adenoma tissue. Lymphoma development could be stimulated by hormones produced by the adenoma. Several hormones [PRL (47, 48), GH (49–51), and gonadotropins (19, 52, 53)] released by either normal or adenomatous pituitary are known to have mitogenic effects both on lymphoma cells and on normal human lymphocytes. Hypopituitarism. Pituitary lymphomas, similar to pituitary adenomas, may present with symptoms of anterior pituitary hormone dysfunction. The developing hypopituitarism associated with expanding pituitary masses frequently follows a characteristic sequence involving initially diminished gonadotropin secretion, followed by GH, TSH, and ACTH deficiency (54). Although this is the classic order of deficiency, variation in the order of pituitary hormone failure may occur (55). More than 50% of patients with primary pituitary lymphomas showed at the time of diagnosis clinical and/or laboratory evidence of pituitary hypofunction. At the time of diagnosis five patients (16, 17–20) showed global anterior hypopituitarism, whereas three patients had partial hypopituitarism (3, 13, 15): three had hyperprolactinemia (13, 15, 17) pointing to a secondary hypopituitarism presumably due to pituitary stalk compression. Of the patients with anterior pituitary failure, five also had diabetes insipidus (Table 1). Therefore, these heterogeneous endocrine findings may suggest different origins of the lymphoproliferative tissue: extrapituitary (with hypopituitarism due to pituitary stalk compression or without hypopituitarism); posterior hypophysis (with diabetes insipidus); and anterior pituitary (partial or global anterior pituitary failure). Neurological findings. Together with hypopituitarism, the neurological signs and symptoms are those of expanding intracranial masses with headache, diplopia, and visual field defects and cranial nerve involvement. Fifty percent of patients with pituitary lymphoma had visual field defects. Varying degrees of optic chiasm involvement have been described. Two of 13 patients had bitemporal hemianopsia. Extension of the pituitary tumor into either the optic nerve or the optic tracts caused blindness in one patient; overall, three patients had variable degrees of optic nerve involvement (Table 1). Headache seems to be the most common neurological presenting symptom for expanding lymphomas of the pituitary (about 75% of patients) and results from erosion of the bony sella turcica or stretching of the diaphragma sellae. No single typical is found in pituitary because not only and but also bitemporal have been reported (Table nerve due to the pituitary lymphoma into the have been reported (about of the findings may also have a more with variable from diminished of the due to nerve involvement to associated with nerve or if the first and second of the nerve are among the neurological the involvement of the optic chiasm or even of the optic nerve seems not to have prognostic (Table Neurological findings of 13 patients with primary pituitary lymphomas in the original Neurological findings of 13 patients with primary pituitary lymphomas in the original and outcome of patients with primary pituitary for patients from 2 and 22 are not time was not detailed in the original and outcome of patients with primary pituitary for patients from 2 and 22 are not time was not detailed in the original lymphomas of the CNS and sella systemic lymphomas. are almost PCNSLs are or diffuse with a B-cell the PCNSLs are at of PCNSLs are largely on the of expression of either or studies have also of and in and metastatic CNS lymphomas. not in all cases of primary pituitary lymphomas reported in the literature is detailed histological description However, of those patients for the results of the histological examination are available (Table had diffuse B lymphoma whereas had lymphoma of high malignancy (Fig. In two cases signs of inflammation were described (Table In two patients (16, (Table adenomatous tissue has been found with for either and or of and and findings in 13 patients with primary pituitary lymphomas and findings in 13 patients with primary pituitary lymphomas The differential diagnosis pituitary and sellar and parasellar masses. Pituitary tumors may a in Clinical findings largely on the tumors are hormone or on the and of tumor and on normal pituitary is (54). pituitary tumors appear with visual including of the visual and decreased signs of hypopituitarism, and symptoms as hyperprolactinemia secondary to stalk compression is common (2). Pituitary lymphomas as sellar and parasellar masses, and similar to pituitary adenomas, may present with symptoms of anterior pituitary hormone dysfunction. symptoms include secondary and, less clinical which may be or by is found at presentation of lesions of the sellar Clinical diabetes insipidus at presentation is of a of a sellar or parasellar mass (2). insipidus may result from involvement or compression of the pituitary or region of the by the In the patients by us, diabetes insipidus was not particularly (less than 50% of patients) but a when associated with Therefore, based on clinical differential diagnosis of pituitary lymphomas is not easy at without GH and signs of hypopituitarism with diabetes insipidus and/or cranial nerve involvement the clinical of a pituitary lymphoma they not other causes of sellar As as of patients with sellar or parasellar masses have of cranial and (2). Headache is a symptom in patients with tumors that to pituitary adenomas, sellar masses may present with diagnosis is on imaging (Fig. The sellar region is of a pituitary but the is not particularly in differential in the patient with primary pituitary lymphoma In AIDS pituitary lymphoma may be with other intracranial lesions typical of this population, as to be the only of the the but tests can now be with to or can usually PCNSL from or other as well as of EBV in the that is and usually for PCNSL The differential diagnosis of primary secondary pituitary lymphomas may include a neurological including examination and with examination to or involvement. In an and may be to systemic lymphoma. In the series of patients with pituitary lymphomas by us, only in one case was the diagnosis lymphoma of the In the of cases diagnosis was pituitary adenoma. of diagnosis was most frequently with surgery In PCNSL, in general the role of is that of the diagnosis mainly a In the case of primary pituitary lymphomas the role of seems more important because the mass among all other cerebral the to the transphenoidal The clinical presentation of pituitary lymphomas may be similar to that of pituitary pituitary adenomas cause compression of the optic chiasm and neurological as well as most of primary pituitary lymphomas at We suggest that in these cases the of the mass if the could not be may have a to the clinical and to allow the particularly when the mass not involve the optic chiasm and/or is not because it is considered to obtain a of the mass and, therefore, is We suggest that in the of masses at a transphenoidal be any other this may allow a treatment in case the mass is diagnosed as pituitary lymphoma. In the so far, pituitary lymphomas as pituitary masses. This not that in the pituitary lymphomas may be therefore, if the pituitary mass is not and there is no visual or neurological it be to the patient and three and the patient to the if a mass is This clinical may be taken with caution due to the almost features of pituitary lymphomas. has been the primary for PCNSL for survival from with surgery to with brain radiotherapy The patients treated with followed by a A was in of but the survival was only The of a to the of disease not intracranial disease or survival In the series of half of have been given (Table Because PCNSL is histologically similar to systemic it to systemic lymphoma for no systemic lymphoma has Two and or and followed by brain radiotherapy is the for the treatment of systemic NHL. and to in PCNSL, and survival were no than with brain radiotherapy was found to be the only factor that outcome This has to with different of which have been in detail to determine an However, chemotherapy can in some including the in survival have been by the of chemotherapy to cranial In patients survival with chemotherapy and survival is to that with radiotherapy half of the patients with pituitary lymphoma only in three cases (3, 13, 17) without cranial were slightly or different in the cases reported so far (Table Therefore, the data available not allow any on the chemotherapy for pituitary lymphomas However, due to the to patient with pituitary lymphoma be considered for this as the first of cranial radiotherapy may or may not be on the clinical age, and to pituitary lymphomas to have a with to all of the patients had adequate is after the whereas in patients with cerebral lymphomas survival is less than the of treatment has to an improved survival also for PCNSL, in As in all other malignancies, diagnosis has to be considered the to a In fact, among cerebral lymphomas, pituitary are those that allow the and less due to the possibility of transphenoidal As when the lesion is already to allow we to obtain in any case as as possible a of the sellar even only with a transphenoidal PCNSL is an important in AIDS patients. The of risk factors for AIDS, of symptoms and not PCNSL is a neoplasm with a and survival even with CNS for pituitary lymphomas, which to have a than PCNSL in AIDS seems to be a prognostic the of all the available reports of pituitary lymphomas it seems that the lesions that or possibly from preexisting pituitary adenomas are among those with a the apparently of those pituitary lymphomas is due to the characteristics of the lesions or to a to treatment it to be Primary pituitary lymphomas are an emerging clinical entity with an increasing number of well described cases in the last decade (3, as well as reported in a series of pituitary masses (2). This report to the first attempt to put all the available on this of cerebral the main of which are clinical and even The data reported so far suggest that pituitary lymphomas are not a clinical entity but that they may the presentation of different processes with either hypophyseal or extra hypophyseal We think that the most interesting of in this field be the understanding of the pathogenetic that to this disease and the reason of the apparently with to cerebral lymphomas in Finally, from cases of primary pituitary lymphomas to be to the data so far and the given by us they can be into the clinical and findings in the patient with primary pituitary lymphoma We and for help in the clinical and and for help the case of pituitary lymphoma. We are to for and to and for the imaging and are also to for and is to for is by of and of immunodeficiency and central nervous Epstein-Barr Hashimoto’s primary CNS lymphoma.