Primary Pituitary Lymphoma : The Endocrinologist

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00019616-200409000-00009ReviewThe EndocrinologistThe Endocrinologist© 2004 Lippincott Williams & Wilkins, Inc.14September 2004 p 288-292Primary Pituitary LymphomaCME Review Article #28Gola, Monica MD*; Doga, Mauro MD†; Bonadonna, Stefania MD‡; Velardo, Antonino MD§; Giustina, Andrea MD∥*Assistant Professor, †Attending Physician, Endocrine Unit, Carlo Poma Hospital, Mantova; ‡Postgraduate Fellow of Endocrinology, ∥Associate Professor of Medicine, Department of Internal Medicine, University of Brescia; and §Associate Professor of Endocrinology, University of Parma, Parma, Italy.The authors have disclosed that they have no significant relationships with or financial interests in any commercial company that pertains to this educational activity.Reprints: Prof. Andrea Giustina, Endocrine Section c/o 2a Medicina, Spedali Civili, 25125 Brescia, Italy. E-mail: [email protected] Editor’s Note:This article is the 28th of 36 that will be published in 2004 for which a total of up to 36 Category 1 CME credits can be earned. Instructions for how credits can be earned precede the CME Examination at the back of this issue.AbstractPrimary central nervous system lymphoma (PCNSL) is an uncommon neoplasm, historically representing approximately 1% of primary brain tumors. However, its incidence has more than tripled in the United States and United Kingdom since the early 1980s. PCNSL represents 3% of intracranial neoplasms in patients with AIDS. Simultaneously, the incidence of description in the literature of pituitary lymphoma has been increasing and emerging clinical entity has been standing. The aim of this paper will be to review the clinical case reports so far available of pituitary lymphomas in order to depict with the most updated information the clomical syndrome correlated. The total number of cases reported is 17 cases of primary pituitary lymphoma (PPL) and 12 cases of secondary localization (male/female ratio is 2/1; the peak incidence occurs around the 5th and 6th decade of age; the mean age (mean ± SD) of the patients is 61 ± 15.8 years). The clinical presentation of PPL may be similar to that of pituitary invasive macroadenomas. As many as 50% of patients showed at the time of diagnosis clinical and/or laboratory evidence of anterior pituitary hypofunction. Of the patients with anterior pituitary failure, 5 had diabetes insipidus; 3 had hyperprolactinemia; 50% of patients had visual field defects; 40% presented cranial nerve involvement; 15 patients underwent transphenoidal surgery; and 63% had diffuse B cell-large lymphoma. Approximately half of the patients received radiation therapy and chemotherapy in different regimens. PPL seems to have a better prognosis with respect to all PCNSLs (70% of the examined patients had survived quite long). The data so far reported suggest that PPLs are not a unique clinical entity but that they may represent the final presentation of different processes with either hypophyseal or extrahypophyseal origin. Neurosurgical intervention or biopsy are at this point to be considered crucial for early diagnosis of the tumor. Disease treatment cannot be difined as peculiar based on as-yet reported experiences but should follow the most updated standards currently used for cerebral lymphomas.Learning ObjectivesRecall the demographic aspects of primary central nervous system lymphoma (PCNSL) in general and primary pituitary lymphoma in particular, and cite possible risk factors.Describe the presenting clinical features of primary pituitary lymphoma and available histopathologic findings.Identify current treatment options for pituitary lymphoma and its prognosis compared with that of other forms of PCNSL.Lymphomas originating in the parasellar region have been anecdotically 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 lymphomasWe have previously showed 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. The aim of this article is to review the clinical case reports so far available of pituitary lymphomas to depict, with the most updated information, the clinical syndrome correlated.EPIDEMIOLOGYThirty-eight cases of hypophyseal lymphoma were found in an autopsy series of 165 patients (approximately 23%) who died of hematologic malignancies, although there was no mention of hypopituitarism during life.1 Recently, some authors have carried out a clinicopathologic examination of brain tissue taken postmortem from patients with primary central nervous system lymphoma (PCNSL) to determine the topographic involvement of the central nervous system. The pituitary gland was involved in 5 of 22 cases (approximately 25%) and particularly the posterior but not anterior lobe.2 In a series recently reported of 1120 patients undergoing transsphenoidal surgery for sellar masses from January 1981 through May 1998, only a single lymphoma was diagnosed (less than 1‰).3 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 29 and specifically 17 cases of primary pituitary lymphoma3–18 and 12 cases of secondary localization or infiltration of the sella turcica.2,19–29Primary pituitary lymphomas have been predominantly observed in males (male/female ratio is 2/1) (Fig. 1). The peak incidence of the disease occurs around the VI and VII decades of age (Fig. 1). The mean age of the patients so far described is 61 ± 15.8 years (mean ± standard deviation). The age of higher incidence of non-Hodgkin lymphoma (NHL) of the pituitary is similar to cerebral lymphomas in general as it is the male prevalence. In the only patients with AIDS so far reported,5 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.JOURNAL/endst/04.03/00019616-200409000-00009/figure1-9/v/2021-02-17T201744Z/r/image-tiff Age and sex distribution of primary pituitary lymphoma (PPL) at diagnosis.RISK FACTORSAmong the established or hypothetical risk factors for pituitary lymphomas, there are AIDS, pituitary adenomas, and lymphocytic hypophysitis.AIDS and Other Immunodeficiency StatesThe main reason for the increase in cases of PCNSL in immunodeficient subjects is the AIDS epidemic, and it is probably the result of the improved survival of AIDS patients. A total of 2.5% of AIDS patients develop PCNSL.30 In autopsy studies, involvement of the pituitary has been reported as a result of direct spread from adjacent structures or metastasis from extraneural sites.Lymphocytic HypophysitisThere has been 1 previous report suggesting lymphocytic hypophysitis to be a likely risk factor for the development of pituitary lymphoma.16 This possibility is also suggested by the case observed by us.14 Therefore, even if with the caution suggested by the so far limited clinical evidence, it can be hypothesized, by analogy with other endocrine gland lymphomas31 that lymphocytic hypophysitis11 may be potentially a risk factor for pituitary lymphomas. Prospective studies on outcome of patients with hypophysitis are needed to possibly confirm this hypothesis.Pituitary AdenomasPatients with pituitary adenomas were reported to have an increased risk of second malignancies, including lymphoma.32 Furthermore, lymphoma cells possess endocrine hormone receptors, and growth of both T and B lymphoma cells can be stimulated by prolactin and other pituitary hormones33 (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.13PATHOGENESISSeveral cases of PCNSL as a concomitant or secondary malignancy after intracerebral or extracerebral neoplasms are on record.34 Often, the preceding tumors had been of high malignancy and treated by chemotherapy and/or radiotherapy thought to have carcinogenic effects on hematopoietic cells,35,36 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, radiotherapy have never been performed and therefore cannot be implicated in the development of pituitary lymphomas.The expression of mutated adhesion molecule on adenomatous pituitary cells may act as lymphocyte “homing” signals to the adenoma tissue.CLINICAL PRESENTATIONHypopituitarismMore than 50% of patients with primary pituitary lymphomas showed, at the time of diagnosis, clinical and/or laboratory evidence of pituitary hypofunction (Fig. 2). At the time of diagnosis, 7 patients10–14,20–21 showed global anterior hypopituitarism, whereas 4 patients had partial hypopituitarism4,7–9,18; 3 had hyperprolactinemia7,9,11 pointing to a secondary hypopituitarism presumably as a result of pituitary stalk compression. Of the patients with anterior pituitary failure, 5 also had diabetes insipidus (Fig. 3). Therefore, these heterogeneous endocrine findings may suggest different origins of the lymphoproliferative tissue: extrapituitary (with hypopituitarism resulting from pituitary stalk compression or no hypopituitarism), posterior hypophysis (with diabetes insipidus), and anterior pituitary (partial or global anterior pituitary failure).JOURNAL/endst/04.03/00019616-200409000-00009/figure2-9/v/2021-02-17T201744Z/r/image-tiff Clinical findings divided by apparatus in a patient with PPL. See text for details.JOURNAL/endst/04.03/00019616-200409000-00009/figure3-9/v/2021-02-17T201744Z/r/image-tiff Endocrine disorders in patients with PPL.Neuroophthalmologic FindingsTogether with hypopituitarism, the neurologic 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 (Fig. 2). Varying degrees of optic chiasm involvement have been described. Three of 16 patients had bitemporal hemianopsia. Extension of the pituitary tumor into either the optic nerve or the optic tracts caused blindness in 1 patient; overall, 3 patients had variable degrees of optic nerve involvement. Headache seems to be the most common neurologic presenting symptom for expanding lymphomas of the pituitary (approximately 70% of patients) and results from erosion of the bone sella turcica or stretching of the diaphragma sellae. No single typical pain pattern is found in pituitary lymphoma-associated headaches, as not only occipital and retroorbital headaches but also bitemporal patterns have been reported (Fig. 2). Cranial nerve involvements resulting from the pituitary lymphoma extending laterally into the cavernous sinus have been reported (approximately 40% of the patients). These findings may also have a more insidious onset, with variable presentations ranging from diminished abduction of the ipsilateral eye resulting from sixth nerve involvement to diplopia associated with ocular motor nerve compression, or facial pain if the first and second branches of the trigeminal nerve are affected. Interestingly, among the neurologic signs, the involvement of the optic chiasm8,13,17 or even of the optic nerve seem not to have negative prognostic significance.HISTOPATHOLOGIC FINDINGSHistologically, lymphomas of the central nervous system and sella resemble systemic lymphomas. They are almost always NHLs. Most PCNSLs are high-grade immunoblastic or diffuse large-cell type with a B-cell immunophenotype.Unfortunately, a detailed histologic description was not given in all cases of primary pituitary lymphomas reported in the literature. However, of those patients for whom the results of the histologic examination are available, 63% had diffuse B cell-large lymphoma, whereas 19% had T-cell lymphoma of high malignancy (Fig. 4). In 2 cases,14,16 signs of inflammation were described. In 2 patients,10,13 coexisting adenomatous tissue has been found with positive immunoassay for either thyroid-stimulating hormone (and chromogranin)10 or follicle-stimulating hormone (50% of cells).13JOURNAL/endst/04.03/00019616-200409000-00009/figure4-9/v/2021-02-17T201744Z/r/image-tiff Histopathologic findings in PPL.TREATMENT AND OUTCOMETreatmentThe clinical presentation of pituitary lymphomas may be similar to that of pituitary invasive macroadenomas. Those pituitary adenomas often cause compression of the optic chiasm and neurologic deficits as well as most of primary pituitary lymphomas at presentation. We suggest that in these cases, the neurosurgical removal of the mass effect (even if the resection could not be complete) may have a double advantage: to improve the clinical conditions and to allow the histopathologic diagnosis. Seldom, particularly when the growing invasive mass does not involve the optic chiasm (lateral and/or inferior expansion), neurosurgical intervention is not performed because it is considered unable to obtain a complete removal of the mass and therefore radiation therapy is directly administered. We suggest that in the presence of such masses, at least a transsphenoidal biopsy should be obtained before any other interventions; this may allow a better (chemotherapy) treatment in case the mass is histopathologically diagnosed as pituitary lymphoma.In the examined series of patients, half of them have been given radiation therapy. Considerable improvements in survival have been accomplished by the addition of chemotherapy to cranial radiotherapy. In addition, many patients achieve substantial disease-free survival with chemotherapy alone, and survival is superior to that with radiotherapy alone.36 Approximately half of the patients with pituitary lymphoma received chemotherapy, only in 3 cases4,7,11 without cranial radiation. Regimens used seemed slightly or clearly different in the various cases so far reported. Therefore, the data available do not allow any conclusions on the best chemotherapy regimen for pituitary lymphomas outcome. However, as a result of the overall good response to chemotherapy, every patient with pituitary lymphoma should be considered for this option as the first line of therapy. Subsequent cranial radiotherapy may or may not be necessary, depending on the patient’s clinical condition, age, and response to initial chemotherapy.OutcomeOverall, pituitary lymphomas seem to have a better prognosis with respect to all PCNSLs. Approximately 70% of the examined patients had survived quite long (>6 months, where adequate follow-up was available) after the diagnosis, whereas in patients with cerebral lymphomas, survival was often less than 6 months (although the improvement of treatment has led to an improved survival also for PCNSL in general). As in all other malignancies, early diagnosis is considered the key to achieve a better outcome. In fact, among cerebral lymphomas, pituitary ones are those that allow the easiest and less invasive diagnostic approach as a result of the possibility of transsphenoidal removal. As mentioned here, when the lesion is already too large to allow complete neurosurgical removal, we propose obtaining as early as possible a sample of the sellar-occupying lesion, even only with a minimally invasive transsphenoidal biopsy.CONCLUSIONThe data so far reported suggest that pituitary lymphomas are not a unique clinical entity, but that they may represent the final presentation of different processes with either hypophyseal or extrahypophyseal origin. Clinical endocrinologists should bear in mind primary pituitary lymphomas as a potential cause of a sellar mass in which early diagnosis and aggressive treatments are far more crucial, being a life-threatening condition, than in largely more frequent occurrences such as pituitary adenomas. Clinical suspicion should be raised in a patient with combined endocrine and severe neuroophthalmic symptoms with a MRI sellar image showing an invasive mass not clearly consistent (infiltrating and not well-circumscribed with respect to surrounding tissues) with a pituitary macroadenomas. Neurosurgical intervention or biopsy is at this point considered crucial for early diagnosis of the tumor. Disease treatment cannot be defined as peculiar based on as-yet reported experiences but should follow the most updated standards currently used for cerebral lymphomas.REFERENCES1.Buchmann E, Schwesinger G. The hypophysis and haemoblastoses. Zentralbl Neurochir. 1979;40:35–42.[Context Link][Medline Link]2.Onda K, Wakabayashi K, Tanaka R, et al. Intracranial malignant lymphomas: clinicopathological study of 26 autopsy cases. Brain Tumor Pathol. 1999;16:29–35.[Context Link][Full Text][CrossRef][Medline Link]3.Freda PU, Post KD. Differential diagnosis of sellar masses. 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