Parasellar T2 Dark Sign on MR Imaging in Patients with Lymphocytic Hypophysitis

Discussion

The present study reviewed a series of clinical and MR imaging findings in 20 patients with LYH. To the best of our knowledge, this study has reviewed original MR imaging findings in the largest number of patients with LYH. We demonstrated a new characteristic parasellar T2 dark sign (dark-signal-intensity area on T2-weighted images around the pituitary gland and in the cavernous sinus) in patients with LYH for the first time. Although sensitivity for the parasellar T2 dark sign was 0.35, lower than that for loss of PPHI, thickened stalk, pituitary symmetry, homogeneous enhancement, or the dural tail, specificity for the parasellar T2 dark sign was 1.00; and this finding was characteristic enough to distinguish with certainty the more common pituitary adenoma from LYH because false-positive cases were not found. T2-weighted images depicted the parasellar involvement of LYH well. Our results also suggest that there are variations of localization of T2 dark areas in LYH.

Some previous studies reported that loss of PPHI, thickened stalk, pituitary symmetry, homogeneous enhancement, and the dural tail were useful for distinguishing LYH from pituitary adenomas,^{2,3,8,11–14} but only 1 previous study investigated this statistically. Gutenberg et al¹⁴ reported that these findings contributed significantly to classifying the outcome as pituitary adenoma or autoimmune hypophysitis (including lymphocytic and granulomatous hypophysitis), and our results were consistent with their findings.¹⁴

Although MR imaging findings such as loss of PPHI, thickened stalk, pituitary symmetry, and homogeneous enhancement showed significant difference in the statistical analysis in the present study, these findings were nonspecific and were observed in both diseases. Loss of PPHI was observed in central diabetes insipidus due to idiopathic, inflammatory, or neoplastic processes, including pituitary adenoma.^8,18–23 The stalk was sometimes unclear due to pituitary tumoral compression. Pituitary symmetry or asymmetry depends on tumor size, location, or invading areas.²⁴ Cystic, necrotizing, or hemorrhagic changes also influence the enhancement pattern.²⁵ Cystic appearance was described in 5% of the patients with LYH.^{1,8,11,12,26–34} Homogeneous enhancement can also be observed in pituitary adenomas.³⁵ On the other hand, parasellar T2 dark sign was a characteristic finding in LYH and can contribute to distinguishing pituitary LYH from adenoma with certainty.

Clinical findings revealed that panhypopituitarism or partial hypopituitarism was seen in 17 patients (85%) with LYH. On the other hand, partial hypopituitarism was seen in only 4 patients (18%) with pituitary adenoma. We think that hypopituitarism may be useful clinical information, suggesting LYH rather than pituitary adenoma. The endocrinologic manifestation of LYH can vary widely, from only hyperprolactinemia, probably due to stalk compression, to panhypopituitarism mimicking Sheehan syndrome.¹ In a recent report, the hormones most frequently impaired were ACTH, followed by TSH, LH/FSH, and vasopressin in patients with LYH.⁸ On the other hand, hypogonadism rather than hypocortisolemia or diabetes insipidus is usually the initial problem in pituitary adenoma.⁴ In the present study, ACTH deficiency was seen in only 2 of 13 patients with LYH who had partial hypopituitarism, and insufficient hormones of the anterior pituitary lobe had some overlaps between pituitary adenoma and LYH. Isolated ACTH deficiency is not specific to LYH because it can be observed in the absence of LYH,³⁶ and isolated deficiencies of other anterior pituitary hormones have been described in LYH.³⁷ We think that MR imaging findings, in addition to endocrinologic studies, can play an important role in distinguishing pituitary adenoma from LYH.

In the previous reports, histopathologic analysis revealed that LYH is extensively infiltrated by lymphoplasmacytic cells, consisting of lymphocytes, plasma cells, and macrophages.³ Lymphoplasmacytic aggregates surround the atrophic acini of pituitary cells, whereas the remaining pituitary tissue showed areas of reactive fibrosis.^26,38 Caturegli et al⁸ reported that fibrosis was common (47% of 267 cases of LYH) and often severe in their pathologic review. We think that dark-signal-intensity areas on T2-weighted images around the pituitary gland and in the cavernous sinus reflected fibrotic changes accompanied by infiltration of lymphoplasmacytic cells. In the present study, the parasellar T2 dark signs were seen in the first MR imaging study in the 5 patients with LYH; however, this sign was not seen in the first MR imaging study of the 2 patients with LYH, but appeared 2–20 months after the first MR imaging study (On-line Table 4).

LYH is a chronic inflammatory disease that affects the pituitary gland and parasellar areas, and the duration of disease in patients with LYH is relatively long.³ We think that fibrotic changes progressed in the clinical course of LYH and appeared as parasellar T2 dark signs. We also think that the sensitivity and specificity of the parasellar T2 dark sign may vary with time, and thus the parasellar T2 dark sign may not be useful for making an initial diagnosis. If the parasellar T2 dark sign was not seen in the initial MR imaging in patients who were suspected of the diagnosis of LYH, further follow-up MR imaging studies may be needed to detect the sign.

In the present study, cases 1 and 2 were diagnosed histologically by transsphenoidal biopsy. In case 2, biopsy specimens showed adenohypophysitis with focal lymphocytic infiltrate with lymphoid follicle formation and attached portions of attenuated hyalinized fibrous tissue; however, fibrous tissue was not found in case 1. We think the reason is that the biopsy specimens included only a small portion of the anterior lobes and did not include fibrous tissue. In the previous reports, approximately 10% of pituitary adenomas contained fibrosis.³⁹ Iuchi et al⁴⁰ reported that the signal intensities on T2-weighted images were significantly correlated with the percentage of collagen content of the pituitary adenomas, and adenomas that showed lower signal intensities on T2-weighted images contained more collagen. However, low signal intensities on T2-weighted images in pituitary adenomas are usually seen in the pituitary masses and not outside the masses in the parasellar areas. However, the histopathologic findings of LYH were characterized by massive infiltration of lymphocytes and plasma cells followed by necrosis or surrounding parenchymal fibrosis.⁴¹ Therefore, the parasellar T2 dark sign is more suitable for LYH that infiltrates around the pituitary. Some previous studies have reported cavernous involvement in patients with LYH,^{5,6,10,42–46} but no studies have mentioned the parasellar T2 dark sign.

In the present study, we focused on the parasellar T2 dark sign in the differential diagnosis between LYH and pituitary adenoma; however, other differential diagnoses for parasellar T2 dark sign should be considered in practical clinical cases. Some cases such as sarcoidosis, lymphoma, or Tolosa-Hunt syndrome could potentially have relatively low signal intensity on T2-weighted images and may show findings similar to those of the parasellar T2 dark sign, though we have no experience of such cases. In particular, sarcoidosis should be carefully considered because it sometimes causes secondary granulomatous hypophysitis,⁴ and its differential diagnosis on MR imaging findings may be very difficult. We think that clinical presentation such as medical history and laboratory findings, in addition to MR imaging findings, needs to be investigated in detail in the diagnosis of LYH.

This study had several limitations. The first is that not all patients with LYH had pathologic confirmation; only 4 of 20 patients with LYH and only 2 of 7 patients with parasellar T2 dark sign had transsphenoidal biopsy. Additionally, there were 5 patients who had a history of autoimmune disease such as IgG4-related disorders, rheumatoid arthritis, and bullous pemphigoid. Other disorders, such as granulomatous hypophysitis or sarcoidosis, could feasibly have similar MR imaging findings. However, the duration of follow-up was relatively long (from 9 months to 9 years) in the 11 patients without pathologic confirmation or a history of autoimmune disease. Sarcoidosis is liable to recur not only in the intracranial area but also in the extracranial portion during longitudinal follow-up, but these 11 patients had no recurrence. In addition, they had no laboratory findings supporting sarcoidosis. Granulomatous hypophysitis is an extremely rare disorder (annual incidence of 1 in 10 million) and is usually diagnosed in postmortem specimens.^4,47 The other limitation was that the present study was retrospective; most of the patients had only had a routine pituitary MR imaging study. If we had been able to prospectively evaluate these patients by using dynamic contrast-enhanced MR imaging⁵ or contrast-enhanced 3D constructive interference in the steady state,⁴⁸ more details of the sellar and parasellar structures and signal intensity would have been shown. Further prospective studies that compare the findings obtained from high-field MR imaging systems or long-term follow-up MR imaging with the histopathologic findings should be conducted.