Abstract
Lymphocytic hypophysitis (LYH) is a rare chronic inflammatory disease characterized by lymphocytic infiltration of the anterior or posterior pituitary gland and hypothalamus. LYH is subdivided into lymphocytic adenohypophysitis (LAH), lymphocytic infundibulo-neurohypophysitis (LINH), and lymphocytic panhypophysitis (LPH) depending on the primary site. Most cases occur in adults, with few cases reported in children, and it is especially important to distinguish LYH from suprasellar malignancies, such as germ cell tumors and other neoplastic diseases. Although a biopsy is necessary for definitive diagnosis, it is desirable to be able to diagnose the disease without biopsy if possible, especially in children, because of the surgical invasiveness of the procedure. Recently, serum anti-rabphilin-3A antibodies have attracted attention as diagnostic markers for LYH, especially in LINH, but there are only a few reports on pediatric patients. In the present study, we experienced two children with LPH and LAH, respectively, who tested positive for anti-rabphilin-3A antibodies. This is the first report of children with LYH other than LINH positive for anti-rabphilin-3A antibodies, and anti-rabphilin-3A antibodies may be a useful non-invasive diagnostic marker not only for LINH but also for LYH in general. We also discuss the sensitivity and specificity of anti-rabphilin-3A antibody testing in cases where histological diagnosis has been made.
LYMPHOCYTIC HYPOPHYSITIS (LYH) is a rare, chronic inflammatory disease with predominantly lymphocytic infiltration of the anterior or posterior pituitary gland and hypothalamic infundibular region with a possible autoimmune mechanism [1]. Depending on the primary site of involvement, the disease is classified into lymphocytic adenohypophysitis (LAH), lymphocytic infundibulo-neurohypophysitis (LINH), and lymphocytic panhypophysitis (LPH) [1]. Most cases of LYH have adult onset [1-3], however, pediatric cases have also been reported, although rarely [4-7]. LYH, especially in LINH, is often difficult to differentiate from suprasellar malignancies, such as germ cell tumors seen in children, requiring biopsy procedures, but the surgical invasiveness associated with the removal of a large enough sample for diagnosis is problematic [8].
Recently, serum anti-rabphilin-3A antibodies, autoantibodies to rabphilin 3A that is found in the posterior pituitary gland, have received attention as diagnostic markers for LINH, which may allow diagnosis without invasive biopsy procedures [9-11]. There have been a few reports of pediatric LINH with positive anti-rabphilin-3A antibodies [12, 13], but these did not include pediatric LYH other than LINH with positive antibodies.
In this report, we describe two children with LYH who tested positive for anti-rabphilin-3A antibodies. This is the first report of children with LYH who tested positive for anti-rabphilin-3A antibodies other than that in LINH. Notably, anti-rabphilin-3A antibodies may be a useful non-invasive diagnostic marker, not only for LINH but also for LYH in general, although they are currently an adjunctive diagnostic method.
Materials and Methods
Immunohistochemistry (IHC)
IHC was performed on formalin-fixed paraffin-embedded (FFPE) specimens with validation of positive and negative controls according to our previously reported protocol [14]. The following antibodies for TTF-1 (clone: 8G7G3/1, Dako, Carpinteria, CA) to detect human pituicytes in the neurohypophysis [15], c-kit (polyclonal, Dako) and Placental alkaline phosphatase, PLAP (clone: 8A950, Dako) to detect germinoma cells, and Langerin (clone: 12D6, Leica Biosystems, Nussloch GmbH) to detect Langerhans cells were used at 1:200, 1:100, 1:50, and 1:200 dilution, respectively.
Detection of anti-rabphilin-3A antibodies by Western blotting
A vector containing the full-length human rabphilin 3A gene was transfected into HEK293FT cells to produce recombinant human rabphilin-3A protein. Expression of recombinant rabphilin-3A protein was confirmed using an anti-V5 antibody. As a control, the same vector without the rabphilin 3A gene was transfected into HEK293FT cells. Anti-rabphilin-3A antibody in the serum was detected by western blotting using recombinant human rabphilin-3A protein lysate as the antigen and serum as the primary antibody. A protein band with a size of 76 kDa appeared in the lysate of cells transfected with rabphilin-3A protein, but not in that of control cells, which was considered to be positive for anti-rabphilin-3A antibody, as reported previously [9, 11].
Case descriptions
Case 1: A 12-year-old girl had been noted to be short since the age of 8 years, and her short stature became pronounced at the age of 11 years, ranging from –2.5 to 3.0 SD. MRI showed an enlarged pituitary gland, pituitary stalk, and cystic lesions in the pineal gland, which prompted her to visit our hospital. At the time of her first visit to our department, she was 133.5 cm tall, weighed 26.4 kg, and was not obese, and performed well in school. She had no visual impairment. Her first menstruation had not yet occurred. Insulin and arginine loading tests showed decreased growth hormone responsiveness (peak serum GH concentration 1.46 and 2.89 ng/mL, respectively) and low IGF-1 levels (57 ng/mL) was observed, which led to a diagnosis of severe growth hormone deficiency-induced short stature. Insulin loading test showed good responsiveness in ACTH and cortisol, TRH loading test showed normal responsiveness in TSH and PRL, and LHRH loading test showed normal responsiveness in LH and FSH. Her mother also had delayed onset menstruation at the age of 15 years, so it was possible that her lack of menarche was due to late menarche. In addition, there was mild polyuria and polydipsia, daily urine amount (per kg body weight) was about 75 mL/kg. Blood tests revealed a decreased plasma ADH concentration of 0.4–0.8 pg/mL, and a serum Na level of 142 mEq/L, which was at the upper normal limit. Urinalysis revealed a low osmolality of 222 mOsm/L. Although a water deprivation test showed an increase in urine osmolality to 337 mOsm/L and reactivity, a vasopressin loading test showed urine concentrations of 501 mOsm/L. Further, MRI showed loss of posterior lobe high signal on T1-weighted images, suggesting central diabetes insipidus (CDI). Contrast-enhanced MRI showed an enlarged pituitary gland and thickened pituitary stalk with strong enhancement, and a cystic lesion with ring enhancement in the pineal gland (Fig. 1A, B). The site of attachment of the pituitary stalk to the pituitary was slightly deviated anteriorly, and there appeared to be a mass lesion from the pituitary stalk to the posterior pituitary, and the anterior pituitary appeared to be mildly compressed anteriorly, but the boundary between the anterior and posterior glands was not well defined. The pituitary lesions could be germ cell tumors, especially germinoma, which can show bifocal lesions in the suprasellar and pineal regions. There were no elevations of human chorionic gonadotropin β-subunit (β-hCG) or α-fetoprotein (AFP) in serum or β-hCG, AFP, or placental alkaline phosphatase (PLAP) in cerebrospinal fluid, and all of these tumor markers were negative. The differential diagnosis included LYH, especially LPH, as well as malignancies such as neurohypophyseal germinoma or Langerhans cell histiocytosis (LCH). A biopsy of the pituitary lesion was performed by endoscopic endonasal transsphenoidal surgery. Pathological findings showed a cellular infiltrate consisting mainly of lymphocytes and plasma cells but no tumor cells (Fig. 2). The immunohistochemistry for TTF-1, a marker of human pituicytes, was performed to identify the neurohypophysis. The main specimens were positive for TTF-1, indicating that the posterior pituitary gland was the main collection site. Anterior pituitary structures were also observed in some of the specimens. Within these sampled specimens, inflammation was found to be predominantly in the posterior pituitary gland, with spillover to parts of the anterior gland. As to the possibility of neoplasms such as a neurohypophysis germinoma and LCH, immunohistochemistry did not reveal c-kit-positive, PLAP-positive, or Langerin-positive cells. Since neoplasms were ruled out, a diagnosis of LPH was made. Additionally, the patient was found to be positive for the anti-rabphilin-3A antibody (Fig. 3), which supported the diagnosis of LYH. Desmopressin was initiated for postoperative worsening of CDI. Growth hormone replacement was continued and her height kept within –2.5 to 3.0 SD. Hydrocortisone was also initiated, but is now only taken abruptly during stress. Estradiol was started at a low dose, but the first menstruation has not yet occurred. Twenty months after the diagnosis, contrast-enhanced MRI showed some shrinkage of the distal portion of the pituitary stalk (Fig. 1C), and no elevations of β-hCG or AFP in serum were found.
Case 2: A 13-year-old girl had a persistent headache around the age of 8 years, which spontaneously resolved within a few months. At the age of thirteen years old, she began to have intermittent headaches that were not related to menstruation and were so persistent that she was unable to attend school. She was 155.7 cm tall, weighed 47.3 kg. An MRI of the head revealed a large pituitary gland (13 mm) and thickening of the pituitary stalk (3 mm), although a high signal was maintained in the posterior pituitary lobe on T1-weighted images (Fig. 1D, E). Contrast-enhanced MRI showed no delayed contrast in the posterior pituitary lobe (data not shown). No electrolyte abnormalities were noted. Endocrinological examination revealed decreased basal levels of ACTH and cortisol (6.9 pg/mL and 3.9 μg/dL, respectively) but normal response to CRH loading test (90.9 pg/mL and 17.0 μg/dL at peak serum level of ACTH and cortisol, respectively), which highlighted the possibility of secondary adrenal insufficiency due to anterior pituitary hypofunction. Other anterior pituitary functions were normal. Moreover, there have been no episodes of polydipsia or polyuria, daily urine amount was about 20 mL/kg. There was no CDI and the posterior pituitary function was preserved. Because of the positive anti-rabphilin-3A antibody result (Fig. 3), a biopsy was not performed owing to concerns about pituitary dysfunction and invasiveness associated with surgery, and she continued to be followed up. Contrast-enhanced follow-up MRI showed no remarkable changes in the pituitary and pituitary stalk at 1, 5, and 7 months after diagnosis (Fig. 1F). To date, no further anterior pituitary dysfunction or CDI has developed. Therefore, we considered LAH as the most likely diagnosis. The patient is currently undergoing follow-up imaging and endocrinological observations because she may develop CDI in the future.
Sensitivity and specificity of anti-rabphilin-3A antibody in pituitary diseases
Table 1 summarizes the positive and negative cases of anti-rabphilin-3A antibody in histologically confirmed pituitary diseases from previous reports [9, 11, 16, 17]. The sensitivity was 100% for LINH, 11.1% for LAH, 75.0% for LPH, 87.5% for LINH and LPH. The overall specificity of the sellar/suprasellar mass was 97.4%, while the specificity of the germinomas was 83.3%. When Case 1 was included in this study, the sensitivity was 80.0% for LPH and 88.9% for LINH and LPH.
Table 1
Positive or negative cases for anti-rabphilin-3A antibodies in histologically verified pituitary diseases in previous reports including ours
|
Iwama S et al. 2015 [11] |
Niri T et al. 2021 [16] |
Arihara Z et al. 2022 [9] |
Takahashi Y et al. 2022 [17] |
The present Case 1 |
Positive cases in LYH |
Sensitivity |
Negative cases in sellar/suprasellar lesion other than LYH |
Specificity |
| LINH |
4/4 |
|
|
|
|
4/4 |
100% |
|
|
| LAH |
2/18 |
|
|
|
|
2/18 |
11.1% |
|
|
| LPH |
|
|
2/3 |
1/1 |
1/1 |
4/5 |
80.0% |
|
|
| LINH and LPH |
|
|
|
|
|
8/9 |
88.9% |
|
|
| Germinoma |
0/5 |
|
1/1 |
|
|
|
|
5/6 |
83.3% |
| Rathke cleft cyst |
0/7 |
|
0/2 |
|
|
|
|
9/9 |
100% |
| Craniopharyngioma |
0/11 |
|
0/1 |
|
|
|
|
12/12 |
100% |
| Nonfunctioning pituitary adenoma |
0/5 |
|
|
|
|
|
|
5/5 |
100% |
| Langerhans cell histiocytosis |
0/1 |
|
|
|
|
|
|
1/1 |
100% |
| Sarcoidosis |
0/1 |
|
|
|
|
|
|
1/1 |
100% |
| Glioma |
0/1 |
|
|
|
|
|
|
1/1 |
100% |
| Pituitary teratoma |
0/1 |
|
|
|
|
|
|
1/1 |
100% |
| Hypertrophic pachymeningitis |
0/1 |
|
|
|
|
|
|
1/1 |
100% |
| Hypothalamic tumor |
0/1 |
|
|
|
|
|
|
1/1 |
100% |
| Hypothalamitis without LINH |
|
0/1 |
|
|
|
|
|
1/1 |
100% |
| Sellar/suprasellar mass |
|
|
|
|
|
|
|
38/39 |
97.40% |
Abbreviations: LINH, lymphocytic infundibulo-neurohypophysitis; LAH, lymphocytic adenohypophysitis; LPH, lymphocytic panhypophysitis; LYH, lymphocytic hypophysitis; Sellar/suprasellar mass; tumors such as germinoma, Rathke cleft cyst, craniopharyngioma, etc.
Discussion
The symptoms of LYH include varying degrees of anterior and/or posterior pituitary dysfunction [18-20]. LINH is a disorder of the posterior pituitary gland caused by inflammation. Further, CDI due to deficient vasopressin secretion is the main symptom, and thickening of the pituitary stalk or enlargement of the posterior pituitary gland and a uniform strong enhancement is observed, often without a high signal in the posterior lobe on T1-weighted images. In pediatric patients, differentiation of LINH from malignancies such as germ cell tumors seen in children is often problematic, and biopsy is considered necessary for differentiation. However, in practice, biopsy is often avoided due to its invasive nature, and a clinical diagnosis is not uncommon [8]. It has been reported that an autoimmune process involving destruction of the neurohypophysis may be involved in many patients with idiopathic CDI [10, 21], and that the etiologies of more than half of children or young adult patients with CDI include inflammatory/autoimmune processes [22]. Because of the high incidence of autoimmune-associated hypophysitis in children and young adults, a diagnosis as non-invasive as possible is warranted.
Recently, it was reported that anti-rabphilin-3A antibodies can be used as diagnostic markers for LINH [9, 11]. Among these, only a few pediatric cases have been reported [12, 13]. All patients who presented with CDI were clinically diagnosed with LINH based on their symptoms and MRI findings, and showed positive serum anti-rabphilin-3A antibodies. None of the patients were biopsied because of invasive concerns.
The detection of serum anti-rabphilin-3A antibodies has been reported not only in LINH, but also in LPH and LAH [9, 11, 16, 17]. Case 1 presented with anterior and posterior pituitary dysfunction and a histopathological diagnosis of LPH was determined. Further, anti-rabphilin-3A antibodies were positive, which supported the pathological diagnosis. Case 2 showed mild anterior pituitary insufficiency without CDI, despite positive anti-rabphilin-3A antibodies. Based on imaging and endocrinological findings, a diagnosis of LAH was made and follow-up is ongoing.
The rabphilin-3A is thought to be a pathogenetic antigen [23], not expressed in the anterior pituitary gland, but is found in the posterior pituitary gland [11]. Arihara et al. reported the rabphilin-3A antibodies positive patient that LPH developed after the onset of CDI, suggesting that the inflammation may spread from the posterior pituitary to the anterior pituitary and then to the entire pituitary gland [9]. However, our two pediatric patients positive for anti-rabphilin-3A antibodies presented with varying degrees of anterior hypopituitarism; anterior pituitary hypopituitarism preceded CDI in our Case 1, and only anterior pituitary hypopituitarism was seen without CDI in Case 2. Anterior pituitary dysfunction is greater in pediatric cases than in adults and may worsen during adolescence in LYH [4, 5, 7]. In children with LYH, even if some degree of mild inflammation occurs in the posterior pituitary gland, it may not lead to CDI onset in the early stage of the disease, and inflammation may spread to the anterior pituitary gland, leading to anterior lobe dysfunction. Thus our Case 2 is currently in the pre-onset stage of CDI and may develop CDI in the future, so follow-up imaging and endocrinological observations should be needed. Of the LYH cases with anti-rabphilin-3A antibody testing, patient age was known in four cases of LPH reported by Arihara Z et al. and one case of LPH by Takahashi Y et al., and all of these cases were adults [9, 17]. Our Case 1 is the first report of pediatric LPH with positive anti-rabphilin-3A antibodies.
In general, surgical decompression is considered in LYH when symptoms caused by the mass effect of pituitary enlargement are unresponsive to steroids. However, surgery for diagnostic purposes, especially in children, should be chosen carefully, taking into account both the risk of additional pituitary dysfunction due to surgical procedure and the possibility of tumor.
Based on our recent report [24], we considered the possibility that Case 1 was a germinoma because it showed bifocal lesions in the suprasellar and pineal regions on imaging, and made the differential diagnosis of LPH as well as neurohypophyseal germinoma. According to the diagnostic guidelines for LYH, the diagnosis of LYH is essentially a diagnosis of exclusion, so a pituitary biopsy is required for a definitive diagnosis [25]. Our recently published guidelines for central nervous system germ cell tumors recommend β-hCG and AFP as established tumor markers [26]. In addition, PLAP in cerebrospinal fluid has recently been reported to be a useful diagnostic marker for germinomas with high sensitivity and specificity [27]. If PLAP is established as a tumor marker for germinoma, noninvasive diagnosis for LYH may be possible in combination with anti-rabphilin-3A antibodies.
There have been a few reports of occult germinomas that were diagnosed as CDI with pituitary stalk thickening, but later grew over time to become a confirmed diagnosis [28]. Therefore, even when LPH is diagnosed on biopsy in our Case 1, long-term follow-up with imaging and tumor markers should be done.
Arihara et al. reported a case of germinoma positive for anti-rabphilin-3A antibodies [9], resulting in the specificity of the germinomas was 83.3%. Anti-rabphilin 3A antibodies are thought to be positive when autoimmune mechanisms are involved, as they are not positive in the posterior lobe destruction and secondary inflammation seen in CDI due to tumor or postoperative changes [11]. Thus, it can be assumed that the patient with germinoma has developed an autoimmune mechanism, i.e., autoantibodies to rabphilin 3A, although the cause is not clear. In a paper by Yasuda et al. [23], lymphocyte infiltration was observed only in the posterior pituitary lobe when mice were immunized with rabphilin 3A, and administration of an inhibitor of lymphocyte activation markedly reduced lymphocyte infiltration as well as urine volume reduction, suggesting that lymphocytes responsive to rabphilin 3A may be involved in the pathogenesis of CDI. In the future, we plan to analyze lymphocytes infiltrating the posterior pituitary gland in human pituitary tissue, including their relationship with rabphilin 3A.
As shown in Table 1, the sensitivity of anti-rabphilin-3A antibody was 100.0% for LINH, 80.0% for LPH and 88.9% for LINH and LPH, and the specificity was 97.4% for distinguishing sellar/suprasellar masses. Thus we believe that anti-rabphilin-3A antibodies may be a useful non-invasive diagnostic marker not only for LINH but also for LYH in general, that when LYH is suspected, an anti-rabphilin-3A antibody test should be performed before proceeding to the biopsy. Of course, a definitive diagnosis cannot be made without biopsy, and long-term follow-up should be performed in children while considering the possibility of neoplasms. Especially in cases with negative anti-rabphilin-3A antibodies and without biopsy, more careful follow-up with MRI is needed. The problems with the anti-rabphilin-3A antibody test are as follows. 1) the test is only an adjunctive diagnostic method at present; 2) the test is not commercially available; 3) with a specificity of 83% for germinoma, it is difficult to exclude germinoma by a negative result. The future work is needed to increase the number of cases of germinoma and to clarify the exact specificity. If the anti-rabphilin-3A antibody test becomes widely available as a commercial test method such as Enzyme-Linked Immuno Sorbent Assay, the data on sensitivity and specificity will be accumulated, and the usefulness of the test will be evaluated more objectively.
Disclosure Statement
There is no COI to disclose in this report.
Ethical Approval
Written informed consent was obtained from the patient and patients’ family for this study and the publication under our approved protocol (No. 1760).
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