Hypopituitarism and cranial nerve involvement mimicking Tolosa-Hunt syndrome as the initially presenting feature of diffuse large B-cell lymphoma: a case report.

BACKGROUND: Early diagnosis of lymphoma involving the central nervous system is sometimes difficult but emergent to avoid the delay of therapeutic initiation. Pituitary insufficiencies are usually associated with lymphoma in the pituitary gland. There have been no cases of lymphoma originating from extra pituitary gland with hypopituitarism that simultaneously presenting unilateral upper cranial nerve palsies and ophthalmalgia. These symptoms are mostly caused by neoplastic involvement of the skull base or benign diseases such as Tolosa-Hunt syndrome (THS). We report a case of lymphoma with unique clinical courses initially presenting hypopituitarism and symptoms mimicking THS with a mass in sphenoidal and cavernous sinuses accompanying sphenoidal bone erosion. CASE PRESENTATION: A 71-year-old woman visited our hospital with left ophthalmalgia, ptosis, and diplopia. Neurological findings revealed left oculomotor, trochlear and abducent nerve palsies. Endocrine tests indicated partial hypopituitarism. Initial CT and MRI revealed that a mass in sphenoidal and cavernous sinuses had invaded the sella with osteolysis of the sphenoid bone. At around four weeks, almost all the symptoms of cranial nerve palsies were relieved. Seven weeks later, she had a high fever and cervical lymph node (CLN) swellings. CLN biopsy revealed CD20-positive B-cells. She was diagnosed with diffuse large B-cell lymphoma (DLBCL). 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) revealed elevated uptake at the erosion lesion of the sphenoidal bone, but not the pituitary gland. After chemotherapy, all the symptoms related to systemic lymphoma were relieved, but partial hypopituitarism remained. The mass in sphenoidal and cavernous sinuses and elevated uptake by PET/CT were dissolved. CONCLUSION: This case of DLBCL had a unique clinical course; initial presentation of hypopituitarism and symptoms mimicking THS. There was also rare demonstration of mass lesions related to DLBCL in the sphenoidal and cavernous sinuses compressing the pituitary gland through an eroded area of the sphenoidal bone. It should be clinically cautioned that DLBCL can be associated with erosion of the sphenoidal bone and cause both hypopituitarism and THS-mimicking symptoms.

Distinct clinical features and prognosis between persistent and temporary thyroid dysfunctions by immune-checkpoint inhibitors.

Immune-related adverse events in the thyroid glands (thyroid irAEs) during treatment with immune-checkpoint inhibitors (ICIs) are most frequent endocrine irAE. Thyroid irAE can be divided into that requiring continuous therapy for thyroid dysfunction (P-THY), and that requiring only temporal treatment (T-THY). However, predictive factors for those differential outcomes are unknown, and susceptibility of human leukocyte antigen (HLA) to thyroid irAE has never been investigated. This study aimed to elucidate clinical courses and prognosis of P-THY in comparison with T-THY in the aspect of thyroid immunity and HLA. Patients with P-THY (n = 15) that required L-T4 supplemental therapy for hypothyroidism for more than 3 months, and patients with T-THY who required no therapy or therapy within 1 month were enrolled in the study. Lower-value of TSH, higher-value of FT4, and lower value of TSH/FT4 were thought to be predictive markers to estimate P-THY. In addition, anti-thyroglobulin antibody (TgAb) levels were significantly higher in patients with P-THY than those in patients with T-THY. HLA-DPA1*01:03 and HLA-DPB1*02:01 allele, and their haplotype frequencies were significantly higher in patients with P-THY than those in controls. P-THY had better survival rate than T-THY. Pre-existing thyroid autoimmunity, the extent of thyroid dysfunction, and predisposing HLA were associated with the differential course of thyroid irAEs. It was suggested that thyroid function tests, TgAb, and HLA typing tests are useful for prediction of clinical course in thyroid irAEs.

Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors.

Immune-related adverse events (irAEs) are often seen during immune-checkpoint inhibitor (ICI) treatment of various malignancies. Endocrine irAEs including thyroid dysfunctions are the most common irAEs, but their biomarkers remain unclear. In order to identify individuals who are susceptible to thyroid irAE for earlier diagnosis and appropriate follow-up, the current study is aimed to investigate biomarkers of thyroid irAE. Herein, patients with advanced malignant diseases who received ICIs treatment were prospectively studied. Clinical and laboratory examination, thyroid function, and autoantibodies were evaluated at baseline, and every 4 wk after first treatment with ICIs. Cytokines/chemokines were measured at baseline and at 4 wk. In vivo effects of ICIs on experimental autoimmune thyroiditis were evaluated. Twenty-six patients with malignant diseases who received ICIs treatment were enrolled in the study. Patients were divided into two groups: those who developed thyroid irAE, and those without irAEs. Comparing the two groups, early increase (≤4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1ß, IL-2, and GM-CSF at baseline, and early decrease of IL-8, G-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen. In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.

Autoimmune polyglandular syndrome type 2 and autoimmune hepatitis with thymoma-associated myasthenia gravis: case report.

BACKGROUND: Autoimmune polyglandular syndrome type 2 (APS-2) is a rare and complex clinical entity, and little is known about its etiology and progression. CASE PRESENTATION: A 52-year-old woman with autoimmune hepatitis (AIH) and bronchial asthma was diagnosed with APS-2; autoimmune Addison's disease (AD), and Hashimoto's thyroiditis (HT), and she underwent prednisolone (PSL) treatment. Five months later, she presented ptosis and was diagnosed with thymoma-associated myasthenia gravis (MG). Thymectomy and PSL treatment with immuno-suppressants appeared to ameliorate MG, AD, AIH, HT, and bronchial asthma. HLA typing analysis revealed that the patient had susceptible HLA alleles to MG, AIH, and HT in a Japanese population. CONCLUSIONS: This case suggests common endocrinological and autoimmune aspects of APS-2 and AIH with thymoma-associated MG, which are considered to be extremely rare complications.

The influence of thyroid autoimmunity on pregnancy outcome in infertile women: a prospective study.

Thyroid dysfunction and thyroid autoimmunity (TAI) have been reported to be linked to infertility, pregnancy loss and preterm birth. Infertile women undergoing assisted reproductive technology are recommended to maintain thyroid stimulating hormone (TSH) levels below 2.5 µIU/mL. It is unclear, however, whether levothyroxine (L-T4) treatment decreases the effects of TAI on fertility and pregnancy outcome in infertile women. We therefore aimed to clarify the influence of TAI on pregnancy undergoing L-T4 treatment for hypothyroidism. Prospectively recruited to this study were the 595 infertile women who visited the Utsunomiya Ladies Clinic between January 2013 and December 2015. Five patients with Graves' disease were excluded. Clinical profiles of 590 women were as follows: proportion of SCH = 19.6%, thyroid peroxidase antibody (TPOAb) positivity = 10.4%, and thyroglobulin antibody (TgAb) positivity = 15.1%. Fertility was not affected by any thyroid-associated factors. Regarding pregnancy outcomes, TPOAb titers were significantly higher in women who had miscarriage than in those progressed to delivery (46.4 ± 114.1 vs. 18.9 ± 54.6 IU/mL, p = 0.039), notably in those undergoing intrauterine insemination (p = 0.046) and in vitro fertilization (p = 0.023). Multivariate logistic regression analysis revealed that higher age (odds ratio 26.4, p < 0.001) and higher TPOAb titer (odds ratio 11.8, p = 0.043) were risk factors for miscarriage. Higher TPOAb titer should be considered as one of the risk factors for miscarriage in infertile women, even if they have been treated with L-T4 for hypothyroidism.

Comparative analysis of human leucocyte antigen between idiopathic and anti-PD-1 antibody induced isolated adrenocorticotropic hormone deficiency: A pilot study.

BACKGROUND: Adult-onset idiopathic isolated adrenocorticotropic hormone deficiency (id-IAD) is a rare disease with unknown aetiology. Recently, numerous cases of anti-PD-1 antibody-induced IAD (PD1-IAD) have been reported, but the clinical course, predictive factors and relationship to id-IAD have not been clarified. Moreover, associations of id-IAD and PD1-IAD with human leucocyte antigen (HLA) require elucidation. METHODS: Clinical characteristics of 13 Japanese patients with id-IAD and eight Japanese patients with PD1-IAD were analysed, and HLA-typing test was performed for each patient. Allele and haplotype frequencies of the patients were compared to those of healthy Japanese controls. RESULTS: In the HLA allele and haplotype analyses of id-IAD, the frequencies of HLA-C*14:02, HLA-DPB1*05:01, HLA-DRB1*04:05-DQB1*04:01-DPB1*05:01 and HLA-DRB1*09:01-DQB1*03:03-DPB1*05:01 were significantly increased. On the other hand, HLA alleles account for PD1-IAD susceptibility as follows: HLA-DQB1*06:01, HLA-DPB1*09:01 and HLA-DRB5*01:02. Moreover, protective effect for HLA-C*03:03 was suggested in combined id-IAD and PD1-IAD patients. Comparison of the effects of HLA on id-IAD and PD1-IAD revealed some differences. Alleles or haplotypes frequencies increased in id-IAD group were as follows: HLA-DPB1*05:01, HLA-DRB1*09:01, HLA-DRB4*01:03:02, HLA-DQB1*03:03 and HLA-DRB1*09:01-DQB1*03:03. In clinical settings, hyponatremia, disturbance of consciousness and hypoglycaemia were less frequently seen in patients with PD1-IAD than in patients with id-IAD. CONCLUSIONS: Distinct clinical characteristics and predisposing HLA allele contributions were proposed between id-IAD and PD1-IAD. Further investigations with greater number of cases are warranted to clarify the detailed mechanisms of id-IAD and PD1-IAD.

[Endocrine Organ Dysfunction with Immune-Checkpoint Inhibitors].

Cytotoxic T-lymphocyte associated antigen 4(CTLA-4), programmed death 1(PD-1), and programmed death-ligand 1 (PD-L1)are referred to as immune-checkpoints. CTLA-4 is located on the surface of activated T-cells, therefore inhibiting binding of CD28 to B7 molecule on antigen presenting cells. The CTLA-4 pathway predominantly acts in lymph nodes. PD-1 is majorly expressed on T-cells. The PD-1 pathway is involved with tumor microenvironment. Immune-checkpoint inhibitors (ICIs)are monoclonal antibodies to these molecules and are promising novel agents for malignant tumor treatment. ICIs promote T-cell-mediated cytotoxicity directed at cancer cell antigens. Approximately 20-30% of patients with advanced cancer were found to be responders of ICIs. However, various adverse events have been reported as immune-related adverse events(irAEs). IrAEs include dermatological, gastrointestinal, hepatic, neurological, and endocrine disorders. In the endocrine system, irAEs in the pituitary glands, thyroid glands, pancreas, and adrenal glands have been reported. Since rapidly progressive fatal endocrine systems failure may provoke during ICI therapy, precise diagnosis and prompt treatment as well as close follow-up is critical. We propose routine monitoring of endocrine functions and related symptoms(ie. worsened fatigue, hyperglycemia, hypoglycemia, hypotension, and hyponatremia), as well as other laboratory tests during ICI therapy. We herein discuss possible mechanisms of endocrine irAEs with ICIs, and highlight diagnostic approaches, treatments, and future prospects of endocrine irAEs during ICI therapy.

Thyroid storm with delayed hyperbilirubinemia and severe heart failure: indication and contraindication of plasma exchange.

SUMMARY: Thyroid storm (TS) is a life-threatening condition that may suffer thyrotoxic patients. Therapeutic plasma exchange (TPE) is a rescue approach for TS with acute hepatic failure, but it should be initiated with careful considerations. We present a 55-year-old male patient with untreated Graves' disease who developed TS. Severe hyperthyroidism and refractory atrial fibrillation with congestive heart failure aggregated to multiple organ failure. The patient was recovered by intensive multimodal therapy, but we had difficulty in introducing TPE treatment considering the risk of exacerbation of congestive heart failure due to plasma volume overload. In addition, serum total bilirubin level was not elevated in the early phase to the level of indication for TPE. The clinical course of this patient instructed delayed elevation of bilirubin until the level of indication for TPE in some patients and also demonstrated the risk of exacerbation of congestive heart failure by TPE. LEARNING POINTS: Our patient with thyroid storm could be diagnosed and treated promptly using Japan Thyroid Association guidelines for thyroid storm. Delayed elevation of serum bilirubin levels could make the decision of introducing therapeutic plasma exchange difficult in cases of thyroid storm with acute hepatic failure. The risk of worsening congestive heart failure should be considered carefully when performing therapeutic plasma exchange.