堀口 健太郎

エナメル上皮型頭蓋咽頭腫の病態については、これまでCTNNB1変異に伴うWnt signal活性など少しずつ解明が進んでいるが、まだ全容解明には至っていない。その要因の一つとして、腫瘍内部は非常にheterogeneityに富んでおり、これまでのbulk検体を対象とした検討では腫瘍細胞本来の性質が隠されてしまうことが挙げられる。今回、この問題をブレイクスルーするシングルセル解析法を用いて本症の病態解明を試みた。その結果、本症の腫瘍細胞には2つのsubtype(Immune rich typeとProliferative epithelial type)があり、それぞれ異なる分子生物学的背景が存在することが明らかになった。

OBJECTIVE Due to the heterogeneous definitions of tumor regrowth and various tumor volume distributions, the nature of small remnants after vestibular schwannoma (VS) surgery and the appropriate timing of adjuvant stereotactic radiosurgery for these remnants remain unclear. In this study, the growth potential of small remnants (< 1 cm³) after VS surgery was compared with that of treatment-naïve (TN) small VSs. METHODS This retrospective single-center study included 44 patients with VS remnants following subtotal resection (STR) of a large VS (remnant group) and 75 patients with TN VS (< 1 cm³; TN group). A 20% change in tumor volume over the imaging interval indicated radiographic progression or regression. Tumor progression-free survival (TPFS) rates were estimated using the Kaplan-Meier method. RESULTS In the remnant group, the mean preoperative tumor volume was 13.8 ± 9.0 cm³ and the mean tumor resection rate was 95% ± 5%. The mean tumor volume at the start of the observation period did not differ significantly between the two groups (remnant vs TN: 0.41 ± 0.29 vs 0.34 ± 0.28 cm³, p = 0.171). The median periods until tumor progression was detected were 15.1 (range 4.9–76.2) months and 44.7 (range 12.6–93.2) months in the TN and remnant groups, respectively. In the remnant group, the TPFS rates were 74% and 70% at 3 and 5 years after the surgery, respectively, compared with 59% and 47% in the TN group. The log-rank test demonstrated a significant difference (p = 0.008) in the TPFS rates between the two groups. Furthermore, 42 patients each from the remnant and TN groups were matched based on tumor volume. TPFS was significantly longer in the remnant group than in the TN group (3-year rates, 77% vs 62%; 5-year rates, 73% vs 51%; p = 0.02). In the remnant group, 18% of the tumor remnants demonstrated regression during follow-up, compared with 9% in the TN group, but this intergroup difference was not significant (p = 0.25). CONCLUSIONS This study demonstrated that the growth potential of small VS remnants was lower than that of TN tumors. Observing for small remnants may be appropriate after STR of a large VS. Given the risk of tumor regrowth, careful observation using MRI should be mandatory during follow-up.

BACKGROUND AND IMPORTANCE: Cholesterol granuloma (CG) is the most common petrous apex (PA) cystic lesion. Posterolateral expansion of a PA CG (PACG) compresses the internal auditory canal (IAC), leading to vestibulocochlear (VC) and facial nerve dysfunction. Even small, symptomatic PACGs are managed surgically. The preferred strategy is not complete removal, but drainage and aeration. PACG with anteromedial expansion using an endoscopic endonasal approach provides natural drainage into the nasal sinus without risking VC and facial dysfunction. Endoscopic endonasal approach is inappropriate for small PACGs without anteromedial expansion because of potential damage to the petrous internal carotid artery. Small PACGs without anteromedial expansion are managed using extradural middle fossa (EMF) approach, which lacks a natural drainage pathway, thus necessitating an artificial drainage pathway for PACG aeration to prevent recurrence. We introduced EMF approach for CG decompression and cyst-to-mastoid antrum (MA) diversion for managing small, symptomatic PACGs without anteromedial expansion. CLINICAL PRESENTATION: A 48-year-old woman presented with headache, vertigo, tinnitus, and left hemifacial spasm with preserved hearing because of IAC compression caused by a small PACG without anteromedial expansion. Using the EMF approach, the CG and IAC were safely decompressed. Effective and long-standing artificial drainage for CG aeration was established by anterior petrosectomy and silicone tubing from the CG into the MA. Surgery resolved the symptoms, which have not recurred in 3 years. CONCLUSION: Granuloma decompression and cyst-to-MA diversion using silicone tubing using the EMF approach is a safe and effective surgical management for small, symptomatic PACG without anteromedial expansion.

成長ホルモン産生下垂体腺腫(GHoma)3例と非機能性下垂体腺腫(NF)8例の手術で摘出された組織および正常下垂体前葉組織4例についてSingle cell RNA sequenceを行い、組織別で比較検討した。その結果、正常前葉組織の細胞とGHoma細胞はともに分泌細胞としての類似した特性を持ち合わせているのに対し、非分泌細胞であるNF細胞では細胞増殖に関わるMDKなどのligand発現が認められ、組織毎にそれぞれ異なる分子生物学的背景が存在することが確認できた。

成長ホルモン産生下垂体腺腫(GHoma)3例と非機能性下垂体腺腫(NF)8例の手術で摘出された組織および正常下垂体前葉組織4例についてSingle cell RNA sequenceを行い、組織別で比較検討した。その結果、正常前葉組織の細胞とGHoma細胞はともに分泌細胞としての類似した特性を持ち合わせているのに対し、非分泌細胞であるNF細胞では細胞増殖に関わるMDKなどのligand発現が認められ、組織毎にそれぞれ異なる分子生物学的背景が存在することが確認できた。

Context: Growth hormone deficiency (GHD) develops early in patients with hypothalamic-pituitary disorder and is frequently accompanied by other anterior pituitary hormone deficiencies, including secondary adrenal insufficiency (AI). A growth hormone-releasing peptide-2 (GHRP2) test, which is widely used for the diagnosis of patients with GHD, is thought to induce release of not only growth hormone (GH) but also ACTH. However, its clinical usefulness in hypothalamic-pituitary disorder is unclear. Objective: We aimed to determine the clinical utility of the GHRP2 test in patients with hypothalamic-pituitary disorders, particularly for AI concomitant with GHD. Methods: The GHRP2 test, a cosyntropin stimulation test, corticotropin-releasing hormone (CRH) tests, and/or insulin tolerance tests (ITTs) were performed on 36 patients with hypothalamic-pituitary disorder. Results: Twenty-two (61%) had severe GHD, and 3 (8%) had moderate GHD by GHRP2. There was no difference in baseline ACTH and cortisol between non-GHD, moderate GHD, and severe GHD participants. However, a cosyntropin stimulation test and subsequent CRH tests and/or ITTs revealed that 17 (47%) had secondary AI and 16/17 (94%) cases of secondary AI were concomitant with severe GHD. ROC curve analysis demonstrated that the ACTH response in the GHRP2 test was useful for screening pituitary-AI, with a cutoff value of 1.55-fold (83% sensitivity and 88% specificity). Notably, the combination of ACTH response and the peak cortisol level in the GHRP2 test using each cutoff value (1.55-fold and 10 µg/dL, respectively) showed high specificity (100%) with high accuracy (0.94) for diagnosis of pituitary-AI. Conclusion: We recommend measuring ACTH as well as GH during the GHRP2 test to avoid overlooking or delaying diagnosis of secondary AI that frequently accompanies GHD.

BACKGROUND Hemifacial spasm (HFS) due to an arachnoid cyst at the cerebellopontine angle is rare. Here, the authors reported such a case and analyzed the mechanism of facial nerve hyperactivity by reviewing the literature. OBSERVATIONS A 40-year-old man presented with right HFS for the past 3 years. Preoperative magnetic resonance imaging revealed a right cerebellopontine angle cystic mass with high intensity on T2-weighted images, low intensity on T1-weighted and diffusion-weighted images, and no contrast effects. Cyst excision and decompression of the facial nerve using a lateral suboccipital approach to monitor abnormal muscle response (AMR) resulted in permanent relief. The cyst was histologically compatible with an arachnoid cyst. LESSONS In the present case, when the cyst was dissected, the AMR disappeared and no offending arteries were detected around the root exit zone. Therefore, the cyst itself was responsible for HFS, for which AMR was useful. Limited cases of HFS due to arachnoid cysts without neurovascular compression have been previously reported. The authors suggested that pulsatile compression by the cyst results in facial nerve hyperactivity and secondary HFS.

シングルセル解析を用いて、分子基盤や細胞間相互作用など、腫瘍内微小環境の探索を行った。非機能性下垂体腺腫(NF)8例、成長ホルモン産生下垂体腺腫(GHoma)3例、正常下垂体前葉組織(normal)4例を対象とした。手術で摘出された組織をcollagenaseを用いてdigestionした後、死細胞除去を行い、Chromium Controllerでemulsion作成/逆転写を行いシークエンスした。計45942細胞に対して解析を行った。クラスター細胞種同定と構成細胞特性の解析では、45942細胞は八つのmajorクラスターに大別され、組織を構成する細胞の割合をみてみると、マクロファージなどの貪食細胞を中心とする免疫細胞が6割ほどを占めていた。Endocrine componentのみを抽出して下流解析を行った。その結果、各クラスターはNF/GHoma/normalのいずれかの細胞が大多数を占めていた。cell-cell interaction解析の結果、GHとnormalでは類似したligand発現を認め、NFでは腫瘍増殖にかかわるMDK signaling pathwayが特異的にみられた。NF/GHoma/normalの腫瘍細胞または正常前葉細胞が受けるシグナルに着目すると、正常前葉細胞にみられたGH、PRL受容体の発現がNFとGHomaの腫瘍細胞には認められなかった。

<sec> <title>BACKGROUND</title> Anatomical variations, such as high jugular bulbs and air cell development in the petrosal bone, should be evaluated before surgery. Most bone defects in the internal auditory canal (IAC) posterior wall are observed in the perilabyrinthine cells. An aberrant vascular structure passing through the petrous bone is rare. </sec> <sec> <title>OBSERVATIONS</title> A 48-year-old man presented with a right ear hearing disturbance. Magnetic resonance imaging revealed a 23-mm contrast-enhancing mass in the right cerebellopontine angle extending into the IAC, consistent with a right vestibular schwannoma. Preoperative bone window computed tomographic scans showed bone defects in the IAC posterior wall, which ran farther posteroinferiorly in the petrous bone, reaching the medial part of the jugular bulb. The tumor was accessed via a lateral suboccipital approach. There was no other major vein in the cerebellomedullary cistern, except for the vein running from the brain stem to the IAC posterior wall. To avoid complications due to venous congestion, the authors did not drill out the IAC posterior wall or remove the tumor in the IAC. </sec> <sec> <title>LESSONS</title> Several aberrant veins in the petrous bone are primitive head sinus remnants. Although rare, their surgical implication is critical in patients with vestibular schwannomas. </sec>

ハイビジョン/4K内視鏡を用いて摘出した頭蓋咽頭腫24症例(男性13例、女性11例、年齢中央値54.5歳)を対象として、内視鏡下経鼻頭蓋底手術の適応と工夫について検討した。摘出方法は経鼻手術15例、脳室鏡併用経鼻手術9例で、全摘出21例、95%以上の亜全摘2例、部分摘出1例であり、残存および再発腫瘍に対して4例に放射線治療を追加した。両群の臨床背景や腫瘍のサイズ、摘出度および下垂体茎温存率に有意差はなく、脳室鏡併用経鼻手術群では実質性腫瘍で視床下部浸潤を伴うPuget grade 2の腫瘍が有意に多かったが、腫瘍の摘出率を低下させることなく安全に摘出できた。また、合併症については脳室鏡併用経鼻手術群で髄液漏の合併が有意に多かったが、その他の合併症に大きな差はなく、頭蓋咽頭腫の摘出において、現時点では視床下部を温存した最大限の摘出が可能な脳室鏡併用経鼻手術が有用である。

下垂体腺腫154検体を対象にRNA-seqとプロテオミクスを施行し、臨床情報との比較検討と総合解析を行った。その結果、マルチオミクス解析では68.7%の遺伝子はmRNA発現と蛋白発現に有意な相関がみられた。NR5A1やGATA2の発現は非機能性腺腫のグループで特異的に高いことが、mRNAとタンパクの両者で確認された。TBX19はACTH産生腫瘍で特異的に発現し、POU1F1はそのlineageのGH産生腺腫、TSH産生腺腫、PRL産生腺腫で高発現が認められた。また、非機能性腺腫の中にもACTH lineageのTBX19を発現する腫瘍が確認された。

OBJECTIVE: The relationship between quantitative posturography results and growth of vestibular schwannomas (VSs) during conservative management has not been studied. We aimed to clarify the relationship between the presence of disequilibrium based on posturographic measurement and VS growth. METHODS: This retrospective, single-center study included 53 patients with VSs (Koos stage I or II) managed conservatively after initial diagnosis. Radiographic progression was considered present if 20% volumetric growth was observed over the imaging interval. Posturography was performed at initial diagnosis, and sway velocity (SV) and sway area were calculated. Tumor growth-free survival was estimated using the Kaplan-Meier method. RESULTS: Mean follow-up period was 2.87 ± 2.58 years, up to tumor growth detection or last follow-up magnetic resonance imaging. Tumor growth incidence was 40.8% and 61.2% at 2 and 5 years, respectively. Cerebellopontine angle extension and SV with eyes open were related to tumor growth. Tumor growth-free survival of patients with cerebellopontine angle extension and patients with intracanalicular tumor at 2 years was 37.3% and 76.4%, respectively. Tumor growth-free survival of patients with SV >2.06 cm/second and patients with SV ≤2.06 cm/second at 2 years was 30.8% and 68.9%, respectively. The Cox hazard model demonstrated a significant risk for future tumor growth with SV >2.06 cm/second (relative risk, 2.475; 95% confidence interval, 1.11-5.37, P = 0.027). CONCLUSIONS: We demonstrated a positive correlation between SV with eyes open and future tumor growth. Posturographic data are objective and quantitative; thus, SV may be a potential predictor of future growth of VSs.

Rathke's cleft cyst (RCC) is a common incidental tumor in the hypothalamic-pituitary region. Some reports have shown that the clinical symptoms and endocrine functions of symptomatic RCCs are temporarily improved by glucocorticoid administration. However, it is still unknown whether glucocorticoid treatment is effective for symptomatic RCCs according to long-term observations. In this study, we describe the long-term clinical outcomes of two cases of glucocorticoid-treated biopsy-proven secondary hypophysitis caused by RCCs. We summarize the symptoms, imaging findings, and endocrine evaluations of two symptomatic RCC patients with concomitant hypophysitis before and after prednisolone treatment. In both evaluated cases, visual impairments and altered endocrine parameters were present due to chiasm and stalk compression; these outcomes improved after shrinkage of RCCs in response to prednisolone administration, and partial recovery of anterior pituitary hormone secretion was observed. However, in both cases, the deficits in anterior pituitary hormone secretion recurred, possibly due to persistent inflammatory infiltration in the RCCs and pituitary glands. After relapse of hypophysitis, anterior hormone secretion did not fully recover. In our cases of secondary hypophysitis caused by RCCs, prednisolone administration had an early effect of cyst shrinkage, followed by partial improvements in clinical symptoms and pituitary functions. However, long-term observation showed that prednisolone treatment did not contribute to complete improvement in anterior pituitary hormone dysfunction.

von Hippel-Lindau (VHL) disease is characterized by neoplastic and cystic lesions, such as central nervous system (CNS) hemangioblastoma and clear cell renal cell carcinoma (RCC), arising in multiple organs. Here, we report a case of an RCC that metastasized to a spinal hemangioblastoma in a patient diagnosed with VHL disease. This is a unique case study because visceral neoplasms rarely metastasize to the CNS. The patient had undergone posterior fossa surgery for the removal of hemangioblastomas in the right cerebellar hemisphere as a child. He was diagnosed with RCC at the age of 20 years, and he underwent partial nephrectomy at the age of 35 years. The patient underwent surgical removal of a spinal tumor from Th8, which was also diagnosed as a hemangioblastoma at the age of 40. However, the residual spinal tumor rapidly regrew within 1.5 years. A second surgery was performed due to progressive leg motor weakness. The resected tumor from the second surgery had two distinct components between the tumor center and the margin. Immunohistochemistry of CD10, PAX 8, and inhibin A demonstrated the predominant region of the tumor was RCC. Pathological findings confirmed tumor-to-tumor metastasis of the RCC migrating into residual spinal hemangioblastoma. It can be challenging to distinguish hemangioblastoma from RCC in neuroimaging. We suggest that tumor-to-tumor metastasis should be considered as a differential diagnosis if benign tumors grow rapidly, even if the pathological diagnosis does not initially confirm malignancy. The biological mechanisms of RCC migrating into residual hemangioblastoma are discussed.

Epstein-Barr virus-associated smooth muscle tumour (EBV-SMT) is a rare disease occurring in immunosuppressed patients, such as those with AIDS, post-transplantation immunodeficiency and congenital immunodeficiency. Intracranial EBV-SMT after solid organ transplantation has been reported. However, intracranial lesions after bone marrow transplantation are extremely rare. We report the case of a 47-year-old man with a history of acute myeloid leukaemia and bone marrow transplantation. He had symptoms of trigeminal neuralgia, and MRI revealed a left cavernous sinus tumour. He started taking oral gabapentin, but his symptoms did not improve. We performed transnasal endoscopic surgery. Postoperative MRI showed complete removal of the cavernous sinus lesion. Pathological examination showed spindle-shaped cells positive for smooth muscle markers and EBV-encoded small RNA in situ hybridisation. EBV-SMT was pathologically diagnosed. His symptoms improved after surgery. No tumour recurrence was noted on follow-up MRI after 15 months without adjuvant radiation or chemotherapy.