Noriko Kimura

The ectopic secretion of growth hormone (GH) or growth hormone-releasing hormone (GHRH) is responsible for fewer than 1% of acromegaly cases. Furthermore, within this small population, GHRH-secreting pheochromocytomas/paragangliomas (PPGLs) are even rarer. A 57-year-old Japanese woman presented to our hospital for treatment of a large left-sided pheochromocytoma (PCC). A physical examination revealed enlargement of the nose and lips as well as macroglossia, thereby raising the suspicion of acromegaly, which was biochemically confirmed by a 75-g oral glucose tolerance test. Magnetic resonance imaging demonstrated a slightly enlarged pituitary gland but no definitive tumor. A left adrenalectomy was performed after careful dose titration of doxazosin and metyrosine. Postoperative biochemical improvement of GH excess and immunohistochemical analysis of the resected tumor confirmed the diagnosis of GHRH-secreting PCC. Given the possibility that PPGLs produce various ectopic hormones and peptides, thorough physical examinations remain fundamental for the accurate diagnosis and optimal management of patients with these tumors.

Pheochromocytoma (PCC) and paraganglioma (PGL) are tumors of the adrenal medulla and sympathetic and parasympathetic paraganglia. Both PCC and PGL (PPGLs) are included in neuroendocrine tumors (NETs) of dispersed neuroendocrine system. The most important issue on PPGLs for pathology has been how to differentiate malignant from benign PPGLs, and the previous articles concentrated on solving this difficult issue. However, the concept of PPGLs was dramatically changed by WHO Blue Book, 4th edition (2017), in which all PPGLs have some metastatic potential, therefore, the previous categories of benign and malignant PPGLs have been eliminated in favor of an approach based on risk stratification. This review article includes following issues; 1. historical review of PPGLs, 2. significance of Ki67 labeling index, 3. comparison of scoring system of PASS, GAPP, COPPS these were cited in WHO Tumour Classification 5th edition (2022) with explanation of each parameter, 4. immunohistochemical approach for histopathologic diagnosis using antibodies for neuroendocrine tumors, the specific markers for catecholamine synthesis such as tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH) for sympathetic PPGL and choline acetyltransferase for parasympathetic PGL, and additional markers such as GATA3 and Phox2B for both sympathetic and parasympathetic PGL. Then markers for familial PPGLs such as SDHB for SDH-deficient PPGLs, CA9 for VHL, and MAX for MAX-related PPGL, and added Algorithm for diagnosis. The other familial type of MEN type2 and NF1 are discussed by some characteristic features in histology. Finally, rare types such as ACTH-producing PPGL, and dopamine-producing PPGL are discussed.

Pheochromocytomas and paragangliomas are characterized by two key features: endocrine disorders with excessive catecholamine secretion and a hereditary or metastatic nature, making early diagnosis and treatment crucial. This clinical practice guideline is a revision of the 2018 edition, which considers recent advances in clinical practice and changes to the health insurance coverage in Japan. Patients presenting with symptoms such as palpitations, headaches, hypertension, or abdominal tumors should undergo screening and confirmation with measurement of fractionated catecholamines and their metabolites in the blood and urine. When the tumor is located in the adrenal glands, it is diagnosed as a pheochromocytoma; when it is located outside the adrenal gland and confirmed by 123I-MIBG scintigraphy or 18F-FDG PET, it is diagnosed as a paraganglioma. Treatment begins with inhibiting catecholamine action using α-blockers, and if that is insufficient, metyrosine is used in combination, followed by laparoscopic tumor removal. Given the metastatic potential, long-term postoperative follow-up is essential. Even in cases of metastasis, tumor debulking should be considered. Treatment options are selected based on the amount of remaining tumor, symptom severity, and lesion progression, including CVD chemotherapy or radionuclide therapies such as 131I-MIBG or 177Lu-DOTATATE. Genetic testing guides the management of different variants, and significant progress has been made in molecularly targeted drug trials. Therefore, further advances in individualized and long-term management are required.

Successful resection and diagnosis of primary gastric myxoid liposarcoma using endoscopic submucosal dissection

A 75‐year‐old woman had been taking a geniposide‐containing herbal medicine for 7 years and was admitted to our hospital for nausea, abdominal pain, and distention. CT revealed colonic wall thickening, whereas CS revealed a dark‐purple edematous mucosa. Furthermore, biopsy specimens revealed small vein hyalinization. Thus, she was diagnosed with idiopathic mesenteric phlebosclerosis (IMP) and underwent surgery. von Kossa staining revealed granules in the mucosal, submucosal, muscular, and subserosal layers, with mesenteric veins demonstrating calcium deposition. Taken together, calcium ion deposition was likely to have accounted for vascular wall calcification in IMP. The patient's course was uneventful for 3 months after surgery.

Pediatric patients with pheochromocytoma (PCC)/paraganglioma (PGL) (PPGL) are rare, and clinicopathological investigations, especially the relationship between gene analysis and histological features, are insufficient. We comprehensively examined the clinical data, germline/somatic variants (mutations), and pathological characteristics of operated tumors using immunohistochemical expression and histological grading by Grading of Adrenal PCC and PGL score. This study included 28 patients (15 males and 13 females) aged <19 years. The age at the diagnosis was 12.8 ± 4.5 years. The included patient often had multiple PPGLs, with 39 tumors, including 21 PCCs and 18 PGLs, with average tumor sizes of 45.0 ± 22.8 and 42.6 ± 23.6 mm, respectively. Genomic types examined by gene mutations and immunohistochemistry of CA9 for VHL, SDHB for SDHx, and MAX for MAX, classified them into 14 VHL (50%), ten SDHx (35.7%), one MAX (3.6%), and three unknown (10.7%) types. Tumor metastasis was limited to two SDHB-related PPGLs, but not to VHL-related PPGLs. In both patients, the metastatic sites were the bones. The average GAPP score of the PPGLs was 2.9 ± 1.5 in VHL and 5.3 ± 1.7 in SDHB, and histological grades were well-differentiated in VHL and moderately differentiated in SDHB. SSTR2 expression was positive in 90% of SDHB-related PPGLs, but negative in 75% and weakly or focally positive in 25% of VHL-related PPGLs. Most pediatric PPGLs (90%) demonstrated mutations in VHL, SDHB, and MAX, with histological features depending on the mutation type. Combined genetic and immunohistochemical examination is desirable for accurate genomic diagnosis, and clinicopathological study.

Vonoprazan has recently been developed and approved for clinical use in Japan 1 as a drug of the potassium-competitive acid blocker (P-CAB) class reported to reversibly inhibit gastric acid output through K +-competitive ionic binding to H + /K +-ATPase. 2 Vonoprazan has been shown to selectively accumulate in gastric parietal cells in the mucosal layer of the rat stomach, 3 and gastric cracked mucosa (GCM), redness, white spots (WS), and gastric polyps (GP) have been reported as P-CAB-associated gastric mucosal lesions. 4-10 However, only a few cases have demonstrated a causal relationship between vonoprazan and gastric mucosal lesions through long-term follow-up from before drug initiation to after its discontinuation. 5,6 We herein report two cases in which GCM, WS, and GP newly appeared after the initiation of vonoprazan treatment and were followed up after switching to proton pump inhibitors (PPIs).

Since the introduction of vonoprazan, a potassium-competitive acid blocker (P-CAB), it has been demonstrated to reversibly inhibit gastric acid secretion by engaging in potassium-competitive ionic binding to H+/K+-ATPase. In contrast, proton pump inhibitors (PPIs) achieve H+/K+-ATPase inhibition through covalent binding to cysteine residues of the proton pump. Reported cases have indicated an emerging trend of P-CAB-related gastropathies, similar to those associated with PPIs, as well as unique gastropathies specific to P-CAB use, such as the identification of web-like mucus. Pathologically, parietal cell profusions, which show a positively correlated with hypergastrinemia, have a higher incidence in P-CAB users compared to PPI users. Thus, this review aims to summarize the endoscopic and pathological findings reported to date concerning P-CAB-related gastric mucosal lesions. Additionally, it seeks to discuss the differences between the PPIs and P-CABs in terms of the formation and frequency of associated gastropathies. This review highlights the evident differences in the mechanism of action and potency of acid inhibition between P-CABs and PPIs, notably contributing to differences in the formation and frequency of associated gastropathies. It emphasizes the necessity to distinguish between P-CAB-related and PPI-related gastropathies in the clinical setting.

Although metastatic spread of breast cancer to the gastrointestinal tract is very rare, it is more likely to occur in invasive lobular carcinoma (ILC) than in ductal carcinoma. Colonic metastasis is particularly rare, and the treatment strategies for these cases are not clearly defined. Herein, we report three cases of ILC with various abdominal symptoms associated with colonic metastasis. Case 1 A 70-year-old female patient with vomiting and melena was referred to our hospital. Endoscopic examination revealed a Dieulafoy ulcer in the rectum and an elevated lesion in the descending colon. She also had two breast nodules, and was diagnosed as ILC with colonic metastasis. Considering her general condition, the best supportive care (BSC) was offered. The patient died 4 months after confirmation of the diagnosis. Case 2 An 80-year-old female patient presented with diarrhea and vomiting. She was diagnosed with ILC with colonic metastasis, and a coloscopy revealed stenosis of the transverse colon with a metastatic lesion. Ileosigmoid bypass surgery was performed for intestinal obstruction, and systemic treatment for breast cancer was initiated. The patient developed peritoneal carcinomatosis and died 1 year and 2 months after surgery. Case 3 A 56-year-old female patient underwent left total mastectomy for ILC, and laparoscopic transverse colectomy was conducted for a colonic lesion 9 years and 2 months after. The diagnosis as colonic metastasis was not confirmed at that time. Two years and 2 months later, torose lesions were detected in the hepatic flexural and descending colon, and histopathological findings indicated that all colon tumors, including the previously resected tumor, were metastatic spread of ILC. Systemic treatment was continued, but the transverse colonic lesion penetrated the abdominal wall, and an abscess formed 2 years and 11 months after the resection. The fistula improved by continuous suction drainage following ileostomy but recurred, and the patient died 3 years and 8 months after colectomy. Colonic metastases from breast cancer can trigger various abdominal symptoms, and the prognosis in these cases is generally poor. In selected cases, surgical treatment for abdominal symptoms and subsequent systemic therapy can contribute to a prolonged prognosis.