Tuberous sclerosis complex (TSC) is an autosomal dominant inherited disorders that is characterized by the systemic hamartomas, along with epilepsy, cognitive impairment and hypopigmented macules. It is caused by genetic mutations in either TSC1 or TSC2 gene which encodes hamartin and tuberin, respectively. As the hamartin-tuberin-complex downregulates the mechanistic/mammalian target of the rapamycin complex1 (mTORC1), dysfunction in either hamartin or tuberin induces the constitutive activation of mTORC1. In fact, almost all the symptoms in TSC are derived from the activation of mTORC1. Therefore, mTORC1 inhibitors improves all the symptoms, including skin lesions and neural symptoms. Among the many symptoms, skin lesions appear earlier than renal or pulmonary lesions and are more specific than neuronal symptoms. Therefore, skin lesions are useful for the diagnosis of TSC. This chapter focuses on the features of skin lesions and mechanistic their potential role in differential diagnosis and therapy including the therapeutic use of mTORC1 inhibitors.

A large number of genetic neurological disorders are accompanied by dermatological manifestations. Among them, neurofibromatosis 1 (NF1, Recklinghausen disease) is characterized by pigmented macules, such as café au lait macules, freckling and numerous neurofibromas. Neurological complications are also seen in NF1 and it is important to conduct appropriate imaging studies for a correct diagnosis. In this report, I will discuss the differential diagnosis of dermatological manifestations of NF1 compared to those of other neurological disorders, such as Legius syndrome or NF2.

A 69-year-old man was brought to our hospital's emergency room with a chief complaint of hematemesis, which had been caused by advanced gastric cancer on the lesser curvature of the stomach's upper body. Subsequently, total gastrectomy with lymph node dissection (D2) was performed. A pathological diagnosis of gastric adenocarcinoma, U, Less, type 2, 100×70mm, tub2, pT3, int, INFb, ly0, v0, pN0 (0/24), pPM0 (30mm), pDM0 (30mm), fStage IIA, was then established. After discharge, the patient was treated with S-1 as adjuvant chemotherapy at a dose of 120mg per day. However, a decrease in the platelet count prompted termination of chemotherapy, which lasted for three courses. Ten months after surgery, serum CEA levels increased to 116.6ng/ml, with enhanced CT showing a solitary splenic tumor with a diameter of 48×52mm suggestive of gastric cancer recurrence. PET/CT revealed no other tumors suggestive of gastric cancer recurrence. Given that only a solitary splenic metastatic tumor was detected, splenectomy was performed eleven months after surgery. Histological findings were the same as the previous gastric cancer, with peritoneal washing cytology being suspicious. Chemotherapy with the SOX regimen (S-1 at a dose of 120mg per day and oxaliplatin at a dose of 100mg/m2) was then started. The patient remained recurrence-free for a half year. Except during the terminal phase, only a few cases of a splenic metastasis from gastric cancer have been reported. We consider splenectomy to be potentially useful for patients with a solitary splenic metastasis from gastric cancer, through which prolonged prognosis could be expected.

Revision of WHO guidelines in 2016 led to the classification of solitary fibrous tumours(SFTs)and haemangiopericytomas(HPCs)as a single tumor entity characterized by NAB2-STAT6 fusion. Standard-of-care treatment involves surgery, but local recurrence and distant metastasis sometimes occur. The average latency to metastasis after surgery is 99 months. A 38-year-old female patient presented with a complaint of headache. An 8×5×2cm lesion showing Gd-T1 enhancement was detected near the superior sagittal sinus. Pathological assessment following resection revealed proliferating, polymorphic, atypical tumor cells with distinct nucleoli in a "patternless pattern." Cellularity was moderate to high, and mitotic figures were observed in 15/10 high power fields. Immunohistochemically, tumor cells tested positive for STAT6, and RT-PCR revealed a NAB2-STAT6 fusion gene(exons 6 and 17, respectively), supporting a diagnosis of SFT/HPC WHO grade III. Despite postoperative radiotherapy, multiple metastases to the spleen were detected 8 months after surgery, and distal pancreatectomy with splenectomy was performed. The pathology of the splenic tumor was similar to that of the intracranial tumor. Recurrent disease in a lymph node was detected 1 month later, and local radiation therapy was administered. The patient died of cancerous peritonitis 5 months later. In this case, exceedingly rapid metastasis to the spleen occurred, despite the administration of vigorous treatment. Here, we review SFT/HPC incidence, treatment, and outcomes to better understand this rare malignancy.

We report a case of long-term survival without recurrence followingresection of hepatic and pulmonary metastases of gastric cancer. A 64-year-old man underwent distal gastrectomy for gastric cancer. Seventeen months later, he underwent partial hepatectomy for hepatic metastasis in S7. Twenty months after the partial hepatectomy, he underwent hepatectomy for right lobe resection for hepatic metastases in S6/S7 and S7. Six months after the hepatectomy, he underwent partial pulmonary resection for lungmetastasis in the right lung(S3). He has remained tumor-free for 5 years after the pulmonary resection.

We report a case of metachronous gastric intramural metastasis following esophageal cancer endoscopic submucosal dissection( ESD). The patient was an 80s man who was referred to the department of gastroenterology of our hospital for earlystage esophageal cancer by a local physician. ESD was performed for a lesion(Lt, 0-Ⅱa+Ⅱc, cT1N0M0, StageⅠ)located 35- 38 cm from the incisors. Pathologic diagnosis revealed that the lesion was a 2.5×2.0 cm-sized, pSM2, 506 mm, well-differentiated squamous cell carcinoma, ly+, v-, pHM0, pVM0. The patient was indicated for additional treatment, but because the patient requested not to undergo operative treatment, radiation therapy, or chemotherapy, strict follow-upwas performed. Upper endoscopy performed 1 year after ESD revealed the presence of a submucosal tumor(diameter of 5 cm)accompanied by ulceration in the gastric cardia, and biopsy findings led to the diagnosis of squamous cell carcinoma. The patient was referred to our department for operative treatment, and considering the possibility of primary squamous cell carcinoma of the stomach, we performed total gastrectomy(D2 dissection, Roux-en-Y)and cholecystectomy. The pathologic diagnosis was well-differentiated squamous cell carcinoma, ly1, v0, SE, N1. Because esophageal cancer and the tissue type were consistent and the primary locus of the tumor was the submucosal layer, the patient was diagnosed with esophageal cancer with gastric intramural metastasis. We report a rare case of metachronous gastric intramural metastasis of esophageal cancer along with a review of the literature.

Metastasis of renal cell carcinoma to the pancreas is a relatively rare condition. We encountered 2 such cases. The first case was a 72-year-old man who underwent a left nephrectomy owing to left renal cancer in 2005. An abdominal dynamic CT scan 12 years after surgery revealed tumors in the pancreatic body and right kidney. A PET-CT scan revealed low intensity uptake of both tumors, and therefore, metastasis of the left renal cell carcinoma to the pancreas was suspected. We then performed partial resections of the pancreatic tail and right kidney. Pathologic findings confirmed that the pancreatic tumor and right renal tumor were metastases of the left renal cell carcinoma. The postoperative course was favorable, and the patient has been followed up in an outpatient setting for 10 months with no signs of recurrence. The second case was a 51- year-old woman with tumors in the left kidney and pancreatic head that were detected by abdominal contrast CT and MRI. We diagnosed the patient with left renal cell carcinoma with metastasis to the pancreas. We performed a radical nephrectomy of the left kidney and full pancreatectomy. Pathologic findings confirmed left renal cell carcinoma, pStage Ⅳ, with metastasis to the pancreas. The postoperative course was favorable without recurrence for 14 years. We report on two cases of metastasis of renal cell carcinoma to the pancreas in patients who underwent radical resections and had favorable postoperative courses, with some bibliographic consideration.

We report a case of breast cancer with cartilaginous differentiation that responded well to chemotherapy, which completely eliminated distant metastasis. A 63-year-old woman visited our hospital complaining of a large hemorrhagic mass measuring 15 cm in diameter with ulceration of the left breast. Palpation revealed swelling of the left axillary and right supraclavicular (SC)lymph nodes, suggesting breast cancer metastasis. A CT scan revealed metastasis in the right lung measuring 2.5 cm in size. She underwent a total mastectomy with axillary dissection. The pathological findings were as follows; breast carcinoma with cartilaginous differentiation accompanied by a single lymph node metastasi(s 1/21)and skin involvement, ly0, v0, ER(-), PgR(-), HER2 0, Ki-67 80%. Four courses of AC therapy were administered as postoperative chemotherapy, which resulted in a decrease in the size of the SC lymph node to 1 cm. Subsequently, 12 courses of weekly paclitaxel yielded a complete response of the lung and SC lymph node metastasis. Oral administration of S-1 after paclitaxel therapy resulted in no recur- rence for 16 months after the operation.

We encountered 2 cases of colorectal liver metastasis with biliarydilatation mimicking cholangiocarcinoma. Case 1: A 70- year-old male patient, who was diagnosed with colorectal cancer and underwent transverse colectomy3 years prior, was preoperativelydiagnosed with cholangiocarcinoma with biliarydilatation of the medial and lateral segments. He underwent left hemi-hepatectomy. The pathological diagnosis was colorectal liver metastasis with intra-biliarytumor thrombosis. Case 2: A 67-year-old male patient was diagnosed with descending colon cancer and cholangiocarcinoma with biliarydilatation of the medial segment. He underwent left hemi-colectomyand left hemi-hepatectomy. The pathological diagnosis was descending colon cancer and colorectal liver metastasis with biliaryinfiltration. The immunopathological findings showed double positivityfor CK20 and CDX2 antibodies and negativityfor CK7 antibodyin these cancer lesions.

A 65-year-old woman with cecum cancer underwent laparoscopic right colectomy.After 3 years, she was diagnosed with a local recurrence with small bowel invasion and underwent tumor resection.One year later, she had a re-recurrent lesion involving her right iliac bone.After one year of chemotherapy, a PET-CT showed no other abdominal lesions suggestive of malignancy.She underwent resection of the re-recurrent tumor involving the right iliac bone and R0 resection was achieved. She was able to ambulate postoperatively and returned home.In selected cases, extended surgery including bone resection can be an option for the local recurrence of advanced colon cancer.

A 27-year-old man was diagnosed with dyskeratosis congenita from DKC1 gene mutation at 9 years of age and had been followed-up regularly.An upper gastrointestinal endoscopy performed for vomiting revealed gastric varices.Further examination resulted in a diagnosis of Stage Ⅳrectal cancer with portal hypertension, splenomegaly, liver, and lung metastasis and he was referred to our department.A laparoscopic splenectomy was performed, followed by a laparoscopic low anterior resection for rectal cancer.Subsequently, resection of the pulmonary and liver metastasis was performed, resulting in macroscopic radical resection.However, 3 months after the hepatectomy, unresectable multiple lung metastasis was detected and he received 5 courses of chemotherapy with cetuximab.A grade 3 skin rash was observed and chemotherapy was discontinued. After 5 courses, he had pneumothorax and received drainage.He had sudden respiratory failure 2 days after pleural adhesion therapy of OK-432 was performed.He was diagnosed with interstitial pneumonia induced by OK-432 and steroid pulse therapy, which resulted in his death without improvement 21 days after admission.

A 76-year-old woman complaining of constipation was diagnosed with advanced rectosigmoid colon cancer with unresectable liver metastases. We performed a laparoscopic high-anterior resection due to the obstruction. The patient then received a capecitabine plus oxaliplatin(CapeOX)plus cetuximab(Cmab)combination chemotherapy. After 7 cycles of CapeOX with Cmab, the multiple liver metastases had reduced remarkably in size. Therefore, a liver metastases resection was performed. The patient underwent 6 cycles of postoperative CapeOX with Cmab therapy and has survived 7 years with no recurrence after the primary surgery.

A 60s man was diagnosed with unresectable advanced rectal cancer with synchronous solitary liver metastasis. Chemotherapy was administered and the primary tumor shrank immediately. However, he still demonstrated dorsal extension; therefore, chemotherapy was continued for approximately 1 year. After long-term chemotherapy, the primary tumor was deemed to be resectable because the dorsal extension had decreased. We achieved curative resection by performing a primary tumor and liver resection and he has shown no recurrence without adjuvant chemotherapy. Although the primary tumor was initially diagnosed as unresectable, it is important to consider the potential for curative resection after long-term chemotherapy.

A 64-year-old woman who received neo-adjuvant chemotherapy and human epidermal growth factor receptor 2(HER2)- targeted therapy underwent modified radical mastectomy and axillary lymph node resection for HER2-positiveright breast cancer. After the surgery, chemotherapy, post-mastectomy radiation therapy, and HER2-targeted therapy were administered as adjuvant therapies. Two years and 6 months postoperatively, she complained of headaches and nausea. Magnetic resonance imaging showed brain metastasis, which was treated with gamma knife surgery. Two weeks later, she was urgently admitted to the hospital because of impaired consciousness. Based on cerebrospinal fluid cytology, she was diagnosed with meningeal metastasis of breast cancer. She developed hydrocephalus; thus, external ventricular drainage was performed, and a ventriculoperitoneal shunt was inserted. She was treated with whole-brain irradiation(30 Gy)and trastuzumab emtansine (T-DM1)as systemic therapy. Treatment of the patient was possible without recurrence continuously for over 12 months and with the maintenance of daily activities. The prognosis of patients with meningeal metastasis of breast cancer is extremely poor, and effective pharmacotherapy has not yet been established. T-DM1 may improvepatie nts' quality of lifeand the clinical outcomes of meningeal metastasis.

Although S-1 is an effective oral anticancer drug in patients with metastatic breast cancer, it is difficult for some patients to continue taking S-1 because of its side effects in the approved regimen of 4 weeks of administration followed by a 2-week rest. When S-1 is administered for 5 days followed by a 2-day rest(5-day on/2-day off), the drug concentration is almost equal to that of the approved regimen, and it can be administered for longer without deterioration of its clinical effect. We retrospectively analyzed the effect and safety in 25 cases in which S-1 was administered using the "5-day on/2-day off" regimen in patients with metastatic breast cancer between November 2006 and August 2014 in our hospital. Patients were all female, and their median age was 68 years(44-87). ER was positive/negative in 15/10 cases, and PS 0/1/2were found in 8/ 10/7 cases. They had no prior chemotherapy and had measurable lesions. S-1 was administered at a dose of 80mg/m2 twice a day on a "5-day on/2-day off" schedule and was reduced when its side effects were appeared. The median treatment duration was 25(3-214)weeks, and CR/PR/long SD/SD/PD as clinical responses were observed in 0/8/5/5/7 cases. The overall response rate was 32% and clinical benefit rate was 52%. There was no difference in response rates whether visceral metastases were present or not. In terms of hematologic toxicity, anemia was seen in one case, and there were no cases of neutropenia. In non-hematologic toxicity, no more than Grade 3 side effects were shown. Discontinuance was observed in only one case because of diarrhea. A "5-day on/2-day off" regimen of S-1 in metastatic breast cancer is well tolerated, and we can continue administering it to elderly patients or those with poor PS without reducing QOL; thus, it can be considered as one of the effective metronomic treatments. In the future, a prospective study is warranted to ascertain these results.

An 82-year-old man with a diagnosis ofintraductal papillary mucinous carcinoma(IPMC)underwent pancreaticoduodenectomy followed by adjuvant chemotherapy with S-1. Six months after surgery, he had upper abdominal pain, and CT demonstrated a recurrent intraabdominal tumor located at the surgical incision scar. It was diagnosed as a solitary peritoneal recurrence, and palliative radiation therapy at a dose of 30 Gy was performed for the relief of abdominal pain after administration ofoxycodone. He was free ofpain without pharmacological therapy and received subsequent chemotherapy with nabpaclitaxel plus gemcitabine(GnP). He remains free ofpain and alive without progression ofthe disease 24 months after recurrence. Hypofractionated-accelerated radiotherapy is feasible and results in pain relief for local recurrence of IPMC.

The patient was a man in his 70s who visited our hospital to undergo an examination for fecal occult blood, which detected a 20 mm, Ⅱa lesion in the lower rectum on colonoscopy. He was diagnosed with SM-invasive cancer and was planned to undergo trans-anal local excision. After the surgery, he had a good postoperative course without complications. The pathological findings were Ⅱa, tub1, 22×16 mm, pT1a(950 mm), int, INF a, ly0, v0, pHM0, pVM0(300 mm). He was followed up after the surgery, but was diagnosed with lateral lymph node recurrence 4 years after a local surgery. The surgery involved right-sided lateral lymphadenectomy with resection of the ureter, spermatic duct, seminal vesicle, and piriformis muscle. He was diagnosed with lymph node metastasis with invasion of the spermatic duct based on pathology. Eight courses of adjuvant chemotherapy containing CapeOX was administered. Unfortunately, primary squamous cell lung cancer was detected, and he died after surgery for recurrence in the second year. It is suggested that it is necessary to note lateral lymph node recurrence on postoperative follow-up for lower rectal cancer at any stage.

We report a case of liver metastasis of intrahepatic cholangiocarcinoma that achieved clinical complete response after gemcitabine(GEM)and cisplatin(CDDP)combination chemotherapy. The patient was a 69-year-old man who was diagnosed with intrahepatic cholangiocarcinoma with hilar invasion and intrahepatic metastasis(cT4N0M0, Stage ⅣA)and was initially treated with right trisegmentectomy with left portal vein resection, lymph node dissection, and reconstruction of the left portal vein and biliary tract after transhepatic portal vein embolization(PTPE). S-1 was administered continuously as postoperative adjuvant chemotherapy, and the patient showed no signs of recurrence. Three years after the surgery, a CT scan showed LDA 10mm in diameter in the middle area of the remnant liver. We suspected liver metastasis when both serum CA19-9 and DUPAN-2 levels were elevated with the increasing size of LDA; liver biopsy was then performed, and he was diagnosed with liver metastasis of intrahepatic cholangiocarcinoma. After 3 courses of combination chemotherapy containing GEM and CDDP, a CT scan revealed that the liver metastasis reduced in size, and PR was achieved based on the RECIST standard. After 12 courses, the liver metastasis disappeared, and the patient had achieved CR based on the RECIST standard. The patient has received S-1 following the combination chemotherapy and survived for 6 years since initial treatment without any other metastatic lesions.

We report a case of recurrent gastric cancer that was successfully treated by S-1 chemotherapy.An 81-year-old woman with advanced gastric cancer[L Less, Type 2, cT4a(SE), cN0H0P0M0, cStageⅡB]underwent distal gastrectomy.Abdominal CT performed 6 months after surgery revealed a low-density area in the liver.She was diagnosed with liver metastasis and started receiving S-1 chemotherapy.The liver metastasis achieved complete response, so S-1 chemotherapy was discontinued 12 months after recurrence.Abdominal CT performed 9 months after the discontinuation of S-1 chemotherapy revealed multiple low-density areas in the liver.She started receiving S-1 chemotherapy again, but S-1 chemotherapy was discontinued because of side effects after 2 courses.The patient died 24 months after receiving S-1 chemotherapy.

There have been few reports discussing treatments for primary duodenal cancer. In this study, 15 cases of primary duodenal cancer that were treated by curative resection in our hospital between April 2005 and December 2017 were analyzed to study appropriate operative procedures. Prognostic analysis revealed that the median of relapse-free survival and overall survival were 49 months and 74 months, respectively. The 5-year survival rate was 47%. On univariate analysis of relapse-free survival, lymph node metastasis(p<0.01)and post-operative adjuvant therapy(p=0.02)were significant independent prognostic factors. Analysis of the relationship between lymph node metastasis and the depth or location of tumors suggested that pancreaticoduodenectomy with lymph node dissection should be performed to achieve radical resection, since there were some cases that involved lymph node metastasis around the pancreatic head or hepatoduodenal ligament.