The relationship between tumor immunity and the cGAS-STING pathway in breast cancer: An immunohistochemical study.

Breast cancer (BC) is classified into four major histological subtypes, namely luminal A, luminal B, HER2, and basal-like, and its treatment is based on these subtypes. The use of immune checkpoint inhibitors against BC depends on the expression of PD-1/PD-L1. Another tumor immune system-the cGAS-STING pathway-is a potential target for cancer immunotherapy. However, the status of the cGAS-STING pathway in BC has not been fully established. Therefore, we investigated the expression status of the cGAS-STING pathway and immune-related proteins in BC. We classified 111 BCs into six groups-29 hormone receptor-positive carcinomas, 12 HER2+ carcinomas (HER2), 8 luminal-HER2 carcinomas, 26 triple-negative breast carcinomas (TNBCs), 21 lobular carcinomas (LC), and 15 carcinomas with apocrine differentiation (CAD)-and investigated the relationship between BC and tumor immunity via the cGAS-STING pathway using histopathological and immunohistochemical methods. Expression of cGAS was high in CADs (100%) and low in TNBCs (35%); STING-positive lymphocytes were high in TNBC (85%, P = 0.0054). Expression of pSTAT3 was significantly high in patients with TNBC (≥10%, 88%). The proportion of PD-L1-positive tumor cells was higher in TNBCs (54%) than in other BCs (30%). SRGN expression was significantly higher in the TNBC group than in the other BC groups (58%). Tumor immune responses may differ among tumor subtypes. The cGAS-STING pathway may be functional in TNBC and CAD but not in LC. Therefore, targeting the cGAS-STING pathway might be useful in BC, particularly TNBC and CAD.

Efficacy of Computed Tomography-Based Evaluation of Myocardial Extracellular Volume Combined With Red Flags for Early Screening of Concealed Cardiac Amyloidosis in Patients With Atrial Fibrillation.

BACKGROUND: The prevalence of transthyretin amyloid cardiomyopathy (ATTR-CM) in atrial fibrillation (AF) patients remains unclear. We explored the efficacy of computed tomography-based myocardial extracellular volume (CT-ECV) combined with red flags for the early screening of concealed ATTR-CM in AF patients undergoing catheter ablation. METHODS AND RESULTS: Patients referred for AF ablation at Oita University Hospital were prescreened using the red-flag signs defined by echocardiographic or electrocardiographic findings, medical history, symptoms, and blood biochemical findings. Myocardial CT-ECV was quantified in red flag-positive patients using routine pre-AF ablation planning cardiac CT with the addition of delayed-phase cardiac CT scans. Patients with high (>35%) ECV were evaluated using technetium pyrophosphate (99 mTc-PYP) scintigraphy. A cardiac biopsy was performed during the planned AF ablation procedure if 99 mTc-PYP scintigraphy was positive. Between June 2022 and June 2023, 342 patients were referred for AF ablation. Sixty-seven (19.6%) patients had at least one of the red-flag signs. Myocardial CT-ECV was evaluated in 57 patients because of contraindications to contrast media, revealing that 16 patients had high CT-ECV. Of these, 6 patients showed a positive 99 mTc-PYP study, and 6 patients were subsequently diagnosed with wild-type ATTR-CM via cardiac biopsy and genetic testing. CONCLUSIONS: CT-ECV combined with red flags could contribute to the systematic early screening of concealed ATTR-CM in AF patients undergoing catheter ablation.

Alpha-fetoprotein producing endometrioid carcinoma arising in an adenomyoma of the uterus.

We report a case of alpha-fetoprotein-producing endometrioid carcinoma (AFP-EC) that originated within an adenomyoma of the uterine corpus. A 76-year-old Japanese woman was incidentally discovered to have a uterine tumor along with multiple lung nodules. Upon surgical removal of the uterus, it was revealed that the tumor was situated within the adenomyoma. The tumor exhibited microfollicular structures and solid growth patterns, with hyaline globules, clear cell glands, and primitive tumor cells. Immunohistochemical analysis indicated the presence of germ cell markers, including AFP, SALL4, and glypican3, leading to final diagnosis of AFP-EC. Histopathologically, AFP-ECs exhibit characteristics similar to those of AFP-producing neoplasms in other organs. Furthermore, a nomenclature issue arises when distinguishing AFP-ECs from yolk sac tumors of the endometrium in older patients due to their shared features. The concept of retrodifferentiation or neometaplasia suggests that "endometrioid carcinoma with yolk sac tumor differentiation" or "endometrioid carcinoma with a primitive phenotype" may serve as more fitting terms for the diverse spectrum of AFP-producing neoplasms in the endometrium. In conclusion, this case underscores the diagnostic challenges posed by AFP-ECs arising from adenomyomas and emphasizes the need for refining the nomenclature and classification of AFP-producing neoplasms within the endometrium.

Pitfalls in the diagnosis and treatment of a hypertensive patient with unilateral primary aldosteronism and contralateral pheochromocytoma: a case report.

BACKGROUND: Primary aldosteronism (PA) is a common cause of secondary hypertension, whereas pheochromocytoma is a rare cause of it. Thus, concomitant PA and pheochromocytoma is a very rare condition. CASE PRESENTATION: A 52-year-old woman was admitted to our hospital with suspected PA based on the presence of hypertension, spontaneous hypokalemia, and a high aldosterone-to-renin ratio. She had no catecholamine excess symptoms other than hypertension. Abdominal computed tomography (CT) showed a right lipid-rich adrenal mass and a left lipid-poor adrenal mass. PA was diagnosed by the captopril challenge test. The 24-h urinary fractionated metanephrines were slightly elevated. Adrenal vein sampling (AVS) confirmed that the right adrenal gland was responsible for aldosterone hypersecretion. Medical therapy with eplerenone was started because the patient refused surgery. Five years later, she requested surgery for PA. The second AVS confirmed right unilateral hyperaldosteronism, as expected. Repeated abdominal CT showed the enlargement of the left adrenal mass. The 24-h urinary fractionated metanephrines had risen to the diagnostic level. 123I- metaiodobenzylguanidine (MIBG) scintigraphy showed a marked tracer uptake in the left adrenal mass with no metastatic lesion. After preoperative management with α-blockade, laparoscopic left partial adrenalectomy was performed. Immunohistochemical examination of the tumor showed chromogranin A positivity leading to the diagnosis of left pheochromocytoma. CONCLUSIONS: We report an extremely rare case of concomitant unilateral PA and contralateral pheochromocytoma. When diagnosing unilateral PA by AVS, especially in cases with a lipid-poor adrenal mass, clinicians should rule out the possibility of the presence of pheochromocytoma before proceeding to undergo unilateral adrenalectomy. Although there is no standard treatment for this rare condition, it is essential to select personalized treatment from the perspective of conserving the adrenal gland.

Apoptosis-related factors are relevant to progression of pancreatic neuroendocrine tumors.

BACKGROUND: Multidisciplinary therapy centered on antitumor drugs is indicated in patients with unresectable pancreatic neuroendocrine tumors (PanNET). However, the criteria for selection of optimal therapeutic agents is controversial. The aim of this study was to assess the malignancy of PanNET for optimal therapeutic drug selection. METHODS: Forty-seven patients with PanNET who underwent surgery were reviewed retrospectively, and immunohistochemical characteristics, including expression of GLUT1, SSTR2a, SSTR5, Survivin, X-chromosome-linked inhibitor of apoptosis protein (XIAP), and Caspase3 in the resected specimens, were investigated. Relapse-free survival (RFS) and overall survival (OS) were evaluated with regard to the characteristics using the Kaplan-Meier method and compared with the log-rank test. RESULTS: GLUT1 expression showed significant correlation with sex (p = 0.036) and mitotic rate (p = 0.048). Survivin and XIAP expression showed significant correlation with T-stage (p = 0.014 and 0.009), p-Stage (p = 0.028 and 0.045), and mitotic rate (p = 0.023 and 0.007). XIAP expression also significantly influenced OS (p = 0.044). CONCLUSIONS: Survivin and XIAP correlated with grade of malignancy, and expression of XIAP in particular was associated with a poor prognosis. Expression of these proteins may be a useful indicator to select optimal therapeutic agents in PanNET.

Enhanced phosphorylation of c-Jun by cisplatin treatment as a potential predictive biomarker for cisplatin response in combination with patient-derived tumor organoids.

Despite recent advances in sequencing technology and large-scale drug screenings employing hundreds of cell lines, the predictive accuracy of mutation-based biomarkers is still insufficient as a guide for cancer therapy. Therefore, novel types of diagnostic methods using alternative biomarkers would be highly desirable. We have hypothesized that sensitivity-specific changes in the phosphorylation of signaling molecules could be useful in this respect. Here, with the aim of developing a method for predicting the response of cancers to cisplatin using a combination of specific biomarker(s) and patient-derived tumor organoids (PDOs), we found that cisplatin-sensitive cell lines or PDOs showed enhanced phosphorylation of c-Jun (p-c-Jun) within 24 h after cisplatin treatment. We also compared the responses of 6 PDOs to cisplatin with the therapeutic effect of neoadjuvant chemotherapy (docetaxel/cisplatin/5-fluorouracil) in 6 matched patients. Mechanistically, the c-Jun induction was partly related to TNF signaling induced by cisplatin. Our data suggest that enhanced phosphorylation of c-Jun in response to cisplatin treatment could be a predictive biomarker for the efficacy of cisplatin in selected cancer patients.

Clinicopathological findings, prognosis, and Epstein-Barr virus infection in rheumatoid arthritis patients with other iatrogenic immunodeficiency-associated T- and NK-cell lymphoproliferative disorders.

BACKGROUND: Other iatrogenic immunodeficiency-associated (OIIA) T- and natural killer (NK)-cell lymphoproliferative disorders (TNK-LPDs) are rare in patients with rheumatoid arthritis (RA). METHODS: We investigated the clinicopathological characteristics, Epstein-Barr virus (EBV) infection, genetic findings, therapeutic response, and prognostic factors in 21 RA patients with OIIA TNK-LPDs and compared these with those of 39 with OIIA B-cell LPDs (B-LPDs) and 22 with non-OIIA B-LPDs. RESULTS: Immunohistologically, 11 patients (52%) showed CD4+ T-LPDs, and 7 had a T follicular helper (TFH) phenotype. The other nine patients (43%) showed CD8+ T-LPDs, and the remaining one (5%) had features of CD3+ CD4- CD8- nasal type TNK-cell lymphoma. CD30+, p53+, and CMYC+ atypical lymphocytes were identified in seven (33%), eight (38%), and five (24%) patients, respectively. In situ hybridisation detected EBV-encoded RNA (EBER) + large atypical lymphocytes in five patients (24%). Nine of 17 patients (53%) showed clonal peaks of TCRγ by polymerase chain reaction. Withdrawal of MTX and biologic drugs was effective in 12 patients (57%), and 8 (38%) received chemotherapies. Two patients with TFH+ or EBV+ CD4+ CD30+ large cell peripheral T-cell lymphoma, one with CD8+ systemic anaplastic large cell lymphoma, and two with systemic EBV+ CD8+ T-cell lymphoma of childhood showed a lethal progressive clinical course within 13 months. Moreover, > 500 U/L LDH, large atypical lymphocytes, expression of CD30, p53, and CMYC, and EBER+ atypical lymphocytes were significantly poor prognostic factors for overall survival (p < 0.05). Median interval from RA onset to OIIA TNK-LPDs was 72 months, which was shorter than 166 months in OIIA B-LPDs (p = 0.003). EBV+ atypical and reactive lymphocytes were frequently found in 15 patients with OIIA TNK-LPDs (71%), in 27 with OIIA B-LPDs (69%), and only in 3 with non-OIIA B-LPDs (14%). CONCLUSIONS: OIIA TNK-LPDs occurred in early phase of RA, compared with OIIA B-LPDs, and occasionally showed a lethal progressive clinical course. Detection of OIIA TNK-LPD patients with poor prognostic factors is necessary. EBV infection in immunosuppressed patients due to persistent RA, MTX, and biologic drugs may play a role in forming the tumour microenvironment and lymphomagenesis of TNK-LPDs.

Histopathologically TMA-like distribution of multiple organ thromboses following the initial dose of the BNT162b2 mRNA vaccine (Comirnaty, Pfizer/BioNTech): an autopsy case report.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has spread worldwide. Vaccination is now recommended as one of the effective countermeasures to control the pandemic or prevent the worsening of symptoms. However, its adverse effects have been attracting attention. Here, we report an autopsy case of multiple thromboses after receiving the first dose of the BNT162b2 mRNA vaccine (Comirnaty, Pfizer/BioNTech) in an elderly woman. CASE PRESENTATION: A 72-year-old woman with a history of diffuse large B-cell lymphoma in the stomach and hyperthyroidism received the first dose of the BNT162b2 mRNA vaccine and died 2 days later. The autopsy revealed multiple microthrombi in the heart, brain, liver, kidneys, and adrenal glands. The thrombi were CD61 and CD42b positive and were located in the blood vessels primarily in the pericardial aspect of the myocardium and subcapsular region of the adrenal glands; their diameters were approximately 5-40 µm. Macroscopically, a characteristic myocardial haemorrhage was observed, and the histopathology of the characteristic thrombus distribution, which differed from that of haemolytic uraemic syndrome and disseminated intravascular coagulation, suggested that the underlying pathophysiology may have been similar to that of thrombotic microangiopathy (TMA). CONCLUSION: This is the first report on a post-mortem case of multiple thromboses after the BNT162b2 mRNA vaccine. The component thrombus and characteristic distribution of the thrombi were similar to those of TMA, which differs completely from haemolytic uraemic syndrome or disseminated intravascular coagulation, after vaccination. Although rare, it is important to consider that fatal adverse reactions may occur after vaccination and that it is vital to conduct careful follow-up.

Correlation of World Health Organization 2010 Classification for Gastroenteropancreatic Neuroendocrine Neoplasms with the Prognosis of Ovarian Neuroendocrine Neoplasms: Kansai Clinical Oncology Group-Protocol Review Committee/Intergroup Study.

BACKGROUND: In 2014, the World Health Organization (WHO) released a classification system introducing neuroendocrine neoplasms (NENs) of the female reproductive tract, excluding the ovaries. This study aimed to evaluate whether retrospective adaption of the gastroenteropancreatic (GEP)-NEN classification is feasible for ovarian NENs (O-NENs) and correlates with prognosis. METHODS: Sixty-eight patients diagnosed with carcinoid, small cell carcinoma (pulmonary type), paraganglioma, non-small/large cell neuroendocrine carcinoma (NEC), mixed NEC, or undifferentiated carcinomas at 20 institutions in Japan were included in this retrospective cross-sectional study. We identified O-NENs through central pathological review using a common slide set, followed by reclassification according to WHO 2010 guidelines for GEP-NENs. A proportional hazards model was used to assess the association of prognostic factors (age, stage, performance status, histology, and residual disease) with overall survival (OS) and progression-free survival (PFS). RESULTS: Of the 68 enrolled patients, 48 were eligible for analysis. All carcinoids (n = 32) were reclassified as NET G1/G2, whereas 14 of 16 carcinomas were reclassified as NEC/mixed adeno-NEC (MANEC) (Fisher's exact test; p < 0.01). The OS/PFS was 49.0/42.5 months and 6.5/3.9 months for NET G1/G2 and NEC/MANEC, respectively. Histology revealed that NEC/MANEC was associated with increased risk of death (HR = 48.0; 95% CI, 3.93-586; p < 0.01) and disease progression (HR = 51.6; 95% CI, 5.54-480; p < 0.01). CONCLUSION: Retrospective adaption of GEP-NEN classification to O-NENs is feasible and correlates well with the prognosis of O-NENs. This classification could be introduced for ovarian tumors.

Clinical significance of sarcoid-like reaction in lymph nodes of gastric cancer patients.

BACKGROUND: Although granulomatous formation (sarcoid-like reaction [SR]) similar to sarcoidosis occasionally occurs in regional lymph nodes of malignant tumors, the pathological significance of SR is unknown. We aimed to elucidate the clinicopathological significance and prognostic relevance of SR in gastric cancer. METHODS: We evaluated 391 patients who underwent curative gastrectomy for gastric cancer between 2007 and 2016 at our hospital. The patients were divided into two groups according to presence of SR in lymph nodes, and clinicopathological factors and prognosis were compared between the two groups. RESULTS: SR was found in 67 (17.1%) of the 391 patients, and 332 (3.3%) of 10,149 lymph nodes examined. Regarding clinicopathological factors, SR-positive group showed significantly higher average age (p < 0.01) and numbers of differentiated tumors than SR-negative group (p < 0.05). Three-year overall survival rate in elderly patients aged ≥75 years was significantly more favorable in SR-positive group (n = 27, 85.2%) versus SR-negative group (n = 97, 63.4%) (p < 0.05). Immunohistochemical studies showed the predominant presence of CD68-positive macrophages for SR, with CD4/CD8-positive T cells and interleukin-10 also positive. CONCLUSION: The presence of SR in gastric cancer is frequent in elderly patients and might be a favorable indicator of prognosis. SR is suggested to reflect immune activation in the host.

A transgenic mouse expressing miR-210 in proximal tubule cells shows mitochondrial alteration: possible association of miR-210 with a shift in energy metabolism.

Previously we reported that the microRNA miR-210 is aberrantly upregulated in clear cell renal cell carcinoma (ccRCC) via deregulation of the VHL-HIF pathway. In the present study, to investigate the biological impact of miR-210 in ccRCC tumorigenesis, we developed a transgenic mouse line expressing miR-210 in proximal tubule cells under control of the mouse SGLT2/Slc5a2 promoter. Light microscopy revealed desquamation of the tubule cells and regeneration of the proximal tubule, suggesting that miR-210 expression led to damage of the proximal tubule cells. Electron microscopy revealed alterations to the mitochondria in proximal tubule cells, with marked reduction of the mitochondrial inner membrane, which is the main site of ATP production via oxidative phosphorylation (OxPhos). An additional in vitro study revealed that this loss of the inner membrane was associated with downregulation of Iscu and Ndufa4, the target genes of miR-210, suggesting that the miR-210-ISCU/NDUFA4 axis may affect mitochondrial energy metabolism. Furthermore, metabolome analysis revealed activation of anaerobic glycolysis in miR-210-transfected cells, and consistent with this the secretion of lactate, the final metabolite of anaerobic glycolysis, was significantly increased. Lactate concentration was higher in the kidney cortex of transgenic mice relative to wild-type mice, although the difference was not significant (p = 0.070). On the basis of these findings, we propose that miR-210 may induce a shift of energy metabolism from OxPhos to glycolysis by acting on the mitochondrial inner membrane. In addition to activation of glycolysis, we observed activation of the pentose phosphate pathway (PPP) and an increase in the total amount of amino acids in miR-210-transfected cells. This may help cells synthesize nucleotides and proteins for building new cells. These results suggest that miR-210 may be involved in the metabolic changes in the early stage of ccRCC development, helping the cancer cells to acquire growth and survival advantages. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Primary clear cell sarcoma of the femur: a unique case with RT-PCR and direct sequencing confirmation of EWSR1/ATF1 fusion gene.

BACKGROUND: It is very rare for clear cell sarcomas (CCS) to arise in the bone. During diagnosis, it is important to distinguish primary CCS of bone from bone metastasis of melanoma because this difference fundamentally changes the therapeutic options. Recently, characteristic fusion genes of CCS have been detected using reverse transcription polymerase chain reaction (RT-PCR) or direct sequencing which allowed to distinguish CCS from melanoma. However, there was no study applying these analyses with positive results. In this case, we describe the use of fusion gene analysis to diagnose a primary CCS of the bone. CASE PRESENTATION: A 36-year-old male presented with a four-months history of left knee pain. Magnetic resonance imaging showed a lesion in the left femoral medial epicondyle. Histological examination of the biopsy specimen revealed proliferating oval or rounded cells. These cells had clear cytoplasm arranged in fascicles or compact nests with frequent deposits of brown pigment. Furthermore, immunohistochemistry analysis revealed that tumor cells were positive for S-100 protein, HMB-45, Melan-A, and SOX10. It stained negative for CD34 and BRAF v600e. Conclusively, detection of the EWSR1/ATF1 fusion gene using RT-PCR and direct sequencing confirmed that the lesion was a primary CCS of the bone. Wide-margin resection and reconstruction with a tumor endoprosthesis were performed. CONCLUSIONS: Herein, we diagnosed a rare case of primary CCS of the bone by detecting EWSR1/ATF1 fusion gene using RT-PCR and direct sequencing. Since fluorescence-in situ hybridization (FISH) and RT-PCR could show false positive by mainly due to technical problems, it is better to perform direct sequencing to confidently diagnose the tumor as a primary CCS especially at very rare site such as bone.

Immunohistochemical Reactivity of Prostate-Specific Markers for Salivary Duct Carcinoma.

OBJECTIVES: NKX3.1, a transcription factor related to androgen expression, has recently been introduced as a diagnostic marker of prostate adenocarcinoma. Salivary duct carcinoma (SDC) is typically positive for androgen receptor (AR). Therefore, we hypothesized that NKX3.1 is a new immunohistochemical marker for SDC and aimed to investigate whether NKX3.1 staining in combination with other immunomarkers of prostate carcinoma could have a diagnostic or prognostic value in SDC. METHODS: Materials obtained from 42 resected SDCs were examined by immunohistochemistry using antibodies against AR, NKX3.1, α-methylacyl-CoA racemase (AMACR), prostatic acid phosphatase (PAP), and prostate-specific antigen (PSA). RESULTS: In immunoreactivity among SDC cases, 81.0, 35.7, 58.5, 33.3, and 0% were positive for AR, NKX3.1, AMACR, PAP, and PSA, respectively. AMACR and PAP immunoreactivity rates were higher in recurrence cases than in cases with no recurrence. CONCLUSIONS: NKX3.1 expression is useful for SDC diagnosis, but decreased NKX3.1 expression was not correlated with SDC progression. The immunoreactivity of AMACR and PAP could be useful for assessing prognosis in SDC, but immunohistochemical staining of prostate-specific markers should be interpreted with caution when determining whether a metastatic tumor is of prostate origin, especially when patients have a history of SDC.

Pulmonary tumor thrombotic microangiopathy associated with extramammary Paget's disease: An autopsy case report.

Pulmonary tumor thrombotic microangiopathy (PTTM) is histologically characterized by micro tumor cell embolism and intimal fibrocellular proliferation of pulmonary arteries or arterioles. We report a secondary case of PTTM associated with extramammary Paget's disease (EMPD). The patient was a 72-year-old man with exertional dyspnea. Clinical examinations found he had pulmonary hypertension and multiple osteolytic lesions of vertebra. Cytological analysis of pulmonary wedge artery sample detected malignant cells and he was dead before treatment was started. Multiple tumor embolisms (>17) were identified in pulmonary arteries or arterioles at autopsy, consistent with PTTM. Metastatic nodules were found in liver and lymph node. Furthermore, disseminated carcinomatosis of the bone marrow (DCBM) was seen. Immunostaining results pointed out that tumor cells possessed mammary gland phenotype. He had 4-years history of EMPD in the left axilla without recurrence, and immunohistochemistry results were the same as the autopsy specimen. Thus, we diagnosed the primary site of PTTM to be EMPD. Our case highlights the usefulness of the recent proposed classification of PTTM, potential association between PTTM and DCBM, and the necessity for long-term follow-up in EMPD. EMPD can rarely cause PTTM to manifest as a paraneoplastic syndrome.

A Case of Dendritic Cell Neurofibroma With Pseudorosettes.

Dendritic cell neurofibroma with pseudorosettes (DCNP) is a rare benign peripheral nerve sheath tumor. Till date, 34 cases of DCNP arising from various sites have been reported. Histopathologically, DCNP is known to present with characteristic pseudorosettes, in which a type II cell is surrounded by type I cells. In the present report, we discuss the rare case of a 63-year-old man diagnosed with DCNP on the left flank (size: approximately 10 mm). On microscopic examination of the resected lesion, we observed the characteristic pseudorosettes with centrally placed type I cells, which exhibited small, dark, slightly irregular oval nuclei with nuclear inclusions, surrounded by type II cells, which showed a large pale nucleus with a constriction, a small nucleolus, and mildly eosinophilic cytoplasm. The type II cells were positive for S-100, CD57, LAMP2, fascin, and factor XIIIa. Although previous reports have suggested that type II cells exhibit a dendritic form, our immunohistochemical analyses revealed that these cells were dermal interstitial dendritic cells.

A Case of Methotrexate-Associated Lymphoproliferative Disorder (Lymphomatoid Granulomatosis) of the Skin.

Iatrogenic lymphoproliferative disorder (LPD) can develop in patients treated with immunosuppressive drugs for autoimmune or other inflammatory diseases. Here, we report a case of lymphomatoid granulomatosis of the skin that occurred as a methotrexate (MTX)-associated LPD. We also review the relevant literature. A 73-year-old woman presented to our department with an approximately 10-year history of MTX therapy for rheumatoid arthritis. Three months earlier, she noticed a small nodule in her right upper arm. It gradually enlarged, and the center began to decay. Grossly, the lesion was 40 × 40 mm in size with ulceration, and the surrounding skin presented dark red erythema. A biopsy specimen was taken for definitive diagnosis. Histologically, infiltrating growth of medium-to-large atypical lymphocytes was observed underneath the ulceration and was accompanied by small reactive lymphocytes. The atypical lymphocytes demonstrated a tendency to infiltrate the vessels, which showed an angiocentric pattern. Immunohistochemistry revealed that the atypical lymphoid cells were positive for CD79a, CD20, and CD30. In addition, in situ hybridization for Epstein-Barr virus (EBV) revealed expression of EBV-encoded small RNAs. The patient was diagnosed with MTX-associated LPD (lymphomatoid granulomatosis), owing to her history of MTX treatment, the expression of the atypical lymphocytes for B-cell markers and EBV-encoded small RNA, and the angiocentric infiltrating pattern. The lesion reportedly disappeared after withdrawal of MTX.

The scab-like sign: A CT finding indicative of haemoptysis in patients with chronic pulmonary aspergillosis?

OBJECTIVES: The aim of this study was to assess the CT findings that characterise haemoptysis in patients with chronic pulmonary aspergillosis (CPA). METHODS: We retrospectively identified 120 consecutive patients with CPA (84 men and 36 women, 17-89 years of age, mean age 68.4 years) who had undergone a total of 829 CT examinations between January 2007 and February 2017. In the 11 patients who underwent surgical resection, CT images were compared with the pathological results. RESULTS: The scab-like sign was seen on 142 of the 829 CT scans, specifically, in 87 of the 90 CT scans for haemoptysis and in 55 of the 739 CT scans obtained during therapy evaluation. In 48 of those 55 patients, haemoptysis occurred within 55 days (mean 12.0 days) after the CT scan. In the 687 CT scans with no scab-like sign, there were only three instances of subsequent haemoptysis in the respective patients over the following 6 months. Patients with and without scab-like sign differed significantly in the frequency of haemoptysis occurring after a CT scan (p<0.0001). Pathologically, the scab-like sign corresponded to a fibrinopurulent mass or blood crust. CONCLUSIONS: The scab-like sign should be considered as a CT finding indicative of haemoptysis. KEY POINTS: • Haemoptysis is commonly found in patients with CPA. • A CT finding indicative of haemoptysis in CPA patients is described. • Scab-like sign may identify CPA patients at higher risk of haemoptysis.

Derivation of thyroid lymphoepithelial cysts from follicular cells.

The pathogenesis of thyroid lymphoepithelial cysts is controversial, and two hypotheses have been proposed, namely derivation from branchial-derived remnants or from squamous metaplasia of the follicular cells. The aim of this study was to clarify the pathogenesis of thyroid lymphoepithelial cysts. We performed pathological and immunohistochemical examination of 21 thyroid lymphoepithelial cysts, 13 non-neoplastic squamous metaplasia samples without thyroid carcinoma, 13 solid cell nests, and 14 lateral cervical cysts. On ultrasound, half of thyroid lymphoepithelial cysts were interpreted as calcified nodules regardless of no calcification. Thyroid lymphoepithelial cysts and squamous metaplasia tended to be located in the central and lower portions of the thyroid, while solid cell nests were located in the upper and central portions (p < 0.05). In 95.2% of patients with thyroid lymphoepithelial cysts and all patients with squamous metaplasia, lesions were histologically associated with chronic thyroiditis forming lymph follicles. Hashimoto's disease was serologically confirmed in 18 patients with lymphoepithelial cysts (85.7%) and 10 patients with squamous metaplasia (76.9%). Immunohistochemically, lymphoepithelial cysts showed nuclear positivity for PAX8, thyroid transcription factor 1, and p63. One lateral cervical cyst (7.1%) showed positive staining for PAX8, while solid cell nests were PAX8-negative. In three (14.3%) cases of thyroid lymphoepithelial cysts, squamous cells located on the superficial layer were focally and weakly positive for CEA. We concluded that thyroid lymphoepithelial cysts originate from follicular cells and are unrelated to solid cell nests and lateral cervical cysts arising from branchial-derived remnants.

Unique cell tropism of HHV-6B in an infantile autopsy case of primary HHV-6B encephalitis.

Human herpes virus 6 (HHV-6) is known to cause primary encephalitis in the frontal lobes/cerebral hemisphere or reactivated encephalitis in the hippocampus, but the pathogenesis remains unclear. HHV-6B has also been detected in hippocampal samples in patients with mesial temporal lobe epilepsy. A 1 year and 3 months old female, who had been clinically diagnosed with exanthema subitum and febrile convulsion, was found dead on the third day after onset. Macroscopic findings showed massive brain edema. Microscopic examination revealed gemistocytic astrocytes and ballooned oligodendrocytes in the frontal white matter, along with neuronal cell death with microglial infiltration in the frontal cortex. Polymerase chain reaction detected HHV-6B in the cerebrospinal fluid and necropsy brain samples. The hippocampus showed a 4-5-fold increase in virus copy number of HHV-6B compared to samples from other brain sites. Immunostaining indicated that HHV-6B had infected vascular endothelial cells, neurons and oligodendrocytes but not astrocytes or microglia. Hippocampal neurons were infected with highly concentrated HHV-6B, but the hippocampus had neither neuronal loss nor reactive glial response. Silent and abundant HHV-6B infection in the hippocampus might be associated with latent infection, reactivation and some hippocampus-oriented disorders, including mesial temporal lobe epilepsy.