An algorithm-based technique for counting mitochondria in cells using immunohistochemical staining of formalin-fixed and paraffin-embedded sections.

PURPOSE: Visualizing mitochondria in cancer cells from human pathological specimens may improve our understanding of cancer biology. However, using immunohistochemistry to evaluate mitochondria remains difficult because almost all cells contain mitochondria and the number of mitochondria per cell may have important effects on mitochondrial function. Herein, we established an objective system (Mito-score) for evaluating mitochondria using machine-based processing of hue, saturation, and value color spaces. METHODS: The Mito-score was defined as the number of COX4 (mitochondrial inner membrane) immunohistochemistry-positive pixels divided by the number of nuclei per cell. The system was validated using four lung cancer cell lines, normal tissues, and lung cancer tissues (199 cases). RESULTS: The Mito-score correlated with MitoTracker, a fluorescent dye used to selectively label and visualize mitochondria within cells under a microscope (R2 = 0.68) and with the number of mitochondria counted using electron microscopy (R2 = 0.79). Histologically, the Mito-score of small cell carcinoma (57.25) was significantly lower than that of adenocarcinoma (147.5, p < 0.0001), squamous cell carcinoma (120.6, p = 0.0004), and large cell neuroendocrine carcinoma (111.8, p = 0.002). CONCLUSION: The Mito-score method enables the analysis of the mitochondrial status of human formalin-fixed paraffin-embedded specimens and may provide insights into the metabolic status of cancer.

Airway disorders associated with immune checkpoint inhibitor therapy: Two case reports and a systematic review.

Immune checkpoint inhibitors (ICI) are widely used for the treatment of various malignant neoplasms. Interstitial lung disease is a well-known immune-related adverse event, however, ICI-induced airway disease remains under-recognized. Herein, we report two similar cases of pembrolizumab-induced tracheobronchitis presenting as persistent chronic cough and dyspnea. Blood tests revealed elevated C-reactive protein levels without eosinophilia. Spirometry demonstrated mild airflow obstruction. Computed tomography revealed diffuse thickening of the tracheobronchial walls and bronchiectasis predominantly in the lower lobes. Bronchoscopy revealed edematous and erythematous tracheobronchial mucosa, and bronchial biopsy tissue exhibited marked inflammation with predominant infiltration of CD8+ lymphocytes. Subsequently, pembrolizumab-induced tracheobronchitis was diagnosed in both cases. Cessation of pembrolizumab and initiation of erythromycin, inhaled corticosteroids, and long-acting beta-agonists gradually improved the symptoms, airflow obstruction, and radiographic findings. These were completely resolved in one case. The other case initially showed a poor response to systemic corticosteroids combined with the aforementioned drugs, but improved gradually and almost completely. These cases exemplify ICI-induced airway disease that is, an under-recognized manifestation of immune-related adverse events. In addition, we have systematically searched the PubMed database for articles on ICI-induced airway disease, categorized the retrieved articles as eosinophilic and non-eosinophilic airway diseases, and reviewed the differences in treatment and prognoses between these two categories.

Pulmonary tumor thrombotic microangiopathy in occult early gastric cancer that was undetectable on upper endoscopy: a case report and review of similar cases.

BACKGROUND: Pulmonary tumor thrombotic microangiopathy (PTTM), a rare manifestation of metastatic cancer with poor prognosis, is characterized by subacute/acute fatal pulmonary hypertension. The main cause of PTTM is gastric cancer, and cases of early gastric cancer confirmed using autopsy have been reported. Moreover, several cases of early gastric cancer that are undetectable on endoscopy or macroscopic postmortem examination have been reported. CASE PRESENTATION: A previously healthy 50-year-old man presented with progressive dyspnea and cough for 1 month. Echocardiography suggested pulmonary hypertension. Computed tomography revealed diffuse lymphadenopathy, whereas blood work revealed an elevation in several serum tumor marker levels. Despite normal upper endoscopic findings, a presumptive diagnosis of PTTM due to gastric cancer was made based on pathological findings of cervical lymph node biopsy, which indicated signet ring cell carcinoma. Imatinib and tegafur/gimeracil/oteracil plus oxaliplatin therapy were started on day 7. The patient's condition was initially stable. However, his symptoms suddenly progressed, and the patient died on day 8. Macroscopic postmortem examination revealed no abnormal gastric wall findings. Microscopically, PTTM was confirmed, and multiple serial sections of the stomach revealed early gastric cancer. CONCLUSIONS: Despite normal endoscopic findings, micro-occult gastric cancer can lead to PTTM. Physicians should be aware of this disease presentation. Taking prompt action is needed when PTTM is suspected, even if the patient appears stable.

An autopsy case of aortic dissection due to giant cell arteritis.

Giant cell arteritis (GCA) is a systemic vasculitis affecting mainly large and medium-sized arteries. GCA sometimes involves the aorta and its major branches and causes aortic dissection as a rare complication. We have experienced an autopsy case of aortic dissection due to GCA. The patient was an 87-year-old Japanese woman with Stanford type A aortic dissection who died 7 days after admission. Two years previously she had been diagnosed as having abdominal aortic aneurysm and undergone endovascular aneurysm repair (EVAR). Although she had no characteristic symptoms of GCA, autopsy revealed marked granulomatous inflammation in the dissected area and coronary arteries. Active arteritis was evident not only in the arteries of the upper extremity but also those in the lower extremity. Granulomatous inflammation was not evident in the aneurysm. The aortic dissection might have been an initial manifestation of GCA. We report the regions of GCA extension and its histology in detail.

High expression of ovarian cancer immunoreactive antigen domain containing 2 (OCIAD2) is associated with poor prognosis in lung adenocarcinoma.

The clinicopathological implications of ovarian cancer immunoreactive antigen domain containing 2 (OCIAD2) in lung adenocarcinoma were investigated. The expression of OCIAD2 in 191 surgically resected lung adenocarcinomas was examined using immunohistochemistry. OCIAD2 expression was quantified using the H-score and dichotomized as high or low. High OCIAD2 protein expression was significantly correlated with vascular invasion (P = 0.0018), lymphatic permeation (P = 0.049), T factor (P = 0.0024), and pathological stage (P = 0.0003). High OCIAD2 expression was significantly associated with poorer overall survival (OS) (n = 191, P = 0.0325). In peripheral-type lung adenocarcinomas (n = 161), high OCIAD2 expression was significantly associated with both poorer OS (P = 0.0214) and poorer disease-free survival (P = 0.0496). Adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) showed weaker OCIAD2 expression than invasive adenocarcinoma. Among small adenocarcinomas measuring 2 cm or less in greatest dimension classified according to the Noguchi's classification (n = 79), invasive adenocarcinomas showed significantly higher OCIAD2 expression than non-invasive adenocarcinomas (P = 0.0007). Interestingly, OCIAD2 was expressed heterogeneously even within a tumor, and its expression was higher in areas of invasion than in areas of in situ spread. Our results suggest that OCIAD2 could be a useful prognostic biomarker of lung adenocarcinoma.

Ductus Aneurysm Ruptured Into the Esophagus With Massive Bleeding.

We report a patient with life-threatening hematemesis caused by the rupture of a ductus aneurysm into the esophagus, which was successfully treated by coil embolism for the esophageal fistula through the aorta and subsequent thoracic endovascular aortic replacement. Second-stage therapy was performed surgically after proactive antibiotic treatment and in consideration of the patient's improved general condition. This included debridement with drainage, aortic encasement with remnant aneurysmal wall, omentopexy, and jejunostomy. The esophagus was preserved, and satisfactory healing and natural closure of the fistula were achieved. Although repeated aspirations were later required for pleural fluid, such inflammatory complications finally subsided.

[A Case of Primary Schwannoma of the Urinary Bladder].

A 68-year-old woman presented with a bladder tumor. She was asymptomatic, and the tumor was incidentally detected with radiological imaging performed during treatment of cervical cancer. Magnetic resonance imaging and computed tomography revealed a solitary submucosal tumor located in the anterior wall of the urinary bladder, with homogeneous contrast enhancement. Cystoscopy showed a submucosal tumor covered by normal mucosa. A paraganglioma was considered in the differential diagnosis, but symptoms suggesting hypercatecholaminemia were not apparent. Moreover, she did not have a family history or symptoms associated with neurofibromatosis-1 (NF-1). She underwent partial cystectomy with a preliminary diagnosis of submucosal bladder tumor. Histopathological diagnosis confirmed a schwannoma arising from the bladder wall. She was followed up without intravesical recurrence or metastases for 6 months. In the literature, only 12 cases of bladder schwannoma have been reported. There was no reported family history or symptoms associated with NF-1 in any of the cases. Although the number of cases is limited, literature review showed a favorable prognosis for bladder schwannoma with local tumor resection in patients without NF-1.

An autopsy case of non-traumatic fat embolism syndrome.

Fat embolism syndrome (FES) occurs after long bone fractures and the symptoms appear 24-72 h after the initial trauma. Fat emboli can affect both the pulmonary and systemic circulation. Apart from the most common type of FES that originates from bone fracture, non-traumatic FES has been also reported. We have experienced an autopsy case of non-traumatic FES. An 81-year-old man with hepatocellular carcinoma associated with alcoholic liver cirrhosis suddenly lost consciousness before transcatheter arterial chemoembolization treatment for his disease and died 5 h after the episode. At autopsy, numerous fat droplets were detected in the alveolar capillaries of the lung and glomerular capillaries of the kidney. Lipid analysis of lung autopsy specimens by thin-layer chromatography showed that the emboli were composed mainly of tristearin. Free fatty acids (FFA) has been considered to be the main component of fat emboli and can be a cause of acute respiratory distress syndrome (ARDS). However, in the present case, the lung specimen contained tristearin and ARDS did not occur. This is the first report of non-traumatic FES in which lipid analysis of human autopsy specimens has been conducted.

Genes and pathology of non-small cell lung carcinoma.

While histopathology has traditionally been the cornerstone of treatment decisions in the management of lung cancer patients, the complexity and heterogeneity of histological classification has had a limited impact in the routine practice of oncology. This has changed dramatically in the last few years, owing to discoveries of genomic aberrations and results of clinical trials of novel and targeted therapies. These discoveries have resulted in a new way of classifying non-small cell lung cancer (NSCLC), based on the occurrence of putative or proven driver and targetable genomic changes. The rapidity by which the landscape of mutation and genomic changes is being identified also has led to a new paradigm and approaches to pathological diagnosis of NSCLC. In this context, international consortia have proposed new classifications of lung adenocarcinoma and guidelines for molecular testing in lung cancer and have provided concrete recommendations on new ways to practice lung cancer pathology.