Mai Matsumura

The pathological features of idiopathic interstitial pneumonia-associated pulmonary adenocarcinomas.

To investigate the pathological features of idiopathic interstitial pneumonia (IIP)‐associated pulmonary adenocarcinoma.

A Histopathological Feature of EGFR-Mutated Lung Adenocarcinomas with Highly Malignant Potential – An Implication of Micropapillary Element -

The purpose of this study was to define histological features determining the malignant potential of EGFR-mutated lung adenocarcinoma (LADC). Surgically resected tumors (EGFR-mutated LADCs with (21) and without (79) lymph node metastasis and EGFR wild-type LADCs with (26) and without (108) lymph node metastasis) and biopsy samples from inoperably advanced tumors (EGFR-mutated LADCs (78) and EGFR wild-type LADCs (99)) were examined. In surgically resected tumors, the EGFR-mutated LADCs with lymph node metastasis had the micropapillary element in a significantly greater proportion than others (Mann-Whitney tests P ≤0.026). The proportion of micropapillary element was higher in the EGFR-mutated LADC at the advanced stage (stage II, III, or IV) than in the tumor at the early stage (stage I) (Mann-Whitney test, P<0.0001). In the biopsy samples from inoperably advanced LADCs (177), EGFR-mutated tumors also had micropapillary element at a higher frequency than EGFR-wild type tumors (53/78 (68%), versus 30/99 (30%), Pearson x2 test, P<0.0001). In stage I EGFR-mutated LADCs (84), the tumors with the micropapillary element (34) exhibited a significantly higher recurrence rate than tumors without micropapillary element (50) (5-year Recurrence-free survival 64.4% versus 93.3%, log-rank test P = 0.028). The micropapillary element may be an exclusive determinant of malignant potential in EGFR-mutated LADC. It is suggested that EGFR-mutated LADC may develop through a distinct histogenesis, in which the micropapillary element is important for promoting progression.

Update on the potential significance of psammoma bodies in lung adenocarcinoma from a modern perspective

Psammoma bodies are concentrically lamellated microscopic structures made of calcium. They are commonly observed in papillary carcinomas of the thyroid gland and serous papillary adenocarcinomas of the ovary, but are also occasionally detected in lung adenocarcinomas. Only one study, published in 1972, has systematically described the significance of psammoma bodies in lung adenocarcinomas. The aim of this study was to update the significance of psammoma bodies in lung adenocarcinomas from a modern perspective.

Alterations in cathepsin L expression in lung cancers

We herein investigated the potential role of cathepsin L in lung carcinogenesis. Lung cancer cell lines and surgically resected tumors were examined for the expression of the cathepsin L protein and copy number alterations in its gene locus. Cathepsin L was stably expressed in bronchiolar epithelial cells. Neoplastic cells expressed cathepsin L at various levels, whereas its expression was completely lost in most of the lung cancer cell lines (63.6%, 7/11) examined. Furthermore, expression levels were lower in a large fraction of lung tumors (69.5%, 139/200) than in bronchiolar epithelia. The expression of cathepsin L was lost in some tumors (16.0%, 32/200). In adenocarcinomas, expression levels were significantly lower in high‐grade tumors than in low‐grade tumors (one‐way ANOVA, P < 0.0500). Copy number alterations were found in 18.0% (36 [32 gain + 4 loss] /200) of lung tumors. No relationship existed between cathepsin L protein expression levels and the copy number of its gene locus (Spearmans rank‐order correlation, P = 0.3096). Collectively, these results suggest that the down‐regulated expression of cathepsin L, which is caused by an undefined mechanism other than copy number alterations, is involved in the progression of lung adenocarcinomas.

Expression of tropomyosins in lung cancer - a potential role in carcinogenesis and its utility in a histopathological diagnosis.

We herein analyzed the relationships between tropomyosin protein expression levels and clinicopathological factors in order to determine the significance of tropomyosins in lung cancers. Although neoplastic cells expressed different isoforms of tropomyosin, overall expression levels were lower than those in bronchial and alveolar epithelial cells. In adenocarcinomas, tropomyosin levels were markedly reduced in poorly differentiated or solid subtype carcinomas, suggesting that a loss in the expression of tropomyosins is involved in the progression of lung adenocarcinomas. The potential utility of the immunohistochemical expression of tropomyosins for a histopathological diagnosis was also investigated. The sensitivity and specificity of a loss in the expression of tropomyosins were 100% and 50%, respectively, which were superior to those for the strong expression of p53 (sensitivity 100% and specificity 44%), a conventional biomarker. An immunohistochemical examination of tropomyosins may assist in the histopathological detection of lung cancer cells in small biopsy specimens.

A molecular pathological study of four cases of ciliated muconodular papillary tumors of the lung: Ciliated muconodular papillary tumor

Ciliated muconodular papillary tumors (CMPTs) are a recently categorized benign or low‐grade malignant neoplasm that develops in the peripheral lung. Only about 40 cases have been reported to date, and the clinicopathological characteristics have yet to be defined in detail. Here, we present four cases of CMPTs with a focus on their immunohistochemical profiles and driver gene mutations. These tumors were a papillary proliferation of a mixture of ciliated, mucous, and basal cells located in the peripheral lung. Ciliated, mucous and basal cells were positive for TTF‐1 when using the clone SPT24, but negative for HNF‐4α. Basal cells were positive for p40. Mucous cells in some tumors were positive for MUC5AC and MUC6. The Ki‐67 index was less than 5%, and strong expression of p53 was not detected. Three of the four tumors had a BRAF (V600E) driver mutation, an EGFR (del E746‐T751/S752V) driver mutation, or driver mutations in both EGFR (E709G) and KRAS (G12V). These mutation types are rare for any histological type of lung cancer. The present results confirmed that CMPT is a neoplasm with immunohistochemical features and driver gene mutations that are distinct from those of common lung tumors.

Secondary pulmonary alveolar proteinosis predominant in the transplanted lung in patients with idiopathic interstitial pneumonia: an autopsy case

A man in his 40 s with idiopathic interstitial pneumonia underwent cadaveric left single-lung transplantation from a brain-dead donor in October 2014. In October 2015, chest high-resolution computed tomography revealed centrilobular ground-glass opacities (GGOs) predominantly in the transplanted left lung, and subsequently, the shadows progressed to a geographic GGO without crazy paving. Bronchoalveolar lavage fluid analysis revealed an opaque and milky appearance, and cytopathology demonstrated foamy alveolar macrophages and abundant granular, acellular, eosinophilic, and amorphous material in the background. There was no evidence of infection. Serum anti-granulocyte-macrophage colony-stimulating factor antibody testing was negative. We diagnosed the patient with secondary pulmonary alveolar proteinosis (PAP) following lung transplantation. Autopsy revealed PAP findings predominant in the transplanted left lung, which also had dilated lymphatic vessels. In addition to defects in alveolar macrophage function from immunosuppressive therapy, impaired lymphatic drainage due to transplantation would contribute to the onset of secondary PAP in the transplanted lung.

The potential significance of alpha-enolase (ENO1) in lung adenocarcinomas – A utility of the immunohistochemical expression in pathologic diagnosis

We herein analyzed the relationships among the immunohistochemical expression of alpha‐enolase (ENO1) and clinicopathological factors in order to define the significance of ENO1 in lung adenocarcinomas (ADCs). ENO1 expression was detected in most of the ADCs examined (95.8%), but not in bronchial and alveolar epithelia. ENO1 expression was typically observed in the cytoplasm among most ADCs (95.8%), but was also detected in the nucleus (56.3%). The levels were significantly higher in terminal respiratory unit (TRU) cytological subtype ADCs. Neither cytoplasmic nor nuclear expression was associated with any other clinicopathological factors including post‐operative survival and growth activity. These results suggest that ENO1 is a crucial factor promoting neoplastic transformation exclusively in TRU subtype ADCs. We also investigated the potential utility of the immunohistochemical expression of ENO1 to differentiate TRU‐type ADC cells from the reactive hyperplasia of pneumocytes and bronchiolar epithelial cells because difficulties are associated with discriminating these lesions in small biopsy specimens. The sensitivity and specificity of ENO1 (cytoplasmic/nuclear) were 87.5%/37.5% and 88.9%/100%, respectively, which are superior to those of p53 (18.8% and 100%). ENO1 has potential as a biomarker to assist in the histopathological detection of TRU subtype ADC cells.

Succinate dehydrogenase B-deficient renal cell carcinoma: A case report with novel germline mutation: SDHB-deficient RCC

Succinate dehydrogenase‐deficient renal cell carcinoma (SDH‐deficient RCC) is a newly introduced histological type of RCC, which is caused by loss of subunit genes of SDH. It is known to frequently demonstrate familial occurrence and be frequently associated with gastrointestinal stromal tumors and paraganglioma. To date, only 53 cases have been reported. Here, we present an additional case of SDH‐deficient RCC occurring in a 40‐year‐old female. The tumor was histologically biphasic, consisting of tubular and solid architectures. The tumor cells possessed oval nuclei with small nucleoli, and an eosinophilic granular cytoplasm with occasional vacuoles. These cells completely lost the immunohistochemical expression of B subunit of SDH (SDHB). Consequently, the tumor was diagnosed as SDHB‐deficient RCC. We identified a novel germ line mutation of the SDHB gene, and also confirmed a hemizygous deletion of the wild‐type allele in the tumor cells. To define the pathological characteristics of SDH‐deficient RCC, precise diagnosis and accumulation of more cases are required.

Intraosseous inflammatory myofibroblastic tumor of the mandible with a novel ATIC-ALK fusion mutation: a case report

BackgroundInflammatory myofibroblastic tumor (IMT) is a rare low-grade malignant neoplasm with a predilection for children and young adults, and typically arises in the lung, abdominopelvic region, and retroperitoneum. IMTs in the maxillofacial region are extreme rare. Approximately 50% of IMT harbor rearrangements of the anaplastic lymphoma kinase (ALK) gene at 2p23 with various fusion partners.Case presentationWe herein report a case of intraosseous IMT of the mandible with a novel ATIC-ALK fusion. Tooth 43 did not erupt after the loss of tooth 83 in an 11-year-old girl with no previous history of trauma. Panoramic tomography showed a unilocular radiolucent lesion in the right anterior mandible resorbing the root of tooth 42 and the medial side of the root of tooth 44. Computed tomography revealed a well- circumscribed 3-cm osteolytic lesion of the right anterior mandible eroding the buccal cortical plate. The entire lesion was curetted out. A histopathological examination revealed the proliferation of plump spindle cells with a storiform architecture and lymphocytes scattered around spindle cells. The spindle cells showed diffuse cytoplasmic staining for ALK by immunohistochemistry. A fluorescence in situ hybridization analysis revealed the translocation of a part of the ALK gene locus at chromosome 2p23. A rapid amplification of cDNA ends analysis confirmed the rearrangement of ALK and identified ATIC as a partner of this ALK fusion mutant.ConclusionTo the best of our knowledge, this is the first case of intraosseous IMT of the mandible with a novel ATIC-ALK fusion. We also herein reviewed similar tumors reported in the literature.