Kazutoshi Shibuya

In triple-negative breast cancer (TNBC), the clinicopathological significance of the expression of a second estrogen receptor, ERβ, remains unclear. Further, although the clinicopathological significance of mutant p53 and androgen receptor (AR) has been investigated in TNBC, they have not been established as therapeutic targets. Experimental studies reported the importance of cross-talk between ERβ and p53 or AR in TNBC. In this study, we immunohistochemically examined ERβ expression in surgical specimens of TNBC obtained from postmenopausal patients who underwent surgery without neoadjuvant therapy and investigated the relationship between ERβ expression and various clinicopathological factors, including clinical outcome, while also considering p53 and AR. No significant difference in clinical outcome was noted according to the ERβ status alone (p = 0.2908). However, the ERβ status did affect the relationship between the clinical outcome and p53 or AR status; p53-positive or AR-positive group exhibited significantly more favorable clinical outcomes than p53-negative or AR-negative group, respectively, in the ERβ-positive group (p53, p = 0.0265; AR, p = 0.0285), but not in the ERβ-negative group (p53, p = 0.7228; AR, p = 0.7734). This may be the result of a functional interaction between ERβ and p53 or AR. The role of ERβ in TNBC will be elucidated in further complex studies considering multiple molecules.

Appropriate biomarkers are required to predict the clinical outcome of triple‐negative breast cancer (TNBC). In this study, we focused on the clinical importance of two representative tumor‐associated proteins, Bcl‐2 and p53. Bcl‐2 expression is usually related to estrogen receptor expression and a favorable outcome in breast cancer. TNBC has been reported to show a high frequency of p53 positivity suggesting TP53 mutations. The expressions of Bcl‐2 and p53 were immunohistochemically examined in TNBC involving two age groups of postmenopausal women (≥75 y/o, n = 75; 55–64 y/o, n = 47), who underwent surgery without neoadjuvant therapy. We examined their associations with each other, or with clinicopathological factors including the outcome. Bcl‐2 expression was inversely correlated with androgen receptor, apocrine morphology, and p53 expressions, and was an independent predictor of a poor outcome in total or in younger women. p53 positivity was associated with a more favorable outcome than p53 negativity in the younger group. In combined analyzes, none of the twenty Bcl‐2‐negative/p53‐positive cases in the younger group exhibited recurrence, resulting in the independent favorable predictive value of Bcl‐2‐negative/p53‐positive. The anti‐apoptotic nature of Bcl‐2 may be apparent in TNBC. The excellent outcome of Bcl‐2‐negative/p53‐positive cases in the younger group warrants further combined investigation of Bcl‐2/p53 in TNBC.

Invasive fungal infection (IFI) has a high mortality rate in patients who undergo hematopoietic stem cell transplantation, and it is often confirmed by postmortem dissection. When IFI is initially confirmed after an autopsy, the tissue culture and frozen section are challenging to secure, and in many cases, formalin-fixed, paraffin-embedded (FFPE) samples represent the only modality for identifying fungi. Histopathological diagnosis is a useful method in combination with molecular biological methods that can achieve more precise identification with reproducibility. Meanwhile, polymerase chain reaction (PCR) using fungal-specific primers helps identify fungi from FFPE tissues. Autopsy FFPE specimens have a disadvantage regarding the quality of DNA extracted compared with that of specimens obtained via biopsy or surgery. In the case of mucormycosis diagnosed postmortem histologically, we examined currently available molecular biological methods such as PCR, immunohistochemistry (IHC), and in situ hybridization (ISH) to identify fungi. It is reasonable that PCR with some modification is valuable for identifying fungi in autopsy FFPE specimens. However, PCR does not always correctly identify fungi in autopsy FFPE tissues, and other approaches such as ISH or IHC are worth considering for clarifying the broad classification (such as the genus- or species-level classification).

Propionibacterium acnes is implicated in the pathogenesis of sarcoidosis. We investigated the usefulness of immunohistochemistry (IHC) with a commercially available P. acnes-specific monoclonal antibody (PAB antibody) for differentiating sarcoidosis from other granulomatous diseases. Formalin-fixed paraffin-embedded tissue samples from 94 sarcoidosis patients and 30 control patients with other granulomatous diseases were examined by the original manual IHC method. We also compared the detection frequency of P. acnes in sarcoid granulomas between manual and automated IHC methods. P. acnes was detected in sarcoid granulomas of samples obtained by transbronchial lung biopsy (64%), video-associated thoracic surgery (67%), endobronchial-ultrasound-guided transbronchial-needle aspiration (32%), lymph node biopsy (80%), and skin biopsy (80%) from sarcoidosis patients, but not in any non-sarcoid granulomas of the samples obtained from control patients. P. acnes outside granulomas, however, was frequently detected in both groups. The detection status of P. acnes in granulomas did not correlate with the clinical characteristics of sarcoidosis patients. The automated Leica system exhibited the best detection sensitivity (72%) and almost an identical localization for P. acnes in sarcoid granulomas compared with the manual method. IHC with a PAB antibody is useful for differentiating sarcoidosis from other granulomatous diseases by detecting P. acnes in granulomas. An automated method by the Leica system can be used in pathology laboratories for differential diagnosis of granulomas by IHC with the PAB antibody.

Purpose. We hypothesized that innate immune response pathways might be involved in thyroid carcinogenesis. To investigate this hypothesis, we aimed at analyzing the expression of several receptors and molecules in the innate immune system in papillary thyroid carcinoma (PTC) and anaplastic thyroid carcinoma (ATC) tissues. Methods. Of the surgically resected specimens, 11 ATC tissues, 25 PTC tissues, and 8 nodular hyperplasia (NH) tissues were selected and examined for the expression of toll-like receptor (TLR) 2, TLR3, TLR4, TLR5, TLR7, TLR9, the myeloid differentiation primary response gene 88 (MyD88), and toll-interleukin-1 receptor domain-containing adaptor inducing INF-β (TRIF) by immunohistochemistry (IHC). Results. Several TLRs were expressed in each tissue. TLR3 was strongly expressed in all tissues. In contrast, TLR4 was not detected in any tissues. While TLR5 was moderately expressed in NH but significantly reduced in PTC and ATC, TLR9 was absent in NH tissue but moderately expressed in both PTC and ATC. On MyD88 expression, no significant difference was found between PTC and ATC. TRIF was significantly upregulated in PTC and ATC compared to NH. Surprisingly, PTC and ATC tissues exhibited similar expression patterns of TLRs, MyD88, and TRIF. Conclusion. These data suggest the involvement of the innate immune system in both PTC and ATC. Specifically, TLR3-mediated TRIF activation was confirmed in PTC and ATC. This provides new insight into thyroid carcinogenesis.

Some patients with thymoma present with a very large mass in the thoracic cavity. Although the most effective treatment for thymoma is surgical resection, it is difficult to perform because of the size of the tumor and the infiltration of tumor into the surrounding organs and vessels. We report a patient with a giant thymoma that was completely resected via a median sternotomy and left anterolateral thoracotomy. A 63-year-old woman presented with a mass in the left thoracic cavity that was incidentally found on a chest X-ray. Chest computed tomography revealed a giant mass (16 × 10 cm) touching the chest wall and diaphragm and pressed against the heart and left upper pulmonary lobe. Complete resection was performed via a median sternotomy and left anterolateral thoracotomy. The tumor was histologically diagnosed as a WHO type B2 thymoma, Masaoka stage II. Giant thymomas tend to grow expansively without invasion into surrounding organs and vessels. Surgical resection that employs an adequate approach must be considered, regardless of the size of the tumor.

A 75‐year‐old man was referred to our hospital with a 1‐year history of persistent dry cough and progressive dyspnoea on exertion. He was treated with aspirin due to thrombosis of internal carotid artery. He was diagnosed with idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP), and started on inhaled N‐acetylcysteine therapy and pirfenidone. Since his clinical condition progressively deteriorated after 6 months, he was switched from pirfenidone to nintedanib. As a result, his general condition worsened rapidly. He was diagnosed with acute exacerbation (AE) of IPF, and was treated with methylprednisolone pulse and recombinant human soluble thrombomodulin. Despite the administration of these treatments, he died of severe haemoptysis four days after the onset of AE. Autopsied lungs revealed significantly dark red‐brown appearance corresponding to diffuse alveolar haemorrhage (DAH) histopathogically with a background pattern of UIP with fibrotic change. Notably, there was no evidence of diffuse alveolar damage suggesting IPF‐AE.

Idiopathic pulmonary arterial hypertension (IPAH) is a rare, fatal disease of unknown pathogenesis. Evidence from our recent study suggests that IPAH pathogenesis is related to upregulation of the Wnt/planar cell polarity (Wnt/PCP) pathway. We used microscopic observation and immunohistochemical techniques to identify expression patterns of cascading proteins—namely Wnt-11, dishevelled-2 (Dvl-2), and dishevelled-associated activator of morphogenesis 1 (Daam-1)—in pulmonary arteries. We analyzed sections of formalin-fixed and paraffin-embedded autopsied lung tissues obtained from 9 IPAH cases, 7 associated pulmonary arterial hypertension cases, and 16 age-matched controls without pulmonary arterial abnormalities. Results of microscopic observation were analyzed in relation to the cellular components and size of pulmonary arteries. Varying rates of positive reactivity to Dvl-2 and Daam-1 were confirmed in all cellular components of pulmonary arteries, namely, endothelial cells, myofibroblasts, and medial smooth muscle cells. In contrast, none of these components was reactive to Wnt-11. No specific expression patterns were observed for endothelial cells or myofibroblasts under any experimental conditions. However, marked expression of Dvl-2 and Daam-1 was confirmed in smooth muscle cells. In addition, Dvl-2 was depleted while Daam-1 expression was elevated in IPAH, in contrast with specimens from associated pulmonary arterial hypertension cases and controls. High Daam-1 expression may upregulate the Wnt/PCP pathway and cause IPAH.