Objective: Develop a consensus for the nomenclature and definition of adrenal histopathologic features in unilateral primary aldosteronism (PA). Context: Unilateral PA is the most common surgically treated form of hypertension. Morphologic examination combined with CYP11B2 (aldosterone synthase) immunostaining reveals diverse histopathologic features of lesions in the resected adrenals. Patients and Methods: Surgically removed adrenals (n = 37) from 90 patients operated from 2015 to 2018 in Munich, Germany, were selected to represent the broad histologic spectrum of unilateral PA. Five pathologists (Group 1 from Germany, Italy, and Japan) evaluated the histopathology of hematoxylin-eosin (HE) and CYP11B2 immunostained sections, and a consensus was established to define the identifiable features. The consensus was subsequently used by 6 additional pathologists (Group 2 from Australia, Brazil, Canada, Japan, United Kingdom, United States) for the assessment of all adrenals with disagreement for histopathologic diagnoses among group 1 pathologists. Results: Consensus was achieved to define histopathologic features associated with PA. Use of CYP11B2 immunostaining resulted in a change of the original HE morphology-driven diagnosis in 5 (14%) of 37 cases. Using the consensus criteria, group 2 pathologists agreed for the evaluation of 11 of the 12 cases of disagreement among group 1 pathologists. Conclusion: The HISTALDO (histopathology of primary aldosteronism) consensus is useful to standardize nomenclature and achieve consistency among pathologists for the histopathologic diagnosis of unilateral PA. CYP11B2 immunohistochemistry should be incorporated into the routine clinical diagnostic workup to localize the likely source of aldosterone production.

The status of tumor-infiltrating lymphocytes (TILs) has been recently proposed to predict clinical outcome of patients with breast cancer. We therefore studied the prognostic significance of CD8+ TILs and FOXP3+ TILs in residual tumors after neoadjuvant chemotherapy (NAC) and the alterations in these parameters before and after NAC in patients with triple-negative breast cancer (TNBC). One hundred thirty-one TNBC patients who received NAC at three institutions were examined. CD8+ TIL and FOXP3+ TIL in residual tumors and biopsy specimens were evaluated by double-staining immunohistochemistry. The CD8+ TIL and FOXP3+ TIL status of the residual tumors was assessed, and the rates of their changes before and after NAC were calculated. TNBC patients with high CD8+ TIL levels or a high CD8/FOXP3 ratio in residual tumors had significantly better recurrence-free survival (RFS) and breast cancer-specific survival (BCSS) than patients with low values of these parameters. In multivariate analyses, CD8+ TIL exhibited strong prognostic significance for RFS, with a hazard ratio (HR) of 3.09 (95 % confidence interval (CI) 1.537–6.614, P=0.0013). The CD8/FOXP3 ratio was also significantly correlated with RFS (HR=2.07, 95 % CI 1.029–4.436, P=0.0412). TNBC with larger residual tumor size and positive lymph node status, which are known prognostic factors, was independently associated with worse RFS (P=0.0064 and P=0.0015, respectively). High CD8+ TIL levels were a markedly powerful indicator of improved BCSS, with an HR of 3.59 (95 % CI 1.499–9.581, P=0.0036). Nodal status was also associated with BCSS (P=0.0024). TNBC with a high rate of CD8+ TIL changes was associated with significantly better RFS compared with the low group (P=0.011). Higher rates of changes in the CD8/FOXP3 ratio were significantly correlated with both better RFS and BCSS compared with lower rates (P=0.011 and P=0.023, respectively). This is the first study to demonstrate that high CD8+ TIL and a high CD8/FOXP3 ratio in residual tumors and increment of these parameters following NAC and accurately predict improved prognosis in TNBC patients with non-pathological complete response following NAC. These parameters could serve as a surrogate one for adjuvant treatment in patients with residual disease in the neoadjuvant setting.

P62/SQSTM1 is a selective substrate of autophagy, and aberrant accumulation of p62 has been observed in various pathological conditions. To understand the roles p62 plays in non‐small‐cell lung cancer (NSCLC), we carried out immunohistochemical analyses of p62 expression in a cohort of patients with annotated clinicopathological data. As analyses of murine and human hepatocellular carcinomas suggested a correlation between p62 and Nrf2 accumulations, we also examined NRF2 expression in the same cohort. The expression of NRF2 and p62 was examined by immunohistochemical methods in 109 NSCLC cases, which included patients with adenocarcinoma (n = 72), squamous cell carcinoma (n = 31), and large cell carcinoma (n = 6). Accumulation of NRF2 and p62 was detected in 34% and 37% of NSCLC patients, respectively. The accumulations of p62 and NRF2 did not correlate with each other, but both were associated with worse lung cancer‐specific survival (P = 0.0003 for NRF2; P = 0.0130 for p62). NRF2 status had an impact on NSCLC prognosis irrespective of histology types, but p62 status did so particularly in adenocarcinoma (P = 0.037). Multivariate analysis indicated that positive immunoreactivities of NRF2 and p62 were both independent factors predicting worse lung cancer‐specific survival (P < 0.0001 for NRF2 and P = 0.04 for p62). This study revealed that both NRF2 and p62 are independent prognostic factors for NSCLC. The prognostic impact of p62 status was pronounced in adenocarcinoma patients, suggesting that molecular mechanisms underlying cancer evolution differ between adenocarcinoma and squamous cell carcinoma. (Cancer Sci 2012; 103: 760–766)

It is well known that sex steroids are involved in the growth of breast cancers, and the great majority of breast carcinomas express estrogen (ER), progesterone (PR), and androgen (AR) receptors. In particular, recent studies have demonstrated that estrogens and androgens are locally produced in breast carcinoma tissues, and total blockade of in situ estrogen production potentially leads to an improvement in prognosis of breast cancer patients. Therefore, it is important to obtain a better understanding of sex steroid-producing enzymes in breast carcinoma tissues. In this review, we summarize recent studies on the expression and regulation of enzymes related to intratumoral production of estrogens (aromatase, 17β-hydroxysteroid dehydrogenase type 1 (17βHSD1), and steroid sulfatase (STS) etc) and androgens (17βHSD5 and 5α-reductase) in human breast carcinoma tissues, and discuss the biological and/or clinical significance of these enzymes. The cellular localization of aromatase in breast carcinoma tissues still remains controversial. Therefore, we examined localization of aromatase mRNA in breast carcinoma tissues by laser capture microdissection/real time-polymerase chain reaction. Aromatase mRNA expression was detected in both carcinoma and intratumoral stromal cells, and the expression level of aromatase mRNA was higher in intratumoral stromal cells than in carcinoma cells in the cases examined. We also examined an association among the immunoreactivity of enzymes related to intratumoral estrogen production and ERs in breast carcinoma tissues, but no significant association was detected. Therefore, the enzymes responsible for the intratumoral production of estrogen may not always be the same among breast cancer patients, and not only aromatase but also other enzymes such as STS and 17βHSD1 may have important therapeutic potential as targets for endocrine therapy in breast cancer patients.

Steroid and xenobiotic receptor (SXR) or human pregnane X receptor (hPXR) has been shown to play an important role in the regulation of genes related to xenobiotic detoxification, such as cytochrome P450 3A4 and multidrug resistance gene 1. Cytochrome P450 enzymes, conjugation enzymes, and transporters are all considered to be involved in the resistance of breast carcinoma to chemotherapeutic or endocrine agents. However, the expression of SXR/hPXR proteins and that of its target genes and their biological or clinical significance have not been examined in human breast carcinomas. Therefore, we first examined SXR/hPXR expression in 60 breast carcinomas using immunohistochemistry and quantitative reverse transcription-PCR. We then searched for possible SXR/hPXR target genes using microarray analysis of carcinoma cells captured by laser microscissors. SXR/hPXR was detected in carcinoma tissues but not in nonneoplastic and stromal cells of breast tumors. A significant positive correlation was detected between the SXR/hPXR labeling index and both the histologic grade and the lymph node status of the carcinoma cases. Furthermore, in estrogen receptor–positive cases, SXR/hPXR expression was also positively correlated with expression of the cell proliferation marker, Ki-67. Microarray analysis showed that organic anion transporting polypeptide-A (OATP-A) was most closely correlated with SXR/hPXR gene expression, and both OATP-A mRNA and protein were significantly associated with SXR/hPXR in both breast carcinoma tissues and its cell lines. These results suggest that SXR/hPXR and its target gene, such as OATP-A, may play important roles in the biology of human breast cancers. (Cancer Res 2006; 66(1): 535-42)