Clear cell hidradenoma (CCH) is an uncommon benign dermal-based tumor that typically presents on the head, neck, and upper extremities as a solitary firm nodule. The clear cytoplasm can resemble benign and malignant clear cell neoplasms from multiple sites; thus, a large differential diagnosis is often considered. When CCH is seen in the breast or axilla, glycogen-rich clear cell carcinoma (GRCCC) of the breast enters the differential diagnosis. Although GRCCC is rare, it is important to recognize as a breast carcinoma variant because most reports have suggested that it has a more aggressive course than typical invasive ductal carcinoma. We report a case of CCH in the upper axilla of a 64-year-old woman who also happened to have a remote history of invasive GRCCC to highlight the potential diagnostic pitfalls when evaluating these two histologically similar clear cell tumors. Although immunohistochemical studies can be helpful, overlapping staining patterns can lead to potential confusion and misclassification. Both of our patient's tumors were negative for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and PAX8. ER and PR are typically negative in hidradenomas and can be negative in up to 50% of GRCCC. Although considered a breast marker, GATA-3 can be negative in GRCCC and positive in skin adnexal tumors. p63 can be especially helpful, as it is expressed in skin adnexal tumors, but lost in most (Thike et al., 2010) invasive breast carcinomas. Finally, periodic acid-Schiff (PAS) with and without diastase highlights intra-cytoplasmic glycogen in GRCCC.
Metastasis is the main cause of death for lung cancer patients. The ex vivo 4D acellular lung model has been shown to mimic this metastatic process. However, the main concern is the model's lack of cellular components of the tumor's microenvironment. In this study, we aim to determine if the intact lung microenvironment will still allow lung cancer metastasis to form. We harvested a heart-lung block from a rat and placed it in a bioreactor after cannulating the pulmonary artery, trachea and tying the right main bronchus for 10–15 days without any tumor cells as a control group or with NSCLC (A549, H1299 or H460), SCLC (H69, H446 or SHP77) or breast cancer cell lines (MCF7 or MDAMB231) through the trachea. We performed lobectomy, H&E staining and IHC for human mitochondria to determine the primary tumor's growth and formation of metastatic lesions. In addition, we isolated circulating tumor cells (CTC) from the model seeded with GFP tagged cells. In the control group, no gross tumor nodules were found, H&E staining showed hyperplastic cells and IHC showed no staining for human mitochondria. All of the models seeded with cancer cell lines formed gross primary tumor nodules that had microscopic characteristics of human cancer cells on H&E staining with IHC showing staining for human mitochondria. CTC were isolated for those cells labeled with GFP and they were viable in culture. Finally, all cell lines formed metastatic lesions with cells stained for human mitochondria. The cellular ex vivo 4D model shows that human cancer cells can form a primary tumor, CTC and metastatic lesions in an intact cellular environment. This study suggests that the natural matrix scaffold is the only necessary component to drive metastatic progression and that cellular components play a role in modulating tumor progression.
New developments in the field of immune therapy for non-small cell lung cancer (NSCLC) are emerging rapidly and the race to identify new targets and new therapeutic agents within this field is intensifying.1 As part of contemporary practice to select patients for immune therapy, pathologists are performing immunohistochemistry (IHC) for programmed death receptor ligand-1 (PD-L1) as the currently favored predictive biomarker test.2–4 This role seems likely to expand considering the June 2016 publication of a study, first presented in part at previous American Society of Clinical Oncology and European Cancer Congress annual meetings, that found that patients with advanced NSCLC responded to nivolumab monotherapy as a first-line therapy.5–7During the past year, the US Food and Drug Administration (FDA) has approved monoclonal antibodies that block inhibitory immune checkpoint molecules (programmed death receptor-1 [or PD-1] and its ligand, PD-L1) for NSCLC and corresponding companion or complementary diagnostics based on PD-L1 IHC.8–10 To date, the immune checkpoint inhibitors have been approved for second-line therapy of advanced NSCLC after progression on first-line therapies. Positive PD-L1 IHC biomarker tests identify those NSCLC patients who are most likely to benefit from treatment with immune checkpoint inhibitors compared to patients whose biomarker test results are negative. It is important to note that a negative IHC result does not always preclude inhibitory therapy response, presumably due to heterogeneous PD-L1 expression. Discussion addressing if PD-LI IHC is the optimal biomarker test along with strategies to address a multiplicity of PD-L1 antibodies and their interpretation relative to patient response is discussed elsewhere in the literature.3 11–14Last year, the FDA expanded the use of nivolumab for second-line treatment for metastatic NSCLC based on the CheckMate 057 clinical trial and approved the PD-L1 IHC 28-8 PharmDx assay (Dako North America, Carpinteria, California) as a complementary diagnostic for nivolumab.8 9 In June 2016, results of the phase I Checkmate 012 trial were published.7 This trial evaluated nivolumab as a first-line monotherapy in 52 advanced NSCLC patients and found an objective response rate (ORR) of 23% (12 of 52) with 4 ongoing complete responses. ORR was 28% (9 of 32) in patients whose NSCLC had PD-L1 expression of any amount versus 14% (2 of 14) in patients whose NSCLC was negative for PD-L1 expression. There was a trend toward greater response to therapy the greater the PD-L1 expression. Currently, 2 phase III trials of first-line nivolumab therapy, CheckMate 026 and CheckMate 227, are investigating PD-L1 expression as a predictive biomarker for nivolumab efficacy.7The potential use of immune checkpoint inhibitors for first-line therapy of advanced NSCLC has implications for biomarker testing by pathologists.7–9,15 Currently immune checkpoint therapy is offered as a possible salvage option in NSCLC patients whose cancer has progressed on traditional first-line chemotherapy. PD-L1 biomarker status may be less clinically relevant in the second-line setting owing to other considerations, namely the paucity of other options for patients progressing after initial cytotoxic therapy and the low response rate of second-line docetaxel. This likely limits the number of requests for PD-L1 testing. However, PD-L1 biomarker status would be expected to be a more important factor in the decision to initially use a new type of therapy (immune therapy) over conventional chemotherapy with its established record as a first-line treatment.7 15 Since PD-L1 expression is likely to carry more weight in the first-line decision-making process than in second-line salvage options, pathologists can expect increased requests for PD-L1 testing if immune therapy becomes an FDA-approved first-line alternative treatment. This situation would place greater demand on laboratories to provide PD-L1 testing for a larger number of advanced NSCLCs, which represent some 70% of all lung cancers at the time of first diagnosis.89Although controversies to PD-L1 biomarker testing remain, increasing demand for PD-LI testing seems inevitable for the foreseeable future as applications of immune checkpoint inhibition both in different stages and different tumor types inexorably continue to grow.
Context.— The interaction between programmed death ligand-1 (PD-L1) and programmed death receptor-1 (PD-1) on activated T cells sends an inhibitory signal that dampens the immune response. Tumors can express PD-L1 and evade the immune system. In advanced non–small cell lung carcinoma, expression of PD-1 in tumor-infiltrating lymphocytes (TILs) correlates with PD-L1 expression in tumor cells (TCs). However, this relationship has not been thoroughly explored in early disease. Objective.— To investigate the correlation of PD-1 and PD-L1 in non–small cell lung carcinoma tumor samples, with emphasis on stage I disease. Design.— Whole tissue sections from non–small cell lung carcinoma tumors were retrospectively evaluated by immunohistochemistry for PD-1 and PD-L1 expression. The scoring was based on the percentage of cells positive for PD-1 in TILs and PD-L1 in TCs and tumor-infiltrating immune cells (ICs). Results.— Expression of PD-1 in TILs was observed in 147 of 161 non–small cell lung carcinoma cases (91%). The majority of cases negative for PD-1 also lacked PD-L1 in TCs. The 68 cases with highest PD-1 expression in TILs included 33 (49%) with expression of PD-L1 in TCs and ICs. Strong correlations were observed in patients with elevated PD-1 expression in TILs and PD-L1 in TCs (P = .01) and ICs (P = .003). Expression of PD-1 also correlated with increased PD-L1 in TCs and ICs when the 2 were grouped together (P < .001). Finally, stage I patients with negative PD-1 and PD-L1 expression showed trends toward increased disease-specific survival. Conclusions.— Expression of PD-1 in TILs correlates with PD-L1 expression in both TCs and ICs. Furthermore, negative expression of PD-1 and PD-L1 suggest trends toward disease-specific survival, even in early disease stages.
Glycogenic hepatopathy (GH) remains underrecognized in adults as most clinicians mistake it for the more common hepatic abnormality associated with uncontrolled diabetes mellitus in this age group, non-alcoholic fatty liver disease. This is also complicated by the fact that both entities are indistinguishable on liver ultrasound. We herein describe a similar predicament in which a young adult female presented with bilateral upper quadrant abdominal pain, tender hepatomegaly, lactic acidosis and a >10-fold increase in liver enzymes, which worsened after the administration of high-dose steroids. Despite intravenous normal saline resuscitation, serum transaminitis persisted in a fluctuating manner. Ultimately, a liver biopsy confirmed GH. Biochemically, GH is driven by high amounts of both circulating glucose and insulin or by the administration of high-dose steroids. Improving glycemic control is the mainstay of treatment for GH. However, in our case, improvement in glycated hemoglobin of just 0.6% was enough to achieve symptomatic relief, supporting recent claims of the involvement of other identified factors in disease development.
