Pathologic features of response to neoadjuvant anti-PD-1 in resected non-small-cell lung carcinoma: a proposal for quantitative immune-related pathologic response criteria (irPRC).

Background: Neoadjuvant anti-PD-1 may improve outcomes for patients with resectable NSCLC and provides a critical window for examining pathologic features associated with response. Resections showing major pathologic response to neoadjuvant therapy, defined as ≤10% residual viable tumor (RVT), may predict improved long-term patient outcome. However, %RVT calculations were developed in the context of chemotherapy (%cRVT). An immune-related %RVT (%irRVT) has yet to be developed. Patients and methods: The first trial of neoadjuvant anti-PD-1 (nivolumab, NCT02259621) was just reported. We analyzed hematoxylin and eosin-stained slides from the post-treatment resection specimens of the 20 patients with non-small-cell lung carcinoma who underwent definitive surgery. Pretreatment tumor biopsies and preresection radiographic 'tumor' measurements were also assessed. Results: We found that the regression bed (the area of immune-mediated tumor clearance) accounts for the previously noted discrepancy between CT imaging and pathologic assessment of residual tumor. The regression bed is characterized by (i) immune activation-dense tumor infiltrating lymphocytes with macrophages and tertiary lymphoid structures; (ii) massive tumor cell death-cholesterol clefts; and (iii) tissue repair-neovascularization and proliferative fibrosis (each feature enriched in major pathologic responders versus nonresponders, P < 0.05). This distinct constellation of histologic findings was not identified in any pretreatment specimens. Histopathologic features of the regression bed were used to develop 'Immune-Related Pathologic Response Criteria' (irPRC), and these criteria were shown to be reproducible amongst pathologists. Specifically, %irRVT had improved interobserver consistency compared with %cRVT [median per-case %RVT variability 5% (0%-29%) versus 10% (0%-58%), P = 0.007] and a twofold decrease in median standard deviation across pathologists within a sample (4.6 versus 2.2, P = 0.002). Conclusions: irPRC may be used to standardize pathologic assessment of immunotherapeutic efficacy. Long-term follow-up is needed to determine irPRC reliability as a surrogate for recurrence-free and overall survival.

Radiologic findings in a patient with frontal parafalcine dendritic cell histiocytoma.

We report the case history and radiologic findings of a patient with a biopsy-proven dendritic cell histiocytoma presenting as a single intracranial extra-axial mass and no systemic disease. Even though this entity is relatively rare, it should nevertheless be considered in the differential diagnosis of dural-based space-occupying central nervous system lesions.

Effects of mixed hematopoietic chimerism in a mouse model of bone marrow transplantation for sickle cell anemia.

Sickle cell anemia (SCA) is an inherited disorder of beta-globin, resulting in red blood cell rigidity, anemia, painful crises, organ infarctions, and reduced life expectancy. Allogeneic blood or marrow transplantation (BMT) can cure SCA but is associated with an 8% to 10% mortality rate, primarily from complications of marrow-ablative conditioning. Transplantation of allogeneic marrow after less intensive conditioning reduces toxicity but may result in stable mixed hematopoietic chimerism. The few SCA patients who inadvertently developed mixed chimerism after BMT remain symptom free, suggesting that mixed chimerism can reduce disease-related morbidity. However, because the effects of various levels of mixed chimerism on organ pathology have not been characterized, this study examined the histologic effects of an increasing percentage of normal donor hematopoiesis in a mouse model of BMT for SCA. In lethally irradiated normal mice that were reconstituted with varying ratios of T-cell-depleted marrow from normal and transgenic "sickle cell" mice, normal myeloid chimerism in excess of 25% was associated with more than 90% normal hemoglobin (Hb). However, 70% normal myeloid chimerism was required to reverse the anemia. Organ pathology, including liver infarction, was present in mice with sickle Hb (HbS) levels as low as 16.8% (19.6% normal myeloid chimerism). Histologic abnormalities increased in severity up to 80% HbS, but were less severe in mice with more than 80% HbS than in those with 40% to 80% HbS. Therefore, stable mixed chimerism resulting from nonmyeloablative BMT may reduce the morbidity from SCA, but prevention of all disease complications may require minimizing the fraction of circulating sickle red cells. (Blood. 2001;97:3960-3965)

Nonpalpable breast cancer: percutaneous diagnosis with 11- and 8-gauge stereotactic vacuum-assisted biopsy devices.

PURPOSE: To compare the accuracy of diagnosis of invasive breast cancer with 11- and 8-gauge stereotactic vacuum-assisted biopsy (SVAB) devices and to correlate lesion diameter and accuracy of breast cancer diagnosis at SVAB. MATERIALS AND METHODS: During a 22-month period, 489 SVAB procedures were performed with an 11-gauge probe and 305 with an 8-gauge probe. SVAB and surgical pathologic results of 104 breast carcinomas were reviewed and correlated with lesion size, number of specimens obtained, and type of SVAB probe used. RESULTS: Four of 38 ductal carcinoma in situ (DCIS) lesions diagnosed with 11-gauge SVAB demonstrated invasion at surgery, whereas one of 23 DCIS lesions diagnosed with 8-gauge SVAB demonstrated invasion at surgery (P =.6). A mean of 12 specimens per lesion were obtained in each group. In lesions 30 mm or larger, the underestimation rate for DCIS was 43% (three of seven) with 11-gauge SVAB and 17% (one of six) with 8-gauge SVAB (P =.6). Overall, the rate of underestimation for DCIS was significantly higher in lesions 30 mm or larger (four of 13) than in smaller lesions (one of 48, P =.006). CONCLUSION: This study demonstrated no difference in breast cancer diagnosis with the 8- and 11-gauge SVAB systems, but the accuracy of breast cancer diagnosis was greater in lesions smaller than 30 mm than in larger lesions.

Solitary pulmonary lymphangioma.

Lymphangioma is an abnormal collection of lymphatics that are developmentally isolated from the normal lymphatic system. Lymphangioma rarely presents as a solitary pulmonary lesion. We present a case of solitary pulmonary lymphangioma and review the literature on its pathogenesis, clinical features, and radiographic findings.

Pulmonary artery aneurysm in a pregnant woman.

We present a patient with a pulmonary artery (PA) aneurysm who has none of the documented causes of PA aneurysm but who is pregnant. We believe that this patient represents a case of primary pregnancy-associated PA aneurysm.

Pulmonary and mediastinal glomus tumors--report of five cases including a pulmonary glomangiosarcoma: a clinicopathologic study with literature review.

Pulmonary and mediastinal glomus tumors are rare lesions, with four previously reported primary pulmonary cases and three mediastinal cases. The authors report one mediastinal glomus tumor, a locally infiltrative type, and four pulmonary glomus tumors, including the first case of primary pulmonary glomangiosarcoma. These tumors show a variety of clinical and pathologic differences from the more common cutaneous variety, including later age at presentation, larger size, and more frequent atypical/malignant features. Mediastinal and pulmonary glomus tumors both have an average patient age at presentation of 45 years. However, compared with their pulmonary counterparts, mediastinal glomus tumors are less common, more often symptomatic, and are larger (average size, 5.4 cm). Additionally, mediastinal glomus tumors more often demonstrate malignant or atypical features. Pulmonary glomus tumors average 3.3 cm in greatest dimension, with the majority measuring less than 2.5 cm. The pulmonary glomangiosarcoma presented was large, measuring 9.5 cm, and showed increased mitotic count (9 mitoses/10 high-power fields), necrosis, cytologic atypia, and was associated with disseminated disease. Regardless of clinical symptoms, histologic features, and even metastases, the vast majority of all benign and malignant glomus tumors are indolent and cured surgically, with adjuvant therapy needed only for occasional patients with more advanced disease. The four patients with glomus tumors reported are currently alive and free of disease as of last follow up. The patient with the glomangiosarcoma developed widespread metastases and died of disease 68 weeks after initial therapy.

HMB-45 immunohistochemical staining of sentinel lymph nodes: a specific method for enhancing detection of micrometastases in patients with melanoma.

Despite the profound therapeutic and prognostic implications of nodal metastases in patients with melanoma, there is no consensus strategy for the optimal detection of metastases in sentinel lymph node biopsies. Traditional microscopic examination may be too crude to detect scattered, individual tumor cells. Conversely, molecular genetic techniques are prone to false-positive results. The authors evaluated the ability of HMB-45 immunohistochemistry to enhance detection of melanoma cells in histologically negative sentinel lymph nodes. Ninety-six sentinel lymph nodes, collected over a 25-month period from 66 consecutive patients with melanoma, were processed routinely and sectioned serially. Slides 1, 3, and 5 were stained with hematoxylin and eosin. HMB-45 staining was performed on an intervening slide in histologically negative nodes. To assess the background incidence of HMB-45-positive cells in lymph nodes draining the skin, the authors stained 244 cervical and axillary lymph nodes from patients without melanoma. Metastases were apparent microscopically in 12 (18%) of the 66 patients with melanoma. Of the remaining 54 patients, four patients (7%) had lymph nodes harboring individual, scattered HMB-45-positive cells. Benign nevocellular aggregates were present in four of the 96 sentinel lymph nodes (4% nodal incidence), but they were HMB-45-negative. The authors did not observe a single HMB-45-positive cell in the 244 lymph nodes from patients without melanoma. Immunohistochemistry appears to represent a specific means of enhancing tumor detection in sentinel lymph nodes from patients with melanoma.

Occult pulmonary synovial sarcoma confirmed by molecular techniques.

We report a unique case of a minute, occult synovial sarcoma of the lung detected intraoperatively during a pneumothorax repair in a 17-year-old boy. No alternative primary site could be detected upon complete body imaging studies and physical examinations. The diagnosis was confirmed by demonstration of the characteristic SYT/SSX gene fusion by reverse transcriptase polymerase chain reaction (RT-PCR) performed upon RNA extracted from the paraffin block of the biopsy. This case demonstrates the utility of this technique in diagnostic pathology.

Repeated delivery of adeno-associated virus vectors to the rabbit airway.

Efficient local expression from recombinant adeno-associated virus (rAAV)-cystic fibrosis (CF) transmembrane conductance regulator (CFTR) vectors has been observed in the airways of rabbits and monkeys for up to 6 months following a single bronchoscopic delivery. However, it is likely that repeated administrations of rAAV vectors will be necessary for sustained correction of the CF defect in the airways. The current study was designed to test the feasibility of repeated airway delivery of rAAV vectors in the rabbit lung. After two doses of rAAV-CFTR to the airways, rabbits generated high titers of serum anti-AAV neutralizing antibodies. Rabbits then received a third dose of a rAAV vector containing the green fluorescent protein (GFP) reporter gene packaged in either AAV serotype 2 (AAV2) or serotype 3 (AAV3) capsids. Each dose consisted of 1 ml containing 5 x 10(9) DNase-resistant particles of rAAV vector, having no detectable replication-competent AAV or adenovirus. Three weeks later, GFP expression was observed in airway epithelial cells despite high anti-AAV neutralizing titers at the time of delivery. There was no significant difference in the efficiency of DNA transfer or expression between the rAAV3 and rAAV2 groups. No significant inflammatory responses to either repeated airway exposure to rAAV2-CFTR vectors or to GFP expression were observed. These experiments demonstrate that serum anti-AAV neutralizing antibody titers do not predict airway neutralization in vivo and that repeated airway delivery rAAV allows for safe and effective gene transfer.

Elemental analysis and clinical implications of calcification deposits associated with silicone breast implants.

Calcification of the fibrous capsule surrounding silicone breast implants is a well-recognized occurrence that increases with time following implantation. These mineralized deposits potentially confound mammographic breast cancer surveillance already made difficult by the obscuring effects of silicone breast implants. The authors performed elemental analysis of silicone breast implant-associated calcifications to define better their chemical composition as related to mammographic and clinical significance. Electron probe microanalysis and infrared spectroscopy revealed all of the calcification deposits to be calcium complexed with tribasic phosphate. No evidence of calcium oxalate, calcium carbonate, silicone, or talc was observed. Caution must be employed in interpreting mammograms in women with silicone breast implants as well as those who have had their silicone breast implants removed. High-density mammographic calcifications indicative of calcium phosphate associated with a silicone breast implant may represent an accepted consequence of implantation or nearby carcinoma. We recommend baseline mammography on women who have had their silicone breast implants removed to prevent unnecessary fine-needle aspiration or tissue biopsy of retained breast capsule calcifications during subsequent routine surveillance for carcinoma.

CT evaluation of mediastinal masses in children: spectrum of disease with pathologic correlation.

The mediastinum is the site of a variety of benign and malignant pathological processes in children. While the chest radiograph may be the initial imaging study to suggest an abnormality, spiral or helical CT provides detailed depiction of anatomic relationships and characteristics of the mass, and may increase the likelihood of a successful examination because of shorter scan times. This article will emphasize the important CT features in the evaluation of common and uncommon mediastinal masses in children. Pathologic correlation is presented for greater understanding. In many clinical settings, CT features such as attenuation, enhancement, calcification, anatomic relationships and extent of disease may suggest a specific diagnosis for a mediastinal mass in a child.

Pulmonary clear cell carcinoid tumor: another entity in the differential diagnosis of pulmonary clear cell neoplasia.

A clear cell variant of primary pulmonary carcinoid tumor is described. The tumor arose in a 53-year-old woman who was incidentally found to have a solitary pulmonary nodule in the left upper lobe during routine chest roentgenography. Histologically, the tumor was composed of predominantly clear to lightly eosinophilic, polygonal cells with bland nuclei arranged in sheets and nests. Nuclear pleomorphism, necrosis, vascular invasion, and mitotic figures were not seen. The tumor cells were negative for oil-red-O and periodic acid-Schiff stains with and without diastase pretreatment on frozen and formalin-fixed sections, respectively. During immunohistochemical evaluation, the tumor cells were focally positive for cytokeratin and diffusely positive for neuron-specific enolase and chromogranin. Electron microscopy performed on paraffin block-retrieved tissue showed the presence of electron-dense, neurosecretory-type granules and variably sized vacuolated areas within the cytoplasm. the nature of which remained unclear. Intracytoplasmic glycogen or lipid were not identified. To our knowledge, this is the first report of pulmonary clear cell carcinoid tumor.

p53 alterations in atypical alveolar hyperplasia of the human lung.

Atypical alveolar hyperplasia (AAH) is a potential precursor lesion from which lung adenocarcinomas arise and may be a good target for studying the early events of lung tumorigenesis. We have previously shown that AAHs are neoplastic epithelial proliferations that often harbor activating mutations of the K-ras oncogene. In the current study, we examined a spectrum of AAHs to determine the frequency and timing of p53 alterations in lung tumorigenesis. We analyzed 37 AAHs and their paired overt lung neoplasms for p53 protein accumulation using the monoclonal antibody DO7. DNA sequence analysis of the p53 gene was performed on those cases demonstrating p53 protein accumulation. AAHs were classified as low-grade, high-grade, or AAH-like carcinoma based on cytoarchitectural features. Accumulation of the p53 protein was found in none (0%) of 20 low-grade AAHs, in 1 (9%) of 11 high-grade AAHs, and in three (50%) of six AAH-like carcinomas. There was a statistically significant trend toward p53 accumulation with increasing grade of the AAHs. A missense mutation in exon 7 of the p53 gene was found in 1 AAH-like carcinoma, whereas mutations in exons 5 through 8 could not be detected in the other three AAHs with p53 protein accumulation. Three of the paired overt carcinomas harbored p53 mutations that were not present in the AAHs. Alterations of p53 do not appear to be common events in AAHs, especially when these lesions exhibit low-grade cytoarchitectural features. Alterations of p53, however, are more frequent at the level of AAH-like carcinoma and may be associated with the transition from a benign to a malignant proliferation of pneumocytes.

Neuroblastoma and peripheral neuroectodermal tumors.

Peripheral neuroblastic tumors in childhood present unique problems in terms of diagnosis, classification, and histologic determinants of prognosis. The proper specimen handling of these neoplasms requires integration of gross and microscopic pathologic examination along with cytogenetic, immunohistochemical, and electron microscopy studies. The appropriate gross examination and processing of these tumors are described with particular emphasis on ancillary studies. Important special studies such as immunohistochemistry, flow cytometry, and genetic and molecular oncologic investigation are stressed, and the appropriate methods of processing materials for these studies are discussed. The handling of small biopsy specimens, fine-needle aspirates, or both is also addressed. The staging of neuroblastoma varies according to Pediatric Oncology Group and Children's Cancer Study Group systems, and the importance of obtaining appropriate information to satisfy either system is noted. Ancillary information for classification of neuroblastoma and related neoplasms is also presented.