Tazelaar, Henry D.

Abstract Purpose: Many studies have highlighted the aberrant expression and prognostic significance of individual proteins in either the Rb (particularly cyclin D1, p16INK4A, and pRb) or the p53 (p53 and p21Waf1) pathways in non–small cell lung cancer. We hypothesize that cumulative abnormalities within each and between these pathways would have significant prognostic potential regarding survival. Experimental Design: Our study population consisted of 106 consecutive surgically resected cases of predominantly early-stage non–small cell lung cancer from the National Cancer Institute-Mayo Clinic series, and assessment of proteins involved both immunohistochemical (cyclin D1, p21Waf1, pRb, p16INK4A, and p53) and mutational analysis (p53) in relationship to staging and survival. Results: Cyclin D1 overexpression was noted in 48% of the tumors, p16INK4A negative in 53%, pRb negative in 17%, p53 immunopositive in 50%, p53 mutation frequency in 48%, and p21Waf1 overexpression in 47%, none with prognostic significance. Cyclin D1 overexpression in pRb-negative tumors revealed a significantly worse prognosis with a mean survival of 2.3 years (P = 0.004). A simultaneous p53 mutation dramatically reduced the mean survival time to 0.9 years (P = 0.007). Cyclin D1 overexpression with either a p53 mutation or a p53 overexpression was also associated with a significantly poorer prognosis (P = 0.0033 and 0.0063, respectively). Conclusions: Some cumulative abnormalities in the Rb and p53 pathways (e.g., cyclin D1 overexpression and p53 mutations) significantly cooperate to predict a poor prognosis; however, the complexity of the cell cycle protein interaction in any given tumor warrants caution in interpreting survival results when specific protein abnormalities are taken in isolation.

Context.— Studies of lungs in patients with COVID-19 have focused on early findings. Objective.— To systematically study histopathologic and imaging features and presence of SARS-CoV-2 RNA in lung tissue from patients in later stages of COVID-19. Design.— Autopsies, explants, surgical lung biopsies, transbronchial biopsies, cryobiopsies, and needle biopsies from patients with COVID-19 whose onset of symptoms/confirmed diagnosis was more than 28 days before the procedure were studied. Available images were reviewed. Reverse transcription droplet digital polymerase chain reaction for SARS-CoV-2 RNA was performed on lung tissue. Results.— Of 44 specimens (43 patients; median age, 59.3 years; 26 [60.5%] male) features of acute lung injury (ALI) were seen in 39 (88.6%), predominantly organizing pneumonia and diffuse alveolar damage, up to 298 days after onset of COVID-19. Fibrotic changes were found in 33 specimens (75%), most commonly fibrotic diffuse alveolar damage (n = 22) and cicatricial organizing pneumonia (n = 12). Time between acquiring COVID-19 and specimen was shorter in patients with diffuse ALI (median, 61.5 days) compared with patients with focal (140 days) or no ALI (130 days) (P = .009). Sixteen (of 20; 80%) SARS-CoV-2 reverse transcription droplet digital polymerase chain reaction tests were positive, up to 174 days after COVID-19 onset. Time between COVID-19 onset and most recent computed tomography in patients with consolidation on imaging was shorter (median, 43.0 days) versus in patients without consolidation (87.5 days; P = .02). Reticulations were associated with longer time to computed tomography after COVID-19 onset (median, 82 versus 23.5 days; P = .006). Conclusions.— ALI and SARS-CoV-2 RNA can be detected in patients with COVID-19 for many months. ALI may evolve into fibrotic interstitial lung disease.

AbstractIntroductionPatients with small‐cell lung cancer (SCLC) have a very poor prognosis. However, a subset of SCLC achieves long‐term survival. The objective of this study was to investigate factors and pattern of long‐term survival in patients with limited‐stage small cell lung cancer (LS‐SCLC) who achieved a complete response (CR) after chemoradiotherapy.Patient and MethodsThis was a single‐center retrospective study. The analysis of hazard ratio (HR) and 95% confidence interval (CI) was performed using Cox proportional hazards model. For pattern analysis, the date of recurrence was used as the endpoint. The nominal categorical variables were analyzed by the χ2 test. Survival was estimated using the Kaplan–Meier model, and the results were reported as the median and interquartile range.ResultsWe identified 162 patients, median age was 64.7 (56.2–70.2) years, and 94 (58%) were females. Eighty‐one patients (50%) had recurrence during follow‐up. Gastroesophageal reflux disease (GERD) (HR, 0.65; 95% CI, 0.45–0.93; p = 0.016) and neurological paraneoplastic syndrome (PNS) (HR, 0.46; 95% CI, 0.29–0.72; p < 0.001) were independent factors associated with improved overall survival (OS). Patients with GERD had prolonged recurrence free survival (RFS) compared to patients without GERD (median, 29.1 months vs. 13.9 months, p < 0.001), whereas patients with neurological PNS had a reduced recurrence rate compared to those patients without neurological PNS (No. [%], 8 [20.5] vs. 73 [59.3], p < 0.001).ConclusionsPatients with LS‐SCLC achieving a CR after chemoradiotherapy, GERD, and neurological PNS were associated with improved OS. GERD and neurological PNS were associated with longer RFS and lower recurrence rate, respectively.

Abstract Objectives Numerous studies on malignant mesothelioma (MM) highlight the prognostic importance of histologic subtype, nuclear grade, and necrosis. This study compares these parameters in paired biopsy and resection specimens of pleural MM. Methods Histologic subtype, percentage of epithelioid morphology, nuclear grade, and the presence or absence of necrosis were compared in 429 paired biopsies and resection specimens of pleural MM from 19 institutions. Results Histologic subtype was concordant in 81% of cases (κ = 0.58). When compared with resection specimens, epithelioid morphology at biopsy had a positive predictive value (PPV) of 78.9% and a negative predictive value (NPV) of 93.5%; sarcomatoid morphology showed high PPV (92.9%) and NPV (99.3%), and biphasic morphology PPV was 89.7% and NPV was 79.7%. Agreement of the percentage of epithelioid morphology was fair (κ = 0.27). Nuclear grade and necrosis were concordant in 75% (κ = 0.59) and 81% (κ = 0.53) of cases, respectively. Nuclear grade showed moderate (κ = 0.53) and substantial (κ = 0.67) agreement from patients with and without neoadjuvant therapy, respectively, and necrosis showed moderate (κ = 0.47 and κ = 0.60) agreement, respectively, in the same subsets of paired specimens. Conclusions Paired biopsy-resection specimens from pleural MM show overall moderate agreement in pathologic parameters. These findings may help guide postbiopsy management and triage of patients with MM.

Abstract Context. —Primary cardiac tumors are rare and the great majority are benign neoplasms. Mass-forming reactive and pseudoneoplastic growths are less common, but recognizing and distinguishing these lesions from the neoplasms they resemble is critical to appropriate patient care. Objective. —The general clinical, imaging, gross pathologic, and histologic features of 5 important pseudoneoplasms (inflammatory myofibroblastic tumor, hamartoma of mature cardiac myocytes, mesothelial/monocytic cardiac excrescences, calcified amorphous tumor, and lipomatous hypertrophy of the atrial septum) are discussed, with an emphasis on features differentiating them from other benign and malignant tumors. Data Sources. —Pertinent citations of the literature and observations from the authors' experience are drawn upon. Conclusions. —While lacking malignant potential, these lesions can be associated with considerable morbidity and occasional mortality. Their recognition is important in guiding patient management, providing both guidance for appropriate therapy and avoidance of inappropriately aggressive and toxic treatments.

Abstract Context. —Management of laboratories and pathology practices is increasingly complex. Residents and fellows in laboratory medicine and pathology need more structured curricula in leadership and management (L&M) training to function as medical and laboratory directors. Objective. —To define a curriculum that provides basic competency in L&M for residents and fellows in pathology. Design. —A year-long formal L&M course included didactic lectures, interactive sessions, case scenarios, team-building exercises, formal team presentations (capstone project), and precourse and postcourse assessment of L&M knowledge. The curriculum meets requirements of American College of Graduate Medical Education and supports goals for leadership training of the College of American Pathologists. Participants evaluated (5-point scale) the content and speakers of all sessions. Trainees were evaluated after considering postcourse examination results, quality of the capstone presentation, and a global assessment. Results. —The 5 non-capstone sessions received evaluation scores ranging from 4.4 (informatics) to 5 (L&M basics). Postcourse test scores showed significant improvement when compared with the pretest scores for the 2003– 2004 and 2004–2005 trainee cohorts. Conclusions. —Short-term results indicate that the course described improves trainee knowledge of L&M issues.

Abstract Context.—Sclerosing hemangioma is an unusual pulmonary tumor. Previously, 4 patients with pulmonary sclerosing hemangioma and lymph node metastases have been described in the literature. Objective.—To report 4 additional cases of metastatic sclerosing hemangioma. Design.—Retrospective review of the authors' consultation files and review of histologic sections of pulmonary tumors and lymph node metastases. Results.—Four cases of a morphologically benign pulmonary sclerosing hemangioma with regional lymph node metastases (including hilar, peribronchial, and interlobar metastases) were identified. The patients (3 female, 1 male) had a mean age of 39 years (range, 10–56 years). The tumors ranged in size (greatest dimension) from 1.5 to 4.7 cm (mean, 3.1 cm). The pulmonary tumors were typical circumscribed sclerosing hemangiomas without mitotic activity, angiolymphatic invasion, or necrosis. One tumor had focal cytologic atypia. The metastases were identified in hilar lymph nodes that were removed at operation for the lung nodule. One patient received adjuvant chemotherapy for adenocarcinoma. All of the patients are alive. No recurrences or residual disease has been detected at a mean follow-up of 4.7 years (range, 2.3–10 years). Conclusions.—On the basis of case data from the 4 patients described here and the 4 patients described previously, metastases to regional lymph nodes from pulmonary sclerosing hemangioma may occur but are rare and do not appear to affect prognosis.

Abstract Context. —Diffuse pulmonary hemorrhage is an uncommon presenting manifestation of angiosarcoma. Objective. —To review the clinical, radiologic, and pathologic findings of patients with metastatic angiosarcoma who presented with diffuse pulmonary hemorrhage. Design. —Patients fulfilling inclusion criteria were identified from the consultation files. Clinical and radiologic data were obtained from referring pathologists. Histologic slides were reviewed in all patients. Results. —Our patients included 6 men and 1 woman, aged 31 to 73 years; 4 patients were younger than 40 years. Six patients presented with hemoptysis, and all had diffuse abnormalities on radiographic studies. Clinical considerations prior to biopsy included pulmonary hemorrhage syndrome (n = 2), acute respiratory failure (n = 1), and infection (n = 1). Metastatic disease was included in the differential diagnosis in only 1 patient. None had a diagnosis of malignancy prior to lung biopsy. All biopsies showed hemorrhage associated with atypical epithelioid and spindle cells, forming anastomosing vascular channels, distributed along and within lymphatics and arteries. Neoplastic cells were immunoreactive for factor VIII–related protein or CD31 in all cases for which special stains were available. Three patients with complete follow-up died of their disease. Primary sites were discovered in all 3 patients who underwent autopsy examination. Two tumors arose in the heart and 1 in the pelvic soft tissues. One additional patient had a likely primary site identified in the right atrium by cardiac ultrasound and was subsequently lost to follow-up. Conclusion. —Angiosarcoma should be included in the differential diagnosis of diffuse pulmonary hemorrhage, especially in young adults.

Abstract We describe a patient with self-induced inhalational pulmonary talcosis originally diagnosed as asthma. A 35-year-old female respiratory technologist developed severe asthma that was refractory to steroids and methotrexate. An open lung biopsy specimen showed scattered aggregates of refractile golden crystals within membranous and respiratory bronchioles. The particles ranged in size from 30 to 100 μm and were birefringent when viewed with polarized light. Following review of the lung biopsy specimen, the patient admitted to regularly inhaling large amounts of hospital baby powder. Analysis of the lung biopsy specimen and a sample of the hospital baby powder by x-ray energy dispersion showed identical spectroscopic peaks, including elemental peaks for magnesium silicate. Many patients with self-induced illness lack the picturesque symptomatology classically attributed to Munchausen syndrome. Awareness of these more subtle and varied patterns of presentation may aid in earlier recognition.

Context.— Idiopathic pulmonary fibrosis is a clinical syndrome characterized by the presence of usual interstitial pneumonia (UIP) radiologically and pathologically. Per consensus criteria adopted in 2011, diagnosis of idiopathic pulmonary fibrosis no longer requires a biopsy in an appropriate context if UIP is seen on imaging. As a result, lung biopsies are now typically reserved for patients having indeterminate clinical or imaging findings or suspicion for alternative diagnoses, but the impact of updated guidelines on pathology practice remains unclear. Objective.— To determine the frequency of histologic UIP before and after 2011. Design.— Surgical lung biopsies from adults were studied within two 4-year periods: July 1, 2006 through June 30, 2010 and January 1, 2012 through December 31, 2015. Pathology slides were reviewed in a fashion blinded to clinical information and were classified using current guidelines. Results.— Biopsies from 177 and 86 patients (mean [SD] age, 62 [12] and 59 [14] years; 50.3% [89 of 177] and 48.8% [42 of 86] men) before and after 2011, respectively, were reviewed. Probable UIP or UIP was less-frequently encountered after 2011 in all patients with fibrosis (9 of 54 [16.7%] versus 41 of 119 [34.5%] before 2011, P = .02) and also in patients 50 years old and older (8 of 46 [17.4%] versus 39 of 109 [35.8%] before 2011, P = .02), with a concomitant rise in cases indeterminate for UIP or showing alternative diagnoses. Conclusions.— Histology for UIP is less frequently encountered in our contemporary practice compared with the historic era. The pretest probability of a non-UIP diagnosis is now high, even in elderly patients, underscoring the need for pathologists to be familiar with the histologic features of alternative diagnoses.