Pulmonary Actinomycosis in a 65-Year-Old Female with Poor Oral Dentition.

Pulmonary actinomycosis is an uncommon clinical entity that can be challenging to diagnose due to its non-specific symptomatology. Misdiagnosis and delayed treatment may result in invasive procedures and extended antimicrobial treatment courses. We report a case involving a 65-year-old female with poor oral dentition admitted for acute respiratory failure subsequently found to have a left-sided pleural effusion and perihepatic abscess formation. Cytopathology examination and microbiology studies confirmed the diagnosis of pulmonary actinomycosis.

The diagnosis of asbestosis in the 21st century: a clinicopathological correlation of 102 cases.

Asbestosis, defined as diffuse pulmonary fibrosis caused by inhalation of asbestos fibers, occurs after heavy exposures to asbestos dust over several decades. Because workplace exposures have been significantly curtailed since the banning of asbestos in insulation products, we were interested in examining the clinicopathological characteristics of cases diagnosed in the 21st century. The consultation files of one of the authors (VLR) were reviewed for cases of asbestosis diagnosed since 1/1/2001. 102 cases were identified, with a median age of 75 years (range: 45-89). There were 100 men and 2 women. The women were from Turkey and Brazil (none from the United States). Malignancies were present in 78 cases, including 38 lung cancers, 29 pleural mesotheliomas, and 8 peritoneal mesotheliomas. The grade of asbestosis was available in 88 cases (median severity of 2; scale: 1-4). Pleural plaque was present in 94% of cases. The most common exposure categories were insulators (39), shipyard workers (16), asbestos manufacturing (9), boiler workers (8) and pipefitter/welders (6). The median duration of exposure was 33 years (range: 2-49 years). Lung fiber burden analysis was performed in 34 cases, with amosite being the predominant fiber type. Results were compared with similar information for 475 cases diagnosed prior to 1/1/2001.

Diagnostic approach to prevascular (anterior) mediastinal lymphomas: when thoracic pathology meets hematopathology.

Lymphomas are among the most common malignant tumors occurring in the anterior/prevascular mediastinum. Their diagnoses can be challenging in small biopsies, the current most common method of sampling of an anterior mediastinal mass. Because the initial clinical and/or imaging impression may not be that of lymphoma, these specimens may first be evaluated by cytopathologists, surgical pathologists, and thoracic pathologists rather than hematopathologists. Therefore, it is crucial for this group of pathologists to have a practical diagnostic approach to these neoplasms, know their common diagnostic pitfalls, and their main differential diagnoses. This is important because the diagnosis of lymphoma carries significant therapeutic implications (chemotherapy and/or radiotherapy and not surgical resection). Similarly, securing and properly triaging a sample at the time of tissue collection will translate into direct patient benefit since a subset of lymphomas (T-lymphoblastic lymphoma) may present exclusively as an anterior mediastinal mass and the tissue obtained from this site may be the only one available to evaluate prognostic markers and potential targetable molecular alterations. Once a proper initial diagnostic work-up has been performed, a case can be transferred to a hematopathologist for assistance with a refined diagnosis. In this review, we focus on the practical diagnostic approach to the most common prevascular/anterior mediastinal lymphomas with an emphasis on the findings in small biopsies and provide best practice tips for case triage.

Diagnostic Approach to Pulmonary B-Cell Lymphomas in Small Biopsies, with Practical Recommendations to Avoid Misinterpretation.

Pulmonary lymphomas are rare. With the current less invasive approaches used to obtain material for diagnosis, the diagnosis of pulmonary lymphoma is now frequently established in a small biopsy rather than in a resection. Therefore, the diagnosis has become more challenging and requires correlation with the clinico-radiologic presentation and with ancillary studies (immunohistochemistry, flow cytometry, cytogenetics, and/or molecular analysis). Due to the rarity of pulmonary lymphomas, clinical suspicion of a lymphomatous process is low at initial presentation, and material may be only submitted for histopathology. For this reason, herein, we provide recommendations to arrive at the correct diagnosis of the most common lung B-cell lymphomas (marginal zone lymphoma of mucosa-associated lymphoid tissue, diffuse large B-cell lymphoma, intravascular large B-cell lymphoma, lymphomatoid granulomatosis) in the setting of small biopsies, utilizing only immunohistochemistry. The differential diagnosis varies according to the lymphoma subtype and includes reactive conditions, solid tumors, and other hematolymphoid malignancies. Although morphology and immunohistochemistry may be sufficient to establish a diagnosis, in some cases, the best recommendation is to obtain additional tissue via a VATS biopsy/wedge resection with material submitted for flow cytometry, cytogenetics, and/or molecular studies to be able to properly classify a pulmonary lymphoid process.

Perioperative outcomes of pulmonary resection after neoadjuvant pembrolizumab in patients with non-small cell lung cancer.

OBJECTIVES: Pembrolizumab is a programmed death receptor-1 masking antibody approved for metastatic non-small cell lung cancer. This Phase 2 study (NCT02818920) of neoadjuvant pembrolizumab in non-small cell lung cancer had a primary end point of safety and secondary end points of efficacy and correlative science. METHODS: Patients with untreated clinical stage IB to IIIA non-small cell lung cancer were enrolled. Two cycles of pembrolizumab (200 mg) were administered before surgery. Standard adjuvant chemotherapy and radiation were encouraged but not required. Four cycles of adjuvant pembrolizumab were provided. RESULTS: Of 35 patients enrolled, 30 received neoadjuvant pembrolizumab and 25 underwent lung resection. Only 1 patient had a delay before surgery attributed to pembrolizumab; this was due to thyroiditis. All patients underwent anatomic resection and mediastinal lymph node dissection; the majority (18/25%, 72%) of patients underwent lobectomy. Of the 25 patients, 23 had an initial minimally invasive approach (92%); 5 of these were converted to thoracotomy (21.7%). R0 resection was achieved in 22 patients (88%), and major pathologic response was observed in 7 of 25 patients (28%). The most common postoperative adverse event was atrial fibrillation, affecting 6 of 25 patients (24%). Median chest tube duration and length of stay were 3 and 4 days, respectively. One patient required readmission to the hospital within 30 days. There was no mortality within 90 days of surgery. CONCLUSIONS: In this study, pembrolizumab was safe and well tolerated in the neoadjuvant setting, and its use was not associated with excess surgical morbidity or mortality. Minimally invasive approaches are feasible in this patient population, but may be more challenging than in cases without neoadjuvant immunotherapy. Pathologic response was higher than typically observed with standard neoadjuvant chemotherapy.

Multi-Institutional Prospective Validation of Prognostic mRNA Signatures in Early Stage Squamous Lung Cancer (Alliance).

INTRODUCTION: Surgical resection is curative for some patients with early lung squamous cell carcinoma. Staging and clinical factors do not adequately predict recurrence risk. We sought to validate the discriminative performance of proposed prognostic gene expression signatures at a level of rigor sufficient to support clinical use. METHODS: The two-stage validation used independent core laboratories, objective quality control standards, locked test parameters, and large multi-institutional specimen and data sets. The first stage validation confirmed a signature's ability to stratify patient survival. The second-stage validation determined which signature(s) optimally improved risk discrimination when added to baseline clinical predictors. Participants were prospectively enrolled in institutional (cohort I) or cooperative group (cohort II) biospecimen and data collection protocols. All cases underwent a central review of clinical, pathologic, and biospecimen parameters using objective criteria to determine final inclusion (cohort I: n = 249; cohort II: n = 234). Primary selection required that a signature significantly predict a 3-year survival after surgical resection in cohort I. Signatures meeting this criterion were further tested in cohort II, comparing risk prediction using baseline risk factors alone versus in combination with the signature. RESULTS: Male sex, advanced age, and higher stage were associated with shorter survival in cohort I and established a baseline clinical model. Of the three signatures validated in cohort I, one signature was validated in cohort II and statistically significantly enhanced the prognosis relative to the baseline model (C-index difference 0.122; p < 0.05). CONCLUSIONS: These results represent the first rigorous validation of a test appropriate to direct adjuvant treatment or clinical trials for patients with lung squamous cell carcinoma.

Talc and mesothelioma: mineral fiber analysis of 65 cases with clinicopathological correlation.

Malignant mesothelioma is strongly associated with prior asbestos exposure. Recently there has been interest in the role of talc exposure in the pathogenesis of mesothelioma. We have analyzed lung tissue samples from a large series of malignant mesothelioma patients. Asbestos bodies were counted by light microscopy and mineral fiber concentrations for fibers 5 µm or greater in length were determined by scanning electron microscopy equipped with an energy dispersive spectrometer. The values were compared with 20 previously published controls. Among 609 patients with mesothelioma, talc fibers were detected in 375 (62%) and exceeded our control values in 65 (11%). Elevated talc levels were found in 48/524 men (9.2%) and 17/85 women (20%). Parietal pleural plaques were identified in 30/51 informative cases (59%) and asbestosis in 5/62 informative cases (8%). Commercial amphiboles (amosite and/or crocidolite) were elevated in 52/65 (80%) and noncommercial amphiboles (tremolite, actinolite or anthophyllite) in 41/65 (63%). Both were elevated in 34/65 (52%). Asbestos body counts by light microscopy were elevated in 53/64 informative cases (83%). A history of working in industries associated with asbestos exposure and increased mesothelioma risk was identified in 36/48 cases in men, and a history of exposure as household contacts of an occupationally exposed individual was identified in 12/17 cases in women. We conclude that among patients with mesothelioma, the vast majority have talc levels indistinguishable from background. Of the remaining 11% with elevated talc levels, the vast majority (80%) have elevated levels of commercial amphibole fibers.

Malignant Diffuse Mesothelioma in Women: A Study of 354 Cases.

We reviewed 354 cases of malignant diffuse mesothelioma (MM) in women from a database of 2858 histologically confirmed MM cases. There was a pleural predominance with 78% pleural MM and 22% peritoneal MM. The pleural tumors consisted of 72% epithelioid, 19% biphasic, and 9% sarcomatoid variant. The peritoneal tumors consisted of 82% epithelioid, 13% biphasic, and 5% sarcomatoid. The immunohistochemical profile was typical of what is well-accepted and previously described for MM. When examining tumor subtype and location, there was a trend toward epithelioid subtype and peritoneal location; however, this did not reach statistical significance. Age at the time of diagnosis ranged from 19 to 93 years with a mean of 60 years. The median age at time of diagnosis for pleural MM was 65 years and for peritoneal MM was 52 years. A further look at age and histologic subtype showed no statistically significant difference in age between MM subtypes. Survival was greatest for epithelioid variant, and this was magnified in the peritoneum. A majority of our cases were exposed to asbestos through a household contact. Asbestosis and parietal pleural plaque were present in 5% and 50% of cases with data, respectively. Fiber analysis data was available in 67 cases; 38 cases had elevated asbestos fiber burden, and tremolite was the most common asbestos fiber type detected. Commercial and noncommercial amphibole asbestos fibers were elevated in nearly equal numbers of cases.

Mesothelioma of the tunica vaginalis testis.

Malignant mesothelioma (MM) arising from the serosal membranes of the tunica vaginalis testis (TVT) is rare. Most examples in the published medical literature are individual case reports. This study presents the clinicopathological findings of mesothelioma of the TVT in one of the largest series to date. Individuals with mesothelioma of the TVT were identified from a database of more than 4000 mesothelioma cases, and their clinicopathological features were recorded. Eighteen men with MM and 2 with well-differentiated papillary mesothelioma of the TVT were identified, which represented 0.6% of males with mesothelioma in study population. The median age at diagnosis was 72 years (range, 32-85 years). A neoplasm was not suspected preoperatively in 12 of the 17 (71%) men whose clinical presentation was known, 7 of whom presented with hydrocele and 5 with inguinal hernia. The other 5 had a clinically recognized mass. Seven of the men underwent herniorrhaphy; 7, radical orchiectomy; 3, hydrocelectomy; and 3, paratesticular mass biopsy or excision as the initial diagnostic procedure. Twelve of the MM cases were epithelioid and 6 were biphasic. Among the 6 men with MM who had ≥6 months of follow-up, 1 was alive with no evidence of disease at 6 months, and 5 were known to have died of disease 8-74 months (median = 31.5 months) following diagnosis. Three men with MM had received either chemotherapy or radiation therapy. Of the 2 men initially diagnosed with well-differentiated papillary mesothelioma, 1 was alive without evidence of disease 5 years after diagnosis, while the other had findings more compatible with MM with peritoneal involvement 2 years following initial diagnosis. In 15 of the 18 cases of MM (83%), there was documented occupational or paraoccupational exposure to asbestos, the average duration of which was 33 years (range, 2-46 years). Information regarding the presence or absence of pleural plaques was available in 5 of the MM cases, and pleural plaques had been found in 4. Lung tissue was not available for fiber analysis in any of the cases. One additional case originally diagnosed at another institution as MM of the TVT was reclassified as adenocarcinoma following performance of additional immunohistochemical testing. TVT is a rare site of MM, the diagnosis of which is often unsuspected preoperatively. Like its counterparts at other serosal sites, MM of the TVT is an aggressive tumor with a poor prognosis that evidence would suggest is etiologically associated with asbestos in at least some cases.

Dusting off the numbers of in situ particle analysis: a 35-year experience.

A variety of fibrotic lung diseases are caused by the inhalation of organic dusts. Many of these disorders have distinctive histopathology and can be readily diagnosed by routine histopathologic examination. However, in some instances, there is overlap in morphology between diseases caused by dust inhalation (mineral pneumoconiosis) and other lung diseases. In such cases, analytical scanning electron microscopy (SEM) can provide valuable information to assist the pathologist in making the correct diagnosis. We report herein our findings in 96 cases in which in situ particle analysis (ISPA) was performed with the SEM. This included 56 cases of pneumoconiosis as well as 40 cases of other types of interstitial lung disease. The most common diagnosis for which ISPA was performed in individuals with pneumoconiosis was mixed dust pneumoconiosis (14 cases). The most common diagnoses for which ISPA was performed in individuals with other diseases were sarcoidosis (13 cases) and hypersensitivity pneumonitis (10 cases). In addition to a detailed description of our methodology, we also report other circumstances in which ISPA assists in the diagnosis of pulmonary disease.

Dendriform pulmonary ossification leading to bilateral lung transplant: a case report.

Metaplastic ossification within the lung is seen in a variety of diseases, usually as sequela of either a separate primary pulmonary parenchymal disease or an underlying cardiac disorder such as valvular disease. Primary intraalveolar ossification or ossification within the alveolar septa is a rare entity. Similarly, it is unusual to see overt, diffuse disease affecting the lung to the point of respiratory failure leading to lung transplant. We present a case of an adult male who underwent bilateral lung transplantation, with the native lung pathology showing diffuse, severe dendriform ossification of the bilateral upper and lower lung lobes. The gross and histologic findings along with the radiographic imaging are reviewed herein. Overall, primary ossification of the lung leading to lung transplant is a rare condition that pulmonologists caring for patients with interstitial lung disease should be aware of as a possible cause of the patient's symptoms and lung dysfunction.

Malignant peritoneal mesothelioma in patients with endometriosis.

AIMS: Florid mesothelial hyperplasia is known to result from endometriosis. Well-differentiated papillary mesothelioma and multiloculated peritoneal inclusion cysts have also been described in women with endometriosis. To our knowledge, peritoneal diffuse malignant mesothelioma (MM) arising in the setting of endometriosis has not been reported. The purpose of this study is to report the clinicopathological characteristics of women with MM and endometriosis. METHODS: The surgical pathology files of a tertiary academic medical centre and the consultation files of one of the study authors were reviewed for cases of MM in females with and without endometriosis. RESULTS: Six women with MM and endometriosis ranging in age from 29 to 55 years (median=45 years) were identified. All had peritoneal MM and endometriosis involving the peritoneum and/or adnexa. Five had epithelioid MM and one had biphasic MM. Two had paraoccupational exposure to asbestos. The median age of women with MM and endometriosis (44.5 years) was significantly less than the median age of cases without endometriosis (58.0 years) (p value=0.01). CONCLUSIONS: To our knowledge, this is the first report of MM in women with endometriosis. Interestingly, MM in the setting of endometriosis has only been observed in the peritoneum and not in other serosal cavities. The findings in the present study suggest that chronic serosal inflammation secondary to endometriosis may be an inducing factor in rare cases of MM of the peritoneum.

Malignant Mesothelioma in Individuals With Nonmesothelial Neoplasms.

CONTEXT: - Malignant mesothelioma (MM) is a component of the BAP1 tumor predisposition syndrome. Other than in BAP1 familial studies, nonmesothelial neoplasms in individuals with MM has not been comprehensively assessed. OBJECTIVE: - To assess the spectrum and prevalence of nonmesothelial neoplasms in individuals with MM. DESIGN: - Individuals with MM and second neoplasms were identified from a database of 3900 MM cases. The expected prevalence of each type of neoplasm was calculated and compared with the actual prevalence in the study population using available Surveillance, Epidemiology, and End Results data and other published data. RESULTS: - Two hundred seventy nonmesothelial neoplasms were identified in 241 individuals (6% of the study population) with MM. Prostate adenocarcinoma was most common. Non-Hodgkin lymphoma, Hodgkin lymphoma, lung carcinoma, urothelial carcinoma, breast carcinoma, chronic lymphocytic leukemia, clear cell renal cell carcinoma, head and neck squamous cell carcinoma, papillary renal cell carcinoma, multiple myeloma/plasmacytoma, meningioma, pleomorphic undifferentiated sarcoma, chronic myelogenous leukemia, ocular melanoma, hepatocellular carcinoma, liposarcoma, and Wilms tumor all were more prevalent than expected. CONCLUSIONS: - Nonmesothelial neoplasms are uncommon in individuals with MM, but certain tumor types are increased in prevalence. In an unselected study population with respect to BAP1 status, the prevalence of several tumor types described in BAP1 mutation carriers, including lung carcinoma, clear cell renal cell carcinoma, breast carcinoma, meningioma, pleomorphic undifferentiated sarcoma, and ocular melanoma, was increased.

Malignant peritoneal mesothelioma and Crohn disease.

AIMS: Mesothelial reaction simulating peritoneal diffuse malignant mesothelioma (MM) has been reported in the setting of Crohn ileitis. To our knowledge, peritoneal MM arising in patients with inflammatory bowel disease (IBD) has not been reported. The purpose of this study is to report the clinicopathological characteristics of patients with peritoneal MM and IBD. METHODS: A database of approximately 3800 MM was reviewed for cases of MM in patients with IBD. RESULTS: Three patients (0.08%) with peritoneal MM and Crohn disease (CD) were identified, including two women and one man ranging in age from 56 to 65 years. All had a long-standing history of diarrhoea and an established diagnosis of CD of 3 years or greater duration. Two had epithelial MM and one had biphasic MM. Only one had documented asbestos exposure. CONCLUSIONS: Peritoneal MM occurs rarely in patients with IBD, but interestingly, has only been observed in the setting of CD and not in patients with ulcerative colitis. Chronic inflammation has been associated with the development of MM in rare instances and these three cases suggest that CD with transmural inflammation may also be a precursor. The precise role of CD-related transmural inflammation in the carcinogenesis of peritoneal MM remains to be determined.

Endogenous pneumoconiosis: Analytical scanning electron microscopic analysis of a case.

Pneumoconiosis is often considered a disease of the lung initiated by exposure to dust or other airborne particles, resulting in injury to the lungs. The term "endogenous pneumoconiosis" has been used in the literature to describe the deposition of compounds on the elastic fibers of the lung, usually in the setting of cardiac failure. In the case we present here, the patient aspirated a foreign body resulting in damage to the lung tissue and subsequent deposition of endogenous compounds on the elastic fibers of the pulmonary parenchyma and vasculature. We determined the composition of this mineral and mapped the distribution of elements using a combination of backscattered electron microscopy and energy dispersive spectrometry.

Abnormalities in hyperpolarized (129)Xe magnetic resonance imaging and spectroscopy in two patients with pulmonary vascular disease.

The diagnosis of pulmonary vascular disease (PVD) is usually based on hemodynamic and/or clinical criteria. Noninvasive imaging of the heart and proximal vasculature can also provide useful information. An alternate approach to such criteria in the diagnosis of PVD is to image the vascular abnormalities in the lungs themselves. Hyperpolarized (HP) (129)Xe magnetic resonance imaging (MRI) is a novel technique for assessing abnormalities in ventilation and gas exchange in the lungs. We applied this technique to two patients for whom there was clinical suspicion of PVD. Two patients who had significant hypoxemia and dyspnea with no significant abnormalities on computed tomography imaging or ventilation-perfusion scan and only mild or borderline pulmonary arterial hypertension at catheterization were evaluated. They underwent HP (129)Xe imaging and subsequently had tissue diagnosis obtained from lung pathology. In both patients, HP (129)Xe imaging demonstrated normal ventilation but markedly decreased gas transfer to red blood cells with focal defects on imaging, a pattern distinct from those previously described for idiopathic pulmonary fibrosis or obstructive lung disease. Pathology on both patients later demonstrated severe PVD. These findings suggest that HP (129)Xe MRI may be useful in the diagnosis of PVD and monitoring response to therapy. Further studies are required to determine its sensitivity and specificity in these settings.

Carcinoma of the lung in the absence of asbestosis: The value of lung fiber burden analysis.

Asbestos is universally recognized as a carcinogen for the lower respiratory tract. However, asbestos is a contributory factor in a small fraction of lung cancers, the vast majority of which are related to cigarette smoking. The challenge for the pathologist is to determine when a lung cancer may be attributed to past asbestos exposure. The finding of asbestosis either clinically or pathologically is a useful marker for such a determination. However, in the absence of asbestosis, it has been suggested that a fiber burden as determined by analytical electron microscopy within the range of asbestosis is sufficient for determination of a causal contribution. We report here an example of a case of lung cancer in which fiber burden studies showed an asbestos concentration within the range of asbestosis as determined by scanning electron microscopy (SEM).

Diffuse malignant mesothelioma and synchronous lung cancer: A clinicopathological study of 18 cases.

OBJECTIVES: To examine the clinicopathologic characteristics of individuals with diffuse malignant mesothelioma (DMM) occurring concurrently with lung cancer (LC). MATERIALS AND METHODS: A database of approximately 3800 patients with DMM was reviewed, from which 18 patients (0.5%) who had synchronous LC were identified. The clinicopathologic features, as well as the occupational exposure history and fiber burden analysis data were examined. RESULTS: The patient median age was 68 years (range 58-84 years). Of the 18 patients (14 male, 4 female), 11 (61%) had epithelial, 5 (28%) had biphasic, and 2 (11%) had sarcomatoid DMM, with the majority (16 cases; 89%) originating in the pleura and only 2 were peritoneal. Among the histologic types of LC, adenocarcinoma was most frequent (12 cases; 67%), while 5 cases of squamous cell carcinoma, and 1 case of small cell carcinoma were observed. Three patients also had a history of prior malignancy (1 with testicular seminoma and bladder carcinoma and 2 with prostate carcinoma). Fifteen patients had a positive smoking history. All but 3 had documented asbestos exposure. Three had histologic features of asbestosis. Mineral analysis performed in 8 showed an elevated asbestos fiber burden in 4 (22%). Amosite was detected in 4 patients, crocidolite in 3, and non-commercial amphiboles in 5. CONCLUSION: The finding of simultaneous carcinoma of the lung and DMM is distinctly unusual. The majority of patients are male smokers with pleural epithelial DMM and lung adenocarcinoma. This study represents the largest cohort of patients reported to date with synchronous malignant mesothelioma and lung cancer, and we propose guidelines for making a diagnosis of synchronous malignant mesothelioma and primary lung cancer.

Malignant mesothelioma not related to asbestos exposure: Analytical scanning electron microscopic analysis of 83 cases and comparison with 442 asbestos-related cases.

Epidemiological studies indicate that 80-90% of mesotheliomas are asbestos related. This suggests that 10-20% are not. Lung fiber burden analysis provides objective information about past exposures to asbestos. We have performed lung fiber burden analysis on a large cohort of mesothelioma cases and compared the findings with a reference population. Herein we report our findings along with demographic and exposure data.