An official European Respiratory Society/American Thoracic Society research statement: interstitial pneumonia with autoimmune features.

Many patients with an idiopathic interstitial pneumonia (IIP) have clinical features that suggest an underlying autoimmune process but do not meet established criteria for a connective tissue disease (CTD). Researchers have proposed differing criteria and terms to describe these patients, and lack of consensus over nomenclature and classification limits the ability to conduct prospective studies of a uniform cohort.The "European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-associated Interstitial Lung Disease" was formed to create consensus regarding the nomenclature and classification criteria for patients with IIP and features of autoimmunity.The task force proposes the term "interstitial pneumonia with autoimmune features" (IPAF) and offers classification criteria organised around the presence of a combination of features from three domains: a clinical domain consisting of specific extra-thoracic features, a serologic domain consisting of specific autoantibodies, and a morphologic domain consisting of specific chest imaging, histopathologic or pulmonary physiologic features.A designation of IPAF should be used to identify individuals with IIP and features suggestive of, but not definitive for, a CTD. With IPAF, a sound platform has been provided from which to launch the requisite future research investigations of a more uniform cohort.

Airway-centered interstitial fibrosis: etiology, clinical findings and prognosis.

BACKGROUND: Airway-centered Interstitial Fibrosis (ACIF) is a common pathologic pattern observed in our practice. OBJECTIVES: The objectives of this study are to describe the causes associated with ACIF in a large sample of patients and its effect on survival. METHODS: A retrospective study in three centers of interstitial lung disease in São Paulo, between January of 1995 and December of 2012. The surgical lung biopsy specimens were reviewed by three pathologists. The clinical, functional and tomographic findings were analyzed by a standardized protocol. RESULTS: There were 68 cases of ACIF, most of them women. The mean age was 57 ± 12 yr. Dyspnea, cough, restrictive pattern at spirometry and oxygen desaturation at exercise were common. A reticular pattern with peribronchovascular infiltrates was found in 79% of the cases. The etiologies of ACIF were hypersensitivity pneumonitis in 29 (42.6%), gastroesophageal reflux disease in 17 (25.0%), collagen vascular disease in 4 (5.9%), a combination of them in 15 cases and idiopathic in 3 (4.4%). The median survival was 116 months (95% CI = 58.5 - 173.5). Lower values of oxygen saturation at rest, presence of cough and some histological findings--organizing tissue in the airways, fibroblastic foci and microscopic honeycombing--were predictors of worse survival. CONCLUSIONS: ACIF is an interstitial lung disease with a better survival when compared with IPF. The main etiologies are HP and GERD. The oxygen saturation at rest, the presence of cough and some histological findings are predictors of survival.

Histopathology of the idiopathic interstitial pneumonias (IIP): A review.

The 2013 American Thoracic Society/European Respiratory Society consensus classification update of the idiopathic interstitial pneumonias (IIP) included several important modifications to the organization and spectrum of the diseases that were proposed in an earlier multidisciplinary consensus document in 2002. The histopathology of the now 'major' and 'rare' IIP is presented here with exposition of the newly included entity of a distinctive upper lobe fibrotic lung disease referred to as idiopathic pleuroparenchymal fibroelastosis. The 'rare histological patterns' of acute fibrinous and organizing pneumonia and bronchiolocentric patterns of interstitial pneumonia are illustrated and discussed.

Histopathologic, immunophenotypic and cytogenetic features of pulmonary mucoepidermoid carcinoma.

Pulmonary mucoepidermoid carcinoma is an uncommon but distinctive manifestation of mucoepidermoid carcinoma. Pulmonary mucoepidermoid carcinoma occurs in adults and children and can cause diagnostic problems, especially in small biopsies. Few studies have characterized the histologic and immunophenotypic features of pulmonary mucoepidermoid carcinoma. t(11;19)(q21;p13) is considered disease-defining for mucoepidermoid carcinoma; its significance in pulmonary mucoepidermoid carcinoma warrants further study. Forty three pulmonary mucoepidermoid carcinomas were re-reviewed and graded according to the Brandwein grading system for mucoepidermoid carcinoma. Four cases were excluded because of a split opinion between pathology report and re-review. These cases were negative for MAML2 rearrangement by FISH. TTF-1, napsin A, p40 and p63 immunostains were scored: 0 (negative), 1 (1-25% tumor cells), 2 (26-50%), 3 (51-75%) or 4 (>75%). FISH to detect MAML2 rearrangement used a MAML2-11q21 break-apart probe. Thirty nine pulmonary mucoepidermoid carcinoma (4 low, 30 intermediate, 5 high grade) contained mucous, epidermoid and intermediate cells and lacked keratinization and in situ carcinoma of the overlying epithelium. All cases with available gross description (n=22) had a central/endo- or peribronchial location. All 25 cases tested for immunohistochemistry were positive (scores 1-4) for p63; 23 also expressed p40. In six cases, the p63 score was higher than p40. TTF-1 and napsin were uniformly negative in all 25 cases. MAML2 rearrangement was identified by FISH in each of the 24 cases tested (3 low, 19 intermediate, 2 high grade). Clinical history was available in 29 patients (15 men) (median age, 48 years) with follow-up in 24 (median, 8.4 years). Five patients died of unrelated causes; one developed metastatic pulmonary mucoepidermoid carcinoma. In conclusion, features helpful in distinguishing pulmonary mucoepidermoid carcinoma from other lung cancers include its central/endo- or peribronchial location together with the presence of mucous cells, p63 expression, lack of keratinization and MAML2 rearrangement. TTF-1 and napsin are typically not expressed.

UIP diagnosed at surgical lung biopsy, 2000-2009: HRCT patterns and proposed classification system.

OBJECTIVE: High resolution CT (HRCT) is diagnostic of usual interstitial pneumonia (UIP) if honeycombing is present. However, biopsy-proven UIP also occurs in patients without honeycombing. Identification of specific HRCT patterns may enable specific diagnosis and allow more patients to enter clinical trials. Pattern may also predict prognosis. We sought to identify specific HRCT patterns in patients with biopsy-proven UIP (2000-2009) and to assess outcomes and serial change in pattern. MATERIALS AND METHODS: We reviewed the HRCT findings in 44 patients with biopsy-proven UIP and identified four distinct patterns: classic UIP (cUIP) with honeycombing, fibrosis without honeycombing (FnoH), minimal fibrosis (Fmin), and ground-glass present (GGOp). We reviewed electronic medical records for outcome information and serial HRCT examinations when available. RESULTS: The extent of fibrosis varied between patterns; findings were always heterogeneous in the cUIP and FnoH patterns. Some Fmin patients had a more homogeneous appearance. The lower lobes were predominantly affected, but upper lobe abnormalities were always present. Mortality from respiratory failure and acute exacerbations occurred regardless of pattern. Serial progression from Fmin to FnoH to cUIP occurred, although in a variable manner. Some individuals had an acute illness (GGOp) as the initial manifestation of UIP. CONCLUSION: The FnoH pattern may be diagnostic of UIP in the proper clinical setting; heterogeneity of HRCT appearance is critical and has not been previously emphasized. Grouping of patients on the basis of pattern may allow more accurate assessment of treatment effects. Further validation and study of these HRCT patterns is warranted. Histologic UIP predicts clinical course.

Sarcoidal granulomas in cytological specimens from intrathoracic adenopathy: morphologic characteristics and radiographic correlations.

BACKGROUND: Clinical experience and literature data suggest that the ability of pathologists to identify granulomas in cytological specimens from intrathoracic lymphadenopathy varies considerably and may negatively influence the yield of transbronchial needle aspiration (TBNA), both conventional and ultrasound-guided (EBUS-TBNA). OBJECTIVES: To describe the cytomorphology of sarcoidal granulomas on TBNA cytology specimens and to analyze the presence of associations between the cytological characteristics of granulomas and the radiographic stage of sarcoidosis. METHODS: TBNA cytological specimens from 123 sarcoidosis patients and 14 tuberculosis patients (control population) were reviewed independently by two pathologists blinded to the clinical-radiological details. RESULTS: Sarcoidal granulomas were small [median (IQR) largest diameter: 0.478 (0.318-0.701) mm] and well-formed, round or elliptical in shape, and almost invariably had a regular contour. Background elements lacked necrotic debris or exudate. The density [median (IQR) number of granulomas per slide: 6.85 (3.66-11) vs. 5.25 (2.5-8), p = 0.073] and size [median (IQR) largest diameter: 0.51 (0.319-0.733) vs. 0.398 (0.318-0.522), p = 0.071] tended to be larger in stage I than in stage II sarcoidosis. A necrotic background was common in the tuberculosis cohort studied (79 vs. 0%, p < 0.0001). CONCLUSIONS: Granulomas can be reliably identified on TBNA cytological material once their characteristic cytomorphology is delineated. A higher density of granulomas in lymphadenopathy of stage I sarcoidosis patients could partly explain the higher success rate constantly obtained by TBNA and EBUS-TBNA in this stage of the disease. A necrotic background suggests a tubercular etiology of the granulomas over a sarcoidal one, in the appropriate clinical setting.

Assessing Pathologic Response in Resected Lung Cancers: Current Standards, Proposal for a Novel Pathologic Response Calculator Tool, and Challenges in Practice.

The efficacy of neoadjuvant treatment for NSCLC can be pathologically assessed in resected tissue. Major pathologic response (MPR) and pathologic complete response (pCR), defined as less than or equal to 10% and 0% viable tumor cells, respectively, are increasingly being used in NSCLC clinical trials to establish them as surrogate end points for efficacy to shorten time to outcome. Nevertheless, sampling and MPR calculation methods vary between studies. The International Association for the Study of Lung Cancer recently published detailed recommendations for pathologic assessment of NSCLC after neoadjuvant treatment, with methodology being critical. To increase methodological rigor further, we developed a novel MPR calculator tool (MPRCT) for standardized, comprehensive collection of percentages of viable tumor, necrosis, and stroma in the tumor bed. In addition, tumor width and length in the tumor bed are measured and unweighted and weighted MPR averages are calculated, the latter to account for the varying proportions of tumor beds on slides. We propose sampling the entire visible tumor bed for tumors having pCR regardless of size, 100% of tumors less than or equal to 3 cm in diameter, and at least 50% of tumors more than 3 cm. We describe the uses of this tool, including potential formal analyses of MPRCT data to determine the optimum sampling strategy that balances sensitivity against excessive use of resources. Solutions to challenging scenarios in pathologic assessment are proposed. This MPRCT will facilitate standardized, systematic, comprehensive collection of pathologic response data with a standardized methodology to validate studies designed to establish MPR and pCR as surrogate end points of neoadjuvant treatment efficacy.

Immunodetection of occult eosinophils in lung tissue biopsies may help predict survival in acute lung injury.

BACKGROUND: Acute lung injury (ALI) is a serious respiratory disorder for which therapy is primarily supportive once infection is excluded. Surgical lung biopsy may rule out other diagnoses, but has not been generally useful for therapy decisions or prognosis in this setting. Importantly, tissue and peripheral blood eosinophilia, the hallmarks of steroid-responsive acute eosinophilic pneumonia, are not commonly linked with ALI. We hypothesized that occult eosinophilic pneumonia may explain better outcomes for some patients with ALI. METHODS: Immunohistochemistry using a novel monoclonal antibody recognizing eosinophil peroxidase (EPX-mAb) was used to assess intrapulmonary eosinophil accumulation/degranulation. Lung biopsies from ALI patients (n = 20) were identified following review of a pathology database; 45% of which (i.e., 9/20) displayed classical diffuse alveolar damage (ALI-DAD). Controls were obtained from uninvolved tissue in patients undergoing lobectomy for lung cancer (n = 10). Serial biopsy sections were stained with hematoxylin and eosin (H&E) and subjected to EPX-mAb immunohistochemistry. RESULTS: EPX-mAb immunohistochemistry provided a >40-fold increased sensitivity to detect eosinophils in the lung relative to H&E stained sections. This increased sensitivity led to the identification of higher numbers of eosinophils in ALI patients compared with controls; differences using H&E staining alone were not significant. Clinical assessments showed that lung infiltrating eosinophil numbers were higher in ALI patients that survived hospitalization compared with non-survivors. A similar conclusion was reached quantifying eosinophil degranulation in each biopsy. CONCLUSION: The enhanced sensitivity of EPX-mAb immunohistochemistry uniquely identified eosinophil accumulation/degranulation in patients with ALI relative to controls. More importantly, this method was a prognostic indicator of patient survival. These observations suggest that EPX-mAb immunohistochemistry may represent a diagnostic biomarker identifying a subset of ALI patients with improved clinical outcomes.

The pleura in health and disease.

A wide variety of local, regional, and systemic diseases may have pleural manifestations. The scope of this pathology encompasses a wide spectrum ranging from minimal inflammatory changes to highly malignant neoplasms. An overview of the normal structure of the pleura is provided, along with the diseases that may be encountered. Pleural specimens from patients with pneumothorax are rarely encountered by pathologists. In contrast, pathologists frequently receive pleural specimens showing evidence of inflammation, repair, or neoplasm. In these circumstances, an awareness of less common (and often clinically highly important) conditions such as epithelioid hemangioendothelioma and primary pleural malignant mesothelioma is essential. Knowledge of the clinical setting (e.g., disease tempo) and radiological picture (e.g., laterality) is often of great value to the pathologist in arriving at a correct diagnosis. Similarly, knowledge of the normal anatomical considerations and familiarity with the expected pleural histopathology for the most clinically relevant pleural diseases are critical assets for pulmonary physicians in providing optimal care for their patients.

Histopathologic Assessment of Suspected Idiopathic Pulmonary Fibrosis: Where We Are and Where We Need to Go.

CONTEXT.­: Accurate diagnosis of idiopathic pulmonary fibrosis (IPF) requires multidisciplinary diagnosis that includes clinical, radiologic, and often pathologic assessment. In 2018, the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and the Latin American Thoracic Society (ATS/ERS/JRS/ALAT) and the Fleischner Society each published guidelines for the diagnosis of IPF, which include criteria for 4 categories of confidence of a histologic usual interstitial pneumonia (UIP) pattern. OBJECTIVE.­: To (1) identify the role of the guidelines in pathologic assessment of UIP; (2) analyze the 4 guideline categories, including potential areas of difficulty; and (3) determine steps the Pulmonary Pathology Society and the greater pulmonary pathology community can take to improve current guideline criteria and histopathologic diagnosis of interstitial lung disease. DATA SOURCES.­: Data were derived from the guidelines, published literature, and clinical experience. CONCLUSIONS.­: Both guidelines provide pathologists with a tool to relay to the clinician the likelihood that a biopsy represents UIP, and serve as an adjunct, not a replacement, for traditional histologic diagnosis. There are multiple challenges with implementing the guidelines, including (1) lack of clarity on the quantity and quality of histologic findings required, (2) lack of recognition that histologic features cannot be assessed independently, and (3) lack of guidance on how pathologists should incorporate clinical and radiographic information. Current criteria for "probable UIP" and "indeterminate for UIP" hinder accurate reflection of the likelihood of IPF. These challenges highlight the need for further morphologic-based investigations in the field of pulmonary pathology.

CT-guided biopsy of perivascular tumor encasement using simultaneous IV contrast enhancement.

OBJECTIVE: The purpose of our study was to describe and review the accuracy of a novel technique for difficult biopsy of arterial tumor encasement using simultaneous IV contrast enhancement and helical CT guidance for coaxial core needle biopsies. CONCLUSION: Diagnostic biopsy specimens can be obtained safely using simultaneous IV contrast-enhanced CT guidance during difficult biopsies of unresectable tumors encasing the celiac, superior mesenteric, or left renal arteries.

Renal ischemia time in laparoscopic surgery: an experimental study in a porcine model.

OBJECTIVES: Laparoscopic nephron sparing surgery is becoming more common, only limited by experience of the surgeon and the renal ischemia time. It is currently unknown if laparoscopic surgery alters the accepted 30 min threshold for renal ischemia. The purpose of this study was to define the normothermic ischemic threshold in the laparoscopic setting. METHODS: Twenty-four domestic female pigs underwent a laparoscopic transperitoneal procedure after randomization to one of five treatment groups: 30, 60, 75, 90, and 120 min of unilateral renal ischemia. One animal was used as a control specimen and was not exposed to any surgery or pneumoperitoneum. The contralateral kidney in each animal was used as an individual control for the corresponding time of pneumoperitoneum. The animals were euthanized after 3 weeks, when both renal units were harvested and data were analyzed. RESULTS: Three animals died secondary to complications from their procedure and were replaced. There was no association between urine volume and ischemic time, but urine creatinine and creatinine clearance decreased significantly as ischemic time increased. The control animal and 30 min ischemic group had similar results. Functional renal parameters decreased in those animals exposed to greater than 75 min of ischemia. The histologic analysis did not show any significant differences among the experimental groups. CONCLUSION: Renal function begins to deteriorate between 75 and 90 min of renal vascular occlusion in this two-renal unit laparoscopic porcine model.

Multifocal microcysts and papillary cystadenoma of the lung in von Hippel-Lindau disease.

von Hippel-Lindau disease is an autosomal dominant inherited disorder characterized by a predisposition to multiple neoplasms. Renal cell carcinoma and hemangioblastomas of the retina and cerebellum are the most common of these, but other neoplasms and cysts also occur throughout the body. We report a distinctive, yet never described lung lesion in a 43-year-old woman with von Hippel-Lindau disease. Molecular genetic studies confirmed the presence of a VHL gene mutation in the cells of this lesion. We discuss the salient features of this novel lesion, and hypothesize on its origin and nature.

Primary pleural epithelioid hemangioendothelioma with rhabdoid phenotype: report and review of the literature.

Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor described in diverse locations including lung and liver. Relative to these sites, primary EHE of the serous cavities is uncommon. EHE in the serous cavities mimics mesothelioma and adenocarcinoma clinically, radiographically, cytologically, and histologically. EHEs have plasmacytoid epithelioid cells with cytoplasmic vacuoles. In addition to these features, we noted eccentric nuclei with abundant eosinophilic cytoplasm and nuclei displaced peripherally by globular cytoplasmic inclusions imparting a "rhabdoid" phenotype. These cells were often seen surrounding a hyaline core. Rhabdoid features are not unique to a single entity, and a comprehensive immunohistochemical panel is essential. We report the occurrence of pleural EHE with rhabdoid features presenting in a pleural effusion, and review the literature of primary serosal EHEs.

A Case of Simultaneous Benign Metastasizing Leiomyomas and Disseminated Peritoneal Leiomyomatosis Following Endoscopic Power Morcellation for Uterine Disease.

Extrauterine spread of leiomyomas is rare and most commonly occurs in the lungs. We present a case of simultaneous metastatic leiomyomatosis to the lungs and peritoneal cavity following laparoscopic myomectomy with power morcellation. The patient presented to our institution for further management where she underwent a robotically assisted hysterectomy with bilateral salpingo-oophorectomy. Leiomyomatous implants measuring up to 2.4 cm were resected from bowel mesentery and bladder peritoneum. Subsequent serial computed tomography imaging confirmed stable pulmonary nodules without new intraperitoneal lesions. Increasing number of cases involving extrauterine spread of leiomyomas has been reported with the introduction of power morcellation. The exact pathogenesis is unknown but is likely multifactorial. We emphasize that although the incidence of spread of benign disease is low, it is important to recognize this phenomenon as we will likely continue to encounter similar cases in the coming years.

Diagnostic Approach to Advanced Fibrotic Interstitial Lung Disease: Bringing Together Clinical, Radiologic, and Histologic Clues.

CONTEXT: - Idiopathic pulmonary fibrosis (IPF) is a distinctive clinicopathologic entity and the most common form of progressive diffuse lung scarring in older adults. Idiopathic pulmonary fibrosis manifests histopathologically as the usual interstitial pneumonia pattern. The usual interstitial pneumonia pattern is distinguished by geographically and temporally heterogeneous fibrosis that is peripherally accentuated, often with honeycombing and traction bronchiectasis. Idiopathic pulmonary fibrosis is not the only disease that leads to end-stage lung fibrosis, however, and several other entities may also cause advanced fibrosis. Surgical lung biopsies often present a diagnostic dilemma when they show clear evidence of advanced fibrosis, but the clinical, imaging, and/or histopathologic subcharacteristics suggest something other than IPF. OBJECTIVE: - To address this dilemma, we review several other fibrotic lung diseases, including connective tissue disease-associated interstitial lung disease, chronic hypersensitivity pneumonitis, advanced pulmonary Langerhans cell histiocytosis, end-stage pulmonary sarcoidosis, Erdheim-Chester disease, Hermansky-Pudlak syndrome, and others, detailing their clinical, radiologic, and histopathologic attributes and emphasizing similarities to and differences from IPF. DATA SOURCES: - Data sources comprised published peer-reviewed literature and personal experience of the authors. CONCLUSIONS: - Often, clues in the lung biopsy may offer the first suggestion of a fibrotic lung disease other than IPF, and accurate classification is important for prognosis, treatment, and the development of future therapies.

Histological and biomechanical evaluation of implanted graft materials in a rabbit vaginal and abdominal model.

OBJECTIVE: The objective of the study was to describe the histologic and biomechanical changes of implanted dermal collagen graft materials. STUDY DESIGN: Twenty rabbits were randomized into 2 groups (6 and 12 weeks, respectively). Each rabbit had 4 graft segments (human dermis, porcine dermis, porcine collagen-coated polypropylene mesh, and autologous fascia) randomly implanted into the abdomen and the vagina. Biomechanical testing and histologic analysis was performed after recovery of graft segments. RESULTS: Dermal graft segments showed a marked decrease in ultimate strength (84% to 86%) and elastic modulus (73% to 82%) that was significantly different from the decrease seen in autologous fascia or coated synthetic mesh (P < .0008 and P < .0001, respectively). The decrease in ultimate strength was associated with vaginal implantation (P = .057). Dermal graft materials had moderate inflammation and minimal collagen infiltration. CONCLUSION: The mechanical properties of dermal graft materials decline after implantation. Vaginal implantation may cause a different tissue response to graft material than abdominal implantation. Dermal graft material caused moderate inflammation and minimal collagen ingrowth remote from implantation.

Pulmonary pathology for the clinician.

The idiopathic interstitial pneumonias are a group of diffuse parenchymal lung diseases that manifest varying patterns of inflammation and fibrosis histopathologically. These disorders are classified most accurately by the combination of histopathology on lung biopsy with clinical and radiographic findings. A pattern-based approach to the histopathology of the lung biopsy, as examined at low magnification, immediately helps narrow the diagnostic possibilities. The technique can be applied by pulmonologists and pathologists in assembling a cogent differential diagnosis. More subtle histopathologic findings in the biopsy (eg, granulomas, necrosis, eosinophils) help narrow this differential. This pattern-based histopathologic technique fosters close interaction between pulmonologists and general pathologists during the evaluation of the patient who has interstitial lung disease and has undergone surgical biopsy.

Pathology of the pleura.

The pleura and lung are intimately associated and share many pathologic conditions. Nevertheless, they represent two separate organs of different embryonic derivation and with different yet often symbiotic functions. In this article, the authors explore the pathologic manifestations of the many conditions that primarily or secondarily affect the pleura.