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Assessment of lung biopsies for the diagnosis of hypersensitivity pneumonitis (HP) is one of the most difficult diagnostic problems for surgical pathologists. It is a form of interstitial lung disease resulting from an immune reaction provoked by an inhaled antigen in susceptible individuals. Although this definition sounds simple, in practice, the diagnosis of HP can be challenging. To address these issues, the American College of Chest Physicians (CHEST) has recently published a guideline for the diagnosis of HP. In this review, we will explore the multidisciplinary diagnostic evaluation of HP with a focus on the pathologic features as outlined in the CHEST guidelines. The histologic criteria are divided into 4 diagnostic categories: (1) Typicalnonfibrotic HP or fibrotic HP; (2) Compatible withnonfibrotic HP or fibrotic HP; (3) Indeterminatefor nonfibrotic or fibrotic HP; and (4) Alternative Diagnosis.It is important to emphasize that patterns 1 to 3 do not represent discrete histologic entities or pathologic diagnoses. Rather, these categories are meant to serve as a practical guide for organizing a complex set of overlapping histologic patterns into an integrated diagnostic framework for facilitating multidisciplinary discussion. High-resolution computed tomography features are also summarized, emphasizing how the correlation of lung biopsies with computed tomography findings can help to favor the diagnosis, particularly in cases where biopsies are not typical for HP. This review highlights details of the histologic spectrum of HP as well as the utility of different types of biopsies and bronchoalveolar lavage. We also emphasize the importance of multidisciplinary discussion and the complex differential diagnosis.

Light chain deposition disease, characterized by nonamyloidogenic deposits of immunoglobulin light chains, is rare in the lung and possibly underdiagnosed due to low clinical suspicion and lack of readily accessible tests. We encountered a case of pulmonary light chain deposition disease (PLCDD) in which light chain deposits appeared crimson red with a Masson trichrome (MT) stain and salmon pink with a sulfated Alcian blue (SAB) stain. This prompted us to characterize a series of PLCDD cases and assess the utility of MT and SAB stains to distinguish them from amyloidosis. From the pathology archives of 2 institutions spanning 10 years, we identified 11 cases of PLCDD, including 7 diagnosed as such and 4 determined retrospectively. The deposits in all cases of PLCDD stained crimson red with MT and salmon pink with SAB, while the cases of pulmonary amyloid (n=10) stained blue-gray and blue-green, respectively. The immunoglobulin light chain nature of the deposits was confirmed in 10 of 11 cases by either immunofluorescence microscopy (n=5) or mass spectrometry (n=5). Transmission electron microscopy revealed osmiophilic, electron-dense deposits in all cases analyzed (n=3). An extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue type was diagnosed in 10 cases and 1 represented a plasma cell neoplasm. Our study highlights the importance of considering PLCDD in the differential diagnosis of amyloid-like deposits in the lung and the value of performing MT and SAB stains to distinguish between PLCDD and amyloidosis.

The diagnostic criteria of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) are not well defined, and DIPNECH can be mistaken for carcinoids associated with neuroendocrine cell hyperplasia (NECH). In this study, we compared clinical, radiologic, histologic, immunohistochemical, and molecular features of DIPNECH and isolated carcinoids with/without NECH. The study population included 151 cases (77 female patients and 74 male patients), 19 with DIPNECH and 132 with carcinoids with/without NECH. None of the cases displayed molecular alterations or anaplastic lymphoma kinase expression. Compared with individuals with carcinoids with/without NECH, patients with DIPNECH were more likely to be female individuals (P<0.0001), nonsmokers (P=0.021), and symptomatic, and to have an obstructive/mixed respiratory defect, peripheral location of the lesions, and air trapping (P<0.0001) on chest computed tomography, and constrictive bronchiolitis on histology (P<0.0001). Among immunohistochemical markers, DIPNECH was associated with higher expression of thyroid transcription factor-1, CD10, and gastrin-releasing peptide/bombesin-like peptide (P<0.0001). Yet, when a purely histopathologic definition of DIPNECH was applied, 40% of isolated carcinoids also met the diagnostic criteria for DIPNECH, even in the absence of symptoms and/or radiologic abnormalities. Therefore, as DIPNECH represents a distinct clinical syndrome, we suggest the term DIPNECH be limited to cases presenting with respiratory symptoms, functional and/or radiologic abnormalities, and constrictive bronchiolitis on histology.

Skeletal coccidioidomycosis is a rare complication of pulmonary coccidioidomycosis that remains incompletely characterized, and its histopathologic features have not been systematically evaluated. All skeletal coccidioidal infections (2000 to 2012) were retrieved from the University of Arizona and Mayo Clinic in Arizona pathology archives. Clinical history and histologic features were reviewed. Among 25 patients (median age 40 y; 17 men), infections involved bones (2 cases), joints (6), or both (17), usually in the distal extremities (68%), especially the wrist (32%). History included previously documented coccidioidomycosis (13), autoimmune disease (8), diabetes (6), malignancy (4), and iatrogenic immunosuppression (10). Common symptoms (median 3 mo) included pain/arthralgia (21) and swelling (10). Cultures and serology were positive in 15 of 17 (88%) and 19 of 22 patients (86%), respectively. Treatment included surgical debridement(s) and chronic antifungal medication(s). Histologic review showed granulomas in all cases, ranging from poorly to well formed, with or without necrosis. Spherule density varied widely (mean 4.8/HPF; range <0.1 to 13.5/HPF). Composition of inflammatory infiltrates, degree of necrosis, and extent of fibrosis did not significantly differ between immunocompetent and immunocompromised patients. Eosinophils were only seen in one third of cases; when present, eosinophils were almost always rare. 10 patients experienced recurrent infection, 8 of whom were immunocompromised; the remaining patients recovered. In conclusion, distal extremities are the most common sites of skeletal coccidioidomycosis encountered by surgical pathologists. This condition is strongly associated with autoimmune disorders and immunosuppression. Spherules are sometimes rare, and multiple modalities including serology, culture, and histology may be required for diagnosis.

Malignant tumors in the lung (both primary and metastatic) rarely may be associated with markedly discohesive tumor cells, resulting in airspace filling reminiscent of “desquamative interstitial pneumonia” (DIP) on histopathology evaluation. A peculiar aspect of this growth pattern is the relatively bland appearance of the tumor cells, in many cases simulating benign alveolar macrophages at scanning magnification. We searched the Charles Carrington Memorial consultation files in the Department of Laboratory Medicine and Pathology at Mayo Clinic Arizona for instances of malignant tumors in lung simulating DIP, from 1992 to 2011. We identified 7 cases involving transbronchial biopsies, needle core samples, or resected lung specimens. Clinical, histopathologic, and immunohistochemical analyses of these 7 patients were performed, including detailed morphometric analysis of the individual tumor cells using calibrated measurement tools on digital images. We compared the results with those of a control group of 4 patients with benign DIP-macrophage reactions in smoking-related lung disease. The study group comprised 5 male and 2 female patients, 48 to 86 years in age (median: 67 y). The radiologic findings included lobar consolidation, localized ground-glass opacities, and 1 or more nodules. None of the patients had typical bilateral infiltrates of DIP. Microscopically, the lung parenchyma was dominated by the presence of prominent tumor cells filling alveolar spaces. Four patients had primary lung carcinoma (adenocarcinoma), whereas 3 had metastases from other sites, including a melanoma. Immunohistochemical staining studies were performed on 6 of 7 cases to establish the diagnosis. Nuclear diameter, cytoplasmic diameter, and nuclearcytoplasmic (NC) ratios in patient and control groups were compared using the Wilcoxon rank sum test. No significant difference in the diameters of nucleus and cytoplasm between cases and control groups (P=0.3447 and 0.7055, respectively) was seen, and only a marginally significant difference in NC ratios (P=0.0890) was seen. A more complex analysis, generalized estimating equation analysis, showed a significant difference in NC ratio between the 2 groups (P=0.0278). A “DIP-growth pattern” of malignant tumors in the lung is presented. Although the NC ratio differences approached statistical significance when compared with controls, the key to diagnosis is the recognition of the malignant cytology of the tumor nuclei. Immunohistochemical studies (keratin or other markers) are helpful in establishing an accurate diagnosis in this setting.

On the basis of seminal studies in the 1980s, appreciable histologic heterogeneity, ranging from 45 to 70 of cases, may be encountered in lung cancer. However, the epidemiologic and histologic landscape of lung cancer in the last 3 decades has radically changed. In this study, 172 consecutive surgically resected primary lung carcinomas evaluated from 2010 to 2012 were entirely sampled and examined according to current histologic classifications. In 129 cases, a positive preoperative biopsy was also available. Major histologic heterogeneity (a single tumor showing at least 2 different histologic types) and minor histologic heterogeneity (a single tumor showing just 1 histologic type but at least 2 different growth patterns) were evaluated in all cases. Immunohistochemical heterogeneity (ie, “aberrant” staining) was also assessed using a panel of markers of adenocarcinoma (TTF-1, napsin, and CK7), squamous cell carcinoma (p63, CK56), and neuroendocrine differentiation (chromogranin and synaptophysin), both on positive biopsies and surgical specimens. Overall, major and minor histologic heterogeneity on resections were disclosed in 4 (7 cases) and 50.6 (87 cases), respectively, whereas just 1 case of minor heterogeneity (pleomorphic carcinoma) was observed on biopsies. Minor heterogeneity was limited to adenocarcinomas (82.6, 8198 cases) and sarcomatoid carcinomas (6 pleomorphic types among 8 sarcomatoid carcinomas). Immunohistochemical heterogeneity was recorded in 22.6 of the cases, with expression of p63 and CK56 in a subset of adenocarcinomas (25 cases, 25.5), CK7 in 17.4 of squamous cell carcinomas, and synaptophysin in 6 cases of non-neuroendocrine tumors (4, 6155). The high rate of adenocarcinomas, accounting for 57 (98 cases) of 172 consecutively resected lung cancers, reflects the new scenario of thoracic oncology and may explain the significant lower rate of major histologic heterogeneity (4) and the higher frequency of different architectural patterns (minor heterogeneity) that we found in lung cancer compared with previous studies.

Lipomatous lesions rarely involve the bronchial tree, and detailed morphologic and molecular cytogenetic analysis of these tumors is lacking. The clinicopathologic features of 12 endobronchial lipomatous neoplasms were studied, with ancillary fluorescence in situ hybridization performed in subsets of cases for CPM, which is amplified in atypical lipomatous tumorswell-differentiated liposarcomas (ALTWDL), and HMGA1and HMGA2, which are often rearranged in lipomas. The cases occurred predominately in older men (91) (age range 44 to 80 y, mean 65 y). Most patients (80) had a former or current history of heavy smoking (20 to 100 pack-years). Three patients had concurrent pulmonary squamous cell carcinoma, and 1 had a history of multiple lung cancers. Most lesions were small (<2.5 cm) and discovered incidentally. A subset of tumors showed atypical morphologic features that would be suggestive of ALTWDL in soft tissue sites, including regions of fibrosis and scattered hyperchromatic stromal cells. However, all cases with atypia were CPMnegative and behaved in a clinically benign manner. Seven cases were tested for HMGA1and HMGA2rearrangement; 4 showed HMGA2rearrangement, and 1 showed HMGA1rearrangement, consistent with lipomas. Two cases were negative for HMGA12rearrangements. We conclude that endobronchial lipomatous neoplasms represent lipomas, even in the presence of morphologic features suggestive of ALTWDL. Ancillary fluorescence in situ hybridization testing may be very valuable in the analysis of these rare tumors, as true ALTWDL seem to be very rare or nonexistent at this anatomic site.

Malignant mesothelioma typically encases lungs as a thick rind, while relatively sparing lung parenchyma. We describe an unusual presentation of mesothelioma characterized by diffuse intrapulmonary growth, with absent or inconspicuous pleural involvement, clinically simulating interstitial lung disease (ILD). We identified 5 patients (median age 56 y, all men) with diffuse intrapulmonary malignant mesothelioma in our pathology consultation practice from 2009 to 2012. Clinical history, imaging, and pathology materials were reviewed. Symptoms included chronic dyspnea (4 cases), cough (3), and acute dyspnea with bilateral pneumothorax (1). Chest imaging showed irregular opacities (5), reticulation (4), pleural effusions (2), and subpleural nodular densities (1), without radiologic evidence of pleural disease or masses. A clinicoradiologic diagnosis of ILD was made in all cases, and wedge biopsies were performed. Histologic evaluation revealed a neoplastic proliferation of bland epithelioid or spindled cells, showing various growth patterns simulating silicotic nodules, desquamative interstitial pneumonia, organizing pneumonia, and Langerhans cell histiocytosis. Some areas mimicked adenocarcinoma, with lepidic, acinar, micropapillary, and solid patterns. Initial diagnoses by referring pathologists included reactive changes (1), hypersensitivity pneumonitis versus drug reaction (1), desquamative interstitial pneumonia versus neoplasm (1), and mesothelioma (2). Microscopic pleural involvement was identified in 4 cases. Immunohistochemistry confirmed the characteristic immunophenotype of mesothelioma in all cases. Median survival of 3 patients treated with chemotherapy was 28 months. Two patients received no therapy and survived 3 and 4 weeks, respectively. “Diffuse intrapulmonary malignant mesothelioma” is a rare variant with a distinctive presentation that clinically mimics ILD. Recognition is essential to avoid misdiagnosis.

Crystal-storing histiocytosis (CSH) localized to the thoracic region is a rare occurrence, often secondary to lymphoproliferative or plasma cell diseases. About 10 case reports have been previously published, and 3 of these have no relationship with clonal hematologic disorders. We collected here the first series of 5 consecutive cases of CSH involving lungs (4 cases) and pleura (1 case). There were 3 women and 2 men with a mean age at diagnosis of 65 years. All cases had an underlying hematologic disorder (2 B-cell marginal-zone lymphomas, 2 monoclonal gammopathy of undetermined significance and 1 pulmonary plasmacytoma). Despite a common morphology characterized by a dense and irregular growth of large eosinophilic histiocytes with intracytoplasmic refractile crystals, 2 cases presented with cystic changes at gross and imaging examinations, calcified amyloid was found in 2 cases, and 1 case showed an interstitial lung disease with nonspecific interstitial pneumonia pattern. Histiocytes were immunoreactive for CD68 (clones PGM-1 and KP-1) but were not for CD1a and S100; the associated lymphoplasmacellular disorder had a clonal profile on molecular analysis with light-chain restriction. Two cases were originally misdiagnosed as cystic fibrohistiocytic tumor and carcinoid tumor, thus confirming that CSH localized to this site may result in a diagnostic challenge with a broad spectrum of differential diagnoses. The presence of intracytoplasmic crystals and a plasma cell infiltrate around a histiocytic proliferation should alert the pathologist to consider CSH and to carefully investigate the presence of clonal hematologic disease.

Solitary fibrous tumor (SFT) is a ubiquitous neoplasm that arises most commonly from the pleura. SFT arising within lung parenchyma (intrapulmonary SFT) has been rarely reported and is therefore not well recognized. We present a clinicopathologic and immunohistochemical study of 24 cases of primary intrapulmonary SFT. Patients’ ages ranged from 44 to 83 years (mean, 58 y). None of the patients had evidence or history of a similar tumor elsewhere. Tumor size ranged from 2.3 to 22 cm (mean, 8.5 cm). On the basis of the degree of cytologic atypia, cellularity, mitotic activity, and areas of necrosis, the lesions were divided into low-grade, intermediate-grade, and high-grade histology. Twenty-one tumors showed the conventional features of SFT of low-grade histology (<5 mitoses per 10 high-power fields), with alternating bands of rope-like collagen flanked by a bland-appearing spindle cell proliferation. Hemangiopericytic, angiofibromatous, and a neural-like plexiform growth pattern were also observed. Five of 21 cases showed an “adenofibromatous” appearance imparted by entrapped normal airspaces at the advancing edges of the lesion. One intermediate-grade tumor showed overall increased cellularity with plump, pleomorphic nuclei, 5 to 10 mitoses per 10 high-power fields, and focal areas of classic SFT. Two cases showed high-grade features at initial presentation, with areas resembling a pleomorphic high-grade sarcoma admixed with foci of conventional, low-grade SFT. Immunohistochemical staining analyses performed in 13 cases showed positivity of the tumor cells for CD34, bcl-2, and CD99 in the majority of cases tested. Clinical follow-up was available in 18 patients, with long-term follow-up (>5 y) in 6. Fourteen (1418) patients were alive and well without evidence of disease 1 month to 14 years after initial diagnosis. Three patients died of their tumors after 4, 5, and 7 years; in 2 of them the initial tumor was of low-grade histology, but the recurrencemetastases showed a high-grade histology; the third fatal case showed a tumor with high-grade histology at initial diagnosis. One patient with intermediate-grade histology also had chest wall metastases at 5 years but was subsequently lost to follow-up. The results of our study indicate that although tumors with overtly malignant histologic features can be expected to behave as high-grade sarcomas, tumors with bland-appearing morphologic features at presentation may also follow an aggressive behavior. Adequate excision with close clinical follow-up, thus, appears to be the most prudent course of action for the management of primary intrapulmonary fibrous tumors.

Diffuse pulmonary lymphatic diseases are typically diagnosed shortly after birth or in childhood, but rarely may become evident in adulthood. We report 3 adult patients who presented with diffuse interstitial lung disease clinically and radiologically but on biopsy were found to have diffuse pulmonary lymphatic disease (2 cases of pulmonary lymphangiectasis and 1 case of pulmonary lymphangiomatosis). These patients presented with the insidious onset of symptoms including shortness of breath and cough. Imaging studies of the chest showed diffuse pulmonary interstitial opacities, often with a perilymphatic distribution. The clinical differential diagnostic considerations before surgical lung biopsy included infection, neoplasm, and interstitial lung disease. The histopathologic features included abnormal vessels and associated fibrosis following lymphatic routes, namely visceral pleura, bronchovascular bundles, and interlobular septa. Lymphangiectasis was characterized by dilation of normally distributed lymphatic spaces, whereas lymphangiomatosis showed a complex anastamosing proliferation of lymphatic vascular spaces without significant dilatation. The dilated lymphatic spaces often had undergone muscularization, which could easily lead to misclassification as veins. Immunohistochemical staining for the lymphatic endothelial marker D2-40 was helpful in correctly classifying these lesions. Diffuse pulmonary lymphatic disease can rarely present in adulthood, wherein the histologic findings can be subtle and could be overlooked as nonspecific reactive changes or misdiagnosed as an idiopathic interstitial lung disease. Recognition of the characteristic lymphangitic distribution of abnormally dilated or reduplicated lymphatic spaces is key to the correct diagnosis.

Pulmonary granulomas represent a common inflammatory reaction to several lung infective or noninfective diseases. However, little is known about the histology and clinical presentation of chickenpox-related granulomas in immunocompetent subjects. We collected a series of 8 adult patients (mean age, 40 y; range, 33 to 53 y) with several bilateral pulmonary granulomas incidentally discovered after imaging studies. All patients were asymptomatic and had experienced a varicella-zoster virus (VZV) infection as adults but were clinically suspected to have a metastatic neoplasm of unknown origin. Chest computed tomography scan revealed numerous, tiny (few millimeters to 1 cm in size) nodules randomly dispersed through the lungs. Positron emission tomography scan performed in 4 patients was negative. All patients underwent video-assisted thoracoscopic surgical resection and were still alive and well. At histology, granulomas consisted of well-defined, rounded, small nodules centered by a deeply eosinophilic, acellular necrosis rimmed by lamellar dense collagen and a chronic inflammatory infiltrate with or without multinucleated giant cells. Chickenpox-related granulomas were included in the differential diagnosis along with several other granulomatous diseases. Polymerase chain reaction–based molecular analysis for VZV performed on paraffin sections detected VZV DNA in all 8 cases. By contrast, 85 cases of pulmonary granulomas of different etiologies were simultaneously studied by molecular analysis with negative results. Pathologists should be familiar with the peculiar morphologic appearance of chickenpox-related granulomas. A careful search for a history of VZV infection in adulthood and molecular studies may be very helpful in confirming the diagnosis.

Liposarcoma rarely occurs in the mediastinum, and most reports predate the current genetically based classification system. We report the clinicopathologic and molecular genetic features of a series of thoracic liposarcomas identified over a 60-year period. Twenty-four confirmed cases were reclassified using the most recent World Health Organization classification. Fluorescent in situ hybridization for CPMamplification andor DDIT3rearrangement was performed on selected cases. The 24 cases occurred in 13 men and 11 women (mean age, 53 y; range, 15 to 73 y) and arose in all mediastinal compartments. All subtypes were encountered with 8 well-differentiated liposarcomas, 6 dedifferentiated liposarcomas (3 of 6 confirmed CPM), 7 pleomorphic liposarcomas (2 of 7 confirmed CPM−, 1 of 7 confirmed DDIT3−), 2 myxoid liposarcomas, and 1 unclassifiable liposarcoma (CPM− and DDIT3−). Unusual histologic features included myxoid well-differentiated liposarcoma mimicking myxoid liposarcoma (2 cases), lipoleiomyosarcoma (1 case), dedifferentiated liposarcoma with “meningothelial”-like dedifferentiation, differentiated myxoid liposarcoma mimicking well-differentiated liposarcoma (CPM−), and pleomorphic liposarcoma with epithelioid and myxoid change. Follow-up information was available for 19 patients (mean, 55 mo; range, 8 to 252 mo). Outcome was strongly associated with histologic subtype, with death from disease occurring in 1 of 6 well-differentiated, 1 of 4 dedifferentiated, 5 of 7 pleomorphic, and 2 of 2 myxoid liposarcomas. The mediastinum shows a preponderance of uncommon subtypes and unusual morphologic variants. Correct classification has important implications, with most patients with well-differentiateddedifferentiated liposarcoma having a protracted clinical course, in contrast to the more rapid disease progression seen in patients with myxoid and pleomorphic liposarcoma.

Amiodarone use is often limited by pulmonary toxicity. Amiodarone lung disease (ALD) classically manifests as organizing pneumonia with intra-alveolar foamy macrophages, but other patterns may also occur. Here we report 2 previously unreported patterns of ALD: lymphoid hyperplasia (LH) and eosinophilic pneumonia (EP). We identified patients with LH or EP as a prominent feature among 75 cases of probable ALD from the authors’ teaching files collected from 1997 to 2010. Clinical history and lung wedge biopsies were reviewed. Twelve patients (7 men) met inclusion criteria (median age, 71 y). The exact amiodarone dose was known in all cases (median, 200 mgd). Treatment duration was known in 10 cases and ranged from 1 to 12 years. Thoracic imaging showed diffuse infiltrates causing concern for a diagnosis of ALD. Histologic review revealed intra-alveolar foamy macrophages in all cases. Eight cases prominently displayed patterns of LH, including diffuse LH (7), follicular bronchiolitis (5), lymphoid interstitial pneumonia (2), and lymphocytic perivascular cuffing (2). Two showed features of acute EP, including diffuse alveolar damage with abundant eosinophils. Two showed features of chronic EP, including interstitial pneumonia with abundant eosinophils, patchy organization, and fibrinous exudates with macrophages and eosinophils. One chronic EP case also showed focal LH. Additional features included intra-alveolar giant cells (6), pleuritis (3), small poorly formed granulomas (3), and thrombi (2). LH and EP are previously unrecognized histopathologic manifestations of ALD, and amiodarone exposure should be included in their differential diagnosis.

Diffuse “true” cystic lung disease is rare, and the specificity of high-resolution computed tomography (HRCT) has reduced the need for biopsy. We present 5 patients with similar clinical and HRCT features of cystic lung disease that were sufficiently atypical to warrant surgical lung biopsies that showed coexistent small airway diseases (SAD). There were 4 female patients and 1 male patient with a mean age of 43 years. All were never smokers. Four had symptoms such as dyspnea (1), cough (2), or both (1). HRCTs showed variably sized thin-walled cystic airspaces without zonal distribution, some with prominent vessels in their walls. One case was unilateral. Surgical lung biopsy showed cystic change comprising localized loss of alveolar density with coexistent SADs chronic bronchiolitis (n=2), eosinophilic bronchiolitis, probable asthma (n=1), and diffuse idiopathic neuroendocrine cell hyperplasia (n=2). Two patients who were tested for Birt-Hogg-Dube-related gene mutations proved negative, and all lacked other features of Birt-Hogg-Dube. We hypothesize that chronic damage to small airways may lead to cystic degeneration in a minority of patients. Precedents in relation to Sjogren syndrome and hypersensitivity pneumonitis raise the possibility of a causal association between pathologies in these 2 anatomic compartments, although HRCT data in relation to common SADs indicate that this would be a rare phenomenon. The driving factor remains unknown.