Diagnostic value of intraoperative fine-needle aspiration cytologic diagnosis versus frozen section-based histopathologic diagnosis in thoracic malignancies: A single institution's experience.

BACKGROUND: Primary lung cancer is the leading cause of cancer death in the United States. Most lung cancers are diagnosed in an outpatient setting, but a subset requires intraoperative diagnosis. Two intraoperative diagnostic methods are available, frozen section (FS) and fine needle aspiration (FNA) cytology. This study compares intraoperative FNA cytology and FS based diagnosis in thoracic malignancies within the same clinical practice. METHODS: Pathology reports from thoracic intraoperative FNA cytology or FS (January 2017-December 2019) were reviewed. Resection diagnosis was the gold standard. If unavailable, concurrent biopsy and final FNA cytology diagnosis were the gold standard. RESULTS: Of 300 FNA specimens (155 patients), 142 (47%) cases were benign, and 158 (53%) were malignant. Adenocarcinoma was the most common malignant diagnosis (40%), followed by squamous cell carcinoma (26%), neuroendocrine tumors (18%), and other (16%). Intraoperative FNA yielded 88% sensitivity, 99% specificity, and 92% accuracy (p < .001). Of 298 FS specimens (252 patients), 215 (72%) cases were malignant and 83 (28%) were benign. Adenocarcinomas was the most common malignant diagnosis (48%), followed by squamous cell carcinoma (25%), metastatic carcinomas (13%), and other (14%). FS yielded 97% sensitivity, 99% specificity, and 97% accuracy (p < .001). CONCLUSION: Our findings confirm FS is the gold standard for intraoperative diagnosis. FNA cytology may be useful as a non-invasive, inexpensive initial diagnostic tool intraoperatively, given the similar specificity (99% FNA, 99% FS) and accuracy (92% FNA, 97% FS). Negative FNA could be followed by the costlier and invasive FS. We encourage surgeons to utilize intraoperative FNA first.

Post-kidney transplant cancers: Racial and ethnic differences in sun-exposed skin versus non-sun-exposed anogenital skin.

BACKGROUND: Transplant recipients have a 2- to 4-fold increased risk of developing malignancies over the general population. Cancer is the second most common cause of death for recipients. The magnitude of the risk depends on the cancer type and increases in viral-related malignancies. Skin cancer is the most common. However, data in most cancer registries is limited to cutaneous melanomas, thereby limiting the epidemiologic examination of cancer risk in non-melanoma skin cancer. Our goal was to evaluate post-kidney transplant cancer cases and sites in our population to guide screening recommendations. METHODS: Between 2009 and 2015, a retrospective study of adult kidney recipients transplanted at East Carolina University was conducted. The first cancer diagnosis after transplant through February 18, 2020, was captured and analyzed. Patient demographics, cancer sites, and histological diagnoses were analyzed and compared. p16 immunohistochemistry was used as a surrogate marker for high-risk human papillomavirus (HPV) infection. RESULTS: Retrospectively, kidney transplant recipients were analyzed (N = 439), the majority were non-Hispanic Black (NHB) individuals, 312 (71.1%), and 127 (28.9%) were non-Hispanic White (NHW) individuals. Of these, 59 (13.4%) developed a posttransplant malignancy, with the majority on sun-exposed skin found in NHW. NHB had all anogenital/mucosa skin cancers on non-sun-exposed skin. Of these detected in NHB, all were squamous cell carcinomas, with five out of six (83.3%) being positive for p16. CONCLUSIONS: Posttransplant malignancy differed significantly by race, site, and potential source of etiology. The majority of malignancies are likely explained by acceleration of precursor lesions from prior exposure to ultraviolet rays or HPV.

A Quantitative and Qualitative Assessment of Frozen Section Diagnosis Accuracy and Deferral Rate Across Organ Systems.

OBJECTIVES: Monitoring of frozen section diagnostic performance provides an important quality improvement measure. METHODS: Surgical specimens involving a frozen section diagnosis over a 3-year period were retrospectively reviewed. Glass slides were reviewed on cases with discordance. Discordance and deferral rates were calculated. RESULTS: Of 3,675 frozen section diagnoses included, 96 (2.7%) were discordant with the final diagnosis. Additionally, 114 frozen section diagnoses (3.1%) were deferred. The organ-specific discordance rates were lowest in breast and genitourinary specimens and highest for pancreas, lymph node, and gynecologic specimens. Deferral rates were highest in musculoskeletal, breast, and hepatobiliary cases and lowest in thyroid, parathyroid, and neuropathology cases. Discordance was explained by block-sampling error (45%), specimen-sampling error (27%), or interpretation error (27%). Discordant frozen section diagnoses from gynecologic specimens were responsible for 81% of specimen-sampling errors; frozen section diagnoses of lymph nodes, head and neck, and pancreas were responsible for 54% of interpretation errors; 51% of block-sampling errors involved lymph node evaluation for metastatic carcinoma. CONCLUSIONS: Careful gross evaluation and microscopic examination of multiple levels should minimize specimen-sampling error and block-sampling error, respectively. Periodic review of accuracy and deferral rates may help reduce errors and improve the overall performance of this essential procedure.

NSCLC Subtyping in Conventional Cytology: Results of the International Association for the Study of Lung Cancer Cytology Working Group Survey to Determine Specific Cytomorphologic Criteria for Adenocarcinoma and Squamous Cell Carcinoma.

INTRODUCTION: Accurate subtyping of NSCLC into lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) is the cornerstone of NSCLC diagnosis. Cytology samples reveal higher rates of classification failures, that is, subtyping as non-small cell carcinoma-not otherwise specified (NSCC-NOS), as compared with histology specimens. This study aims to identify specific algorithms on the basis of known cytomorphologic features that aid accurate and successful subtyping of NSCLC on cytology. METHODS: A total of 13 expert cytopathologists participated anonymously in an online survey to subtype 119 NSCLC cytology cases (gold standard diagnoses being LUAD in 80 and LUSC in 39) enriched for nonkeratinizing LUSC. They selected from 23 predefined cytomorphologic features that they used in subtyping. Data were analyzed using machine learning algorithms on the basis of random forest method and regression trees. RESULTS: From 1474 responses recorded, concordant cytology typing was achieved in 53.7% (792 of 1474) responses. NSCC-NOS rates on cytology were similar among gold standard LUAD (36%) and LUSC (38%) cases. Misclassification rates were higher in gold standard LUSC (17.6%) than gold standard LUAD (5.5%; p < 0.0001). Keratinization, when present, recognized LUSC with high accuracy. In its absence, the machine learning algorithms developed on the basis of experts' choices were unable to reduce cytology NSCC-NOS rates without increasing misclassification rates. CONCLUSIONS: Suboptimal recognition of LUSC in the absence of keratinization remains the major hurdle in improving cytology subtyping accuracy with such cases either failing classification (NSCC-NOS) or misclassifying as LUAD. NSCC-NOS seems to be an inevitable morphologic diagnosis emphasizing that ancillary immunochemistry is necessary to achieve accurate subtyping on cytology.

Age-specific prevalence of human papillomavirus and abnormal cytology at baseline in a diverse statewide prospective cohort of individuals undergoing cervical cancer screening in Mississippi.

BACKGROUND: Mississippi (MS) has among the highest rates of cervical cancer incidence and mortality in the United States, with disproportionately higher rates among Blacks compared to Whites. Here, we evaluate the prevalence of high-risk human papillomavirus (HPV) and abnormal cytology in a representative baseline sample from a diverse statewide cohort of individuals attending cervical screening in MS from the STRIDES Study (STudying Risk to Improve DisparitiES in cervical cancer). METHODS: We included individuals aged 21-65 years undergoing screening at the University of Mississippi Medical Center (UMMC) and the Mississippi State Department of Health (MSDH) from May to November 2018. We calculated age-specific HPV prevalence, overall and by partial HPV16/18 genotyping, and abnormal cytology by race. RESULTS: A total of 6871 individuals (mean age 35.7 years) were included. HPV prevalence was 25.6% and higher in Blacks (28.0%) compared to Whites (22.4%). HPV prevalence was significantly higher in Blacks aged 21-24 years (50.2%) and 30-34 years (30.2%) compared to Whites in the same age groups (32.1% and 20.7%; p < 0.0001, respectively). The prevalence of high-grade cytologic abnormalities, a cytologic sign of cervical precancer, peaked earlier in Blacks (ages 25-29) compared to Whites (35-39). For comparison, we also analyzed HPV prevalence data from the National Health and Nutrition Examination Survey (NHANES, 2013-2016) and observed similar racial differences in HPV prevalence among women aged 21-24 years. CONCLUSIONS: Our findings suggest that Blacks undergoing cervical cancer screening in MS have higher prevalence of other high-risk 12 HPV types at younger ages and experience an earlier peak of high-grade cytologic abnormalities compared to Whites.

STRIDES - STudying Risk to Improve DisparitiES in Cervical Cancer in Mississippi - Design and baseline results of a Statewide Cohort Study.

Cervical cancer rates in Mississippi are disproportionately high, particularly among Black individuals; yet, research in this population is lacking. We designed a statewide, racially diverse cohort of individuals undergoing cervical screening in Mississippi. Here, we report the baseline findings from this study. We included individuals aged 21 years and older undergoing cervical screening with cytology or cytology-human papillomavirus (HPV) co-testing at the Mississippi State Health Department (MSDH) and the University of Mississippi Medical Center (UMMC) (December 2017-May 2020). We collected discarded cytology specimens for future biomarker testing. Demographics and clinical results were abstracted from electronic medical records and evaluated using descriptive statistics and chi-square tests. A total of 24,796 individuals were included, with a median age of 34.8 years. The distribution of race in our cohort was 60.2% Black, 26.4% White, 7.5% other, and 5.9% missing. Approximately 15% had abnormal cytology and, among those who underwent co-testing at MSDH (n = 6,377), HPV positivity was 17.4% and did not vary significantly by race. Among HPV positives, Black individuals were significantly less likely to be HPV16/18 positive and more likely to be positive for other high-risk 12 HPV types compared to White individuals (20.5% vs. 27.9%, and 79.5% and 72.1%, respectively, p = 0.011). Our statewide cohort represents one of the largest racially diverse studies of cervical screening in the U.S. We show a high burden of abnormal cytology and HPV positivity, with significant racial differences in HPV genotype prevalence. Future studies will evaluate cervical precancer risk, HPV genotyping, and novel biomarkers in this population.

Donor-Derived Neuroendocrine Carcinoma Transmission to Two Kidney Transplant Recipients Demonstrated by Short Tandem Repeat Analysis: A Case Report.

Cancer transmission from a donor organ to a transplant recipient is a rare but not infrequently fatal event. We report a case of lung cancer transmission from a deceased donor to 2 kidney recipients. Approximately 1 year after uneventful kidney transplantation, both recipients developed acute kidney failure. Computed tomography imaging of abdomen and pelvis for both recipients showed masses in the transplanted kidneys along with innumerable masses in the livers. Pathologic examinations for both cases demonstrated high-grade neuroendocrine carcinoma with "mirror image" histologic findings in the transplant kidneys with liver metastases. Short tandem repeat (STR) analyses were performed to determine the origin of the tumors. STRs of both tumors were nearly identical to that of the donor, proving that both tumors were from the same donor. Immunohistochemical analyses showed that both tumors were positive for thyroid transcription factor 1, supporting a lung primary. One recipient died as a direct sequela to metastatic tumor, and the other required transplant nephrectomy and chemotherapy. Awareness of this largely nonpreventable complication and prompt molecular testing if cancer transmission is suspected are important.

Racial differences in HPV type 16 prevalence in women with ASCUS of the uterine cervix.

BACKGROUND: Understanding racial influences on human papillomavirus (HPV) distribution in women with atypical squamous cells of undetermined significance (ASCUS) cytology via partial genotyping in a statewide population can inform HPV-based prevention efforts. METHODS: Women aged 21 to 65 years with any cytology result and partial HPV genotyping for ASCUS triage between January 1, 2014, and December 31, 2017, were included. All women attended a Mississippi State Department of Health clinic. Age, race, cytopathologic, and HPV data were extracted from the electronic health record and analyzed. Cytologic specimens were processed with ThinPrep and HPV testing with the Cobas 4800 assay. HPV genotypes were evaluated in hierarchical categories. Chi-square tests and multinomial logistic regression models evaluated associations between race and type prevalence. RESULTS: There were 43,106 women who underwent cervical cancer screening with cytology and ASCUS triage. Of these, 34,363 (80.2%) had normal cytology, 4672 (10.9%) had ASCUS, 2683 (6.3%) had a low-grade squamous intraepithelial lesion, and 633 (1.5%) had a high-grade squamous intraepithelial lesion. Blacks represented 69.3% of the sample and had a higher proportion of HPV-positive ASCUS (6.5%) in comparison with whites (5.6%). Blacks had significantly decreased odds of HPV-16 (odds ratio [OR], 0.66; 95% confidence interval [CI], 0.6-0.9; P = .002) and significantly increased odds for 12 other types (OR, 1.37; 95% CI, 1.2-1.5; P < .0001) in comparison with whites. CONCLUSIONS: In a diverse population, significant differences in HPV genotypes are shown by race. Importantly, blacks with ASCUS are less likely to be positive for HPV-16 in comparison with whites. Ongoing work is evaluating the individual genotype prevalence and genotype-specific risk of precancer by race.

Precancerous cervical lesions and HPV genotypes identified in previously unsatisfactory cervical smear tests after inexpensive glacial acetic acid processing.

OBJECTIVE: To determine the effectiveness of using glacial acetic acid (GAA) to convert unsatisfactory bloody ThinPrep (TP) cervical smear test to satisfactory, and identify associated missed diagnoses and high-risk HPV (hrHPV) genotypes. METHODS: In a retrospective descriptive cross-sectional analysis, all TP tests performed in Mississippi, USA, 2012-2016, were evaluated for unsatisfactory results owing to blood. Tests that were converted to satisfactory by GAA treatment, and corresponding anomalies and HPV genotypes were identified. RESULTS: Among 106 384 TP tests, there were 1460 (1.37%) unsatisfactory results, of which 1442 (98.77%) were converted to satisfactory after GAA treatment. Laboratory preprocessing with GAA increased costs minimally. Precancerous lesions were detected in 166 (11.51%) of 1442 GAA-treated samples, of which 12 (7.2%) were high-grade lesions, 110 (66.3%) were atypical squamous cells of undetermined significance, and 63 (57.3%) tested positive for hrHPV. Of 60 genotyped samples, 39 (65%) had non-HPV16 and non-HPV18. Including mixed infections, 48 (80%) contained less-common hrHPV types, reflecting an unexpected distribution in bloody specimens. CONCLUSIONS: GAA pretreatment of bloody TP tests would reduce the incidence of unsatisfactory results and missed high-grade lesions, and prevent the cost of repeat tests and delayed treatment. Clinicians without access to GAA should consider HPV testing.

Best Practices Recommendations for Diagnostic Immunohistochemistry in Lung Cancer.

Since the 2015 WHO classification was introduced into clinical practice, immunohistochemistry (IHC) has figured prominently in lung cancer diagnosis. In addition to distinction of small cell versus non-small cell carcinoma, patients' treatment of choice is directly linked to histologic subtypes of non-small cell carcinoma, which pertains to IHC results, particularly for poorly differentiated tumors. The use of IHC has improved diagnostic accuracy in the classification of lung carcinoma, but the interpretation of IHC results remains challenging in some instances. Also, pathologists must be aware of many interpretation pitfalls, and the use of IHC should be efficient to spare the tissue for molecular testing. The International Association for the Study of Lung Cancer Pathology Committee received questions on practical application and interpretation of IHC in lung cancer diagnosis. After discussions in several International Association for the Study of Lung Cancer Pathology Committee meetings, the issues and caveats were summarized in terms of 11 key questions covering common and important diagnostic situations in a daily clinical practice with some relevant challenging queries. The questions cover topics such as the best IHC markers for distinguishing NSCLC subtypes, differences in thyroid transcription factor 1 clones, and the utility of IHC in diagnosing uncommon subtypes of lung cancer and distinguishing primary from metastatic tumors. This article provides answers and explanations for the key questions about the use of IHC in diagnosis of lung carcinoma, representing viewpoints of experts in thoracic pathology that should assist the community in the appropriate use of IHC in diagnostic pathology.

Interobserver Variation among Pathologists and Refinement of Criteria in Distinguishing Separate Primary Tumors from Intrapulmonary Metastases in Lung.

Multiple tumor nodules are seen with increasing frequency in clinical practice. On the basis of the 2015 WHO classification of lung tumors, we assessed the reproducibility of the comprehensive histologic assessment to distinguish second primary lung cancers (SPLCs) from intrapulmonary metastases (IPMs), looking for the most distinctive histologic features. An international panel of lung pathologists reviewed a scanned sequential cohort of 126 tumors from 48 patients and recorded an agreed set of histologic features, including tumor typing and predominant pattern of adenocarcinoma, thereby opining whether the case was SPLC, IPM, or a combination thereof. Cohen κ statistics of 0.60 on overall assessment of SPLC or IPM indicated a good agreement. Likewise, there was good agreement (κ score 0.64, p < 0.0001) between WHO histologic pattern in individual cases and SPLC or IPM status, but the proportions diversified for histologic pattern and SPLC or IPM status (McNemar test, p < 0.0001). The strongest associations for distinguishing between SPLC and IPM were observed for nuclear pleomorphism, cell size, acinus formation, nucleolar size, mitotic rate, nuclear inclusions, intraalveolar clusters, and necrosis. Conversely, the associations for lymphocytosis, mucin content, lepidic growth, vascular invasion, macrophage response, clear cell change, acute inflammation keratinization, and emperipolesis did not reach significance with tumor extent. Comprehensive histologic assessment is recommended for distinguishing SPLC from IPM with good reproducibility among lung pathologists. In addition to main histologic type and predominant patterns of histologic subtypes, nuclear pleomorphism, cell size, acinus formation, nucleolar size, and mitotic rate strongly correlate with pathologic staging status.

The histopathological classification, diagnosis and differential diagnosis of mucinous appendiceal neoplasms, appendiceal adenocarcinomas and pseudomyxoma peritonei.

The vermiform appendix is the primary site of several distinctive benign and malignant neoplasms. Some can produce the clinical syndrome of pseudomyxoma peritonei (PMP). A consensus on their terminology was reached by an international panel of pathologists and clinicians working under the auspices of the Peritoneal Surface Oncology Group International (PSOGI), and this review discusses the application of the PSOGI classification to routine reporting. We discuss diagnosis and differential diagnosis together with implications for patient management, covering low-grade appendiceal mucinous neoplasms, high-grade appendiceal mucinous neoplasms, serrated polyps, adenomas and adenocarcinomas. We do not cover goblet cell tumours or neuroendocrine neoplasms in this paper.

The Use of Immunohistochemistry Improves the Diagnosis of Small Cell Lung Cancer and Its Differential Diagnosis. An International Reproducibility Study in a Demanding Set of Cases.

INTRODUCTION: The current WHO classification of lung cancer states that a diagnosis of SCLC can be reliably made on routine histological and cytological grounds but immunohistochemistry (IHC) may be required, particularly (1) in cases in which histologic features are equivocal and (2) in cases in which the pathologist wants to increase confidence in diagnosis. However, reproducibility studies based on hematoxylin and eosin-stained slides alone for SCLC versus large cell neuroendocrine carcinoma (LCNEC) have shown pairwise κ scores ranging from 0.35 to 0.81. This study examines whether judicious use of IHC improves diagnostic reproducibility for SCLC. METHODS: Nineteen lung pathologists studied interactive digital images of 79 tumors, predominantly neuroendocrine lung tumors. Images of resection and biopsy specimens were used to make diagnoses solely on the basis of morphologic features (level 1), morphologic features along with requested IHC staining results (level 2), and all available IHC staining results (level 3). RESULTS: For the 19 pathologists reading all 79 cases, the rate of agreement for level 1 was 64.7%, and it increased to 73.2% and 77.5% in levels 2 and 3, respectively. With IHC, κ scores for four tumor categories (SCLC, LCNEC, carcinoid tumors, and other) increased in resection samples from 0.43 to 0.60 and in biopsy specimens from 0.43 to 0.64. CONCLUSIONS: Diagnosis using hematoxylin and eosin staining alone showeds moderate agreement among pathologists in tumors with neuroendocrine morphology, but agreement improved to good in most cases with the judicious use of IHC, especially in the diagnosis of SCLC. An approach for IHC in the differential diagnosis of SCLC is provided.

Utilization of ancillary studies in the cytologic diagnosis of respiratory lesions: The papanicolaou society of cytopathology consensus recommendations for respiratory cytology.

The Papanicolaou Society of Cytopathology has developed a set of guidelines for respiratory cytology including indications for sputum examination, bronchial washings and brushings, CT-guided FNA and endobronchial ultrasound guided fine needle aspiration (EBUS-FNA), as well as recommendations for classification and criteria, ancillary testing and post-cytologic diagnosis management and follow-up. All recommendation documents are based on the expertise of committee members, an extensive literature review, and feedback from presentations at national and international conferences. The guideline documents selectively present the results of these discussions. The present document summarizes recommendations for ancillary testing of cytologic samples. Ancillary testing including microbiologic, immunocytochemical, flow cytometric, and molecular testing, including next-generation sequencing are discussed. Diagn. Cytopathol. 2016;44:1000-1009. © 2016 Wiley Periodicals, Inc.

A Histomorphologic Grading System That Predicts Overall Survival in Diffuse Malignant Peritoneal Mesothelioma With Epithelioid Subtype.

Diffuse malignant peritoneal mesothelioma (MPeM) is rare and arises from peritoneal serosal surfaces. Although it shares similar histomorphology with its counterpart, malignant pleural mesothelioma, etiologies, clinical courses, and therapies differ. Nuclear grading and level of mitoses have been correlated with prognosis in malignant pleural mesothelioma with epithelioid subtype. Whether nuclear grading and level of mitoses correlate with prognosis in MPeM is still unknown. Our study utilizes a 2 tier system incorporating nuclear features and level of the mitoses to stratify cases of MPeM with epithelioid subtype. Fifty-one cases of MPeM with clinical follow-up underwent retrospective microscopic review. From that subset, 46 cases were of epithelioid subtype, which were then stratified into a low-grade or high-grade tier. Survival times were calculated on the basis of Kaplan-Meier analysis. The low-grade tier had higher overall survival with a median of 11.9 years and 57% at 5 years when compared with the high-grade tier with a median of 3.3 years and 21% at 5 years (P=0.002). Although not statistically significant, the low-grade tier had higher progression-free survival with a median of 4.7 years and 65% at 5 years when compared with the high-grade tier with a median of 1.9 years and 35% at 5 years (P=0.089). Our study is first to specifically evaluate and correlate nuclear features and level of mitoses with overall survival in MPeM with epithelioid subtype.

Standardized terminology and nomenclature for respiratory cytology: The Papanicolaou Society of Cytopathology guidelines.

BACKGROUND: The Papanicolaou Society of Cytopathology has developed a set of guidelines for respiratory cytology including indications for cytologic testing, techniques for cytologic sampling, terminology and nomenclature for respiratory diseases, ancillary testing, and recommendations for postcytologic diagnosis follow-up and management. METHODS: All documents are based on the expertise of the authors, an extensive literature review and discussions of the draft documents at national and international meetings over a 12-month period. This document selectively presents the results of these discussions and reports a proposed standardized terminology scheme for respiratory cytology that correlates cytologic diagnosis with biologic behavior and patient management. RESULTS: The classification and terminology scheme recommends a six-tiered system composed of: nondiagnostic, negative, atypical, neoplastic (benign and neoplasms of low malignant potential), suspicious, and positive for malignancy. CONCLUSION: The scheme recommends statements on specimen adequacy followed by the major classification category and then a subclassification and/or comments section. Each of the six main diagnostic categories is associated with an estimated risk of malignancy. Subsequent documents will propose ancillary testing recommendations, techniques for cytologic sampling, indications for cytologic study and postcytologic diagnosis management and follow-up recommendations.

The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification.

The 2015 World Health Organization (WHO) Classification of Tumors of the Lung, Pleura, Thymus and Heart has just been published with numerous important changes from the 2004 WHO classification. The most significant changes in this edition involve (1) use of immunohistochemistry throughout the classification, (2) a new emphasis on genetic studies, in particular, integration of molecular testing to help personalize treatment strategies for advanced lung cancer patients, (3) a new classification for small biopsies and cytology similar to that proposed in the 2011 Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification, (4) a completely different approach to lung adenocarcinoma as proposed by the 2011 Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification, (5) restricting the diagnosis of large cell carcinoma only to resected tumors that lack any clear morphologic or immunohistochemical differentiation with reclassification of the remaining former large cell carcinoma subtypes into different categories, (6) reclassifying squamous cell carcinomas into keratinizing, nonkeratinizing, and basaloid subtypes with the nonkeratinizing tumors requiring immunohistochemistry proof of squamous differentiation, (7) grouping of neuroendocrine tumors together in one category, (8) adding NUT carcinoma, (9) changing the term sclerosing hemangioma to sclerosing pneumocytoma, (10) changing the name hamartoma to "pulmonary hamartoma," (11) creating a group of PEComatous tumors that include (a) lymphangioleiomyomatosis, (b) PEComa, benign (with clear cell tumor as a variant) and