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Interlaboratory Comparison Program in Non-Gynecologic Cytopathology (NGC)

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YEAR END SUMMARY REPORT

© 2005 College of American Pathologists. The College does not permit reproduction of any substantial portion of the material in this Report without its written authorization. The College hereby authorizes participants in the program to use the material in this Report solely for educational purposes within their own institutions. The College prohibits use of the material in the Report - and any unauthorized use of the College’s name or logo - in connection with promotional efforts by marketers of laboratory equipment, reagents, materials, or services. Data from this program do not necessarily indicate the superiority or inferiority of instruments, reagents, or other materials used by participating laboratories. Use of these data to suggest such superiority or inferiority may be deceptive and misleading. The College will take all steps open to it under the law to prevent unauthorized reproduction of substantial portions of the material in this Report, deceptive use of any such material, and any unauthorized use of the College’s name or logo in connection with promotional efforts by marketers of laboratory equipment, reagents, materials, or services.

2005

Figure1 Follicular lymphoma: A mixture of large and small cells (compare to the histiocyte nucleus). This type of lymphoma is easily mistaken for a reactive process due to the variation in size of the lymphoid population which may mimic the polymorphous population in a reactive lymph node (Papanicolaou stain, x 100)

Figure 2 Mantle cell lymphoma: Mantle cell lymphoma is usually made up of monotonous small sized cells with coarse chromatin. Rarely, larger cells are seen which may overlapwith the cells of large cell lymphoma. Most of the cells in this field are smaller than the nucleus of the histiocyte and have coarse chromatin. (Papanicolaou stain, x100)

Figure 3 Burkitt lymphoma: There are numerous tingible body macrophages present in Burkitt lymphoma, with nuclei about the size of the histiocyte nuclei. There is coarse chromatin with multiple chromocenters, easily seen on the Pap stain (Papanicolaou stain x 100)

Figure 4 Lymphoblastic lymphoma: Lymphoblastic lymphoma has deceptively bland chromatin usually without nucleoli. Note the mitoses in this aggressive lymphoma usually seen in children. (Papanicolaou stain x 100)

TABLE OF CONTENTS Program Description.............................................................................................................1 General Oberservations.........................................................................................................2 Fine Needle Aspiration of Lymph Node ...................................................................................5 Fine Needle Aspiration of Liver ............................................................................................10 Tables 1 thru 67................................................................................................................17

Non-Gynecologic Cytopathology Working Group

David C. Wilbur MD, Chair

Ann T. Moriarty, MD, Vice Chair Margaret H. Neal, MD George G. Birdsong, MD Dina R. Mody, MD Camilla J. Cobb, MD Marianne Unger Prey, MD Barbara S. Ducatman, MD Andrew A. Renshaw, MD Michael Ross Henry, MD Tamela Miles Snyder, MD Jonathan H. Hughes, MD,PhD Nancy A. Young, MD

Front Cover Image - Metastatic Adenocarcinoma: Large, disordered sheets of cytologically malignant cells with gland lumen formation. There is no endothelial rimming, and the tumor cells do not resemble hepatocytes. The intracellular pigment is hemosiderin not bile. (Papanicolaou stain, 60x)

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2005 Interlaboratory Comparison Program in Non-Gynecologic Cytopathology (NGC) Year End Summary Report

PROGRAM DESCRIPTION The College of American Pathologists (CAP) started the Interlaboratory Comparison Program in Non-Gynecologic Cytopathology (NGC) in 1997. In 2005, there was an enrollment of 1,750 laboratories and 7,776 participants enrolled in the NGC program. Most participating laboratories are in the United States. However, international laboratories from Australia to Canada also subscribe to this program. The NGC program is strictly educational and not graded. There is a quarterly mailing of five glass slides with accompanying clinical histories. The interpretive menu is provided using a bubble answer format. After receiving the faxed Laboratory answer sheet, the NGC computer server is programmed to fax back within 20 minutes the reference responses and a profile of slide performance. This provides both the targeted reference response and benchmarking data so laboratory can review slides before returning them to the CAP. Also provided in the same fax is a brief description of the interpretive entities included in the challenge along with pertinent references. Specific comments regarding each slide including immunohistochemical or flow cytometric findings may, in some cases, also be provided. These particular findings may not have been included with the initial clinical information because in many cases it would have made the diagnosis obvious. In addition, presentation of these findings would not simulate actual laboratory practice, as cases would routinely have been initially evaluated without the benefit of these additional results. The intent of this educational program is for participants to consider the differential diagnoses based on the material submitted for review, and to select the most appropriate answer from the interpretive menu, based on initial morphologic evaluation. The College is investigating methods that will integrate the results of pertinent ancillary studies including radiographs and special immunologic or special stains, in a fashion that will closely mimic routine laboratory practice. DETAILS OF THE NON-GYN PROGRAM The Program answer sheet consists of two parts. The first part is the general interpretive category, which is divided into four series:

• 001: Benign/negative for malignant cells. This category includes benign neoplasms as well as infectious conditions and normal material.

• 002: Suspicious for malignant cells. • 003: Positive for malignancy (including neuroendocrine neoplasms such as

carcinoid tumors) • 004: Unsatisfactory. Although criteria for unsatisfactory is not well defined in

many areas of non-gynecologic cytology, this program is attempting to determine the frequency and circumstances in which the unsatisfactory category is used in non-gynecologic cytology across its participant base.

The second part of the answer sheet, is a specific reference interpretive menu for each specific organ or site. Each interpretation has a specific code. The participant reviews the slide along with the accompanying clinical information and selects the most appropriate answer from the interpretive menu provided. An answer is considered correct from the reporting and benchmarking point of view if it is within the appropriate general interpretive

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series (see above). The Committee realizes that interpretive thresholds vary between individuals especially in cases with low cellularity or for well differentiated neoplasms, or those of uncertain malignant potential. While participants may often feel confident in reaching a Positive interpretation, there will be cases in which an answer in the Suspicious series will be equally valid from a clinical point of view. Therefore, a “Suspicious” interpretation in such cases is not counted as a wrong answer. A diagnosis of 001 (Negative series), however, for a case in the 002 or 003 (Suspicious or Positive) series is scored as incorrect. A case in the 004 (Unsatisfactory) series that is interpreted as Suspicious (002) or Positive (003) is also scored as incorrect. Benchmarking data is provided for each specific reference interpretation. Intra-laboratory and interlaboratory comparisons can be made using this information. Statistics are generated for each diagnostic category as well as for each slide. (See Tables 1-67) Cases in the Non-Gynecologic Program are contributed by the members of the CAP Cytopathology Resource Committee and are reviewed at screening sessions for consensus prior to inclusion in the program. Submitted cases must be validated by two Cytopathology Resource Committee cytopathologists who agree on the general and specific interpretation, and who also agree that the slide is representative and has no technical inadequacies that might inhibit an accurate assessment. Cases involving the respiratory tract include bronchial brushings and washings, bronchial alveolar lavage (BAL) and sputa. Gastrointestinal tract cases include esophageal and gastric brushings and washings, and other gastrointestinal and biliary tract brushings. Additionally, body cavity fluids from pleural, peritoneal and pericardial sites as well as pelvic washings are included in the diagnostic menu. Urinary tract cases include catheterized, voided urine specimens, and bladder washings. Cerebrospinal fluids, fine needle aspiration (FNA) biopsies from breast, lung, pleura, mediastinum, liver, biliary system, lymph nodes, pancreas, salivary gland, thyroid/parathyroid, kidney and subcutaneous and soft tissue are well represented in the circulating slide material. An interpretive menu developed for each site includes normal, benign reactive changes, infectious agents, and benign and malignant neoplasms. The malignant neoplasms represent examples from both primary and metastatic sites. Fine needle aspiration (FNA) biopsies prepared from specimens at the surgical cutting bench were initially accepted to launch the program. Currently, however, sufficient clinical aspiration biopsy smears have been obtained such that bench aspirate cases are retained in the program only in cases where they represent excellent examples of rare or unusual cases. All routine bench FNA specimens have been removed from the program and are no longer accepted as donations. GENERAL OBSERVATIONS When body sites with more than 100 laboratory responses were evaluated, there was a positive or negative response rate of greater than 80% concordance in most cases with the notable exception of salivary gland neoplasm which is known to be a difficult diagnostic area.1,2 See Table A. In general, laboratories performed well in 2005, especially in respiratory cytology (BAL, bronchial washes and brushes as well as lung FNA), many fluids, as well as breast fine needle aspiration. Instances where less than 80% concordance was reached are predictable diagnostic dilemmas. Mesothelioma was a category with less than 80% Positive diagnoses but there were 14.7% Suspicious responses. Likewise, lymphoma

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in pleural fluids had an 18.7% Suspicious response and a 74.9% Positive response. The combined Suspicious (14.7%) and Positive (75%) responses for Mesothelioma are also above 80%. Likewise, voided urine samples identifying high grade urothelial carcinoma is accurate when the Positive (78.3%) and Suspicious (10.3%) results are combined. Adenoid cystic and acinic cell carcinoma have low Positive rate, and this is a well recognized area of diagnostic difficulty. Most Negative responses were understandably identified as pleomorphic adenoma. Table A Laboratory response rates >100 for diagnostic entities Site Reference Diagnosis Negative Positive BAL Negative 94.3% Bronchial Brush Negative 95.7% Squamous cell Carcinoma 95.3% Adenocarcinoma 92.5% Non small cell Carcinoma 95.0% Bronchial Washing Negative 92.7% Squamous cell carcinoma 93.8% Adenocarcinoma 86.5% Non small cell carcinoma 91.0% Pneumocystis 99.3% CSF Lymphoma/hematopoietic 93.3% Metastatic disease 83.4% GI Brushing Adenocarcinoma 82.2% Esophageal brush/wash Negative 97.3% Squamous cell Carcinoma 91.9% Pelvic wash Adenocarcinoma 93.7% Pleural fluid Adenocarcinoma 90.5% Small cell carcinoma 97.8% Non small cell carcinoma 90.3% Mesothelioma 77.7%a Negative 78.9% Lymphoma 74.9%b Pericardial fluid Adenocarcinoma 95.5% Peritoneal fluid Adenocarcinoma 91.9% Mesothelioma 75.0%c FNA Lung Squamous carcinoma 94.1% Adenocarcinoma 96.7% Small cell Carcinoma 95.4% Non Small cell 95.9% Metastases 92.5% FNA Subcutaneous Melanoma 97.4% Negative 90.5% Spindle cell lesion 84.4% Metastases/primary

malignancy 94.1%

FNA Breast Cyst 94.0% Fibrocystic change 89.2% Fibroadenoma 90.7% Mastitis 96.2%

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Ductal Carcinoma 89.9% Mucinous carcinoma 80.5% FNA Salivary Gland Pleomorphic Adenoma 94.2% Warthin’s Tumor 95.0% Adenoid Cystic 68.3%d Acinic Cell Carcinoma 32.2%e FNA Pancreas Adenocarcinoma 88.5% FNA Thyroid Goiter 88.5% Cyst 82.5%*

*

Hashimoto’s 80.6% Papillary Carcinoma 82.7% FNA Kidney Renal cell Carcinoma 91.2% Bladder Wash High grade urothelial

carcinoma 84.9%

Urine, instrumented High grade urothelial carcinoma

85.0%

Urine, voided High grade urothelial carcinoma

78.3% f

a an additional 14.7% of cases were reported as suspicious b an additional 18.7% of cases were reported as suspicious c an additional 14.7% of cases were reported as suspicious d 13.8% were reported as pleomorphic adenoma e 19.5% were reported as pleomorphic adenoma f an additional 10.3% of cases were reported as suspicious

The 2005 Year End Summary Report (YESR) continues the tradition of reviewing two specific topics in the NGC program as initiated in the 2003 annual summary. In 2003, effusion and salivary gland were studied. In 2004, lung and thyroid gland were selected for in-depth review. In 2005, lymph node and liver were selected as organ systems for specific and detailed review. Additionally, photomicrographs have been used to illustrate specific topics for both lymph node reference diagnosis and liver fine needle aspirate analysis. The results are detailed in the sections below. In general, when figures are given, they represent the Laboratory response data unless otherwise specified. These Laboratory responses are generally most relevant; cytotechnologists and pathologists work together as a team to arrive at a diagnosis. Remember, however, that the NGC program is strictly an educational program in which cytotechnologists and pathologists arrive at a diagnosis based upon a single slide and history, without the aid of ancillary morphologic studies, additional clinical consultation or radiological studies. It is artificial and represents a strictly morphologic approach to cytology. It is understood that the evaluation of these slides does not mimic daily practice and represents an educational challenge. Any conclusions and comparisons identified in the YESR are generally recognized as evaluations of a broad art of interpretation.

References: 1. Hughes JH, Volk EE, Wilbur DC, for the Cytopathology Resource Committee,

College of American Pathologists. Pitfalls in salivary gland fine needle aspiration cytology: lessons from the College of American Pathologists’ Interlaboratory Comparison Program in Non-Gynecologic Cytology Pathology. Arch Pathol Lab Med. 2005;129:26-31

2. The Interlaboratory Comparison Program Non-Gynecologic Cytopathology (NGC): 2004 year. End Summary Report Northfield, IL: College of American Pathologists; 2004

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Fine Needle Aspiration of Lymph Node The most challenging aspect of aspiration biopsy of lymph nodes is the diagnosis and classification of lymphoproliferative disorders. Differentiating reactive processes from a malignant lymphoma is part of the challenge. Metastatic malignancies to lymph nodes including metastatic carcinoma, sarcoma, and melanoma are frequently straightforward and look like the primary or metastases at other sites. The WHO classification for lymphoma is now the standard classification system used for the diagnosis of lymphoproliferative disorders, integrating morphology, immunophenotyping, and genetic abnormalities. Unfortunately the CAP NGC program cannot give the immunophenotypic information in the clinical history without removing the challenge of the case and identifying the lesion up front as malignant lymphoma. Therefore, the lymphoma categories in the CAP NGC program have been revised to fit the realities and constraints of this type of educational exercise. Program participants are first asked to classify each slide into one of four general diagnostic categories of “negative”, “positive”, “suspicious”, or “unsatisfactory”, and then to assign each case to one of 14 specific reference diagnoses. Of these specific reference diagnoses, there are 13 for which at least 100 total participant (pathologist and cytotechnologist) responses were received in 2005 as noted below in table B. For the specific diagnosis of lymphoma, participants are given three broad categories to choose from—Hodgkin Lymphoma, large cell lymphoma, and non-Hodgkin lymphoma other than large cell (NHL, OTL). A second set of codes were developed for the NHL, OTL category based upon additional immunophenotypic information so that when answers go back to participants, they will receive a more specific write up tailored to the case. This second set of codes assigned by the Cytopathology NGC working group also permits collection of more detailed response information for lymphomas composed of smaller cells. Although these codes allow for data collection and appropriate fax back information, participants are not expected to subclassify these small cell lymphomas further without adequate immunophenotypic information or ancillary studies. The participant’s responses based solely upon the cytomorphology does give insight into the differential diagnosis of various lymphoma subtypes. This program is designed as an educational exercise for participants and not a test of proficiency in the diagnosis of lymphoproliferative disorders by FNA. “Negative” cases circulated to more than 100 laboratories exhibited a high degree of diagnostic accuracy among the NGC program participants. The correct general interpretation of Negative was provided by 81.5% of the laboratories. A correct specific interpretation of Negative/Reactive/Hyperplastic lymph nodes was provided by 72.8% of the laboratories. Although 15.3% of the laboratories responded with a malignant false-positive specific interpretation, 9.6% of these were interpreted as NHL, OTL which is a reasonable interpretation in the absence of available immunophenotypic information. The second most common false positive interpretation (3%) was large cell lymphoma and may also be a reasonable interpretation in the setting of a reactive lymph node without immunophenotypic information. Slides with “metastatic disease” with 100 laboratory responses demonstrated an extremely high degree of diagnostic accuracy with the correct general interpretation of “positive” for metastatic adenocarcinoma (97.6%), metastatic squamous cell carcinoma (95.6%), metastatic small cell carcinoma (96.5%), metastatic melanoma (97.9%), and metastatic

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carcinoma not otherwise specified (NOS) (94.5%). In each of these reference interpretations, the most common specific response by laboratories matched the reference interpretation in spite of the fact that participants did not have access to immunohistochemistry stains, multiple slide preparations including cell blocks, and had only limited clinical histories provided to them. For the reference diagnosis of metastatic small cell carcinoma, 70.2% of the responses matched the reference interpretation followed by metastatic malignancy NOS (5.8%) and large cell NHL (5.3%). For the reference diagnosis of metastatic adenocarcinoma, 52.5% of the responses matched the reference interpretation followed by metastatic carcinoma NOS (28.7%) metastatic malignancy (8.1%) and squamous cell carcinoma (2.7%) reflecting the difficulty of rendering a specific diagnosis of adenocarcinoma, particularly in poorly differentiated cases. For metastatic squamous cell carcinoma 66.1% of laboratory responses matched the reference interpretation followed by metastatic carcinoma, NOS (16.3%), metastatic malignancy (4.4%) and metastatic adenocarcinoma (3.3%). For the reference diagnosis of metastatic melanoma, the responses matched the reference interpretation in 66.8% of cases. Less specific diagnoses of metastatic malignancy (15.9%) and metastatic carcinoma, NOS (2.5%) were also given reflecting the difficulty in rendering a more specific interpretation in the absence of confirmatory immunohistochemistry studies, limited material to review and limited clinical history. Interestingly, 4.6% of the responses for melanoma were large cell NHL. Metastatic melanoma demonstrates morphologic overlap with many other entities including large cell lymphoma. In daily practice, immunohistochemistry plays an essential role in differentiating these entities. For the reference diagnosis of NHL, Large cell, participants were able to identify the cases as malignant in 80.8% of the time and 47.5% responded with the correct reference diagnosis. The second most common malignant diagnosis was NHL, OTL (16.7%). Depending on the percentage of small and large cells and in the absence of immunophenotyping and limited clinical information, this interpretation may be appropriate. A false negative general diagnosis was given 14.6% of the time; 13.1% of NHL, Large cell were called Negative/Reactive/Hyperplastic lymph nodes and 1.5% called Specific Infections/Granulomatous. Immunophenotyping is obviously needed, even in cases of large cell lymphoma, particularly when there is a mixture of both small and large cells, to establish a diagnosis of malignancy. For the reference diagnosis of NHL, OTL, an amazing 79.0% of laboratory responses identified the cases as malignant. Most of the laboratories (66.8%) correctly identified these cases as not large cell and only 0.4% of participants gave a reference diagnosis of large cell lymphoma. Of the 15.3% laboratory responses responding “negative,” the most common response was Negative/Reactive/Hyperplastic. This response is quite reasonable and expected when only one slide is available to review and in the absence of immunophenotypic information. For Hodgkin Lymphoma, 81.4% of the laboratories were able to identify the aspirate as malignant and 77.8% were correct to the reference diagnosis of Hodgkin lymphoma. Of the 13.2% negative general responses, the most common was Negative/Reactive/Hyperplastic lymph node underscoring the difficulty at times of identifying diagnostic Reed/Sternberg cells. The second most common negative interpretation given was Specific Infections/Granulomatous (4.2%), which may be a reasonable choice in cases of Hodgkin lymphoma that are often accompanied by granulomatous inflammation. Again, one must realize that participants are only given one slide on which to base their interpretations and do not have access to immunohistochemistry stains.

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Table B: Lymph Node Reference Diagnoses

Benign (number of participant responses) Malignant (number of participant responses) Negative/Reactive/Hyperplastic (1631) Metastatic Malignancy (40)

Specific Infections/Granulomatous (190)

Metastatic Carcinoma, NOS (1511)

Branchial cleft cyst (287)

Undifferentiated Carcinoma (23)

Metastatic Adenocarcinoma (2388)

Metastatic Squamous Cell Carcinoma (2726)

Metastatic Small Cell Carcinoma (712)

Metastatic Melanoma (1027)

Hodgkin Lymphoma (605)

NHL, Large Cell (765)

NHL, OTL (1223)

Whereas the above data represent the results for 2005, Tables C-D represents cumulative data from May 2001 to December 2005. Table D further divides the responses for NHL, OTL according to the subtype of small cell lymphoma. It is interesting to note that for follicular lymphoma, the second most common response was Negative/Reactive. This result is not surprising considering the polymorphous mixture of small and large cells of follicular lymphoma overlaps morphologically with reactive lymph nodes. (Figure 1) For mantle cell lymphoma, most were identified as NHL, OTL, but a small percentage were identified as large cell lymphoma, an entity well recognized as being in the differential diagnosis of mantle cell lymphoma. (Figure 2) Small lymphocytic lymphomas are usually quite small but can contain scattered large cells. On occasion one may obtain a number of cells from a proliferation zone. Although the overwhelming majority of participants recognized these cases as NHL, OTL, it is not surprising that large cell lymphoma, metastatic malignancy and Negative/Reactive responses were given by participants. There were only 2 cases of Marginal Zone/MALT lymphoma circulated, however 11 of the laboratories recognized these cases as NHL, OTL, and 2 laboratories reported results of metastatic small cell carcinoma, a reasonable response in the absence of additional preparations or immunophenotypic information. For Burkitt Lymphoma, all 18 laboratory responses given were malignant and were almost evenly divided between NHL, OTL (8) and NHL, large cell (10). These results are to be expected considering it is very difficult to distinguish Burkitt lymphoma from Large Cell lymphoma based upon morphology alone. (Figure 3) Finally, for lymphoblastic lymphoma there was a wide range of specific responses. Of the 40 laboratory responses, the most common was Negative/Reactive (14) followed by the correct reference response of NHL,OTL(13). These results can be expected based on the often deceptively bland appearance of lymphoblastic lymphoma in which the cells are small and often have inconspicuous nucleoli. A high mitotic rate and necrosis along with the clinical history of an aggressive clinical course are clues to the correct diagnosis. (Figure 4) However, without

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immunophenotyping and only one slide to review, one can see how this highly aggressive lymphoma can be interpreted as reactive or a low grade lymphoma, underscoring the need for a high index of suspicion when making a diagnosis of lymphoblastic lymphoma.

Table C: Cumulative Laboratory Responses for Lymphoma Diagnoses (2001-2005)

Diagnosis (Lab responses)

NHL-LC

NHL-OTL

Hodgkin Negative Blank Metastases Unsat Infection

NHL-LC (446) 207 103 10 42 16 60 3 5 NHL-OTL(138) 5 89 2 27 5 9 - 1 Hodgkin (464) 17 17 357 33 9 13 3 15

Table D: Cumulative Laboratory Responses for Lymphoma by Subtype (2001-2005)

Subtype Diagnosis (Lab Responses)

NHL-LC NHL-OTL Hodgkin Negative Blank Metastases

Small Lymphocytic (165) 10 106 8 16 11 14 Follicular (107) 5 67 - 30 - 5 Mantle cell (33) 3 29 - 1 - - Lymphoblastic (40) 3 13 - 14 - 10 Burkitt (18) 10 8 - - - - MALT (13) - 11 - - - 2

Summary for Lymph Node FNA specimens:

The cumulative 2005 NGC program results for lymph node FNA show that participants were able to identify benign from malignant aspiration biopsies for negative, reactive, and metastatic malignancies. Identifying the exact reference diagnosis for adenocarcinoma, squamous cell carcinoma, and melanoma was sometimes a challenge without access to immunohistochemistry or additional cytologic preparations. For malignant lymphoma, laboratories performed surprisingly well and were often able to identify the correct general diagnostic category even without immunophenotypic information. Interestingly, for both NHL, large cell and NHL, OTL, the spectrum of specific responses given is consistent with a reasonable differential diagnosis based on cytomorphology alone.

References:

1. Young NA, Al-Saleem TI, Ehya H, Smith MR. Utilization of fine needle aspiration cytology and flow cytometry in the diagnosis and subclassification of primary and recurrent lymphoma. Cancer Cytopathology 1998;84:252-261.

2. Young NA, Al-Saleem T. Diagnosis of lymphoma by fine-needle aspiration

cytology in the REAL era. Cancer Cytopathology. 1999;87:325-345.

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Fine Needle Aspiration of Liver

Fine Needle Aspiration (FNA) of the liver is a common specimen in most pathology practices and may present difficult interpretation challenges. Most of the studies looking at liver FNA have been generated at large academic centers, which may be biased when compared to the overall practice in the community at large. The data accumulated by the CAP NGC Program provides a unique opportunity to assess the accuracy and limitations of liver FNA across a broad and diverse spectrum of practicing pathologists and cytotechnologists, including those affiliated with academic centers, commercial laboratories and both large and small private practices. In 2005 the CAP NGC Program received 1,465 laboratory responses for liver FNA slides. In addition, there were 3,324 individual responses from pathologists and 2,063 individual responses from cytotechnologists. Program participants were asked to classify each slide into one of the four general diagnostic categories of “Negative”, “Positive”, “Suspicious”, or “Unsatisfactory” and also assign each case to a specific reference diagnosis to be chosen from a list of 17 coded reference diagnoses. Cases with one of 13 different diagnoses were circulated in 2005. Of these, there were 5 for which at least 100 laboratory responses were received. (Table E)

Table E: Liver Reference Diagnoses with at least 100 Laboratory Responses

Reference Diagnosis Number of Responses Adenocarcinoma (includes primary and metastatic) 517 Hepatocellular Carcinoma 276

Metastatic Carcinoma: Not Otherwise Specified 232

Neuroendocrine Tumor / Carcinoid 131 Metastatic Small Cell Carcinoma 120

Evaluation of reference diagnoses in liver FNA with greater than 100 laboratory responses for the 2005 NGC Program

Circulated cases of liver FNA which received greater than 100 laboratory responses exhibited a very high degree of diagnostic accuracy in making a diagnosis of “positive for malignancy”. False negative rates ranged from a low of 0.8% for metastatic small cell carcinoma to only 3.8% for neuroendocrine carcinoma (carcinoid). However, as may be expected the accuracy in making the correct specific reference diagnosis is not as good. Adenocarcinoma (including primary and metastatic) was the most common circulated entity with 517 laboratory responses (Table F). (Figure 5 and Cover.) While a positive general interpretation of “positive” or “suspicious” was made in 97.4% of cases, a correct specific diagnosis was only made by 46.4% of the respondents. It may be argued that the diagnoses of metastatic carcinoma NOS and metastatic malignancy are clinically equivalent diagnoses and if these responses (19.9% and 8.7% respectively) are added the accuracy rate increases to 75.0%. The most common incorrect specific diagnoses were hepatocellular carcinoma at 10.6% and neuroendocrine carcinoma (carcinoid) at 5.4%. Similar findings were seen in the category of metastatic carcinoma NOS (Table G). The correct general interpretation of positive or suspicious was made in 98.7% of the cases but the specific diagnosis was made in only 26.3%. Again when the diagnoses of metastatic carcinoma NOS, adenocarcinoma (31.9%), metastatic small cell carcinoma (8.2%) and

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metastatic malignancy (11.6%) are added together the response rate increases to 78.0%. The most common incorrect specific diagnoses were hepatocellular carcinoma at 6.9% and neuroendocrine carcinoma (carcinoid) at 4.7%. The second most common circulated specific diagnostic category was hepatocellular carcinoma (Table H). The correct general interpretation of positive or suspicious was made in 96.4% of the cases and the correct specific diagnosis was made in 73.9%. Adenocarcinoma (9.8%) was the most common incorrect answer followed by metastatic carcinoma NOS (3.3%), metastatic melanoma (2.5%) and metastatic malignancy, neuroendocrine carcinoma and normal liver all at 1.4%. The results for the specific category of neuroendocrine carcinoma (carcinoid) were similar (Table I) (Figure 6). The overall correct general diagnosis was made in 96.2% and the correct specific response in 73.3% of the cases. Adenocarcinoma and metastatic small cell carcinoma were the most common incorrect answers at 5.3%, followed by metastatic carcinoma (3.8%) and hepatocellular carcinoma, metastatic malignancy, lymphoma/hematopoietic malignancy and normal liver all at 2.3%. Evaluation of reference diagnoses in liver FNA with fewer than 100 laboratory responses for the 2005 NGC Program.

The only category of liver FNA with a relatively poor performance in the general response category was that of normal/non neoplastic liver. (Figure 7) While only 49 laboratory responses were received, the results are still informative (Table J). There was a false positive general interpretation of “positive” or “suspicious” in a total of 18.3% of these slides. A correct interpretation of normal/non neoplastic liver was only made in 53.1% of these cases with incorrect benign specific diagnoses of inflammatory/abscess/granuloma (10.2%), hepatocellular adenoma (10.2%) and benign neoplasm (6.1%). The most common incorrect malignant diagnosis was hepatocellular carcinoma (10.2%) followed by neuroendocrine carcinoma and adenocarcinoma (both at 2.0%). Summary for Liver FNA Evaluation of the 2005 NGC Program results for FNA of the liver highlight interesting and important points and possible interpretive pitfalls. First, it must be mentioned that the NGC Program is an educational exercise with an attendant “expectation bias” and does not exactly mimic everyday practice. Only one slide is available for evaluation and special stains are also not provided. In addition, one answer must be selected rather than using a more equivocal diagnosis or possibly sending the case for consultation. With that understanding, the overall ability of practicing pathologists and laboratories to make a correct diagnosis of malignancy in liver FNA in this program is quite good. However the high false positive rate of 18.3% in normal liver FNA suggests that there may be some difficulty in “over-interpreting” normal liver as well differentiated hepatocellular carcinoma (WDHCC). This is a well recognized problem and the differentiation of WDHCC from benign liver or a benign process such as adenoma or focal nodular hyperplasia is probably the most difficult differential diagnosis for liver FNA. (Figure 8) Close attention to cellular characteristics such as, hypercellular samples with arborescent clusters of broad trabeculae and transgressing or peripheral endothelial cells is imperative. The cytologic features of the individual hepatocytes are often similar in benign reactive lesions and WDHCC and thus may not be helpful in differentiating these lesions. However, subtle features such as an increased nuclear to cytoplasmic ratio in WDHCC may be indicative of malignancy. Benign liver

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aspirates often contain a mixture of benign bile ducts as well as hepatocytes but hepatic adenomas will lack these elements. Another diagnostic pitfall demonstrated in the 2005 data is the difficulty in distinguishing poorly differentiated hepatocellular carcinomas from metastatic lesions. The vast majority of liver lesions sampled by FNA are metastatic and the most common of these are metastatic carcinomas from the colon, pancreato-biliary system, breast and lung. The cytologic features of each of these is well described in the literature and close attention to cytologic criteria as well as clinical history will help in the diagnosis of these lesions. Additionally special stains ranging from mucin to immunohistochemistry are often used to differentiate these lesions in daily practice. Cytokeratin 7 and 20 tends to be negative in hepatocellular carcinoma and at least one of the keratins should be positive in metastatic carcinoma. HepPar 1 positivity and pericanalicular staining with polyclonal CEA indicates a hepatocellular origin. Cytologically, poorly differentiated hepatocellular carcinoma may show peripheral or transgressing endothelial cells or, rarely, bile production. The finding of cirrhosis or other clinical diseases associated with the development of HCC such as hepatitis or hemochromatosis may also suggest a primary hepatic neoplasm. References:

1. Renshaw AA, Haja J, Wilbur DC, Miller TE. Fine-needle aspirates of adenocarcinoma/metastatic carcinoma that resemble hepatocellular carcinoma: Correlating cytologic features and performance in the College of American Pathologists Non-Gynecologic Cytology Program. Arch Pathol Lab Med 2005;129:1217-1221.

2. Young NA, Mody DR and Davey DD. Misinterpretation of Normal Cellular Elements

in Fine-Needle Aspiration Biopsy Specimens. Arch Pathol Lab Med 2002; 126: 670–675.

Table F Site, General and Reference Interpretation

Evaluation of Participant Responses Interpretive Groups of > 100 Laboratory Responses

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Anatomic Site: FNA Liver

General Response Category: PositiveReference Interpretation: Adenocarcinoma (includes primary and metastatic)

Pathologist CT LaboratoryGeneral Response Category N % N % N %Negative 27 2.3% 17 2.6% 11 2.1%Positive 1128 95.1% 604 93.9% 496 95.9%Suspicious 24 2.0% 19 3.0% 8 1.5%Unsatisfactory 7 0.6% 3 0.5% 2 0.4%Total 1186 100.0% 643 100.0% 517 100.0%

Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma (includes primary and metastatic ) 534 45.0% 230 35.8% 240 46.4%Hepatocellular carcinoma 129 10.9% 174 27.1% 55 10.6%Metastatic carcinoma, NOS 253 21.3% 100 15.6% 103 19.9%Metastatic malignancy 105 8.9% 60 9.3% 45 8.7%Metastatic small cell carcinoma 29 2.4% 15 2.3% 8 1.5%Neuroendocrine carcinoma (Carcinoid) 77 6.5% 19 3.0% 28 5.4%Unsatisfactory 4 0.3% 2 0.3% 1 0.2%Blank/Other 55 4.6% 43 6.7% 37 7.2%Total 1186 100.0% 643 100.0% 517 100.0%

Table G Site, General and Reference Interpretation


13


General Response Category: PositiveReference Interpretation: Metastatic carcinoma, NOS


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma (includes primary and metastatic ) 170 31.4% 101 28.1% 74 31.9%Hepatocellular carcinoma 25 4.6% 89 24.7% 16 6.9%Metastatic carcinoma, NOS 140 25.8% 70 19.4% 61 26.3%Metastatic malignancy 70 12.9% 57 15.8% 27 11.6%Metastatic small cell carcinoma 51 9.4% 19 5.3% 19 8.2%Metastatic squamous cell carcinoma 30 5.5% 9 2.5% 8 3.4%Neuroendocrine carcinoma (Carcinoid) 21 3.9% 9 2.5% 11 4.7%Blank/Other 35 6.5% 6 1.7% 16 6.9%Total 542 100.0% 360 100.0% 232 100.0%

Table H Site, General and Reference Interpretation


14


General Response Category: PositiveReference Interpretation: Hepatocellular carcinoma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma (includes primary and metastatic) 72 11.7% 43 10.6% 27 9.8%Hepatocellular adenoma 7 1.1% 4 1.0% 3 1.1%Hepatocellular carcinoma 465 75.9% 316 77.8% 204 73.9%Metastatic carcinoma, NOS 17 2.8% 11 2.7% 9 3.3%Metastatic malignancy 11 1.8% 6 1.5% 4 1.4%Metastatic melanoma 16 2.6% 1 0.2% 7 2.5%Neuroendocrine carcinoma (Carcinoid) 10 1.6% 2 0.5% 4 1.4%Normal/non neoplastic liver 7 1.1% 6 1.5% 4 1.4%Blank/Other 8 1.3% 17 4.2% 14 5.1%Total 613 100.0% 406 100.0% 276 100.0%

Table I Site, General and Reference Interpretation


15


General Response Category: PositiveReference Interpretation: Neuroendocrine carcinoma (Carcinoid)


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma (includes primary and metastatic ) 8 2.8% 18 9.6% 7 5.3%Hepatocellular carcinoma 7 2.5% 10 5.3% 3 2.3%Lymphoma/hematopoietic malignancy 11 3.9% 13 7.0% 3 2.3%Metastatic carcinoma, NOS 6 2.1% 12 6.4% 5 3.8%Metastatic malignancy 6 2.1% 7 3.7% 3 2.3%Metastatic small cell carcinoma 13 4.6% 16 8.6% 7 5.3%Neuroendocrine carcinoma (Carcinoid) 215 76.2% 82 43.9% 96 73.3%Normal/non neoplastic liver 5 1.8% 14 7.5% 3 2.3%Blank/Other 11 3.9% 15 8.0% 4 3.1%Total 282 100.0% 187 100.0% 131 100.0%

Table J Site, General and Reference Interpretation

Evaluation of Participant Responses Interpretive Groups of <= 100 Laboratory Responses

16


General Response Category: NegativeReference Interpretation: Normal/non neoplastic liver


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma (includes primary and metastatic) 2 1.7% 0 0.0% 1 2.0%Benign neoplasm, NOS 6 5.0% 3 7.3% 3 6.1%Hepatocellular adenoma 19 15.7% 6 14.6% 5 10.2%Hepatocellular carcinoma 9 7.4% 2 4.9% 5 10.2%Inflammatory/Abscess/Granulomas 22 18.2% 9 22.0% 5 10.2%Neuroendocrine carcinoma (Carcinoid) 4 3.3% 2 4.9% 1 2.0%Normal/non neoplastic liver 53 43.8% 18 43.9% 26 53.1%Unsatisfactory 3 2.5% 1 2.4% 1 2.0%Blank/Other 3 2.5% 0 0.0% 2 4.1%Total 121 100.0% 41 100.0% 49 100.0%

TABLES 1-67

The following represent selected tables of additional data with greater than 100 responses accumulated from the 2005 NGC program for further participants information.

Table 1 Site, General and Reference Interpretation


17

Anatomic Site: Bronchioloalveolar lavage

General Response Category: NegativeReference Interpretation: Normal/Reactive


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma including bronchioloalveolar 10 2.0% 7 1.9% 4 1.8%Infection, Fungal 11 2.2% 8 2.2% 7 3.1%Infection, Herpes 15 3.0% 2 0.5% 1 0.4%Infection, PCP 16 3.3% 5 1.4% 4 1.8%Infection, Parasitic 8 1.6% 3 0.8% 3 1.3%Lymphoma/hematopoietic malignancy 3 0.6% 11 3.0% 3 1.3%Normal/Reactive 403 81.9% 297 81.6% 177 78.0%Pulmonary alveolar proteinosis 10 2.0% 14 3.8% 8 3.5%Unsatisfactory 3 0.6% 3 0.8% 2 0.9%Blank/Other 13 2.6% 14 3.8% 18 7.9%Total 492 100.0% 364 100.0% 227 100.0%



18

Anatomic Site: Bronchioloalveolar lavage

General Response Category: NegativeReference Interpretation: Infection, PCP


Pathologist CT LaboratoryInterpretation Choices N % N % N %Infection, Fungal 7 2.3% 4 2.1% 3 2.0%Infection, PCP 248 80.0% 140 73.3% 120 79.5%Normal/Reactive 33 10.6% 35 18.3% 19 12.6%Pulmonary alveolar proteinosis 15 4.8% 6 3.1% 3 2.0%Unsatisfactory 2 0.6% 1 0.5% 0 0.0%Blank/Other 5 1.6% 5 2.6% 6 4.0%Total 310 100.0% 191 100.0% 151 100.0%



19

Anatomic Site: FNA Lung

General Response Category: PositiveReference Interpretation: Squamous cell carcinoma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma including bronchioloalveolar 30 4.5% 14 4.1% 10 3.5%Infectious/Inflammatory 12 1.8% 3 0.9% 3 1.0%Non small cell carcinoma 123 18.4% 52 15.2% 55 19.1%Small cell undifferentiated carcinoma 17 2.5% 4 1.2% 7 2.4%Squamous cell carcinoma 453 67.6% 255 74.6% 193 67.0%Unsatisfactory 9 1.3% 5 1.5% 1 0.3%Blank/Other 26 3.9% 9 2.6% 19 6.6%Total 670 100.0% 342 100.0% 288 100.0%



20


General Response Category: PositiveReference Interpretation: Adenocarcinoma including bronchioloalveolar


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma including bronchioloalveolar 480 41.3% 262 39.6% 199 40.8%Carcinoid 41 3.5% 18 2.7% 13 2.7%Metastatic carcinoma, NOS 50 4.3% 16 2.4% 16 3.3%Non small cell carcinoma 460 39.6% 260 39.3% 204 41.8%Small cell undifferentiated carcinoma 42 3.6% 20 3.0% 15 3.1%Squamous cell carcinoma 43 3.7% 60 9.1% 16 3.3%Unsatisfactory 2 0.2% 0 0.0% 0 0.0%Blank/Other 45 3.9% 25 3.8% 25 5.1%Total 1163 100.0% 661 100.0% 488 100.0%



21


General Response Category: PositiveReference Interpretation: Small cell undifferentiated carcinoma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma including bronchioloalveolar 15 3.3% 5 1.7% 5 2.6%Carcinoid 10 2.2% 8 2.8% 3 1.5%Lymphoma/hematopoietic malignancy 6 1.3% 5 1.7% 1 0.5%Non small cell carcinoma 42 9.3% 36 12.5% 26 13.3%Normal/Reactive 8 1.8% 21 7.3% 6 3.1%Small cell undifferentiated carcinoma 354 78.1% 195 67.9% 141 72.3%Squamous cell carcinoma 3 0.7% 6 2.1% 4 2.1%Unsatisfactory 1 0.2% 1 0.3% 1 0.5%Blank/Other 14 3.1% 10 3.5% 8 4.1%Total 453 100.0% 287 100.0% 195 100.0%



22


General Response Category: PositiveReference Interpretation: Non small cell carcinoma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma including bronchioloalveolar 287 17.7% 228 23.5% 119 18.1%Infectious/Inflammatory 17 1.0% 11 1.1% 8 1.2%Non small cell carcinoma 857 52.8% 475 49.0% 368 56.1%Small cell undifferentiated carcinoma 159 9.8% 66 6.8% 40 6.1%Squamous cell carcinoma 218 13.4% 154 15.9% 77 11.7%Unsatisfactory 3 0.2% 1 0.1% 0 0.0%Blank/Other 81 5.0% 34 3.5% 44 6.7%Total 1622 100.0% 969 100.0% 656 100.0%



23




Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma including bronchioloalveolar 58 16.8% 49 22.2% 29 18.2%Carcinoid 10 2.9% 3 1.4% 2 1.3%Metastatic carcinoma, NOS 180 52.0% 98 44.3% 91 57.2%Non small cell carcinoma 44 12.7% 34 15.4% 18 11.3%Normal/Reactive 7 2.0% 8 3.6% 4 2.5%Other malignancy 8 2.3% 1 0.5% 1 0.6%Small cell undifferentiated carcinoma 5 1.4% 9 4.1% 1 0.6%Squamous cell carcinoma 7 2.0% 12 5.4% 2 1.3%Unsatisfactory 7 2.0% 1 0.5% 2 1.3%Blank/Other 20 5.8% 6 2.7% 9 5.7%Total 346 100.0% 221 100.0% 159 100.0%



24

Anatomic Site: FNA Subcutaneous/soft tissue

General Response Category: PositiveReference Interpretation: Metastatic melanoma

Pathologist CT LaboratoryGeneral Response Category N % N % N %Negative 5 1.9% 18 11.2% 3 2.6%Positive 259 97.7% 142 88.2% 112 97.4%Suspicious 1 0.4% 1 0.6% 0 0.0%Total 265 100.0% 161 100.0% 115 100.0%

Pathologist CT LaboratoryInterpretation Choices N % N % N %Inflammatory/Abscess 6 2.3% 5 3.1% 3 2.6%Leukemia/Lymphoma/Other hematopoietic malignancy 3 1.1% 1 0.6% 2 1.7%Metastatic malignancy 26 9.8% 24 14.9% 8 7.0%Metastatic melanoma 192 72.5% 103 64.0% 90 78.3%Myeloma/Plasmacytoma 6 2.3% 2 1.2% 3 2.6%Other benign lesions including cysts 0 0.0% 9 5.6% 0 0.0%Primary/metastatic carcinoma/NOS 21 7.9% 11 6.8% 5 4.3%Blank/Other 11 4.2% 6 3.7% 4 3.5%Total 265 100.0% 161 100.0% 115 100.0%



25


General Response Category: NegativeReference Interpretation: Other benign lesions including cysts


Pathologist CT LaboratoryInterpretation Choices N % N % N %Basal cell carcinoma 4 1.1% 3 1.3% 2 1.3%Benign spindle cell neoplasm 5 1.4% 3 1.3% 1 0.6%Fat necrosis/Foreign body reaction 21 5.9% 13 5.8% 6 3.8%Inflammatory/Abscess 50 14.1% 31 13.8% 23 14.6%Lipoma 8 2.3% 8 3.6% 3 1.9%Metastatic malignancy 4 1.1% 6 2.7% 0 0.0%Myxoid liposarcoma 5 1.4% 1 0.4% 2 1.3%Other benign lesions including cysts 200 56.5% 104 46.2% 86 54.4%Pilomatrixoma 16 4.5% 12 5.3% 9 5.7%Primary/metastatic carcinoma/NOS 8 2.3% 5 2.2% 3 1.9%Unsatisfactory 9 2.5% 16 7.1% 5 3.2%Blank/Other 24 6.8% 23 10.2% 18 11.4%Total 354 100.0% 225 100.0% 158 100.0%



26


General Response Category: PositiveReference Interpretation: Spindle cell sarcoma, NOS


Pathologist CT LaboratoryInterpretation Choices N % N % N %Benign spindle cell neoplasm 58 7.6% 31 5.9% 21 6.6%Leukemia/Lymphoma/Other hematopoietic malignancy 12 1.6% 6 1.1% 6 1.9%Metastatic malignancy 58 7.6% 64 12.2% 25 7.8%Metastatic melanoma 5 0.7% 25 4.8% 2 0.6%Myxoid liposarcoma 87 11.4% 54 10.3% 38 11.9%Nodular fascitis 27 3.5% 16 3.0% 10 3.1%Primary/metastatic carcinoma/NOS 43 5.6% 64 12.2% 20 6.2%Rhabdomyosarcoma 15 2.0% 26 5.0% 3 0.9%Spindle cell sarcoma, NOS 425 55.8% 216 41.1% 174 54.4%Unsatisfactory 0 0.0% 1 0.2% 1 0.3%Blank/Other 32 4.2% 22 4.2% 20 6.2%Total 762 100.0% 525 100.0% 320 100.0%



27


General Response Category: PositiveReference Interpretation: Primary/metastatic carcinoma/NOS


Pathologist CT LaboratoryInterpretation Choices N % N % N %Leukemia/Lymphoma/Other hematopoietic malignancy 27 1.4% 21 1.9% 12 1.4%Merkel cell tumor 31 1.6% 16 1.4% 11 1.3%Metastatic malignancy 708 37.1% 539 47.9% 318 38.0%Metastatic melanoma 35 1.8% 35 3.1% 17 2.0%Primary/metastatic carcinoma/NOS 928 48.7% 425 37.8% 390 46.6%Spindle cell sarcoma, NOS 24 1.3% 13 1.2% 8 1.0%Unsatisfactory 5 0.3% 0 0.0% 1 0.1%Blank/Other 149 7.8% 76 6.8% 80 9.6%Total 1907 100.0% 1125 100.0% 837 100.0%



28

Anatomic Site: FNA Breast

General Response Category: NegativeReference Interpretation: Cyst contents, benign


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma, ductal type 9 1.0% 51 8.2% 4 1.0%Atypical epithelial cells, indeterminate 27 2.9% 19 3.1% 10 2.6%Benign lesion, NOS 55 5.9% 75 12.1% 17 4.4%Cyst contents, benign 443 47.4% 210 33.8% 196 50.8%Fibroadenoma 12 1.3% 10 1.6% 4 1.0%Fibrocystic changes 325 34.8% 213 34.2% 121 31.3%Papillary lesion 19 2.0% 9 1.4% 8 2.1%Unsatisfactory 11 1.2% 4 0.6% 4 1.0%Blank/Other 34 3.6% 31 5.0% 22 5.7%Total 935 100.0% 622 100.0% 386 100.0%



29


General Response Category: NegativeReference Interpretation: Fibrocystic changes


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma, ductal type 6 2.0% 8 3.9% 3 2.2%Atypical epithelial cells, indeterminate 18 6.1% 12 5.9% 5 3.6%Benign lesion, NOS 25 8.5% 23 11.3% 12 8.6%Cyst contents, benign 48 16.4% 29 14.3% 26 18.7%Fat Necrosis, Foreign body reaction 7 2.4% 3 1.5% 2 1.4%Fibroadenoma 49 16.7% 63 31.0% 27 19.4%Fibrocystic changes 115 39.2% 57 28.1% 53 38.1%Lactating adenoma/pregnancy related changes 4 1.4% 2 1.0% 2 1.4%Papillary lesion 10 3.4% 2 1.0% 4 2.9%Unsatisfactory 4 1.4% 0 0.0% 0 0.0%Blank/Other 7 2.4% 4 2.0% 5 3.6%Total 293 100.0% 203 100.0% 139 100.0%



30


General Response Category: NegativeReference Interpretation: Fibroadenoma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma, ductal type 19 3.0% 43 9.3% 10 3.7%Atypical epithelial cells, indeterminate 16 2.6% 7 1.5% 3 1.1%Benign lesion, NOS 32 5.1% 19 4.1% 16 6.0%Fibroadenoma 489 78.0% 334 72.1% 199 74.3%Fibrocystic changes 19 3.0% 19 4.1% 5 1.9%Papillary lesion 14 2.2% 12 2.6% 6 2.2%Phyllodes tumor 18 2.9% 3 0.6% 10 3.7%Unsatisfactory 2 0.3% 0 0.0% 0 0.0%Blank/Other 18 2.9% 26 5.6% 19 7.1%Total 627 100.0% 463 100.0% 268 100.0%



31


General Response Category: PositiveReference Interpretation: Adenocarcinoma, ductal type


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma, ductal type 3058 72.5% 1736 70.2% 1347 74.7%Adenocarcinoma, lobular type 257 6.1% 205 8.3% 105 5.8%Atypical epithelial cells, indeterminate 127 3.0% 53 2.1% 53 2.9%Carcinoma, NOS 274 6.5% 124 5.0% 90 5.0%Fibroadenoma 119 2.8% 62 2.5% 38 2.1%Medullary carcinoma 66 1.6% 88 3.6% 27 1.5%Mucinous carcinoma 36 0.9% 42 1.7% 15 0.8%Papillary lesion 76 1.8% 47 1.9% 23 1.3%Unsatisfactory 11 0.3% 0 0.0% 3 0.2%Blank/Other 193 4.6% 117 4.7% 103 5.7%Total 4217 100.0% 2474 100.0% 1804 100.0%



32


General Response Category: PositiveReference Interpretation: Mucinous carcinoma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma, ductal type 108 22.5% 128 38.9% 56 26.7%Adenocarcinoma, lobular type 19 4.0% 16 4.9% 12 5.7%Atypical epithelial cells, indeterminate 15 3.1% 10 3.0% 7 3.3%Benign lesion, NOS 7 1.5% 6 1.8% 5 2.4%Carcinoma, NOS 21 4.4% 12 3.6% 8 3.8%Fibroadenoma 30 6.2% 30 9.1% 8 3.8%Fibrocystic changes 8 1.7% 2 0.6% 3 1.4%Medullary carcinoma 7 1.5% 8 2.4% 2 1.0%Mucinous carcinoma 221 46.0% 90 27.4% 90 42.9%Papillary lesion 21 4.4% 14 4.3% 9 4.3%Unsatisfactory 5 1.0% 3 0.9% 2 1.0%Blank/Other 18 3.8% 10 3.0% 8 3.8%Total 480 100.0% 329 100.0% 210 100.0%



33


General Response Category: NegativeReference Interpretation: Mastitis/Abscess


Pathologist CT LaboratoryInterpretation Choices N % N % N %Benign lesion, NOS 5 2.2% 3 2.2% 3 2.8%Cyst contents, benign 2 0.9% 6 4.4% 1 0.9%Epidermal inclusion cyst 7 3.1% 0 0.0% 2 1.9%Fat Necrosis, Foreign body reaction 11 4.8% 10 7.4% 5 4.7%Fibrocystic changes 2 0.9% 6 4.4% 2 1.9%Lactating adenoma/pregnancy related changes 3 1.3% 5 3.7% 2 1.9%Mastitis/Abscess 188 82.5% 94 69.1% 81 76.4%Silicone granulomas 2 0.9% 2 1.5% 1 0.9%Unsatisfactory 0 0.0% 2 1.5% 0 0.0%Blank/Other 8 3.5% 8 5.9% 9 8.5%Total 228 100.0% 136 100.0% 106 100.0%



34

Anatomic Site: Gastric/GI brushing

General Response Category: PositiveReference Interpretation: Adenocarcinoma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma 283 77.7% 205 82.7% 123 75.5%Carcinoma, NOS 19 5.2% 11 4.4% 7 4.3%Infection, Candida species 5 1.4% 3 1.2% 2 1.2%Normal/Reactive 40 11.0% 20 8.1% 16 9.8%Unsatisfactory 3 0.8% 1 0.4% 1 0.6%Blank/Other 14 3.8% 8 3.2% 14 8.6%Total 364 100.0% 248 100.0% 163 100.0%



35

Anatomic Site: FNA Salivary gland

General Response Category: NegativeReference Interpretation: Pleomorphic adenoma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenoid cystic carcinoma 11 1.0% 16 2.5% 3 0.7%Benign neoplasm, NOS 20 1.9% 31 4.9% 9 2.0%Monomorphic adenoma 53 5.0% 25 3.9% 16 3.5%Mucoepidermoid carcinoma, low grade 8 0.7% 14 2.2% 6 1.3%Normal salivary gland/Sialoadenosis 5 0.5% 16 2.5% 2 0.4%Pleomorphic adenoma 928 86.8% 443 70.0% 381 84.5%Unsatisfactory 2 0.2% 3 0.5% 1 0.2%Blank/Other 42 3.9% 85 13.4% 33 7.3%Total 1069 100.0% 633 100.0% 451 100.0%



36


General Response Category: NegativeReference Interpretation: Warthin tumor


Pathologist CT LaboratoryInterpretation Choices N % N % N %Benign neoplasm, NOS 16 2.9% 20 7.8% 6 2.5%Lymphoepithelial lesions/Lymphoepithelial cyst 51 9.2% 23 9.0% 23 9.5%Lymphoma 12 2.2% 0 0.0% 4 1.7%Normal salivary gland/Sialoadenosis 3 0.5% 14 5.5% 5 2.1%Oncocytoma 18 3.2% 7 2.7% 8 3.3%Pleomorphic adenoma 31 5.6% 22 8.6% 9 3.7%Sialoadenitis/Granulomas 31 5.6% 23 9.0% 12 5.0%Unsatisfactory 1 0.2% 0 0.0% 0 0.0%Warthin tumor 357 64.3% 132 51.6% 157 64.9%Blank/Other 35 6.3% 15 5.9% 18 7.4%Total 555 100.0% 256 100.0% 242 100.0%



37


General Response Category: PositiveReference Interpretation: Adenoid cystic carcinoma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Acinic cell carcinoma 2 0.6% 8 4.7% 3 2.4%Adenocarcinoma, NOS 25 7.4% 6 3.5% 6 4.9%Adenoid cystic carcinoma 136 40.5% 69 40.6% 55 44.7%Benign neoplasm, NOS 6 1.8% 3 1.8% 3 2.4%Lymphoepithelial lesions/Lymphoepithelial cyst 11 3.3% 1 0.6% 2 1.6%Lymphoma 20 6.0% 11 6.5% 7 5.7%Monomorphic adenoma 32 9.5% 2 1.2% 9 7.3%Mucoepidermoid carcinoma, high grade 4 1.2% 2 1.2% 2 1.6%Mucoepidermoid carcinoma, low grade 6 1.8% 5 2.9% 2 1.6%Papillary carcinoma 8 2.4% 1 0.6% 2 1.6%Pleomorphic adenoma 45 13.4% 23 13.5% 17 13.8%Small cell undifferentiated carcinoma 12 3.6% 7 4.1% 3 2.4%Undifferentiated carcinoma 8 2.4% 11 6.5% 2 1.6%Warthin tumor 10 3.0% 7 4.1% 4 3.3%Blank/Other 11 3.3% 14 8.2% 6 4.9%Total 336 100.0% 170 100.0% 123 100.0%



38


General Response Category: PositiveReference Interpretation: Acinic cell carcinoma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Acinic cell carcinoma 70 29.3% 18 17.8% 34 28.8%Adenocarcinoma, NOS 3 1.3% 1 1.0% 1 0.8%Adenoid cystic carcinoma 5 2.1% 6 5.9% 1 0.8%Benign neoplasm, NOS 18 7.5% 13 12.9% 11 9.3%Lymphoepithelial lesions/Lymphoepithelial cyst 8 3.3% 3 3.0% 4 3.4%Lymphoma 3 1.3% 1 1.0% 1 0.8%Monomorphic adenoma 33 13.8% 15 14.9% 13 11.0%Mucoepidermoid carcinoma, low grade 2 0.8% 2 2.0% 2 1.7%Normal salivary gland/Sialoadenosis 19 7.9% 12 11.9% 10 8.5%Pleomorphic adenoma 52 21.8% 20 19.8% 23 19.5%Sialoadenitis/Granulomas 4 1.7% 1 1.0% 3 2.5%Warthin tumor 15 6.3% 7 6.9% 9 7.6%Blank/Other 7 2.9% 2 2.0% 6 5.1%Total 239 100.0% 101 100.0% 118 100.0%



39


General Response Category: PositiveReference Interpretation: Hepatocellular carcinoma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma (includes primary and metastatic ) 72 11.7% 43 10.6% 27 9.8%Hepatocellular adenoma 7 1.1% 4 1.0% 3 1.1%Hepatocellular carcinoma 465 75.9% 316 77.8% 204 73.9%Metastatic carcinoma, NOS 17 2.8% 11 2.7% 9 3.3%Metastatic malignancy 11 1.8% 6 1.5% 4 1.4%Metastatic melanoma 16 2.6% 1 0.2% 7 2.5%Neuroendocrine carcinoma (Carcinoid) 10 1.6% 2 0.5% 4 1.4%Normal/non neoplastic liver 7 1.1% 6 1.5% 4 1.4%Blank/Other 8 1.3% 17 4.2% 14 5.1%Total 613 100.0% 406 100.0% 276 100.0%



40


General Response Category: PositiveReference Interpretation: Neuroendocrine carcinoma (Carcinoid)


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma (includes primary and metastatic) 8 2.8% 18 9.6% 7 5.3%Hepatocellular carcinoma 7 2.5% 10 5.3% 3 2.3%Lymphoma/hematopoietic malignancy 11 3.9% 13 7.0% 3 2.3%Metastatic carcinoma, NOS 6 2.1% 12 6.4% 5 3.8%Metastatic malignancy 6 2.1% 7 3.7% 3 2.3%Metastatic small cell carcinoma 13 4.6% 16 8.6% 7 5.3%Neuroendocrine carcinoma (Carcinoid) 215 76.2% 82 43.9% 96 73.3%Normal/non neoplastic liver 5 1.8% 14 7.5% 3 2.3%Blank/Other 11 3.9% 15 8.0% 4 3.1%Total 282 100.0% 187 100.0% 131 100.0%



41


General Response Category: PositiveReference Interpretation: Adenocarcinoma (includes primary and metastatic)


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma (includes primary and metastatic ) 534 45.0% 230 35.8% 240 46.4%Hepatocellular carcinoma 129 10.9% 174 27.1% 55 10.6%Metastatic carcinoma, NOS 253 21.3% 100 15.6% 103 19.9%Metastatic malignancy 105 8.9% 60 9.3% 45 8.7%Metastatic small cell carcinoma 29 2.4% 15 2.3% 8 1.5%Neuroendocrine carcinoma (Carcinoid) 77 6.5% 19 3.0% 28 5.4%Unsatisfactory 4 0.3% 2 0.3% 1 0.2%Blank/Other 55 4.6% 43 6.7% 37 7.2%Total 1186 100.0% 643 100.0% 517 100.0%



42




Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma (includes primary and metastatic ) 170 31.4% 101 28.1% 74 31.9%Hepatocellular carcinoma 25 4.6% 89 24.7% 16 6.9%Metastatic carcinoma, NOS 140 25.8% 70 19.4% 61 26.3%Metastatic malignancy 70 12.9% 57 15.8% 27 11.6%Metastatic small cell carcinoma 51 9.4% 19 5.3% 19 8.2%Metastatic squamous cell carcinoma 30 5.5% 9 2.5% 8 3.4%Neuroendocrine carcinoma (Carcinoid) 21 3.9% 9 2.5% 11 4.7%Blank/Other 35 6.5% 6 1.7% 16 6.9%Total 542 100.0% 360 100.0% 232 100.0%



43


General Response Category: PositiveReference Interpretation: Metastatic small cell carcinoma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma (includes primary and metastatic ) 6 2.4% 10 5.5% 3 2.5%Hepatocellular carcinoma 2 0.8% 6 3.3% 4 3.3%Inflammatory/Abscess/Granulomas 4 1.6% 2 1.1% 1 0.8%Lymphoma/hematopoietic malignancy 5 2.0% 1 0.5% 1 0.8%Metastatic carcinoma, NOS 20 7.8% 6 3.3% 9 7.5%Metastatic malignancy 15 5.9% 17 9.3% 8 6.7%Metastatic small cell carcinoma 184 72.2% 118 64.8% 78 65.0%Neuroendocrine carcinoma (Carcinoid) 16 6.3% 9 4.9% 7 5.8%Unsatisfactory 2 0.8% 0 0.0% 2 1.7%Blank/Other 1 0.4% 13 7.1% 7 5.8%Total 255 100.0% 182 100.0% 120 100.0%



44

Anatomic Site: FNA Pancreas



Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma 730 79.2% 429 73.1% 322 78.5%Carcinoma, NOS 76 8.2% 63 10.7% 29 7.1%Islet cell/neuroendocrine tumor 15 1.6% 15 2.6% 5 1.2%Mucinous Cystic Neoplasm 35 3.8% 17 2.9% 18 4.4%Pancreatitis/Reactive/Repair 35 3.8% 20 3.4% 15 3.7%Unsatisfactory 6 0.7% 1 0.2% 3 0.7%Blank/Other 25 2.7% 42 7.2% 18 4.4%Total 922 100.0% 587 100.0% 410 100.0%



45

Anatomic Site: FNA Thyroid/parathyroid

General Response Category: NegativeReference Interpretation: Nodular/non-neoplastic goiter (Adenomatous nodule)


Pathologist CT LaboratoryInterpretation Choices N % N % N %Cystic lesions, non-diagnostic 101 7.0% 64 7.6% 38 6.4%Follicular neoplasm, suspicious for malignancy 108 7.5% 73 8.6% 38 6.4%Hurthle cell neoplasm suspicious for malignancy 39 2.7% 15 1.8% 9 1.5%Lymphocytic thyroiditis (Hashimoto's) 84 5.8% 76 9.0% 27 4.5%Nodular/non-neoplastic goiter (Adenomatous nodule) 961 66.5% 529 62.6% 412 69.2%Papillary carcinoma 43 3.0% 23 2.7% 13 2.2%Parathyroid hyperplasia/adenoma 23 1.6% 15 1.8% 7 1.2%Thyroiditis, NOS 19 1.3% 27 3.2% 8 1.3%Unsatisfactory 30 2.1% 6 0.7% 7 1.2%Blank/Other 37 2.6% 17 2.0% 36 6.1%Total 1445 100.0% 845 100.0% 595 100.0%



46


General Response Category: NegativeReference Interpretation: Cystic lesions, non-diagnostic


Pathologist CT LaboratoryInterpretation Choices N % N % N %Cystic lesions, non-diagnostic 163 61.7% 99 63.5% 80 66.7%Hurthle cell neoplasm suspicious for malignancy 5 1.9% 5 3.2% 2 1.7%Lymphocytic thyroiditis (Hashimoto's) 9 3.4% 4 2.6% 4 3.3%Nodular/non-neoplastic goiter (Adenomatous nodule) 55 20.8% 29 18.6% 20 16.7%Papillary carcinoma 4 1.5% 1 0.6% 2 1.7%Thyroiditis, NOS 4 1.5% 5 3.2% 0 0.0%Unsatisfactory 19 7.2% 6 3.8% 4 3.3%Blank/Other 5 1.9% 7 4.5% 8 6.7%Total 264 100.0% 156 100.0% 120 100.0%



47


General Response Category: NegativeReference Interpretation: Lymphocytic thyroiditis (Hashimoto's)


Pathologist CT LaboratoryInterpretation Choices N % N % N %Follicular neoplasm, suspicious for malignancy 38 4.9% 32 6.8% 15 4.4%Hurthle cell neoplasm suspicious for malignancy 29 3.7% 29 6.2% 15 4.4%Lymphocytic thyroiditis (Hashimoto's) 549 70.9% 297 63.5% 253 74.2%Lymphoma 23 3.0% 8 1.7% 8 2.3%Medullary carcinoma 15 1.9% 14 3.0% 5 1.5%Nodular/non-neoplastic goiter (Adenomatous nodule) 26 3.4% 32 6.8% 11 3.2%Papillary carcinoma 33 4.3% 14 3.0% 13 3.8%Thyroiditis, NOS 39 5.0% 17 3.6% 12 3.5%Undifferentiated carcinoma/Anaplastic 3 0.4% 12 2.6% 1 0.3%Unsatisfactory 7 0.9% 2 0.4% 1 0.3%Blank/Other 12 1.6% 11 2.4% 7 2.1%Total 774 100.0% 468 100.0% 341 100.0%



48


General Response Category: PositiveReference Interpretation: Papillary carcinoma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Follicular neoplasm, suspicious for malignancy 75 8.0% 75 11.5% 28 6.7%Hurthle cell neoplasm suspicious for malignancy 37 3.9% 30 4.6% 9 2.2%Lymphocytic thyroiditis (Hashimoto's) 13 1.4% 8 1.2% 5 1.2%Medullary carcinoma 37 3.9% 15 2.3% 11 2.7%Nodular/non-neoplastic goiter (Adenomatous nodule) 36 3.8% 33 5.1% 13 3.1%Papillary carcinoma 703 74.6% 465 71.2% 326 78.6%Undifferentiated carcinoma/Anaplastic 11 1.2% 6 0.9% 7 1.7%Blank/Other 30 3.2% 21 3.2% 16 3.9%Total 942 100.0% 653 100.0% 415 100.0%



49

Anatomic Site: FNA Lymph node



Pathologist CT LaboratoryInterpretation Choices N % N % N %Metastatic adenocarcinoma 165 17.6% 116 20.2% 70 17.6%Metastatic carcinoma, NOS 362 38.6% 149 26.0% 155 38.9%Metastatic malignancy 138 14.7% 99 17.2% 57 14.3%Metastatic melanoma 18 1.9% 15 2.6% 6 1.5%Metastatic small cell carcinoma 27 2.9% 26 4.5% 12 3.0%Metastatic squamous cell carcinoma 93 9.9% 61 10.6% 40 10.1%Negative/Reactive/Hyperplastic lymph nodes 23 2.5% 11 1.9% 7 1.8%Non-Hodgkin Lymphoma, large cell 49 5.2% 40 7.0% 17 4.3%Undifferentiated carcinoma 12 1.3% 26 4.5% 4 1.0%Unsatisfactory 4 0.4% 1 0.2% 2 0.5%Blank/Other 46 4.9% 30 5.2% 28 7.0%Total 937 100.0% 574 100.0% 398 100.0%



50


General Response Category: NegativeReference Interpretation: Negative/Reactive/Hyperplastic lymph nodes


Pathologist CT LaboratoryInterpretation Choices N % N % N %Hodgkin lymphoma 15 1.5% 13 2.1% 8 1.8%Metastatic small cell carcinoma 13 1.3% 6 1.0% 4 0.9%Negative/Reactive/Hyperplastic lymph nodes 714 69.6% 392 64.8% 319 72.8%Non-Hodgkin Lymphoma, large cell 46 4.5% 38 6.3% 13 3.0%Non-Hodgkin lymphoma, other than large cell 98 9.6% 92 15.2% 42 9.6%Specific Infections/Granulomatous 106 10.3% 38 6.3% 33 7.5%Unsatisfactory 3 0.3% 0 0.0% 0 0.0%Blank/Other 31 3.0% 26 4.3% 19 4.3%Total 1026 100.0% 605 100.0% 438 100.0%



51


General Response Category: PositiveReference Interpretation: Non-Hodgkin lymphoma, other than large cell


Pathologist CT LaboratoryInterpretation Choices N % N % N %Hodgkin lymphoma 10 1.4% 15 3.0% 5 1.7%Metastatic carcinoma, NOS 18 2.5% 15 3.0% 10 3.4%Metastatic malignancy 6 0.8% 16 3.2% 3 1.0%Metastatic small cell carcinoma 8 1.1% 15 3.0% 5 1.7%Negative/Reactive/Hyperplastic lymph nodes 106 14.5% 76 15.4% 40 13.6%Non-Hodgkin Lymphoma, large cell 62 8.5% 48 9.7% 19 6.4%Non-Hodgkin lymphoma, other than large cell 494 67.7% 283 57.4% 197 66.8%Specific Infections/Granulomatous 6 0.8% 10 2.0% 3 1.0%Unsatisfactory 2 0.3% 0 0.0% 0 0.0%Blank/Other 18 2.5% 15 3.0% 13 4.4%Total 730 100.0% 493 100.0% 295 100.0%



52


General Response Category: PositiveReference Interpretation: Hodgkin lymphoma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Hodgkin lymphoma 266 73.3% 138 57.0% 130 77.8%Metastatic carcinoma, NOS 4 1.1% 11 4.5% 1 0.6%Metastatic malignancy 10 2.8% 9 3.7% 1 0.6%Negative/Reactive/Hyperplastic lymph nodes 31 8.5% 33 13.6% 15 9.0%Non-Hodgkin Lymphoma, large cell 11 3.0% 12 5.0% 4 2.4%Non-Hodgkin lymphoma, other than large cell 12 3.3% 18 7.4% 5 3.0%Specific Infections/Granulomatous 22 6.1% 4 1.7% 7 4.2%Unsatisfactory 2 0.6% 0 0.0% 0 0.0%Blank/Other 5 1.4% 17 7.0% 4 2.4%Total 363 100.0% 242 100.0% 167 100.0%



53


General Response Category: PositiveReference Interpretation: Metastatic adenocarcinoma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Metastatic adenocarcinoma 737 48.5% 437 50.4% 351 52.5%Metastatic carcinoma, NOS 481 31.6% 170 19.6% 192 28.7%Metastatic malignancy 116 7.6% 118 13.6% 54 8.1%Metastatic melanoma 16 1.1% 15 1.7% 7 1.0%Metastatic squamous cell carcinoma 51 3.4% 37 4.3% 18 2.7%Negative/Reactive/Hyperplastic lymph nodes 17 1.1% 10 1.2% 4 0.6%Non-Hodgkin Lymphoma, large cell 42 2.8% 29 3.3% 15 2.2%Unsatisfactory 5 0.3% 0 0.0% 3 0.4%Blank/Other 56 3.7% 51 5.9% 25 3.7%Total 1521 100.0% 867 100.0% 669 100.0%



54


General Response Category: PositiveReference Interpretation: Metastatic squamous cell carcinoma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Branchial cleft cyst 29 1.7% 19 1.8% 11 1.4%Metastatic adenocarcinoma 57 3.3% 62 5.9% 26 3.3%Metastatic carcinoma, NOS 306 17.8% 127 12.1% 127 16.3%Metastatic malignancy 67 3.9% 83 7.9% 34 4.4%Metastatic small cell carcinoma 27 1.6% 15 1.4% 8 1.0%Metastatic squamous cell carcinoma 1156 67.1% 670 63.7% 515 66.1%Unsatisfactory 5 0.3% 1 0.1% 2 0.3%Blank/Other 76 4.4% 75 7.1% 56 7.2%Total 1723 100.0% 1052 100.0% 779 100.0%



55


General Response Category: PositiveReference Interpretation: Metastatic small cell carcinoma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Metastatic carcinoma, NOS 23 5.6% 25 8.3% 8 4.7%Metastatic malignancy 17 4.1% 25 8.3% 10 5.8%Metastatic small cell carcinoma 302 73.7% 176 58.3% 120 70.2%Negative/Reactive/Hyperplastic lymph nodes 7 1.7% 10 3.3% 5 2.9%Non-Hodgkin Lymphoma, large cell 29 7.1% 12 4.0% 9 5.3%Non-Hodgkin lymphoma, other than large cell 12 2.9% 17 5.6% 5 2.9%Undifferentiated carcinoma 10 2.4% 15 5.0% 5 2.9%Unsatisfactory 3 0.7% 0 0.0% 0 0.0%Blank/Other 7 1.7% 22 7.3% 9 5.3%Total 410 100.0% 302 100.0% 171 100.0%



56


General Response Category: PositiveReference Interpretation: Metastatic melanoma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Hodgkin lymphoma 29 4.6% 22 5.6% 8 2.8%Metastatic adenocarcinoma 12 1.9% 14 3.5% 3 1.1%Metastatic carcinoma, NOS 16 2.5% 21 5.3% 7 2.5%Metastatic malignancy 89 14.1% 43 10.9% 45 15.9%Metastatic melanoma 423 66.9% 238 60.3% 189 66.8%Metastatic squamous cell carcinoma 6 0.9% 14 3.5% 3 1.1%Non-Hodgkin Lymphoma, large cell 28 4.4% 16 4.1% 13 4.6%Unsatisfactory 3 0.5% 3 0.8% 2 0.7%Blank/Other 26 4.1% 24 6.1% 13 4.6%Total 632 100.0% 395 100.0% 283 100.0%



57


General Response Category: PositiveReference Interpretation: Non-Hodgkin Lymphoma, large cell


Pathologist CT LaboratoryInterpretation Choices N % N % N %Hodgkin lymphoma 19 3.9% 12 4.4% 10 5.1%Metastatic carcinoma, NOS 11 2.2% 10 3.7% 4 2.0%Metastatic malignancy 11 2.2% 12 4.4% 5 2.5%Metastatic melanoma 1 0.2% 7 2.6% 3 1.5%Metastatic small cell carcinoma 11 2.2% 6 2.2% 6 3.0%Negative/Reactive/Hyperplastic lymph nodes 76 15.4% 36 13.2% 26 13.1%Non-Hodgkin Lymphoma, large cell 243 49.3% 102 37.5% 94 47.5%Non-Hodgkin lymphoma, other than large cell 94 19.1% 69 25.4% 33 16.7%Specific Infections/Granulomatous 9 1.8% 1 0.4% 3 1.5%Undifferentiated carcinoma 4 0.8% 5 1.8% 2 1.0%Unsatisfactory 3 0.6% 1 0.4% 2 1.0%Blank/Other 11 2.2% 11 4.0% 10 5.1%Total 493 100.0% 272 100.0% 198 100.0%



58

Anatomic Site: FNA Kidney

General Response Category: PositiveReference Interpretation: Renal cell carcinoma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Oncocytoma 13 3.7% 3 1.6% 4 2.5%Renal cell carcinoma 283 80.4% 178 92.2% 132 83.0%Urothelial carcinoma 33 9.4% 5 2.6% 8 5.0%Unsatisfactory 1 0.3% 0 0.0% 0 0.0%Blank/Other 22 6.2% 7 3.6% 15 9.4%Total 352 100.0% 193 100.0% 159 100.0%



59

Anatomic Site: Bladder washing

General Response Category: PositiveReference Interpretation: High grade urothelial carcinoma/CIS/high grade urothelial dysplasia


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma 55 7.4% 59 12.6% 20 6.0%High grade urothelial carcinoma/CIS/dysplasia 611 81.9% 369 78.7% 273 82.5%Instrumentation derived urine/wash 20 2.7% 4 0.9% 6 1.8%Normal/Reactive 11 1.5% 8 1.7% 7 2.1%Reactive changes 30 4.0% 16 3.4% 12 3.6%Unsatisfactory 1 0.1% 0 0.0% 1 0.3%Blank/Other 18 2.4% 13 2.8% 12 3.6%Total 746 100.0% 469 100.0% 331 100.0%



60

Anatomic Site: Pelvic washing



Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma 657 87.8% 440 86.4% 282 88.4%Atypical cells, indeterminate-carcinoma/mesotheli oma 45 6.0% 7 1.4% 11 3.4%Non small cell carcinoma 21 2.8% 39 7.7% 7 2.2%Normal/Reactive mesothelial cells 13 1.7% 4 0.8% 4 1.3%Blank/Other 12 1.6% 19 3.7% 15 4.7%Total 748 100.0% 509 100.0% 319 100.0%



61

Anatomic Site: Urine, Catheterized



Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma 28 3.7% 40 8.3% 18 5.4%High grade urothelial carcinoma/CIS/dysplasia 622 82.9% 387 80.6% 273 81.7%Infectious/Inflammatory 14 1.9% 3 0.6% 4 1.2%Instrumentation derived urine/wash 19 2.5% 8 1.7% 6 1.8%Reactive changes 53 7.1% 17 3.5% 19 5.7%Squamous cell carcinoma 3 0.4% 17 3.5% 3 0.9%Blank/Other 11 1.5% 8 1.7% 11 3.3%Total 750 100.0% 480 100.0% 334 100.0%



62

Anatomic Site: Pleural Fluid



Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma 3435 74.0% 2085 74.4% 1456 73.5%Atypical cells, indeterminate-carcinoma/mesothelioma 281 6.1% 91 3.2% 98 4.9%Lymphocytic effusion, indeterminate 60 1.3% 40 1.4% 22 1.1%Mesothelioma 169 3.6% 181 6.5% 80 4.0%Non small cell carcinoma 360 7.8% 219 7.8% 142 7.2%Normal/Reactive mesothelial cells 215 4.6% 81 2.9% 74 3.7%Unsatisfactory 6 0.1% 3 0.1% 0 0.0%Blank/Other 114 2.5% 103 3.7% 110 5.5%Total 4640 100.0% 2803 100.0% 1982 100.0%



63


General Response Category: PositiveReference Interpretation: Small cell undifferentiated carcinoma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma 47 6.6% 34 7.9% 20 6.2%Atypical cells,indeterminate-carcinoma/mesothelioma 14 2.0% 1 0.2% 3 0.9%Non small cell carcinoma 42 5.9% 18 4.2% 15 4.6%Small cell undifferentiated carcinoma 565 79.9% 363 84.4% 267 82.4%Blank/Other 39 5.5% 14 3.3% 19 5.9%Total 707 100.0% 430 100.0% 324 100.0%



64




Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma 211 55.5% 131 56.2% 80 51.6%Atypical cells, indeterminate-carcinoma/mesothelioma 14 3.7% 13 5.6% 6 3.9%Lymphocytic effusion, indeterminate 6 1.6% 3 1.3% 1 0.6%Lymphoma/hematopoietic malignancy 4 1.1% 10 4.3% 4 2.6%Mesothelioma 17 4.5% 22 9.4% 3 1.9%Metastatic melanoma 5 1.3% 2 0.9% 1 0.6%Non small cell carcinoma 89 23.4% 30 12.9% 40 25.8%Normal/Reactive mesothelial cells 17 4.5% 6 2.6% 6 3.9%Small cell undifferentiated carcinoma 5 1.3% 6 2.6% 3 1.9%Squamous cell carcinoma 3 0.8% 5 2.1% 3 1.9%Unsatisfactory 1 0.3% 0 0.0% 1 0.6%Blank/Other 8 2.1% 5 2.1% 7 4.5%Total 380 100.0% 233 100.0% 155 100.0%



65


General Response Category: PositiveReference Interpretation: Mesothelioma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma 52 16.9% 42 25.6% 26 18.2%Atypical cells,indeterminate-carcinoma/mesothelioma 37 12.0% 11 6.7% 15 10.5%Lymphocytic effusion, indeterminate 7 2.3% 1 0.6% 3 2.1%Mesothelioma 168 54.5% 92 56.1% 80 55.9%Non small cell carcinoma 7 2.3% 5 3.0% 2 1.4%Normal/Reactive mesothelial cells 25 8.1% 6 3.7% 8 5.6%Squamous cell carcinoma 4 1.3% 5 3.0% 0 0.0%Blank/Other 8 2.6% 2 1.2% 9 6.3%Total 308 100.0% 164 100.0% 143 100.0%



66


General Response Category: NegativeReference Interpretation: Normal/Reactive mesothelial cells


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma 12 3.8% 6 2.6% 8 5.6%Atypical cells, indeterminate-carcinoma/mesotheliom a 28 8.9% 13 5.7% 15 10.6%Infection, Fungal 3 0.9% 6 2.6% 3 2.1%Inflammation, non-specific 69 21.8% 31 13.5% 25 17.6%Lymphocytic effusion, indeterminate 23 7.3% 14 6.1% 7 4.9%Non small cell carcinoma 2 0.6% 7 3.1% 1 0.7%Normal/Reactive mesothelial cells 170 53.8% 144 62.9% 76 53.5%Unsatisfactory 1 0.3% 1 0.4% 0 0.0%Blank/Other 8 2.5% 7 3.1% 7 4.9%Total 316 100.0% 229 100.0% 142 100.0%



67


General Response Category: PositiveReference Interpretation: Lymphoma/hematopoietic malignancy


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma 26 1.9% 27 3.4% 12 2.0%Atypical cells, indeterminate-carcinoma/mesothelioma 54 4.0% 17 2.2% 21 3.6%Inflammation, non-specific 35 2.6% 16 2.0% 10 1.7%Lymphocytic effusion, indeterminate 270 19.8% 101 12.8% 96 16.3%Lymphoma/hematopoietic malignancy 869 63.9% 535 68.0% 407 69.1%Metastatic melanoma 10 0.7% 14 1.8% 4 0.7%Non small cell carcinoma 21 1.5% 18 2.3% 3 0.5%Normal/Reactive mesothelial cells 38 2.8% 15 1.9% 11 1.9%Unsatisfactory 16 1.2% 5 0.6% 3 0.5%Blank/Other 22 1.6% 39 5.0% 22 3.7%Total 1361 100.0% 787 100.0% 589 100.0%



68

Anatomic Site: Pericardial Fluid



Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma 197 77.6% 143 78.1% 100 75.8%Atypical cells,indeterminate-carcinoma/mesothelioma 12 4.7% 5 2.7% 5 3.8%Mesothelioma 8 3.1% 10 5.5% 1 0.8%Metastatic melanoma 2 0.8% 5 2.7% 2 1.5%Non small cell carcinoma 25 9.8% 10 5.5% 14 10.6%Normal/Reactive mesothelial cells 1 0.4% 3 1.6% 3 2.3%Small cell undifferentiated carcinoma 3 1.2% 4 2.2% 1 0.8%Blank/Other 6 2.4% 3 1.6% 6 4.5%Total 254 100.0% 183 100.0% 132 100.0%



69

Anatomic Site: Urine, Voided



Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma 24 2.7% 28 4.7% 11 2.9%High grade urothelial carcinoma/CIS/dysplasia 733 82.2% 506 84.3% 306 81.0%Infection, Polyoma virus 14 1.6% 3 0.5% 4 1.1%Infectious/Inflammatory 32 3.6% 11 1.8% 5 1.3%Intestinal loop urine 17 1.9% 7 1.2% 7 1.9%Reactive changes 54 6.1% 20 3.3% 24 6.3%Squamous cell carcinoma 8 0.9% 18 3.0% 3 0.8%Unsatisfactory 3 0.3% 2 0.3% 0 0.0%Blank/Other 7 0.8% 5 0.8% 18 4.8%Total 892 100.0% 600 100.0% 378 100.0%



70

Anatomic Site: Cerebrospinal Fluid

General Response Category: PositiveReference Interpretation: Leukemia/Lymphoma/Other hematopoietic malignancy


Pathologist CT LaboratoryInterpretation Choices N % N % N %Acute and chronic inflammation/Reactive 19 2.2% 11 2.3% 3 0.8%Leukemia/Lymphoma/Other hematopoietic malignancy 798 92.1% 416 86.8% 331 92.7%Metastatic malignancy 3 0.3% 19 4.0% 1 0.3%Normal sample 7 0.8% 9 1.9% 2 0.6%Small blue cell tumors, non hemopoietic 9 1.0% 8 1.7% 1 0.3%Unsatisfactory 6 0.7% 0 0.0% 0 0.0%Blank/Other 24 2.8% 16 3.3% 19 5.3%Total 866 100.0% 479 100.0% 357 100.0%



71

Anatomic Site: Cerebrospinal Fluid

General Response Category: PositiveReference Interpretation: Metastatic malignancy


Pathologist CT LaboratoryInterpretation Choices N % N % N %Acute and chronic inflammation/Reactive 22 3.8% 14 3.6% 6 2.2%Leukemia/Lymphoma/Other hematopoietic malignancy 27 4.6% 33 8.4% 14 5.2%Macrophages including hemosiderin laden macrophage 9 1.5% 4 1.0% 4 1.5%Metastatic malignancy 471 80.7% 315 80.4% 210 77.5%Normal sample 32 5.5% 17 4.3% 19 7.0%Unsatisfactory 10 1.7% 2 0.5% 4 1.5%Blank/Other 13 2.2% 7 1.8% 14 5.2%Total 584 100.0% 392 100.0% 271 100.0%



72

Anatomic Site: Peritoneal Fluid



Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma 2292 81.2% 1319 77.3% 1009 80.5%Atypical cells, indeterminate-carcinoma/mesothelioma 143 5.1% 50 2.9% 51 4.1%Mesothelioma 82 2.9% 95 5.6% 33 2.6%Non small cell carcinoma 116 4.1% 114 6.7% 38 3.0%Normal/Reactive mesothelial cells 115 4.1% 50 2.9% 47 3.8%Blank/Other 75 2.7% 79 4.6% 75 6.0%Total 2823 100.0% 1707 100.0% 1253 100.0%



73

Anatomic Site: Peritoneal Fluid

General Response Category: PositiveReference Interpretation: Mesothelioma


Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma 141 34.1% 70 30.4% 54 36.5%Atypical cells, indeterminate-carcinoma/mesothelioma 66 16.0% 26 11.3% 24 16.2%Mesothelioma 146 35.4% 103 44.8% 52 35.1%Normal/Reactive mesothelial cells 48 11.6% 20 8.7% 11 7.4%Blank/Other 12 2.9% 11 4.8% 7 4.7%Total 413 100.0% 230 100.0% 148 100.0%



74

Anatomic Site: Esophageal Brushing/Washing



Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma 5 2.1% 3 1.7% 1 0.9%Barrett's esophagitis 93 39.6% 84 47.2% 40 35.7%Infection, Candida species 22 9.4% 9 5.1% 11 9.8%Infection, Herpes 4 1.7% 1 0.6% 1 0.9%Normal/Reactive 104 44.3% 71 39.9% 51 45.5%Squamous cell carcinoma 3 1.3% 6 3.4% 1 0.9%Unsatisfactory 1 0.4% 1 0.6% 0 0.0%Blank/Other 3 1.3% 3 1.7% 7 6.2%Total 235 100.0% 178 100.0% 112 100.0%



75

Anatomic Site: Esophageal Brushing/Washing



Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma 7 2.5% 4 3.1% 1 0.8%Carcinoma, NOS 13 4.7% 1 0.8% 3 2.4%Normal/Reactive 15 5.5% 6 4.7% 4 3.3%Squamous cell carcinoma 231 84.0% 112 86.8% 109 88.6%Blank/Other 9 3.3% 6 4.7% 6 4.9%Total 275 100.0% 129 100.0% 123 100.0%



76

Anatomic Site: Bronchial brushing



Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma including bronchioloalveolar 25 2.7% 6 1.2% 6 1.4%Carcinoid 10 1.1% 11 2.2% 1 0.2%Ferruginous bodies 12 1.3% 2 0.4% 7 1.7%Infection, Fungal 10 1.1% 13 2.6% 2 0.5%Normal/Reactive 814 88.2% 447 88.2% 381 90.7%Small cell undifferentiated carcinoma 16 1.7% 6 1.2% 6 1.4%Unsatisfactory 5 0.5% 4 0.8% 1 0.2%Blank/Other 31 3.4% 18 3.6% 16 3.8%Total 923 100.0% 507 100.0% 420 100.0%



77




Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma including bronchioloalveolar 15 3.3% 13 5.0% 6 3.1%Non small cell carcinoma 100 22.3% 38 14.6% 29 15.0%Small cell undifferentiated carcinoma 7 1.6% 0 0.0% 5 2.6%Squamous cell carcinoma 313 69.9% 202 77.4% 147 76.2%Blank/Other 13 2.9% 8 3.1% 6 3.1%Total 448 100.0% 261 100.0% 193 100.0%



78




Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma including bronchioloalveolar 152 36.2% 117 44.3% 72 36.0%Metastatic carcinoma, NOS 19 4.5% 14 5.3% 9 4.5%Non small cell carcinoma 174 41.4% 98 37.1% 89 44.5%Normal/Reactive 33 7.9% 8 3.0% 12 6.0%Small cell undifferentiated carcinoma 8 1.9% 2 0.8% 1 0.5%Squamous cell carcinoma 20 4.8% 16 6.1% 7 3.5%Unsatisfactory 5 1.2% 0 0.0% 2 1.0%Blank/Other 9 2.1% 9 3.4% 8 4.0%Total 420 100.0% 264 100.0% 200 100.0%



79




Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma including bronchioloalveolar 136 19.1% 129 33.2% 67 20.9%Non small cell carcinoma 398 55.9% 184 47.3% 180 56.2%Normal/Reactive 17 2.4% 3 0.8% 9 2.8%Small cell carcinoma 33 4.6% 7 1.8% 12 3.8%Squamous cell carcinoma 104 14.6% 62 15.9% 35 10.9%Blank/Other 24 3.4% 4 1.0% 17 5.3%Total 712 100.0% 389 100.0% 320 100.0%



80

Anatomic Site: Bronchial washing



Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma including bronchioloalveolar 11 1.4% 3 0.6% 2 0.6%Infection, Fungal 24 3.1% 20 4.3% 10 3.0%Infection, PCP 13 1.7% 15 3.2% 2 0.6%Normal/Reactive 652 84.5% 378 80.8% 282 85.2%Small cell undifferentiated carcinoma 13 1.7% 8 1.7% 6 1.8%Squamous cell carcinoma 17 2.2% 19 4.1% 5 1.5%Unsatisfactory 9 1.2% 2 0.4% 2 0.6%Blank/Other 33 4.3% 23 4.9% 22 6.6%Total 772 100.0% 468 100.0% 331 100.0%



81




Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma including bronchioloalveolar 7 1.5% 10 3.2% 4 1.9%Non small cell carcinoma 39 8.1% 15 4.8% 19 9.1%Squamous cell carcinoma 411 85.3% 282 89.5% 168 80.8%Unsatisfactory 2 0.4% 0 0.0% 0 0.0%Blank/Other 23 4.8% 8 2.5% 17 8.2%Total 482 100.0% 315 100.0% 208 100.0%



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Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma including bronchioloalveolar 151 48.1% 111 54.7% 61 46.6%Infection, Fungal 8 2.5% 8 3.9% 5 3.8%Non small cell carcinoma 92 29.3% 55 27.1% 38 29.0%Normal/Reactive 26 8.3% 9 4.4% 7 5.3%Small cell undifferentiated carcinoma 15 4.8% 7 3.4% 7 5.3%Squamous cell carcinoma 12 3.8% 8 3.9% 1 0.8%Blank/Other 10 3.2% 5 2.5% 12 9.2%Total 314 100.0% 203 100.0% 131 100.0%



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Pathologist CT LaboratoryInterpretation Choices N % N % N %Adenocarcinoma including bronchioloalveolar 125 19.8% 99 25.6% 52 19.5%Infection, Fungal 7 1.1% 4 1.0% 3 1.1%Non small cell carcinoma 329 52.1% 167 43.3% 144 54.1%Normal/Reactive 23 3.6% 4 1.0% 10 3.8%Small cell carcinoma 42 6.6% 21 5.4% 9 3.4%Squamous cell carcinoma 84 13.3% 74 19.2% 33 12.4%Unsatisfactory 5 0.8% 0 0.0% 1 0.4%Blank/Other 17 2.7% 17 4.4% 14 5.3%Total 632 100.0% 386 100.0% 266 100.0%

Figure 5 Metastatic adenocarcinoma: Disordered sheets of cytologically malignant cells. The tumor cells possess intracytoplasmic mucin vacuoles. Although a trabecular architecture is present, no endothelial rimming is seen, and the tumor cells do not resemble hepatocytes. (Papanicolaou stain, 60x)

Figure 6 Metastatic Carcinoid tumor: Cellular aspirate composed of atypical cells present singly and in loosely cohesive rosettes. The tumor cells are plasmacytoid and exhibit a “salt and pepper” chromatin pattern with minimal nuclear pleomorphism. (Papanicolaou stain, x60)

Figure 7 Normal liver: Benign hepatocytes arranged in thin trabeculae. The hepatocytes possess abundant granular cytoplasm with small nuclei and low nuclear: cytoplasmic ratios. Note the cluster of benign bile duct epithelial cells at the upper left. (Papanicolaou stain, 60x)

Figure 8 Well differentiated hepatocellular carcinoma(Hepatoma: Markedly thickened trabeculae composedof atypical hepatocytes with increased nuclear: cytoplasmic ratios. The trabeculae are lined by a thin layer of endothelium. (Papanicolaou stain, 60x)

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