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Background
Lung cancers have a variety of histopathological patterns which may present a diagnostic problem for the surgical pathologist.
OUTLINE
Histopathological Features and Variants Special Stains/
Immunohistochemistry/
Electron MicroscopyDifferential Diagnosis Commonly Used Terms Internet Links
HISTOLOGICAL
TYPESCHARACTERIZATION GENERAL Adenocarcinoma has become the most common lung cancer in women and possibly in men as well. Squamous cell and small cell carcinomas have the strongest associations with a smoking history MARGINS Bronchial margins in lung cancer resection specimens: utility of frozen section and gross evaluation.
Maygarden SJ, Detterbeck FC, Funkhouser WK.
Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Mod Pathol. 2004 Sep;17(9):1080-6. Abstract quote
Pathology reports for all lobectomy and pneumonectomy specimens at UNC Hospitals between 1991 and 2000 (n=405) were reviewed for correlation between frozen section and final bronchial margin, gross distance between tumor and margin and tumor type.
Frozen section was performed in 268 cases (66%). A total of 243 were true negatives (90.6 %), 16 (6.0%) were true positives, four (1.5%) were false positives and five (1.9%) were false negatives. The site of tumor in true-positive cases was mucosal (11), submucosal (three), lymphatics (one), peribronchial (one). The site of tumor in false-negative cases was submucosal (two), lymphatics (one), peribronchial (two). In 137 cases, no bronchial frozen section was performed; there was one case (0.7%) with positive margin. There was no correlation between final margin positivity and distance between gross tumor and margin.
Tumor distance to margin in positive margin cases varied from grossly involved to 3 cm away. There were 72 cases in which wedge resection was performed before lobectomy in which no gross tumor remained in the lobectomy, and in all cases final bronchial margins were negative. In all, 373 of cases (92%) were nonsmall carcinomas. Of these, 10 (2.7%) had positive margins. Tumors other than nonsmall cell carcinoma accounted for a disproportionate number of positive margins. In all, 3/6 of adenoid cystic/mucoepidermoid carcinoma, 1/7 small cell carcinoma and 1/1 lymphoma cases had positive margins. In conclusion, frozen section evaluation of bronchial margins is helpful in central lung tumors. Mucosal tumor is preferentially identified in frozen section.
Gross evaluation of margins is problematic, as intramucosal carcinoma or tumor in lymphatics may not be detected, but 3 cm was a 'safe' distance for gross tumor from margin. In lobectomies following wedge resection in which no gross tumor remained, all had negative margins. Salivary gland-type tumors have a high incidence of positive margins, and frozen section is particularly indicated in these tumors.PREMALIGNANT
LESIONSATYPICAL ADENOMATOUS HYPERPLASIA Focal lesion, often 5 mm or less in diameter, with involved alveoli and respiratory bronchioles are lined by monotonous slightly atypical cuboidal to low columnar epithelia cells with dense nuclear chromatin, inconspicuous nucleoli, and scanty cytoplasm Mod Pathol 2001:14;72-84
Histologic criteria:
Irregularly bordered focal proliferations of atypical cells spreading along the preexisting alveolar framework
Prominent cuboidal to low columnar alveolar epithelial cells with variable degree of atypia but less than that seen in adenocarcinoma Increased cell size and nuclear-cytoplasmic ratio with hyperchromasia and prominent nucleoli
Generally intact intercellular attachment of atypical cells with occasional empty-looking spaces between them without high cellularity and without tufting or papillary structures
Slight thickening of the alveolar walls on which the AAH cells have spread, with some fibrosis but without scar formation or significant chronic inflammation of the surrounding lung tissueAAH may play a role in the development of pulmonary adenocarcinoma and particularly in the development of BACs.
Any putative precursor lesion of any cancer should fulfill some requirements:
Should be present and identified before the development of the disease
Should show evidence of cellular atypia, molecular changes, or both, consistent with progressive cellular transformation.
Should not occur so infrequently that transformation to neoplasia is a rare eventConclusion:
AAH is a probable but not proven precursor lesion of pulmonary adenocarcinomaLung adenocarcinoma with bronchioloalveolar carcinoma component is frequently associated with foci of high-grade atypical adenomatous hyperplasia.
Koga T, Hashimoto S, Sugio K, Yonemitsu Y, Nakashima Y, Yoshino I, Matsuo Y, Mojtahedzadeh S, Sugimachi K, Sueishi K.
Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Am J Clin Pathol 2002 Mar;117(3):464-70 Abstract quote We assessed the occurrence of atypical adenomatous hyperplasia (AAH) in whole lung lobes with primary cancer lesions.
Following surgical resection, tissue specimens were sliced to a thickness of 4 mm (3,641 specimens from 61 cases; mean = 59.7 specimens per case). A total of 119 AAH foci were found and an association was evident in 25 (57%) of 44 adenocarcinomas, 3 (30%) of 10 squamous cell carcinomas, and 2 (29%) of 7 other lung cancers. Histologic evaluation showed that 108 AAH foci were categorized as low-grade and the other 11 as high-grade AAH. These 11 foci of high-grade AAH were present in 7 patients with adenocarcinoma, and in 1 patient there was a synchronous double primary lung adenocarcinoma. High-grade AAH was closely associated with bronchioloalveolar carcinoma (BAC) type adenocarcinoma, and low-grade AAH with non-BAC adenocarcinoma. The mean +/- SD Ki-67 labeling index in high-grade AAH (3.5%+/-2.9%) was significantly higher than for the low-grade index (1.4%+/-1.6%).
We propose that foci of high- but not low-grade AAH may be potential precursor lesions of lung adenocarcinoma, especially with the BAC component.
DYSPLASIA (BRONCHIAL EPITHELIAL DYSPLASIA)
Mod Pathol. 2006 Mar;19(3):429-37. Abstract quote
Pulmonary epithelium is known to undergo a preneoplastic process prior to the development of lung carcinoma. Squamous dysplasia and atypical adenomatous hyperplasia have been identified and classified as preinvasive lesions of squamous cell carcinoma and peripheral pulmonary adenocarcinoma, respectively. However, these commonly recognized preinvasive lesions do not completely explain the development of all histological types of lung carcinoma.
By examining 114 resection lung specimens, we concluded that there are four histological patterns of bronchial epithelial dysplasia based on morphological features (basal cell dysplasia, columnar cell dysplasia, bronchial epithelial dysplasia with transitional differentiation, and squamous dysplasia).
The histological patterns were further characterized by immunohistochemistry. Basal cell dysplasia was focally positive for cytokeratin (CK) 17 and 10/13; columnar cell dysplasia was generally positive for CK7, 8, and 18; bronchial epithelial dysplasia with transitional differentiation had a heterogeneous immunoprofile, while squamous dysplasia was positive for CK10/13 and focally positive for CK17. Various degrees of abnormal expression of p53 and Ki-67 were found in the different types of bronchial epithelial dysplasia. The cases were divided into three groups based on degree and extent of bronchial epithelial dysplasia. By Crosstabs McNemar test, the Mann-Whitney U-test (for two independent groups), the Kruskal-Wallis one-way nonparametric ANOVA (for >2 independent groups) and Spearman correlation analysis, the degree and extent of bronchial epithelial dysplasia was shown to be positively correlated with the incidence of bronchogenic carcinoma and multifocal primary lung carcinoma (P<0.05).
These findings indicated the following: (1) bronchial epithelium can develop various patterns of dysplasia with abnormal/ambiguous cell differentiation and abnormal expressions of p53 and Ki-67. Thus, these bronchial epithelial dysplastic lesions may represent a preneoplastic process. (2) The degree of bronchial epithelial dysplasia may significantly predispose individuals to bronchogenic carcinoma and multifocal primary lung carcinoma.INCIDENCE OF MAIN HISTOLOGIC TYPES Squamous cell carcinoma 25-40% Adenocarcinoma 25-40% Acini and tubules lined by mucin-producing cells resembling bronchial gland or bronchial lining cells
Solid nests of cells with mucin formation Adenocarcinoma with Small cell carcinoma 20-25% Large cell carcinoma 10-15% Combined Small cell carcinoma with additional non-small cell component IMPORTANT HISTOLOGIC VARIANTS ADENOCARCINOMA
- Pulmonary Adenocarcinomas With Enteric Differentiation: Histologic and Immunohistochemical Characteristics Compared With Metastatic Colorectal Cancers and Usual Pulmonary Adenocarcinomas.
Inamura K, Satoh Y, Okumura S, Nakagawa K, Tsuchiya E, Fukayama M, Ishikawa Y.
From the *Department of Pathology, Cancer Institute, and double daggerDepartment of Chest Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan; daggerDepartment of Human and Diagnostic Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan; and section signKanagawa Cancer Center Research Institute, Yokohama, Kanagawa, Japan
Am J Surg Pathol. 2005 May;29(5):660-665. Abstract quote
Primary pulmonary adenocarcinomas with enteric differentiation (PAED) are mainly composed of tall-columnar cells that show similarity to intestinal epithelia and colorectal carcinomas.
In this study, we analyzed the immunostaining profiles of 7 PAEDs in comparison with 14 metastatic colorectal carcinomas (MCRs) and 30 usual pulmonary adenocarcinomas (PACs), using antibodies against CDX-2, cytokeratin 7 (CK7), cytokeratin 20 (CK20), TTF-1, surfactant apoprotein-A (SP-A), Napsin A, and MUC2. The positive rates for CDX-2, CK7, CK20, TTF-1, SP-A, Napsin A, and MUC2 were 71%, 100%, 43%, 43%, 14%, 0%, and 43%, respectively, in the PAEDs; 100%, 0%, 86%, 0%, 0%, 0%, and 57% in the MCRs; 3%, 100%, 0%, 93%, 73%, 90%, and 0% in PACs. As expected, immunoreactivity of CDX-2, CK20, and MUC2 was detected in PAEDs.
The observed decrease or loss of immunoreactivity for TTF-1, SP-A, and Napsin A indicates that these lesions demonstrate a shift away from their pulmonary phenotype, although CK7 expression was retained.
The results indicate that CK7 and CK20 may be useful markers for distinction of PAEDs from MCRs.
Koji Tsuta, MD, etal.
We report 6 cases of adenocarcinoma with massive lymphocyte infiltration. This adenocarcinoma is found in 0.7% of surgically resected primary lung adenocarcinomas.The tumor was located in the peripheral portion in all cases. Lymph node metastasis was detected in 4 cases. The mean follow-up period was 49.8 months; all patients were alive without recurrence despite advanced pathologic stage.
Histologically, the tumors revealed an acinar and glandular structure, and the cancer epithelium was destroyed by infiltrating lymphocytes. The lung parenchyma was destroyed by the severe inflammatory cell infiltration without dense fibrosis. Immunohistochemical staining revealed that most infiltrating lymphocytes were positive for CD3 or CD20. None of the tumors were positive for latent membrane protein-1, bcl-2, or Epstein-Barr virus–encoded small RNA-1.
This type of adenocarcinoma occurs in old age, and good outcome and distinctive histologic features were observed. We refer to it as primary lung adenocarcinoma with massive lymphocyte infiltration.
Topographical distribution of allelic loss in individual lung adenocarcinomas with lymph node metastases.
Yoshikawal T, Aoyagi Y, Kodama K, Kamijo T, Yonou H, Yokose T, Ishii G, Oda T, Takamochi K, Nagai K, Nishiwaki Y, Shimizu N, Ochiai A.
Pathology Division, National Cancer Center Research Institute East, Kashiwa, Chiba, Japan.
Mod Pathol. 2004 Feb;17(2):204-13 Abstract quote.
Adenocarcinomas of the lung are characterized by morphological heterogeneity, and since carcinogenesis has been suggested to be a multistep process involving sequential accumulation of multiple genetic alterations, the morphological heterogeneity may represent a cross-sectional view of genetic alterations within individual tumors.
Therefore, to elucidate whether, and which, genetic alterations accumulated in relation to morphological cancer progression, we examined 56 microdissected sites for topographical distribution of loss of heterozygosity (LOH) in 12 adenocarcinomas of the lung with bronchioloalveolar (BA) and invasive components in their primary tumors and metastases to lymph nodes. The morphological changes from noninvasive BA lesions to invasive and metastatic components were characterized by a significant rise in the prevalence of allelic losses (P<0.05). Individually, eight cases (67%) showed accumulation of genetic alterations from BA lesions to metastases. LOHs in multiple foci in one case were compared to determine whether they were shared at all tumor sites as an early event or localized in metastases as an additional event. LOHs at 5q and 17p may be crucial steps in the early phase of development to metastasis, while 18q loss may be an additional step.
These findings suggested that the cancer cells in some pulmonary adenocarcinomas evolved from the BA lesions to the invasive and metastatic lesions.Grade of Stromal Invasion in Small Adenocarcinoma of the Lung: Histopathological Minimal Invasion and Prognosis
Sakurai, Hiroyuki MD*†; Maeshima, Arafumi MD‡; Watanabe, Shun MD*; Suzuki, Kenji MD*; Tsuchiya, Ryosuke MD*; Maeshima, Akiko M MD‡; Matsuno, Yoshihiro MD†; Asamura, Hisao MD*
From the *Division of Thoracic Surgery and †Clinical Laboratory, National Cancer Center Hospital, and the ‡Pathology Division, National Cancer Center Research Institute, Tokyo, Japan.
The American Journal of Surgical Pathology : Volume 28(2) February 2004 pp 198-206 Abstract quote The pathologic features of invasion such as stromal disruption and pleural/vascular involvement have been shown to be of prognostic value in adenocarcinoma. However, the relationship between the degree of invasion, histologic subtype of adenocarcinoma, and prognosis remains unclear.
We retrospectively studied 380 peripheral adenocarcinomas of =2.0 cm in diameter with regard to histology and clinical profiles. Their degree of invasive growth was classified into four grades as follows according to the structural deformity and its location in the adenocarcinoma lesion: Grade 0 had a pure bronchioloalveolar growth pattern and no evidence of stromal invasion. Grade 1 had stromal invasion in the area of bronchioloalveolar growth. Grade 2 had stromal invasion localized on the periphery of a fibrotic focus. Grade 3 had stromal invasion into the center of a fibrotic focus. The clinicopathological data were obtained from medical records. The distribution of the histologic grade of invasion was as follows: grade 0 in 85 tumors (22%), grade 1 in 37 (10%), grade 2 in 46 (12%), and grade 3 in 212 (56%). This histologic grade of invasion was closely related to other indicators of tumor spread. Vascular/lymphatic permeation was seen in none of grade 0, in 1 lesion each of grade 1 and grade 2, and 144 (68%) of grade 3. Lymph node metastasis was seen in 57 (27%) lesions of grade 3 but not in grades 0, 1, or 2. The 5-year disease-free survival rates were 100%, 100%, 100%, and 59.6% for tumors with grade 0, grade 1, grade 2, and grade 3 invasion, respectively. Tumors with grade 1 and grade 2 invasion, like tumors with grade 0 invasion (bronchioloalveolar carcinoma), showed an excellent prognosis. Therefore, tumors with grade 1 and grade 2 invasion could be considered minimally invasive or early adenocarcinomas.Because of the advent of high-resolution computed tomography (CT) and the consequent availability of more detailed images and screening programs, small lung cancers are being found more often.12 Most of these have an adenocarcinoma histology and arise in the periphery of the lung parenchyma.1 It has also been repeatedly reported that lymph node metastasis is found in approximately 20% of peripheral adenocarcinomas, even if the tumor diameter is small, such as <2.0 cm.2,11,13,15,17,22
On the other hand, another histologic category of adenocarcinoma, bronchioloalveolar carcinoma (BAC), has also been discussed with regard to its histologic features and prognosis.5,6,8,14,23 This subcategory is classified as a subtype of adenocarcinoma, which histologically shows a unique replacing growth pattern of tumor cells along the alveolar wall. According to radiologic studies by high-resolution CT, the replacing growth pattern of adenocarcinoma cells seen in BAC presents as a focal, hazy increase in attenuation called ground-glass opacity.3 Radiologic-pathologic studies have demonstrated that the ground-glass opacity appearance represents patent alveolar spaces and the preservation of bronchial and vascular margins.16,18
In the recently revised histologic classification of lung and pleural tumors by the World Health Organization (WHO),29 adenocarcinomas have been classified into five histologic subtypes: BAC, acinar, papillary, solid with mucin, and adenocarcinoma with mixed subtypes. The WHO classification describes BAC as a form of adenocarcinoma with a pure bronchioloalveolar growth pattern and no evidence of stromal, vascular, or pleural invasion. Accordingly, BAC is the only subtype without any invasive features. Obviously, an excellent prognosis can reasonably be expected for noninvasive BACs, and invasive features seen in adenocarcinoma are thought to be prognostic. However, the relationship between the degree of pathologic invasion and prognosis has not yet been clarified.
In this retrospective study, we histopathologically graded the degree of invasion and explored the relationship between invasion and the prognosis of patients with adenocarcinoma, which might contribute to establishing the concept of curable lung cancer.
ADENOSQUAMOUS Adenocarcinoma and squamous cell carcinoma must comprise at least 10% of the entire tumor BASALOID Basaloid appearance with lobular, trabecular, or palisading growth patterns, consisting of small monomorphic cuboidal to fusiform cells with moderately hyperchromatic nuclei, finely granlar chromatin, absent or only focal nucleoli, scant cytoplasm, and high mitotic rate
No intercellular bridges or individual keratinization is present
Basal cell (basaloid) carcinoma of the lung: a new morphologic and phenotypic entity with separate prognostic significance.
Brambilla E, Moro D, Veale D, Brichon PY, Stoebner P, Paramelle B, Brambilla C.
Department of Pathology, CHRU de Grenoble, France.
Hum Pathol 1992 Sep;23(9):993-1003 Abstract quote On review of 115 poorly or undifferentiated lung cancers from 671 lung tumors resected over a 7-year period, we have found 38 cases of basaloid carcinoma.
The cardinal histopathologic features distinguishing this tumor from other non-small cell lung cancers are a lobular growth pattern of small cells with moderately hyperchromatic nuclei, with no prominent nucleoli, and with scant cytoplasm, a high mitotic rate, and peripheral palisading. Basaloid carcinoma was present in a pure form in 19 cases and the other 19 tumors were of a mixed, but prominent, basaloid type associated with squamous cell carcinoma, large cell carcinoma, or adenocarcinoma. The immunophenotype of basaloid cancers was close to that of basal bronchial epithelial cells, with a low level of expression of low molecular weight cytokeratins. Staining for neuroendocrine markers was infrequent and inconsistent.
Ultrastructural study showed an absence of neurosecretory granules and the presence of some squamous and/or glandular differentiation. This morphologic and immunologic phenotype suggests that basaloid carcinoma is derived from a pluripotent reserve cell or a basal bronchial epithelial stem cell. This unique histologic form of lung tumor has a poor prognosis, with a median survival rate of 22 months for stage I and II disease.
This justifies classification of basaloid carcinoma as a distinct form of lung cancer, separate from small cell lung carcinoma.
BRONCHIO-
ALVEOLAR CARCINOMA
N. Paul Ohori, MD, and Edward L. Santa Maria, MD
We identified 29 bronchial washing, bronchoalveolar lavage, sputum, and fine-needle aspiration specimens with corresponding surgical pathology specimens with features of bronchioloalveolar carcinoma (BAC). Surgical pathology correlates were reclassified according to the 1999 World Health Organization classification into pure BAC, mixed adenocarcinoma–BAC (AD-BAC), and papillary adenocarcinoma (PAP-AD).
Twelve cases of invasive pulmonary adenocarcinoma (INV-AD) without a bronchioloalveolar component were reviewed for comparison. The cytology slides were evaluated for 12 features of BAC. No statistically significant feature permitted separation of BAC from AD-BAC or from PAP-AD. However, comparison of BAC with INV-AD identified 9 statistically significant cytologic features: clean background, absence of 3-dimensional clusters, neoplastic cells in flat sheets, orderly arrangement of cells with round uniform nuclei, predominance of mucinous cells, absence of nuclear overlap, absence of irregular nuclear membranes, fine granular chromatin, and nuclear grooves that were features of BAC cases.
Although cytologic evaluation cannot prospectively diagnose BAC, the bronchioloalveolar pattern may be recognized and suggests in situ proliferation that is present in BAC, AD-BAC, or PAP-AD. The bronchioloalveolar pattern must be correlated with clinical, radiographic, and histologic parameters to determine whether the tumor is localized, multifocal, or diffuse and whether there is parenchymal invasion.CLEAR CELL CARCINOMA Must exclude metastatic renal cell carcinoma ENTERIC-TYPE (INTESTINAL TYPE)
- Pulmonary intestinal-type adenocarcinoma does not show enteric differentiation by immunohistochemical study.
Yousem SA.
1Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Mod Pathol. 2005 Jun;18(6):816-21. Abstract quote
Six cases of an unusual variant of primary pulmonary adenocarcinoma resembling colorectal and sinonasal adenocarcinoma are presented.
Pulmonary intestinal-type adenocarcinoma occurs in elderly Caucasians and is associated with a histology characteristic of colorectal/enteric adenocarcinoma: a garland-like architecture with a 'gland in gland' periphery, central 'dirty' necrosis, and elongated stratified columnar cells, lacking significant goblet or signet ring differentiation.
While a resemblance to intestinal adenocarcinoma by light microscopy is present, immunohistochemical studies comparing these carcinomas with metastatic colorectal adenocarcinoma clearly show a respiratory phenotype with the neoplastic cells expressing thyroid transcription factor-1 and cytokeratin 7 to the exclusion of cytokeratin 20, and failing to express CDX-2. Stains for a variety of epithelial mucins (MUC1, MUC2, MUC5AC) also support this observation.
The differential diagnosis with other pulmonary adenocarcinomas, especially those with mucinous differentiation, is discussed.FETAL Glands resemble fetal lung tubules with glycogen rich cytoplasm, non ciliated, and sub and supranuclear vacuoles
Good survival
No p53 mutationsLARGE CELL NEUROENDOCRINE CARCINOMA Features of organoid nesting, trabecular, rosette-like and palisading patterns that suggest neuroendocrine differentiation-this is confirmed by immunohistochemistry or electron microscopy
Usually high mitotic counts >10/10 hpf
LYMPHO-EPITHELIOMA-LIKE CARCINOMA Similar to nasopharyngeal carcinoma
Most commo in Southeast Asia and associated with Epstein-Barr virus infection
Department of Pathology, Division of Anatomic Pathology, University of Pittsburgh Medical Center, Presbyterian University Hospital, Pittsburgh, PA 15213, USA.
Primary lymphoepithelioma-like carcinoma of the lung (LELC) shares some morphologic and clinical characteristics with malignancies associated with microsatellite instability (MSI). The aims of our study were to determine the MSI status in LELC and compare these findings with stage I non-small cell lung carcinoma (NSCLC) with marked lymphocytic host response (MLHR).
We assessed MSI by a DNA-based polymerase chain reaction assay using mononucleotide (BAT25 and BAT26) and dinucleotide (D2S123, D5S346, and D17S250) repeats. MSI was detected in 2 (29%) of 7 LELC cases with only 1 marker (D17S250), and in 3 (19%) of 16 NSCLC cases with MLHR with only 2 markers (1D2S123 and 2 D17S250). Loss of heterozygosity (LOH) was detected at 1 or 2 of 3 dinucleotide repeats in 11 NSCLC cases (69%) with MLHR and 3 LELC cases (43%) (P = .36). The overall frequencies of LOH in NSCLC with MLHR were 29% and 19% in LELC (P = .55). MSI is very uncommon in LELC, indicating that MSI is not an important event in carcinogenesis for this tumor subtype.
The presence of LOH suggests a probable role of tumor suppressor genes in LELC carcinogenesis.
Eber- and LMP-1-expressing pulmonary lymphoepithelioma-like carcinoma in a caucasian patient.Morbini P, Riboni R, Tomaselli S, Rossi A, Magrini U.
Hum Pathol. 2003 Jun;34(6):623-5. Abstract quote Primary lymphoepithelioma-like carcinoma (LELC) of the lung is a rare tumor that preferentially affects Asian patients, with only 15 cases described in Caucasians to date. Epstein-Barr virus (EBV) infection is present in most lung LELCs in Asians, but it has never been shown in Caucasians.
EBV small nuclear RNA and latent membrane protein-1 were identified in the neoplastic cells of primary LELC of the lung diagnosed by endobronchial biopsy in a 25-year-old Italian male.
Despite advanced locoregional disease, with neoplastic infiltration of the main right bronchus, the carina, and the pulmonary artery, which prevented surgical resection, partial response and 1-year symptom-free follow-up were achieved after combined chemotherapy and radiotherapy.
Lymphoepithelioma-like Carcinoma of the Lung With a Better Prognosis A Clinicopathologic Study of 32 Cases
An-jia Han, MD, Min Xiong, MD, Ying-ying Gu, MD, Su-xia Lin, MD, and Mai Xiong, MD
Am J Clin Pathol 2001;115:841-850 Abstract quote
The purpose of our study was to clarify the prognosis of lymphoepithelioma-like carcinoma (LELC) of the lung, which is rare. We analyzed the clinicopathologic features of 32 cases of pulmonary LELC and compared the cases with 84 cases of pulmonary non-LELC with available long-term follow-up information.
The results show that LELC of the lung as a distinct entity has a better prognosis than non-LELC. We found a significant difference in the survival rates between patients with LELC and patients with non-LELC in stage II and stages III and IV, respectively. Tumor recurrence and necrosis (5% or more of tumor) are associated with a poor prognosis. It seems that the histologic typing (Regaud type and Schmincke type) of pulmonary LELC is of no clinical value.
New aspects in clinicopathologic and oncogene studies of 23 pulmonary lymphoepithelioma-like carcinomas.Chang YL, Wu CT, Shih JY, Lee YC.
Departments of Pathology (Y.-L.C., C.-T.W.), Internal Medicine (J.-Y.S.), and Surgery (Y.-C.L.), National Taiwan University Hospital, Taipei, Taiwan.
Am J Surg Pathol 2002 Jun;26(6):715-23 Abstract quote Lymphoepithelioma-like carcinoma, an uncommon epithelial tumor, has been described as being closely associated with Epstein-Barr virus (EBV) infection in many organs, especially the nasopharynx.
We experienced 23 cases of lymphoepithelioma-like carcinoma arising in the lung from 2498 lung cancer patients in the Cancer Registry of our hospital. Seven patients were male and 16 were female. All patients were Chinese. Their ages ranged from 42 to 80 years. Six patients were smokers and 17 were nonsmokers. The tumor sizes ranged from 1.2 to 11.0 cm. All tumors showed the typical syncytial growth pattern of undifferentiated epithelial cells with a significant CD8+ T-lymphocyte reaction. EBV serology revealed prior infection in all 15 serum-available patients, all of whom were also found by in situ hybridization to have the virus genome. In addition, the higher the EBV serology titer, the larger the tumor size and the higher the staging would be. EBV viral capsid antigen IgG level remained elevated despite response to therapy.
Nearly all cases had bcl-2 oncoprotein expression, but the detection rate of latent membrane protein-1, p53, and c-erb B-2 expression was extremely low. The encouraging chemotherapy response for advanced stage disease is also discussed.
MICROPAPILLARY Micropapillary Component in Lung Adenocarcinoma
A Distinctive Histologic Feature With Possible Prognostic SignificanceMitual B. Amin, M.D.; Pheroze Tamboli, M.D.; Shakil H. Merchant, M.D.; Nelson G. Ordóñez, M.D.; Jungsil Ro, M.D.; Alberto G. Ayala, M.D.; Jae Y. Ro, M.D., Ph.D.
From the Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A.
Am J Surg Pathol 2002;26:358-364 Abstract quote Micropapillary carcinoma or a micropapillary carcinoma component has been reported in the ovary, breast, and urinary bladder and is generally thought to have prognostic significance. However, little has been written on micropapillary differentiation in lung carcinoma.
We studied 35 cases of primary lung adenocarcinoma with a micropapillary component seen at the M.D. Anderson Cancer Center. The micropapillary component in these tumors ranged from focal to prominent and was seen at both primary and metastatic sites. This component was not associated with any particular histologic subtype of lung adenocarcinoma. Of the 15 cases with available material, 14 (93%) stained positive for cytokeratin 7, whereas only two of the 15 cases (13%) stained positive for cytokeratin 20. Thyroid transcription factor-1 immunostaining of tumor nuclei was seen in 12 of the 15 cases (80%). Immunostaining was seen in areas both with and without micropapillary differentiation. Thirty-three of 35 patients (94%) developed metastases, which occurred most commonly in the lymph nodes (n = 26), and also in the lung (n = 17), brain (n = 9 cases), bone (n = 9 cases), and other sites. Most metastases had a prominent micropapillary component, irrespective of the extent of the micropapillary carcinoma component in the primary lung tumor. Adequate clinical follow-up information was available for 29 patients. The mean follow-up was 25 months. At their last follow-up, 16 of 29 patients (55%) were still alive with disease, 5 (17%) were dead of disease, and 8 (28%) were alive with no evidence of disease.
We believe that a micropapillary component occurring in lung adenocarcinoma should be reported, as this component may be more likely to metastasize. The presence of this component should alert the clinician to search more carefully for metastases and have a closer follow-up on these patients. It is also important to recognize this component in evaluating a metastasis from an unknown primary site, as it should alert the pathologist to a possible primary in the lung in addition to breast, urinary bladder, and ovary.
Early-stage lung adenocarcinomas with a micropapillary pattern, a distinct pathologic marker for a significantly poor prognosis.Miyoshi T, Satoh Y, Okumura S, Nakagawa K, Shirakusa T, Tsuchiya E, Ishikawa Y.
Am J Surg Pathol 2003 Jan;27(1):101-9 Abstract quote Adenocarcinomas with a micropapillary pattern (MPP), featuring small papillary tufts lacking a central fibrovascular core, are thought to have a poor prognosis.
To examine whether the MPP is a predictor of prognosis, clinicopathologic characteristics of adenocarcinomas were analyzed with particular reference to survival of early-stage patients. The subjects were 344 consecutive patients (female/male ratio 163:181) for whom complete surgical resection was undertaken at the Cancer Institute Hospital, Japan, during 1986-1995. Histologically, they were divided into two groups: MPP-positive (n = 139; 40%) and MPP-negative (n = 205; 60%).
The following items were significantly more frequent in the MPP-positive group: metastasis to lymph nodes (p <0.001), pleural invasion (p = 0.02), intrapulmonary metastasis (p <0.001), and nonsmoking status (p = 0.002). In stage I patients (i.e., without lymph node metastasis, n = 154), 5-year survival of the MPP-positive group (n = 45) was 79%, significantly lower than the MPP-negative group (n = 109) of 93% (p = 0.004). In many cases of the c-stage I MPP-positive group, upstaging was necessary on the basis of pathologic findings for metastases, and the survival was between stage I and stage II.
Our study clearly indicated that the MPP is a distinct prognostic marker for lung adenocarcinoma, particularly regarding apparent stage I diseases.
MIXED
Lung adenocarcinoma with mixed bronchioloalveolar and invasive components: clinicopathological features, subclassification by extent of invasive foci, and immunohistochemical characterization.Terasaki H, Niki T, Matsuno Y, Yamada T, Maeshima A, Asamura H, Hayabuchi N, Hirohashi S.
Am J Surg Pathol. 2003 Jul;27(7):937-51 Abstract quote A significant proportion of small lung adenocarcinomas consists of two components: bronchioloalveolar carcinoma (BAC) and invasive carcinoma.
The purpose of this study was to compare their clinicopathologic features with those of BAC and those of invasive cancer without BAC, and to define "early invasive" lesions based on the extent of invasive foci.
We reviewed 484 lesions of resected lung adenocarcinoma and classified them into three groups according to tumor growth pattern: group 1 (n = 102, BAC), group 2 (n = 216, adenocarcinoma consisting of BAC and invasive carcinoma), and group 3 (n = 166, invasive adenocarcinoma without BAC component). Group 2 was further subdivided according to the extent of the invasive area: group 2a (n = 54), BAC with invasive foci </=5 mm; group 2b (n = 162), BAC with invasive foci >5 mm. These groups were compared with regard to their clinicopathologic features, expression of Ki-67 and p53, and expression of laminin-5, a putative marker for tumor invasion. The positivity rates of vascular, lymphatic, and pleural invasion in each group were as follows: 0%, 0%, and 0% in group 1; 5.5%, 14.8%, and 1.9% in group 2a; 45.7%, 41.4%, and 25.9% in group 2b; and 84.9%, 61.4%, and 60.8% in group 3. Notably, no lymph node metastasis occurred in either group 2a or group 1, but it was observed in 24.1% of group 2b and 47.0% of group 3.
The mean Ki-67 labeling index, the frequency of p53 overexpression, and the frequency of laminin-5 overexpression increased from group 1 (11%, 4%, and 0%) to group 2a (16%, 20%, and 7%) to group 2b (24%, 41%, and 23%) to group 3 (35%, 38%, and 38%). In contrast, no clear differences were observed when lesions were subdivided according to size. Based on the distribution pattern of Ki-67-positive tumor cells, lesions were classified into two groups: marginal type (63%) and nonmarginal type (37%). The latter showed a significantly higher labeling index than the former. Moreover, the proportion of the marginal type clearly decreased from group 1 (85%) and group 2a (87%) to group 2b (55%) to group 3 (19%). Group 2 lesions showed characteristics intermediate between the BAC and invasive adenocarcinoma.
According to the extent of the invasive area, we were able to define a subgroup of mixed-type adenocarcinomas (group 2a) that could be regarded as early invasive cancer because they showed low rates of vascular, lymphatic, and pleural invasion, and no nodal involvement.MUCINOUS (COLLOID) Tumor cells floating in pools of mucin
Primary mucinous (so-called colloid) carcinomas of the lung: a clinicopathologic and immunohistochemical study with special reference to CDX-2 homeobox gene and MUC2 expression.
Rossi G, Murer B, Cavazza A, Losi L, Natali P, Marchioni A, Migaldi M, Capitanio G, Brambilla E.
Department of Pathologic Anatomy and Forensic Medicine, University of Modena and Reggio Emilia, Modena, Italy.
Am J Surg Pathol. 2004 Apr;28(4):442-52. Abstract quote
Herein we describe the clinicopathologic and immunohistochemical features of 13 primary mucinous (colloid) carcinomas (MCs) of the lung, an uncommon and controversial tumor. The patients, 7 males and 6 females, ranged in age from 50 to 79 years (mean, 64.5 years). All the tumors presented as a peripheral solitary nodule with gelatinous cut-surface and well circumscribed but lacking a complete fibrous wall. The size ranged from 1 to 5.5 cm.
Microscopically, they consisted of neoplastic elements floating in large mucin pools and focally lining the alveolar spaces. Eleven cases were predominantly composed of tall, columnar goblet cells (goblet cell-type MC), while 2 consisted of signet-ring tumor cells (signet-ring cell-type MC). Five tumors were incidentally discovered by chest radiographs, while the others were symptomatic. All patients underwent complete surgical resection (six lobectomies and seven wedge resections). Postoperative chemotherapy was performed in 3 cases.
Overall, the median follow-up was 26 months (mean 33 months; range 9-95 months). All patients with goblet cell-type MC were alive and well, while the 2 patients with signet-ring cell-type MC died of disease.
Immunohistochemically, all the 11 goblet cell-type MCs were strongly stained with CDX-2 and MUC2, 8 reacted with TTF-1, 6 with cytokeratin 20 (CK20), 9 with cytokeratin 7 (CK7), and 2 with MUC-5AC. Conversely, the two signet-ring cell-type MCs were stained with TTF-1, CK7, and MUC5AC but were negative for CDX-2, MUC2, and CK20. Surfactant apoprotein-A (SP-A) was positive in four goblet cell-type and one signet-ring cell-type MC. When compared with 10 mucinous bronchioloalveolar carcinomas (m-BAC), the latter reacted with CK7, CK20, MUC5AC, TTF-1, SP-A, CDX-2, and MUC2 in 100%, 90%, 100%, 30%, 10%, 0%, and 0% of the cases, respectively.
In summary, MC of the lung represents an entity with two distinct clinicopathologic and immunophenotypic variants: 1) the goblet cell-type, presenting a more indolent clinical behavior and frequently co-expressing markers of intestinal and pulmonary differentiation; and 2) the more aggressive signet-ring cell-type, which retains only markers of pulmonary origin.
On morphologic and immunohistochemical grounds, MCs are easily distinguishable from m-BAC. Since goblet cell-type MC strongly stains with CDX2, MUC2, and CK20, differential diagnosis with metastatic colorectal carcinoma is very challenging and requires appropriate clinical correlation.MUCINOUS CYSTADENO-CARCINOMA Cystic carcinoma with mucin PAPILLARY ADENOCARCINOMA
Cesar A. Moran, MD, etal.
Three cases of primary pulmonary papillary carcinomas with a prominent "morular" component involved 2 women and 1 man (age range, 25-68 years). The patients had symptoms related to the pulmonary mass, including chest pain, cough, and dyspnea.
Radiographic evaluation of the thorax revealed the presence of a pulmonary mass. Surgical biopsies were obtained and reported as non–small cell carcinoma. All patients underwent lobectomy. Two tumors were located in the right upper lobe and 1 in the left upper lobe. The tumors were soft, white to tan, without evidence of necrosis or hemorrhage, and 2.5 to 3.5 cm in greatest diameter. The tumors were characterized predominantly by papillary architecture containing numerous "morules" composed of spindle cells without nuclear atypia or mitotic activity. Some morules were floating freely within papillary spaces; others seemed to detach from the papillary structures. Immunohistochemical studies of 2 tumors showed positivity for thyroid transcription factor-1, keratin, and carcinoembryonic antigen and negativity for thyroglobulin. The morules showed positive thyroid transcription factor-1 staining, weak keratin staining, and negative staining for smooth muscle actin, desmin, and HMB-45.
These cases highlight an unusual phenomenon, that of primary papillary carcinomas of the lung with a prominent morular component.PLEOMORPHIC K-ras gene mutational analysis supports a monoclonal origin of biphasic pleomorphic carcinoma of the lung.
Pelosi G, Scarpa A, Manzotti M, Veronesi G, Spaggiari L, Fraggetta F, Nappi O, Benini E, Pasini F, Antonello D, Iannucci A, Maisonneuve P, Viale G.
Department of Pathology and Laboratory Medicine, European Institute of Oncology and University of Milan School of Medicine, Milan, Italy.
Mod Pathol. 2004 May;17(5):538-46. Abstract quote
We investigated 27 pleomorphic carcinomas of the lung for exon 1 K-ras gene mutations using polymerase chain reaction-single-strand conformation polymophism analysis and direct sequencing.
All pleomorphic carcinomas were biphasic, that is, composed of an adeno-, squamous- or large-cell-carcinomatous component associated with a spindle- and/or giant-cell component. Of 27 cases, six (22%) showed K-ras codon 12 mutations, which is a figure higher than that previously reported on in pure sarcoma-like pleomorphic carcinomas. Five tumors displayed the same mutation in both the epithelial and the sarcomatoid components, whereas in one tumor the mutation was restricted to the epithelial component. All mutations occurred in smokers, and were transversions, including GGT (glycine) to TGT (cysteine) change in two cases, to GCT (alanine) in two and to GTT (valine) in two. No significant relationships were found between the occurrence and type of mutations and patients' survival or any other clinicopathological variable, suggesting that K-ras mutations are early events in the development of these tumors.
Our results indicate that most, though not all, biphasic pleomorphic carcinomas of the lung are monoclonal in origin, and that cigarette smoking may have a causative role in the development of K-ras alterations in these tumors, as all mutations are transversions.PULMONARY BLASTOMA RHABDOID
Carcinoma of lung with rhabdoid features.
Tamboli P, Toprani TH, Amin MB, Ro JS, Ordonez NG, Ayala AG, Ro JY.
Hum Pathol. 2004 Jan;35(1):8-13 Abstract quote.
Lung tumors with rhabdoid features, included as variants of large cell carcinoma in the 1999 World Health Organization classification of lung tumors, are rare and have an aggressive clinical course. We report 11 patients with primary lung tumors with rhabdoid features and review the literature on this uncommon tumor.
We examined samples from 7 primary (6 resections, 1 biopsy) and 4 metastatic tumor samples. All specimens were stained with immunohistochemical stains for pancytokeratin (CK), cytokeratin 7 (CK7), cytokeratin (CK20), thyroid transcription factor-1 (TTF-1), and vimentin. The patients were 7 men and 4 women whose ages ranged from 35 to 70 years. Nine patients presented with respiratory symptoms, and 9 patients had a history of heavy smoking. One patient had TNM stage I tumor, 3 had stage III tumors, and 6 had stage IV tumors at presentation; tumor stage could not be determined in 1 patient. Histological examination of these tumors showed typical rhabdoid cells: large cells with abundant cytoplasm, a large eccentric nucleus with a central macronucleolus, and a rounded eosinophilic cytoplasmic inclusion that sometimes caused nuclear indentation. These cells constituted 10% to 90% of the tumor. The "parent" neoplasm was sarcomatoid carcinoma and adenocarcinoma in 4 cases each and was large cell undifferentiated carcinoma in 3 cases. Cytoplasmic staining in the rhabdoid cells was seen in 9 of 11 cases for CK, in 4 of 10 cases for CK7, and in all 11 cases for vimentin. Nuclear staining for TTF-1 in the rhabdoid cells was absent in all 11 cases, and cytoplasmic staining for CK20 was negative in the rhabdoid cells in all 10 cases studied. Of the 9 patients with available follow-up information, 8 died of disease, and 1 is alive with no evidence of disease 20 months after the initial diagnosis.
We conclude that rhabdoid features can occur in a variety of lung tumors, including sarcomatoid carcinoma. Recognizing these lesions is important because of their possibly aggressive clinical course.SIGNET RING
Primary Lung Carcinoma With Signet-ring Cell Carcinoma Components: Clinicopathological Analysis of 39 Cases.
Tsuta K, Ishii G, Yoh K, Nitadori J, Hasebe T, Nishiwaki Y, Endoh Y, Kodama T, Nagai K, Ochiai A.
*Clinical Laboratory Division, and daggerThoracic Oncology Division, National Cancer Center Hospital East, Chiba, Japan; and double daggerPathology Division, National Cancer Center Research Institute East, Chiba, Japan; and section signDepartment of Respiratory Oncology, National Cancer Center Hospital, Tokyo, Japan.
Am J Surg Pathol. 2004 Jul;28(7):868-874. Abstract quote
The clinical and histologic profiles of primary lung carcinomas with signet-ring cell carcinoma (SRCC) components were analyzed. The SRCC components were seen in 39 cases (1.5%) of 2640 cases of surgically resected primary lung carcinomas. The patients' mean age was 54.6 years (range, 32-76 years), and the male-to-female ratio was 1.16:1.00. Twenty-six patients (66.7%) were smokers.
The SRCC component was seen as part of an adenocarcinoma in 36 cases (acinar, 27 cases; mixed bronchioloalveolar and acinar, 9 cases) and as part of an adenosquamous cell carcinoma in 2 cases; one lesion consisted of only SRCC cells. The morphologic appearance of cancer nests containing SRCC was classified into three patterns: solid, tubuloacinar, and discohesive. Each case was composed of a varying proportion of these three patterns. The carcinomas with SRCC components were divided into two groups, according to those in which the SRCC component occupied <50% of the lesion (L-SRCC; n = 20) and those in which the SRCC component occupied >/=50% of the lesion (H-SRCC; n = 19). The frequencies of blood vessel invasion, lymph vessel invasion, and lymph node metastasis were significantly higher in the H-SRCC group than in 1634 adenocarcinoma, and adenosquamous cell carcinomas (non-SRCC). The 5-year survival rates of patients non-SRCC, with l-SRCC, or with H-SRCC were 52.7%, 50%, and 28.4%, respectively. The 5-year survival rate of patients with H-SRCC and of patients without SRCC were significantly different.
Based on these clinicopathologic characteristics, we classified primary lung carcinomas with SRCC components into the following two groups: 1) SRCC, in which the SRCC component occupies >/=50% of the lesion, and 2) signet-ring feature, in which the SRCC components occupies <50% of the lesion.Primary Signet-Ring Cell Carcinoma of Lung Immunohistochemical Study and Comparison With Non-Pulmonary Signet-Ring Cell Carcinomas
Shakil H. Merchant, M.D. ; Mitual B. Amin, M.D. ; Pheroze Tamboli, M.D. ; Jungsil Ro, M.D. , Ph.D. ; Nelson G. Ordóñez, M.D. ; Alberto G. Ayala, M.D. ; Bogdan A. Czerniak, M.D. , Ph.D. ; Jae Y. Ro, M.D. , Ph.D.
From the Department of Pathology (S.H.M., M.B.A., P.T., N.G.O., A.G.A., B.A.C., J.Y.R.), University of Texas, M.D. Anderson Cancer Center and Medical Oncology (J.R.), MacGregor Clinic, Houston, Texas, U.S.A.
Am J Surg Pathol 2001;25:1515-1519 Abstract quote
Signet-ring cell carcinoma (SRCC) of lung is a rare variant of pulmonary adenocarcinoma. In view of this rarity, the question of whether an SRCC is primary pulmonary or metastatic arises frequently because the majority of SRCCs seen in lung are metastatic tumors having arisen in stomach, colon, or breast. On routine histologic examination it is difficult to distinguish between pulmonary SRCC from SRCC metastasizing from other organs. Thyroid transcription factor-1 (TTF-1) is a homeodomain-containing transcription factor that is almost exclusively expressed in thyroid and pulmonary epithelial cells. TTF-1 expression has been demonstrated in various neoplasms of lung; however, the expression of TTF-1 in SRCCs has not been investigated so far.
In the present study, using an immunoperoxidase staining procedure on paraffin sections, we investigated the expression of TTF-1, cytokeratin 7, cytokeratin 20, and villin (a specific marker expressed in tumors of the digestive tract, renal proximal tubules, and hepatic bile ducts) in 32 SRCCs from various organs (17 lung, 5 breast, 5 stomach, and 5 colon). Fourteen (82.4%) of 17 pulmonary SRCCs exhibited TTF-1 positivity, whereas none of the SRCCs of other organs were positive for TTF-1. A cytokeratin profile (CK7+/CK20–) was identified in 94.1% of pulmonary SRCC, and although it differed from the profile exhibited in colonic SRCCs (CK7–/CK20+), a similar profile was seen in breast SRCCs and some SRCCs arising in the stomach. Villin was identified in 29.4% of pulmonary SRCCs and 20% (one case) arising in the breast. Although the pattern of villin immunostaining exhibited by nondigestive tract SRCCs (cytoplasmic) differed from those of digestive tract SRCCs (membranous), distinguishing between the two groups based on their pattern of immunostaining alone would be difficult.
The results of this study indicate that TTF-1 is expressed in a high percentage of pulmonary SRCCs and is very specific and that TTF-1 would be extremely valuable in distinguishing pulmonary SRCCs from those arising in other organs.
SALIVARY GLAND TYPE CARCINOMA Includes:
Mucoepidermoid carcinoma
Adenoid cystic carcinomaCombined large cell neuroendocrine carcinoma and spindle cell carcinoma of the lung
Mahmoud Khalifa, MD, FRCPC
George Hruby, MD, FRANZC
Lisa Ehrlich, MD, FRCPC
Cyril Danjoux, MD, FRCPC
Bayardo Perez-Ordoñez, MD, FRCPCFrom the Departments of Anatomic Pathology and Nuclear Medicine, Sunnybrook and Women's College Health Science Centre, Toronto; and the Department of Radiation Oncology, Toronto-Sunnybrook Regional Cancer Centre and University of Toronto, Toronto, Ontario, Canada.
Ann Diagn Pathol 5: 240-245, 2001 Abstract quote
We report a unique case of a combined pulmonary large-cell neuroendocrine carcinoma and spindle-cell carcinoma.
The patient was a 54-year-old female smoker who presented with a 4-month history of increased left-sided chest pain and exertional dyspnea. The left upper lobectomy specimen revealed an 8.0-cm mass with central necrosis. Microscopically, the epithelial areas were composed of well-defined nests of large cells with peripheral palisading expressing low-molecular-weight keratin, synaptophysin, chromogranin, and neuron-specific enolase. The spindle-cell component consisted of pleomorphic cells arranged in fibrosarcoma and malignant fibrous histiocytoma-like patterns. These spindle cells were positive for low-molecular-weight keratin and vimentin with focal expression of CD68 and muscle-specific actin. Electron microscopy in the spindle-cell areas showed cell junctions and numerous tonofilaments, indicative of epithelial differentiation. The tumor behaved aggressively and the patient died with extensive metastases 4 months after surgery.
The combination of neuroendocrine malignancies and spindle-cell carcinomas appears to be uncommon in the lung. Previous reports have described this association in single case reports of anaplastic small-cell carcinoma and atypical carcinoid, but not in large-cell neuroendocrine carcinoma.
SARCOMATOID CARCINOMA
Pleomorphic carcinomas of the lung show a selective distribution of gene products involved in cell differentiation, cell cycle control, tumor growth, and tumor cell motility: a clinicopathologic and immunohistochemical study of 31 cases.
Pelosi G, Fraggetta F, Nappi O, Pastorino U, Maisonneuve P, Pasini F, Iannucci A, Solli P, Musavinasab HS, De Manzoni G, Terzi A, Viale G.
Department of Pathology and Laboratory Medicine, Institute of European Oncology and University of Milan School of Medicine, Italy.
Am J Surg Pathol. 2003 Sep;27(9):1203-15. Abstract quote
We investigated 31 cases of pleomorphic carcinomas of the lung, with a double component of neoplastic epithelial cells and of spindle and/or giant cells.To correlate the morphologic diversity of these two cell components with their immunophenotype, we evaluated the expression of several gene products involved in cell differentiation (cytokeratins, epithelial membrane antigen, carcinoembryonic antigen, vimentin, S-100 protein, smooth muscle actin, desmin), cell cycle control and apoptosis (p53, p21Waf1, p27Kip1, FHIT), tumor growth (proliferative fraction, assessed by Ki-67 antigen, and microvascular density, assessed by CD34 immunostaining), and tumor cell motility (fascin).
We found the epithelial component to be significantly more immunoreactive for cytokeratins, epithelial membrane antigen, carcinoembryonic antigen, cell cycle inhibitors p21Waf1, p27Kip1 and tumor suppressor gene FHIT, whereas the sarcomatoid component, independent of tumor stage and size, was more immunoreactive for vimentin, fascin, and microvascular density. Accordingly, we suggest a model of tumorigenesis whereby the mesenchymal phenotype of pleomorphic cells is likely induced by the selective activation and segregation of several molecules involved in cell differentiation, cell cycle control, and tumor cell growth and motility.
Whether pleomorphic carcinomas of the lung are tumors with a dismal prognosis still remains an unsettled issue. In our series, however, stage I pleomorphic carcinomas have the same clinical behavior as ordinary non-small cell lung cancer, and only a high proliferative index (Ki-67 labeling index >35%) is associated with a worse prognosis in these tumors.
Pulmonary carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements: a clinicopathologic and immunohistochemical study of 75 cases.Rossi G, Cavazza A, Sturm N, Migaldi M, Facciolongo N, Longo L, Maiorana A, Brambilla E.
Am J Surg Pathol 2003 Mar;27(3):311-24 Abstract quote We collected 75 primary pulmonary carcinomas with pleomorphic, sarcomatoid, or sarcomatous elements to better define their clinical, histologic, and immunohistochemical profile.
The patient's age ranged from 42 to 81 years (mean 65 years), and the male-to-female ratio was 9.7:1. Sixty-nine patients (92%) were smokers. Cough and hemoptysis were the most frequent presenting symptoms. Fifty-nine patients (65%) died of disease: only stage significantly predicts overall survival (p = 0.0273).
Microscopically, based on the WHO criteria, 58 cases were classified as pleomorphic carcinoma (51 with an epithelial component, 7 composed exclusively of spindle and giant cells), 10 as spindle cell carcinoma, 3 as giant cell carcinoma, 3 as carcinosarcoma, and 1 as pulmonary blastoma. Immunohistochemically, in the tumors composed exclusively of spindle and/or giant cells, thyroid transcription factor-1 (TTF-1) and cytokeratin 7 were positive in 55% and 70% of the cases, respectively, whereas surfactant protein-A was always negative. In pleomorphic carcinomas with an epithelial component, cytokeratin 7, TTF-1, and surfactant protein-A were positive in the sarcomatoid component in 62.7%, 43.1%, and 5.9% of the cases, respectively, whereas they were always negative in the sarcomatous part of carcinosarcomas and blastoma. In the epithelial component of pleomorphic carcinomas, cytokeratin 7, TTF-1, and surfactant protein-A were positive in 76.4%, 58.8%, and 39.2% of the cases, respectively, whereas the same antibodies did not react with the epithelial component of carcinosarcomas; in the case of blastoma, the epithelial part of the tumor was positive for cytokeratin 7 and TTF-1, whereas it was negative for surfactant protein-A. Cytokeratin 20 was always negative.
In our opinion, this study: 1) supports the metaplastic histogenetic theory for this group of tumors; 2) shows that cytokeratin 7 and TTF-1, but not surfactant protein-A, are useful immunohistochemical markers in this setting; 3) confirms that stage is at the moment the only significant prognostic parameter, as in conventional non-small cell lung carcinomas; and 4) shows that this group of tumors has a worse prognosis than conventional non-small cell lung carcinoma at surgically curable stages I, justifying their segregation as an independent histologic type in the WHO classification.
Molecular pathogenesis of pulmonary carcinosarcoma as determined by microdissection-based allelotyping.Dacic S, Finkelstein SD, Sasatomi E, Swalsky PA, Yousem SA.
Department of Pathology, Division of Anatomic Pathology, University of Pittsburgh Medical Center, Presbyterian University Hospital, Pittsburgh, Pennsylvania, U.S.A.
Am J Surg Pathol 2002 Apr;26(4):510-6 Abstract quote Pulmonary carcinosarcoma is a rare, biphasic tumor composed of malignant epithelial and mesenchymal elements. Its histogenesis is controversial in light of the presence of divergent cell lineages and the clonal nature of malignancy.
To address these issues, we performed an extensive comparative genotypic analysis using microdissection to secure representative mesenchymal and epithelial components from each of six cases of pulmonary carcinosarcoma. Loss of heterozygosity was analyzed with a panel of 12 polymorphic microsatellite markers designed to indicate allelic loss and situated in proximity to known tumor suppressor genes located on 1p, 3p, 5q, 9p, 10q, and 17p. In accordance with the relatively greater biologic aggressiveness of this tumor type, both the epithelial and mesenchymal components showed extensive allelic loss, most notably for 3p, 5q, and 17p.
More importantly, we found overall equivalent patterns of acquired allelic loss between the two components on an individual case basis, strongly supporting the monoclonal origin of these neoplasms. Minor differences in the allelic fingerprint between the two cell lineages could be explained by progressive accumulation of allelic loss alterations that appear to occur more frequently in the mesenchymal component of the tumor.
The data support the efficacy of microdissection-based allelic fingerprinting to delineate the relationship between different morphologic components of a single neoplasm.
SQUAMOUS CELL CARCINOMA, PERIPHERAL
Clinicopathologic characteristics of peripheral squamous cell carcinoma of the lung.Funai K, Yokose T, Ishii G, Araki K, Yoshida J, Nishimura M, Nagai K, Nishiwaki Y, Ochiai A.
Am J Surg Pathol. 2003 Jul;27(7):978-84. Abstract quote Squamous cell carcinoma of the lung can be divided into two types according to the location of the primary site: the central type and the peripheral type. The clinicopathologic factors in the peripheral type of lung squamous cell carcinoma have not yet been fully evaluated.
A total of 204 surgically resected lung squamous cell carcinomas were reviewed with special reference to their location, histologic characteristics based on tumor growth patterns, and clinicopathologic factors. The central type and the peripheral type accounted for 95 and 109 cases, respectively. Although the patient population of the peripheral type was older, with a lower pathologic stage, lower lymphatic vessel involvement, and lymph node metastasis, the Kaplan-Meier survival proportions did not differ significantly between these two groups.
Based on the histologic growth pattern, the peripheral type was classified under three subgroups as follows: 1) the alveolar space-filling type, 2) the expanding type, and 3) the combined type. Among these three types, the alveolar space-filling type showed neither lymphatic vessel invasion nor lymph node metastasis and had the most favorable prognosis.
The central and peripheral types of lung squamous cell carcinoma have different clinicopathologic characteristics and should be classified under respectively different categories.TERMINAL RESPIRATORY UNIT TYPE ADENOCARCINOMA
- EGFR Mutation Is Specific for Terminal Respiratory Unit Type Adenocarcinoma.
Yatabe Y, Kosaka T, Takahashi T, Mitsudomi T.
From the *Department of Pathology and Molecular Diagnostics, daggerDepartment of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan, double daggerDivision of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, Japan.
Am J Surg Pathol. 2005 May;29(5):633-639. Abstract quote
We have previously reported that terminal-respiratory-unit (TRU) type adenocarcinoma is a distinct subset of lung adenocarcinoma in terms of molecular pathway for carcinogenesis and phenotypic profiles.
This type of cancer shows TRU features, characterized by distinct cellular morphology and the expression of TTF-1 and surfactant proteins. Recently, two groups published novel mutations of the epidermal growth factor receptor (EGFR) that are closely associated with clinical response to gefitinib. The clinicopathologic features of gefitinib responders overlap with those of TRU-type adenocarcinoma, and the characteristics of TRU are likely to correspond to the bronchioloalveolar features reported as a predictor of gefitinib response.
We therefore examined the characteristics of EGFR-mutated pulmonary adenocarcinomas with special reference to TRU-type adenocarcinoma. EGFR mutation was detected in 97 of 195 adenocarcinomas, 91 of 149 TRU-type adenocarcinomas and 6 of 46 tumors of other types. Conversely, 91 of 97 EGFR-mutated adenocarcinomas were categorized as TRU-type adenocarcinomas. This type-specific involvement was confirmed by logistic regression model. In addition, EGFR mutation was detected in some cases of atypical adenomatous hyperplasia, a preinvasive lesion of TRU-type adenocarcinoma.
These findings further confirm that TRU-type-adenocarcinoma is a distinct adenocarcinoma subset in which a particular molecular pathway is involved.
SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHERCHARACTERIZATION CD117
The spectrum of Kit (CD117) immunoreactivity in lung and pleural tumors: a study of 96 cases using a single-source antibody with a review of the literature.
Butnor KJ, Burchette JL, Sporn TA, Hammar SP, Roggli VL.
Department of Pathology, University of Vermont, Burlington, VT, USA.
Arch Pathol Lab Med. 2004 May;128(5):538-43. Related Articles, Links
CONTEXT: The development of successful chemotherapeutic agents directed against the Kit receptor tyrosine kinase protein has generated intense interest in the Kit (CD117) immunoreactivity of various neoplasms. Immunoreactivity for Kit in small cell lung carcinoma (SCLC) has been well established. However, data on Kit immunostaining in other lung tumors is limited. Likewise, while solitary fibrous tumors of the gastrointestinal tract have been examined for Kit expression, the Kit staining characteristics of their counterpart in the pleura, namely, localized fibrous tumor, are not well known.
OBJECTIVE: To characterize the Kit immunohistochemical profiles of major types of lung and pleural tumors.
DESIGN: We stained 60 lung carcinomas, including 11 SCLCs, 4 large cell neuroendocrine carcinomas, 22 squamous cell carcinomas, 23 adenocarcinomas, 11 pulmonary carcinoid tumors, 19 pleural malignant mesotheliomas, and 6 localized pleural fibrous tumors with a commonly used polyclonal Kit antibody.
RESULTS: Small cell lung carcinomas demonstrated Kit staining in 82% of cases, nearly all of which demonstrated moderate to intense immunoreactivity. Immunostaining was observed in 25% of large cell neuroendocrine carcinomas. Focal staining was observed in 9% of squamous cell carcinomas and 17% of adenocarcinomas. None of the pulmonary carcinoid tumors were immunoreactive. Moderately intense immunostaining was present in 50% of localized fibrous tumors. Malignant mesotheliomas were nonimmunoreactive for Kit in 95% of cases.
CONCLUSION: Non-small cell lung carcinomas showed very limited expression of Kit. Lung tumors with neuroendocrine differentiation exhibited a wide spectrum of Kit immunoreactivity, ranging from rare in pulmonary carcinoid tumors to frequent in SCLC. The high frequency of Kit immunostaining in SCLC has important potential therapeutic implications. Demonstration of Kit positivity in some localized fibrous tumors in this study contrasts with absent immunoreactivity in solitary fibrous tumors of the gastrointestinal tract. The paucity of Kit staining in malignant mesothelioma suggests these tumors are unlikely to respond to currently available tyrosine kinase inhibitors.Cdx2
Am J Clin Pathol 2004;122:421-427 Abstract quote
We studied the diagnostic value of Cdx2 to distinguish mucinous bronchioloalveolar carcinoma from mucinous colorectal adenocarcinoma metastatic to the lung.
We retrieved 92 via the hospital computer system, including 30 mucinous bronchioloalveolar carcinomas, 32 nonmucinous bronchioloalveolar carcinomas, and 30 mucinous colorectal adenocarcinomas metastatic to the lung. All cases were confirmed by clinical history and surgical resection with occasional immunohistochemical studies.
Cases were stained with antibodies against Cdx2, thyroid transcription factor-1 (TTF-1), cytokeratin (CK) 7, and CK20. Bronchioloalveolar carcinoma, mucinous type, showed positive staining for Cdx2, TTF-1, CK7, and CK20 in 0 (0%), 5 (17%), 30 (100%), and 18 (60%) of 30 cases, respectively; nonmucinous tumors were positive in 0 (0%), 30 (94%), 32 (100%), and 0 (0%) of 32 cases, respectively. For colorectal adenocarcinoma, the positive staining for Cdx-2, TTF-1, CK7, and CK20 was 29 (97%), 0 (0%), 7 (23%), and 29 (97%) of 30 cases, respectively.
Our results demonstrated Cdx2 as a sensitive and specific marker for differentiating metastatic colorectal adenocarcinoma from mucinous bronchioloalveolar adenocarcinoma.CYTOKERATINS
Giulio Rossi, MD,etal.Am J Clin Pathol 2004;122:884-893 Abstract quote
We selected a 4-stain immunopanel including thyroid transcription factor (TTF)-1, cytokeratin (CK) 7, 34bE12, and CD56/neural cell adhesion molecule (NCAM) to subclassify a series of 45 pulmonary large cell carcinomas (LCCs) on bronchial biopsy. All cases consisted of a large tumor cell proliferation with abundant cytoplasm, vesicular nuclei, and prominent nucleoli.
Immunohistochemically, 27 tumors (60%) were subclassified as adenocarcinoma (TTF-1+/CK7+, 24; CK7+ only, 3), 10 (22%) as squamous cell carcinoma (34bE12+ only), and 4 (9%) as LCC with neuroendocrine differentiation (CD56+, variably stained with TTF-1 and CK7, 34bE12–). In 4 cases, the tumors coexpressed CK7 and 34bE12 (3 cases) or were completely unstained (1 case). Surgically resected tumors matched exactly with the corresponding original biopsy specimens in 21 of 23 cases; consistent CD56 expression was a reliable marker in confirming a diagnosis of large cell neuroendocrine carcinoma even on biopsy.
Our results suggest that the proposed 4-stain set of commercially available markers might help subclassify LCC even in small biopsy material, validating expression-profiling studies aimed at lung cancer classification and permitting more consistent patient enrollment for trials with targeted treatments.
- Immunohistochemical analysis of lung carcinomas with pure or partial bronchioloalveolar differentiation.
Sarantopoulos GP, Gui D, Shintaku P, Hong L, Wang YY, Yap CS, Fishbein MC.
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, Calif 90095, USA.
Arch Pathol Lab Med. 2004 Apr;128(4):406-14. Abstract quote
CONTEXT: In 1999, the World Health Organization redefined bronchioloalveolar carcinomas (BACs) as those neoplasms with only a pure lepidic growth pattern and no invasion.
OBJECTIVES: The present study examined 45 lung cancers with a BAC component (1) to determine whether these tumors would be classified as BACs by current World Health Organization standards, (2) to quantitate the BAC component within these tumors, and (3) to see if phenotypic differences exist between the so-called invasive and noninvasive regions of these tumors.
DESIGN: Retrospective review of hematoxylin-eosin-stained slides and classification of histologic grade, tumor subtype, and percentage of pure BAC pattern, with further characterization by immunohistochemical staining for thyroid transcription factor 1, cytokeratin 7, cytokeratin 20, and Ki-67 antibodies.
RESULTS: Only 7 (15.6%) of the 45 tumors examined could be classified as BAC by current strict World Health Organization criteria. Those tumors, classified as nonmucinous and mixed, showed similar immunohistochemical staining for cytokeratin 7, cytokeratin 20, and thyroid transcription factor 1; mucinous tumors showed disparate staining. Significant differences in immunohistochemical staining and tumor cell proliferation were seen for the regions of tumors designated as lepidic, infiltrative, and leading edge and for the regions of tumors with different histologic grades (ie, well, moderately, and poorly differentiated).
CONCLUSIONS: Nonmucinous and mixed BACs are phenotypically similar and show identical immunohistochemical staining patterns; mucinous tumors, on the other hand, show disparate immunohistochemical staining. Pulmonary neoplasms designated as adenocarcinomas with a BAC component represent a heterogenous group with a range of cell types, differentiation, growth, and immunophenotypes. Within an individual neoplasm, there are regional differences in these parameters as well.Differential Expression of Cytokeratins 7 and 20 and Thyroid Transcription Factor-1 in Bronchioloalveolar Carcinoma An Immunohistochemical Study in Fine-Needle Aspiration Biopsy Specimens
Aylin Simsir, MD Xiao-Jun Wei, MD,, Herman Yee, MD, PhD, Andre Moreira, MD, PhD, and Joan Cangiarella, MDAm J Clin Pathol 2004;121:350-357 Abstract quote
We studied the staining patterns of bronchioloalveolar carcinoma (BAC) with antibodies to cytokeratin (CK) 7, CK20, and thyroid transcription factor-1 (TTF-1) to determine the diagnostic usefulness of this panel in differentiating BAC from metastatic adenocarcinoma in material obtained by fine-needle aspiration biopsy (FNAB) of the lung.
We identified 16 cases of BAC. Of these, 6 were mucinous, 4 were nonmucinous, and 6 were mixed with focal mucinous differentiation. Immunohistochemical analysis with antibodies to CK7, CK20, and TTF-1 was performed on cell-block sections. Of the 6 mucinous BACs, 4 (67%) were CK7+, CK20+, and TTF-1–. All 4 nonmucinous BACs were CK7+ and CK20–, and 2 (50%) were TTF-1+. All 6 mixed BACs were diffusely positive for CK7 and focally positive for CK20; 5 (83%) were TTF-1+. Nonmucinous BACs display CK7, CK20, and TTF-1 immunoreactivity similar to conventional pulmonary adenocarcinoma. Mucinous and mixed BACs have an immunohistochemical phenotype that is different from that of conventional pulmonary adenocarcinoma.
Knowledge of these staining patterns is crucial for distinguishing mucinous and mixed BACs from metastatic adenocarcinoma involving the lungs.
Expression of thyroid transcription factor-1, cytokeratin 7, and cytokeratin 20 in bronchioloalveolar carcinomas: an immunohistochemical evaluation of 67 cases.Lau SK, Desrochers MJ, Luthringer DJ.
Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
Mod Pathol 2002 May;15(5):538-42 Abstract quote Distinguishing primary pulmonary adenocarcinoma from metastatic adenocarcinoma involving the lung is a common challenging task. The distinction between mucinous bronchioloalveolar carcinoma (BAC) and metastatic mucinous carcinoma of other sites, in particular, is difficult by routine histology.
Immunohistochemical expression of thyroid transcription factor-1 (TTF-1), as well as cytokeratin 7 (CK 7) and cytokeratin 20 (CK 20), has proven diagnostic utility in discerning primary from metastatic neoplasms in the lung. Rigorous studies assessing the expression of these markers in BACs, particularly in regard to nonmucinous and mucinous subtypes, have not been performed. In this study, we evaluated the immunohistochemical expression of TTF-1, CK 7, and CK 20 in 67 BACs (48 nonmucinous, 12 mucinous, and 7 of mixed histology). Overall, 42 (63%) of the 67 BACs were positive for TTF-1. When stratified according to subtype, all 12 mucinous BACs were observed to be TTF-1 negative.
This trend toward absence of TTF-1 expression in mucinous areas was also maintained among tumors with mixed histology. Sixty-three (94%) of 67 BACs were CK 7 positive, with no differences in expression observed upon subtype stratification. Three cases were noted to be positive for CK 20; all exhibited mucinous morphology. These results indicate that in contrast to the immunophenotypic profile exhibited by most pulmonary neoplasms, mucinous BACs are TTF-1 negative and may express CK 20.
This suggests that in the context of differentiating mucinous BACs from extrapulmonary mucinous tumors metastatic to the lung, evaluation of TTF-1 and CK 20 expression may have limited diagnostic utility.
Expression of cytokeratin 20 in mucinous bronchioloalveolar carcinoma.Shah RN, Badve S, Papreddy K, Schindler S, Laskin WB, Yeldandi AV.
Department of Pathology, Northwestern University, Chicago, IL.
Hum Pathol 2002 Sep;33(9):915-20 Abstract quote Mucinous bronchioloalveolar carcinomas (BACs) can closely mimic metastatic adenocarcinoma to the lung both clinically and morphologically. Several studies have demonstrated that the differential expression of cytokeratin 7 (CK7) and cytokeratin 20 (CK20) is a valuable diagnostic tool in differentiating primary pulmonary adenocarcinomas (PPAs) (usually CK7 positive/CK20 negative) from metastatic colonic adenocarcinoma (usually CK7 negative/CK20 positive).
The present study is designed to correlate the histologic subtypes of PPA with expression of 7 and 20. A total of 113 cases of bonafide PPA were selected and classified according to the 1999 World Health Organization criteria as adenocarcinoma, NOS (n = 80), nonmucinous BAC (n = 14), and mucinous BAC (n = 19). Representive sections of all the tumors were immunohistochemically analyzed for CK7 and CK20 expression. To evaluate the diagnostic utility of CK7 and CK20 expression, 6 cases of colonic adenocarcinoma metastatic to the lung were tested with the same antibodies and compared with mucinous BAC. Results were expressed in a semiquantitative fashion based on the percentage of positive tumor cells: <10%, focal; 10% to 25%, 1+; 26% to 75%, 2+; >/=76%, 3+. All 113 PPAs exhibited strong, diffuse CK7 expression.
With respect to CK20 expression, 17 of the 19 cases (89.4%) of mucinous BAC showed moderate to strong expression of this protein, whereas only 10 cases of conventional adenocarcinomas and 4 cases of nonmucinous BAC exhibited expression. All 6 examples of metastatic colonic adenocarcinomas were negative for CK7 and strongly positive for CK20. In summary, mucinous BAC is distinct from other PPAs by virtue of its CK20 expression.
Although the CK7/CK20 immunoprofile is a valuable diagnostic marker for differentiating primary lung adenocarcinoma from metastatic colonic adenocarcinoma, caution should be exercised when dealing with mucinous BAC.
ESTROGEN RECEPTOR
Detection of estrogen receptor by immunohistochemistry in pulmonary adenocarcinoma.Dabbs DJ, Landreneau RJ, Liu Y, Raab SS, Maley RH, Tung MY, Silverman JF.
Department of Pathology, Allegheny General Hospital, Pittsburgh, Pennsylvania, USA.
Ann Thorac Surg 2002 Feb;73(2):403-5; discussion 406 Abstract quote BACKGROUND: The distinction between primary adenocarcinoma and metastatic breast carcinoma in the lung is important for therapeutic purposes. There is a good deal of morphologic overlap between primary pulmonary adenocarcinoma and breast carcinoma metastatic in the lung. Many diagnosticians rely upon the presence of estrogen receptor (ER) in tumors of the lung in women in order to make a pathologic diagnosis of metastatic breast carcinoma. There are conflicting data in the literature regarding the presence of ER in lung carcinomas. In this study, we examined primary lung adenocarcinomas with monoclonal antibodies to two different clones to ER (clone 6F11 and clone 1D5), and progesterone receptor by the immunoperoxidase method in order to ascertain if ER is detectable in primary lung adenocarcinomas.
METHODS: Twenty-five resected solitary pulmonary nonmucinous bronchioalveolar carcinomas (15 female, 10 male) and 20 resected solitary pulmonary adenocarcinomas of no special type (12F, 8 mol/L) were studied by the immunohistochemical method using heat-induced epitope retrieval. Immunostaining was semiquantitated, and positive results included nuclear staining for ER and progesterone receptor. All of these tumors were documented as primary pulmonary adenocarcinomas clinically and pathologically.
RESULTS: Nuclear ER was seen only with the 6F11 clone, in 56% of the bronchioalveolar type and 80% of the no special type. No nuclear ER was seen in carcinomas utilizing the 1D5 clone. There was no progesterone receptor detectable in carcinomas.
CONCLUSIONS: Estrogen receptor is present in the majority of lung adenocarcinomas, and detection of ER in lung adenocarcinomas is dependent upon the antibody clone that is used. Epitope recognition may account for the differences in immunoreactivity between these two antibodies, although a cross-reactive antibody reaction cannot be completely excluded. Further study is warranted to discern the nature of the 6F11 clone immunoreactivity with nuclei of lung adenocarcinomas. The clinical significance and ramifications of ER in pulmonary adenocarcinomas remain unknown. Caution should be exercised by clinicians and pathologists in accepting a diagnosis of metastatic breast carcinoma in lung based on the presence of ER detected by clone 6F11.
MUC4
We examined the expression of MUC1, MUC2, MUC5AC, and MUC6 by immunohistochemical staining in atypical adenomatous hyperplasia (AAH), bronchioloalveolar carcinoma (BAC), and adenocarcinoma with mixed subtypes (MX) to study the association between the biologic features of adenocarcinoma of the lung and mucin expression.
MUC1 expression was decreased significantly in the progression from AAH through BAC to MX, while the levels of expression of MUC2, MUC5AC, MUC6, and depolarized MUC1 were increased significantly. Alterations in the expression of depolarized MUC1, MUC5AC, and MUC6 were correlated significantly with p53 gene abnormalities. Depolarized MUC1 expression also was correlated significantly with Ki-67 expression, and down-regulation of MUC1 expression and up-regulation of MUC6 expression were correlated significantly with tumor size.
Our results suggest that the expression of these mucins might be associated with the progression of adenocarcinoma of the lung.
Diagnostic value of MUC4 immunostaining in distinguishing epithelial mesothelioma and lung adenocarcinoma.
Llinares K, Escande F, Aubert S, Buisine MP, de Bolos C, Batra SK, Gosselin B, Aubert JP, Porchet N, Copin MC.
Unite INSERM U560 Laboratoire de Recherche Gerard Biserte, Place de Verdun, Lille, France.
Mod Pathol. 2004 Feb;17(2):150-7. Abstract quote
The distinction between pleural malignant mesothelioma and pleural infiltration by adenocarcinomas has complex therapeutic and medicolegal implications.
Although the panel of adenocarcinoma-associated antibodies and one or two mesothelioma markers is useful in this purpose, most of these antibodies are not totally specific. We determined the diagnostic value of MUC4 immunostaining in this issue. MUC4 gene expression was also studied by in situ hybridization and RT-PCR. MUC4 is a membrane-bound mucin that has been suggested to be implicated in malignant progression in humans and rats. The MUC4 gene is expressed in various normal epithelial tissues of endodermic origin and carcinomas. In the respiratory tract, MUC4 transcripts have been detected in normal respiratory epithelium and lung carcinomas. MUC4 protein was expressed in 32 of 35 (91.4%) lung adenocarcinomas on paraffin-embedded tissue. None of the 41 malignant mesotheliomas nor the 32 cases of benign mesothelial cells expressed MUC4 at the protein and mRNA levels.
We conclude that MUC4 is a very specific (100%) and sensitive (91.4%) marker of lung adenocarcinomas on paraffin-embedded tissue that could be useful in diagnostic practice in the distinction between malignant mesothelioma and adenocarcinoma.p63 p63 expression in assessment of bronchioloalveolar proliferations of the lung.
Sheikh HA, Fuhrer K, Cieply K, Yousem S.
Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Mod Pathol. 2004 Sep;17(9):1134-40. Abstract quote
Discrimination of well-differentiated pulmonary adenocarcinoma from reactive bronchioloalveolar epithelium can be difficult on routine histology, especially with small biopsies. Ancillary studies to help in this distinction are desirable. p63, a p53-homologous nuclear protein, is a marker of reserve cells of the bronchus and terminal lobular unit.
In this study, 33 cases of adenocarcinoma (20 open lung and 13 transbronchial/percutaneous biopsies) and 43 cases of benign lungs with fibrosis and metaplasia (22 open lung and 21 transbronchial/percutaneous biopsies) were studied for nuclear p63 expression by immunohistochemistry (Dako, Carpinteria, CA, USA). Five additional cases each of atypical adenomatous hyperplasia and adenosquamous carcinoma and three cases of squamous carcinoma (all open lung biopsies) were also stained. The diagnostic categories of benign lung conditions were usual interstitial pneumonia, parenchymal scar, cryptogenic organizing pneumonia and diffuse alveolar damage. In neoplastic cases, p63 positivity was calculated as percentage of all tumor cells examined. In areas of normal lung, p63 decorated the reserve cells of large and small airways and occasional cells of the distal lobular unit. In fibrotic reactive processes, an interrupted but distinct pattern of nuclear staining was present in all cases, with staining of basal cells of the airways as well as bronchiolar- and squamous-metaplastic epithelium (43/43, 100%). p63 immunoreactivity was less uniform in areas of acute lung injury within these cases. One adenocarcinoma and two cases of atypical adenomatous hyperplasia showed strong immunoreactivity (>80%), while three adenocarcinomas highlighted only rare tumor nuclei (<5% of tumor cells). Morphologic areas where p63 immunostaining was not helpful included the junction of normal lung and lepidic growth of adenocarcinoma, and retrograde spread of adenocarcinoma into small airways.
Our results highlight the differential expression of p63 across various bronchioloalveolar lesions. Moreover, p63 may be helpful in distinguishing reactive from neoplastic glandular proliferations in the lung.p63 and TTF-1 Immunostaining
A Useful Marker Panel for Distinguishing Small Cell Carcinoma of Lung From Poorly Differentiated Squamous Cell Carcinoma of Lung
Maoxin WuMD, PhD
Beverly WangMD
Joan GilMD
Edmond SaboMD
Lorraine MillerPhD
Li GanMD
David E. BursteinMDAm J Clin Pathol 2003;119:696-702 Abstract quote We studied the usefulness of p63 and thyroid transcription factor–1 (TTF-1) immunostains for differen-tiating poorly differentiated squamous cell carcinoma (PDSCC) from small cell lung carcinoma (SCLC).
We used monoclonal antibodies reactive to p63 or TTF-1 to stain 4-µm-thick sections from 30 formalin-fixed, paraffin-embedded lung biopsy and resection specimens and 7 alcohol-fixed, formalin-postfixed, paraffin-embedded cell blocks from lung fine-needle aspirations (FNAs). For p63, we used a streptavidin-biotin kit, diaminobenzidine as the chromogen, and a hematoxylin counterstain. We used automated immunostaining for TTF-1.
The 37 cases included 23 SCLCs, 13 PDSCCs, and 1 carcinoma initially diagnosed as PDSCC.
All 23 SCLCs were negative or, rarely, equivocal for p63; 20 (87%) of 23 were TTF-1+; nuclear staining ranged from strong and/or frequent to weak and/or uncommon. All 13 PDSCCs were TTF-1–/p63+ with intense staining of 50% to 100% of tumor cells. One case originally diagnosed as PDSCC was TTF-1+/p63–, suggestive of SCLC; after morphologic reexamination and immunostaining for neuroendocrine markers, it was reclassified as intermediate-type SCLC. TTF-1 immunostaining showed equal or increased sensitivity in alcohol-fixed cytologic cell block samples compared with formalin-fixed biopsy material; in 1 SCLC case, the biopsy specimen was TTF-1–; however, the FNA cell block stained positively.
p63 and TTF-1 appear to be useful for differentiating SCLC from lung PDSCC in formalin-fixed and alcohol-fixed, formalin-postfixed material.
p63 In pulmonary epithelium, pulmonary squamous neoplasms, and other pulmonary tumors.Wang BY, Gil J, Kaufman D, Gan L, Kohtz DS, Burstein DE.
Department of Pathology and Ruttenberg Cancer Center, Mount Sinai School of Medicine, the Mount Sinai Medical Center, New York, NY.
Hum Pathol 2002 Sep;33(9):921-6 Abstract quote p63 is a p53-homologous nuclear protein that appears to play a crucial role in regulation of stem cell commitment in squamous and other epithelia.
In this study, p63 expression was examined in benign lung and in neoplasms of pulmonary origin. Eighty sections from routinely fixed and processed archival bronchoscopic biopsy or lobectomy specimens were pretreated with citric acid (pH 6.0) for antigen retrieval, then incubated overnight with anti-p63 monoclonal antibody 4A4. Slides were stained using a streptavidin-biotin kit and diaminobenzidine as chromagen, and were counterstained with hematoxylin. In normal lung, p63 intensely stained nuclei of bronchial reserve cells but did not stain ciliated cells, alveolar epithelial cells, or nonepithelial cells. The lower strata of squamous metaplastic bronchial epithelium stained positively.
All squamous-cell carcinomas stained positively (n = 30). In some well-differentiated carcinomas, staining was found at the periphery of tumor nests but was negative in central zones showing squamous maturation. Poorly differentiated carcinomas showed very high proportions (80% to 100%) of p63-positive nuclei. All small-cell carcinomas were p63 negative (n = 9). Staining of bronchioloalveolar carcinomas (n = 7) and adenocarcinomas (n = 23) was variable: some tumors showed no detectable staining, others showed heterogeneously positive staining. Adenosquamous carcinomas (n = 5) displayed a unique basalar staining pattern. Carcinoid tumors were almost entirely negative (n = 5).
We conclude that p63 is expressed in benign bronchial stem cells, in neoplastic cells with either squamous differentiation or squamous differentiating potential, and in a subpopulation of adenocarcinomas. p63 immunostaining may also aid in some histopathologic distinctions, such as in small biopsies where the differential diagnosis is poorly differentiated squamous carcinoma versus small-cell carcinoma. A stem cell biology-based classification system for squamous carcinomas is proposed.
THYROID TRANSCRIPTION FACTOR
- Variable sensitivity and specificity of TTF-1 antibodies in lung metastatic adenocarcinoma of colorectal origin.
Comperat E, Zhang F, Perrotin C, Molina T, Magdeleinat P, Marmey B, Regnard JF, Audouin J, Camilleri-Broet S.
1Service d'Anatomopathologique de l'Hotel-Dieu, place du Parvis Notre Dame, Paris, France.
Mod Pathol. 2005 Oct;18(10):1371-6. Abstract quote
Thyroid transcription factor-1 (TTF-1) is considered as a reliable marker for differential diagnosis in distinguishing primary adenocarcinomas of the lung from extrathoracic origins.
We previously reported the first case of lung metastasis of colorectal origin, with nuclear expression of TTF-1. As most previous studies were performed on series of extrathoracic primary tumors, we raised the question of a possible role of lung microenviroment in TTF-1 expression.
We investigated the rate of TTF-1 expression in lung metastases of extrathoracic adenocarcinomas and compared results of immunohistochemistry performed with different primary antibodies. Two different clones of antibodies (8G7G1/1 from Dako, SPT24 from Novocastra) raised against TTF-1 were used on 56 lung-metastatic malignant tumors, 41 from colorectal origin. A series of primary colorectal (90 cases) and primary pulmonary adenocarcinomas (86 cases) were also investigated. Four of 41 (10%) lung metastases of colorectal adenocarcinomas displayed a nuclear staining for TTF-1 with SPT24 clone. Three of the four positive cases displayed similar nuclear staining in primary and/or other extrathoracic metastatic sites as well as four of 90 (5%) primary colorectal adenocarcinomas, ruling out the role of lung microenvironment. None of them was positive with 8G7G1/1 clone. Sensitivity between two sets of antibodies was compared in 86 primary pulmonary adenocarcinomas. Nuclear staining was detected in 72 cases (84%) with Novocastra's antibody and 56 cases (65%) with Dako's. Significant discordance was observed (P< 0.01).
These results suggest that the diagnostic virtue of TTF-1 detection depends on the used antibody's clone. The SPT24 clone seems to have a stronger affinity for TTF-1 protein but may lead to a few positive colorectal adenocarcinomas.Value of Thyroid Transcription Factor-1 Immunostaining in Distinguishing Small Cell Lung Carcinomas From Other Small Cell Carcinomas
Nelson G. Ordóñez, M.D. Wick MR, ed.
From the University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A.
Am J Surg Pathol 2000;24:1217-1223 Abstract quote
The distinction between small cell lung carcinoma (SCLC) and small cell carcinomas of other sites is difficult by routine histology. Thyroid transcription factor-1 (TTF-1) is a homeodomain-containing transcription factor that is selectively expressed in thyroid and pulmonary epithelial cells. TTF-1 expression has also been demonstrated in adenocarcinomas of the thyroid and lung, and SCLC. However, the value of TTF-1 immunostaining in discriminating between SCLC and nonpulmonary small cell carcinomas has not been investigated.
In the present study using an immunoperoxidase staining procedure on paraffin sections, we investigated the expression of TTF-1 and cytokeratin 20 (CK20), a marker that has previously been demonstrated in small cell carcinomas of the skin (Merkel cell carcinomas), in 82 small cell carcinomas from a wide variety of sites (28 lung, 18 skin, 12 gastrointestinal tract, 8 sinonasal, 5 bladder, 3 prostate, 3 uterine cervix, 2 thyroid, 2 salivary gland, and 1 pancreas).
Twenty-seven (96%) of the 28 SCLCs were positive for TTF-1. Among the nonpulmonary small cell carcinomas, two tumors of the gastrointestinal tract, one of the bladder, and one of the uterine cervix exhibited TTF-1 positivity. Sixteen (89%) of the 18 Merkel cell carcinomas and one SCLC were CK20-positive. All other small cell carcinomas were negative for this marker.
These results indicate that although TTF-1 is not a specific marker for SCLC, it may assist in distinguishing SCLC from some nonpulmonary small cell carcinomas, particularly Merkel cell carcinoma, especially when it is used in conjunction with CK20.
Value of Thyroid Transcription Factor-1, E-Cadherin, BG8, WT1, and CD44S Immunostaining in Distinguishing Epithelial Pleural Mesothelioma From Pulmonary and Nonpulmonary Adenocarcinoma
Nelson G. Ordóñez, M.D.
From the University of Texas M.D. Anderson Cancer Center, Houston, Texas, U.S.A.
Am J Surg Pathol 2000;24:598-606 Abstract quote
The distinction between malignant pleural mesotheliomas and adenocarcinomas, particularly those originating in the lung, is a difficult diagnostic problem that can be facilitated by the use of immunohistochemical markers.
In this study, the immunoreactivity of thyroid transcription factor-1 (TTF-1), E-cadherin, BG8, WT1, and CD44S was investigated in 50 epithelial mesotheliomas, and 40 pulmonary and 95 nonpulmonary adenocarcinomas. After analyzing the results, it was concluded that E-cadherin and BG8 are useful markers for distinguishing between epithelial mesotheliomas and adenocarcinomas of various origins, including the lung.
Because TTF-1 expression is found almost exclusively in adenocarcinomas of the lung but is absent in mesotheliomas, immunostaining for this marker is particularly useful for distinguishing between these two malignancies. Although WT1 immunostaining may also be useful, its value, as determined in this study, is lower than that reported by other investigators. CD44S immunostaining does not have any practical value in discriminating between epithelial mesothelioma and lung adenocarcinoma.
Mucinous and Nonmucinous Bronchioloalveolar Adenocarcinomas Have Distinct Staining Patterns With Thyroid Transcription Factor and Cytokeratin 20 Antibodies
Neal S. Goldstein, MD, and Maria Thomas, MD
Am J Clin Pathol 2001;116:319-325 Abstract quote
We studied 14 mucinous and 26 nonmucinous bronchioloalveolar adenocarcinomas (BACs) with thyroid transcription factor (TTF), cytokeratin (CK) 7, CK20, and villin to characterize their staining patterns with these antibodies and identify staining differences between the neoplasms. We also stained 11 mucinous colon adenocarcinomas with the same antibodies to compare their reaction patterns with mucinous BACs.
All pulmonary neoplasms were confirmed pulmonary primary BACs. Three (21%) of 14 mucinous neoplasms had weak TTF reactivity in fewer than 25% of neoplastic cell nuclei, and the other 11 (79%) were nonreactive. In contrast, 24 (92%) of 26 nonmucinous BACs were strongly TTF reactive. Eleven mucinous BACs (79%) had CK20 reactivity in more than 25% of neoplastic cells, whereas only 1 nonmucinous BAC (4%) had reactivity in fewer than 50% of the cells. One mucinous BAC (7%) had villin reactivity in approximately 10% of the neoplastic cells. All mucinous colon adenocarcinomas were diffusely reactive with CK20 and villin.
Mucinous and nonmucinous BACs have disparate staining patterns with TTF and CK20. Mucinous BACs are usually TTF nonreactive and CK20 reactive, but nonreactive with villin, which distinguishes them from mucinous colon adenocarcinomas.
Thyroid transcription factor 1 and cytokeratins 1, 5, 10, 14 (34E12) expression in basaloid and large-cell neuroendocrine carcinomas of the lung
Nathalie Sturm, MD
Sylvie Lantuéjoul, MD
Marie-Hélène Laverrière, MD
Mauro Papotti, MD
Pierre-Yves Brichon, MD
Christian Brambilla, MD
Elisabeth Brambilla, MDHum Pathol 2001;32:918-925. Abstract quote
Basaloid carcinoma (BC) and large-cell neuroendocrine carcinoma (LCNEC) are 2 recently recognized variants of large-cell lung carcinomas that may overlap in their morphology, and are discriminated by expression of neuroendocrine markers in LCNEC.
Because thyroid transcription factor 1 (TTF-1) is expressed in lung adenocarcinomas but not in squamous cell carcinomas (SCC), and 34E12 recognizes a set of high-molecular-weight cytokeratins characteristic of basal stem cells, we hypothesized that these 2 markers could help in distinguishing BC from LCNEC.
Immunostaining for TTF-1 was detected in 40.9% of pure LCNEC but in no BC or basaloid variant of SCC. In contrast, immunoreactivity for 34E12 was shown in all BC and basaloid variant of SCC but in only 1 LCNEC. Bouin fixation was less efficient than formalin in the immunodetection of both markers for its well-known deleterious effect on antigen preservation. Specificity of TTF-1 for LCNEC (100%) and that of 34E12 for BC (98.3%) exceeded that of NE markers for distinction of these 2 entities.
These data show that TTF-1 and 34E12, in association with specific neuroendocrine markers, represent a useful panel of antibodies in differentiating carcinomas presenting with a solid pattern, palisading, or pseudorosettes, the expression of TTF-1 excluding the diagnosis of BC, and staining with 34E12 excluding pure LCNEC.
The Value of Thyroid Transcription Factor-1 in Cytologic Preparations as a Marker for Metastatic Adenocarcinoma of Lung Origin
Jonathan L. Hecht, MD, PhD, Jack L. Pinkus, PhD, Lisa J. Weinstein, MD, and Geraldine S. Pinkus, MD
Am J Clin Pathol 2001;116:483-488 Abstract quote
In tissue sections, thyroid transcription factor-1 (TTF-1) is a sensitive marker for adenocarcinomas of lung and thyroid origin. This immunohistochemical study evaluates the effectiveness of TTF-1 as a marker for pulmonary adenocarcinomas in paraffin sections of cell block preparations derived from effusion and fine-needle aspiration specimens.
We evaluated 122 cell blocks including 8 primary and 39 metastatic pulmonary adenocarcinomas, 11 pulmonary neoplasms of other types, 50 specimens with nonpulmonary metastatic tumors, and 14 mesotheliomas.
TTF-1 was reactive in 42 (89%) of 47 pulmonary adenocarcinomas. Only 1 of 4 pulmonary small cell/neuroendocrine tumors was TTF-1 positive, while 1 of 7 squamous cell carcinomas was weakly reactive. Of 50 metastatic tumors of nonpulmonary origin, focal weak reactivity was noted only for 1 metastatic ovarian carcinoma. All mesotheliomas were nonreactive.
In cytologic preparations, TTF-1 is a highly selective marker for pulmonary adenocarcinoma and also can have a role in the distinction between pulmonary adenocarcinoma and mesothelioma.
TTF-1 expression in pulmonary adenocarcinomas.Yatabe Y, Mitsudomi T, Takahashi T.
Department of Anatomic and Molecular Diagnostic Pathology, Aichi Cancer Center Hospital, Aichi Cancer Center Research Institute, Nagoya, Japan.
Am J Surg Pathol 2002 Jun;26(6):767-73 Abstract quote Tissue-specific gene expression is mediated largely by transcription factors, and a master regulatory gene is thus a potential marker of cellular lineage.
Using normal fetal through adult pulmonary tissues and 64 consecutive lung adenocarcinomas, we examined the expression of thyroid transcription factor (TTF-1), which plays a crucial role in normal lung function and morphogenesis. TTF-1 was expressed consistently throughout the life stages and uniformly in the terminal respiratory unit, which is comprised of peripheral airway cells and small-sized bronchioles.
Furthermore, the expression was maintained in 72% of adenocarcinomas that exhibited high correlation with surfactant apoprotein (p <0.001) and morphologic resemblance to terminal respiratory unit cells (p <0.001). The staining pattern was also uniform in the adenocarcinomas despite histologic and microenvironmental diversity in individual tumors and their metastatic foci. This consistency and uniformity, therefore, suggested that TTF-1 expression could be used as a lineage marker of terminal respiratory unit.
We also identified interesting distinctions between TTF-1-positive and -negative adenocarcinomas based on their clinicopathologic features and expression of various cancer-associated genes. TTF-1-positive adenocarcinomas had statistically significant prevalence of female (p <0.01), nonsmoker (p <0.05), negative p53 staining (p <0.01), less frequent RB loss (p <0.05), and preserved expression of p27 (p <0.01).
The results supported the TTF-1 lineage marker and suggested that molecular pathogenesis may in part be characterized by cellular lineage.
Expression of thyroid transcription factor-1 in normal and neoplastic lung tissues.Nakamura N, Miyagi E, Murata S, Kawaoi A, Katoh R.
Department of Pathology, Yamanashi Medical University, Yamanashi, Japan.
Mod Pathol 2002 Oct;15(10):1058-67 Abstract quote The expression of thyroid transcription factor-1 in normal and neoplastic tissues and cell lines of the human lung was investigated using immunohistochemistry and in situ hybridization in conjunction with reverse transcription polymerase chain reaction. In normal lung tissues, immunoproducts of thyroid transcription factor-1 were observed in the nuclei of alveolar cells and bronchiolar cells.
Interestingly, in distal bronchioles, immunohistochemistry and in situ hybridization revealed that thyroid transcription factor-1 was present not only in nonciliated cells (Clara cells) but also in ciliated cells and basal cells. In neoplastic tissues, thyroid transcription factor-1 was demonstrated in adenocarcinomas and small cell lung carcinomas with high frequency: 96% and 89% of cases, respectively.
Thyroid transcription factor-1 was not detected in squamous cell carcinomas and large cell carcinomas. The strong immunoreactivity of thyroid transcription factor-1 or simultaneous expressions of thyroid transcription factor-1 and surfactant protein A tended to correlate with the differentiation phenotypes in adenocarcinomas; they were more frequently present in the well-differentiated type than were moderately and/or poorly differentiated types. By reverse transcription polymerase chain reaction, expression of thyroid transcription factor-1 messenger RNA was observed in squamous cell carcinomas in addition to in adenocarcinomas and small cell lung carcinomas, and this finding was confirmed in the cell lines from squamous cell carcinomas. Only one case of 99 adenocarcinomas that originated in various organs other than lung and thyroid immunohistochemically expressed thyroid transcription factor-1.
Our results suggest that thyroid transcription factor-1 can play an important role for the maintenance and/or differentiation process in bronchiolar and alveolar cells. Thyroid transcription factor-1 expression associates with histologic types and/or differentiation of lung cancers and can be a valuable marker for the better understanding of their biological nature and pathological behavior.
DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES APICAL CAP Pulmonary Apical Cap A Distinctive But Poorly Recognized Lesion in Pulmonary Surgical Pathology
Samuel A. Yousem
Am J Surg Pathol 2001;25:679-683 Abstract quote
Thirteen cases of pulmonary apical cap (PAC), resected for the exclusion of a clinical diagnosis of lung carcinoma, were reviewed, and their distinctive morphology was described.
PAC occurred in older individuals, particularly in the apices of the upper lobes, and by radiographic examination appeared as spiculated subpleural masses ranging from 0.7 to 5.2 cm in diameter.
Microscopically, these subpleural scars were pyramid shaped with overlying pleural adhesions and hyaline pleural plaques. They were characterized by a dense basophilic fibrosis of the pulmonary parenchyma with air spaces filled with old, mature collagen and the underlying elastic skeleton contracted in an accordion-like fashion with reduplicated curls of elastic fibers. Scar emphysema was prominent at the periphery of these fibrous nodules.
PAC should be recognized for its unique histology because its appearance in the surgical pathology laboratory will likely increase in incidence with the evolution of more sensitive pulmonary radiographic studies. A chronic ischemic etiology is favored.
BONE MARROW TRANSPLANT ASSOCIATED ATYPICAL CELLS Atypical Cells in Bronchoalveolar Lavage Specimens From Bone Marrow Transplant Recipients
A Potential Pitfall
H. Evin Gulbahce, MD,1 K. Scott Baker, MD,2 Pragati Kumar, MD,1 Klint Kjeldahl, CT(ASCP),3 and Stefan E. Pambuccian, MDAm J Clin Pathol 2003;120:101-106 Abstract quote
Numerous nonneoplastic conditions of the lungs may result in atypical cells in bronchoalveolar lavage (BAL) specimens mimicking malignant neoplasms. Bone marrow transplant (BMT) recipients have many predisposing factors that would lead to atypical cells in BAL specimens, presenting diagnostic challenges.
We reviewed BAL specimens from BMT recipients and correlated our findings with clinical information. During a 5.5-year period, 21 BMT recipients had atypical cells in 27 BAL specimens at Fairview-University Medical Center, Minneapolis, MN. The atypical cells had the cytologic features of squamous or glandular cells. The nuclear/cytoplasmic ratio, atypical cells per case, and background varied from case to case. Most of the patients had 1 or more of the clinical findings that would lead to atypia in BAL specimens: 13 had recent cytoreductive treatment, 9 had positive cultures, and 7 had graft-vs-host disease.
There was substantial overlap between the reactive atypia and carcinoma. Clinical correlation was the most important factor in making accurate diagnosis.DIFFUSE ALVEOLAR DAMAGE WITH SQUAMOUS METAPLASIA WITH ATYPIA Extensive squamous metaplasia with cytologic atypia in diffuse alveolar damage mimicking squamous cell carcinoma: a report of 2 cases.
Ogino S, Franks TJ, Yong M, Koss MN.
Department of Pathology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Hum Pathol 2002 Oct;33(10):1052-4 Abstract quote Squamous metaplasia in the setting of diffuse alveolar damage, a form of acute lung injury, in rare cases can be very extensive with cytologic atypia, mimicking squamous cell carcinoma.
We describe 2 such cases that posed diagnostic difficulty in the evaluation of biopsy specimens.
These cases demonstrate that histologic findings must be correlated with clinical and radiologic information to avoid a misdiagnosis of malignancy.
ENDOMETRIAL STROMAL SARCOMA, METASTATIC
Endometrial stromal sarcoma metastatic to the lung: a detailed analysis of 16 patients.Aubry MC, Myers JL, Colby TV, Leslie KO, Tazelaar HD.
Department of Laboratory Medicine and Pathology (M.-C.A., J.L.M., H.D.T.), Mayo Clinic, Rochester, Minnesota, and the Department of Laboratory Medicine and Pathology (T.V.C., K.O.L.), Mayo Clinic, Scottsdale, Arizona, U.S.A.
Am J Surg Pathol 2002 Apr;26(4):440-9 Abstract quote Pulmonary metastases of endometrial stromal sarcoma (ESS) are uncommon and can pose diagnostic problems.
We reviewed lung specimens from 16 patients with metastatic ESS. Patients were 31-77 years of age at the time of lung biopsy. Uterine ESSs were diagnosed an average of 9.8 years before lung biopsy in 11 patients. Uterine ESSs were originally called smooth muscle tumors in three additional patients. Thirteen patients were evaluated for new pulmonary nodules, seven of whom were asymptomatic. Nodules were multiple in 14 and solitary in four, ranging from 1.0 to 8.0 cm in greatest dimension. One patient died of metastatic disease; 14 were alive and seven of these were without disease (mean follow-up 4.1 years).
Diagnostic considerations in 12 consultation cases included ESS, sclerosing hemangioma, carcinoid tumor, lymphangioleiomyomatosis, endometriosis, hemangiopericytoma, and lymphoma. Tumors were well circumscribed and usually solid, composed of plump spindle cells arranged in short fascicles. Two tumors were predominantly cystic. Sex cord-like stromal differentiation was identified in three. Neoplastic cells stained for vimentin (93%), estrogen and progesterone receptor (100%), smooth muscle actin (57%), desmin (50%), and keratin (46%). Metastatic ESS should be included in the differential diagnosis of nonepithelial neoplasms in women.
MESOTHELIAL CELLS, REACTIVE Use of a Panel of Markers in the Differential Diagnosis of Adenocarcinoma and Reactive Mesothelial Cells in Fluid Cytology
Ellen C. Ko, MD, Nirag C. Jhala, MD, Jana J. Shultz, MT(ASCP)SH, QIHC, and David C. Chhieng, MD
Am J Clin Pathol 2001;116:709-715 Abstract quote
To evaluate the use of a panel of markers to differentiate adenocarcinoma and reactive/ inflammatory process in fluid cytology, we stained 29 formalin-fixed, paraffin-embedded cell blocks of effusion fluid from patients with metastatic adenocarcinoma and 24 cell blocks from patients with benign effusion with mucicarmine and antibodies to carcinoembryonic antigen (CEA), B72.3, and calretinin.
Positive staining with CEA, B72.3, and mucicarmine was seen in 22 (76%),20 (69%), and 18 (60%) adenocarcinoma cases, respectively. All except 1 adenocarcinoma was negative for calretinin. No benign cases were positive for B72.3 and mucicarmine. In 1 benign case, scattered epithelial cells demonstrated weak positivity for CEA. The majority of combinations were 100% specific for adenocarcinoma. The highest sensitivity (86%) for adenocarcinomas was achieved with the staining combination of negative for calretinin and positive for any adenocarcinoma marker (CEA, B72.3, or mucicarmine).
The use of a panel of markers that recognize adenocarcinoma and mesothelial cells is useful in the differential diagnosis between metastatic adenocarcinoma and reactive/inflammatory process. The profile of positive staining with at least one of the adenocarcinoma markers and negative calretinin staining is highly specific and sensitive for identifying adenocarcinoma in fluid cytology.
MICROCYSTIC FIBROMYXOMA
Departments of *Pulmonary and Mediastinal Pathology daggerSoft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC double daggerDepartment of Anatomic Pathology, Memorial Sloan Kettering Cancer Center, New York, NY section signDepartment of Pathology, University Medical Center, Groningen, Netherlands paragraph signServico de Anatomia Patologica, Centro Hospitalar de Vila Nova de Gaia, Portugal.
Three cases of pulmonary myxoid tumors showing a variable degree of microcystic change are described. They are presented as incidental solitary peripheral lung nodules on routine radiologic studies. The patients included 2 women, 45 and 65 years old, and 1 man, 33 years old.
Clinical work-up showed no evidence of neoplasia in other sites. Following surgical resection, no evidence of disease was observed after a mean follow-up of 48 months. The tumors ranged in size from 1 to 2.3 cm (mean 1.4 cm). Microscopically, the lesions were well circumscribed with conspicuous cystic change and myxoid stroma. Innocuous, widely-spaced, spindled to stellate tumor cells showed minimal nuclear pleomorphism and absence of mitotic activity. The myxoid stroma contained acid mucopolysaccharides, sensitive to hyaluronidase digestion. No epithelial, chondroid, neural, myofibroblastic, lipomatous or vascular differentiation was evident on immunohistochemical studies.
Although these cases display cytologic features, myxoid stroma and benign clinical course characteristic of pulmonary myxomas; the presence of microcystic architecture is unique to the current series, and thus a descriptive designation "microcystic fibromyxoma" is suggested.MUCINOUS CYSTIC NEOPLASMS
Zu-hua Gao, MD, PhD, FRCPC, and Stefan J. Urbanski, MD
We describe 10 new cases and review 66 previously reported cases of primary pulmonary mucinous cystic neoplasia (PMCN). The 3 men and 7 women were 44 to 73 years old (mean, 60.0 years) at diagnosis. Lesions were found by chest radiograph (featuring a solitary, lobulated nodule with soft tissue density that enlarged slowly), or patients had major bronchial occlusion by mucus or hemoptysis.
Tumors were well-circumscribed, lobulated soft masses with a central cavity filled with gray to greenish translucent mucus and were 1.5 to 5.5 cm in greatest dimension (mean, 3.3 cm). Microscopically, confluent lakes of mucin characterized all cases. Tumor epithelium ranged from bland to focal cytologic atypia to frankly malignant. The adjacent lung parenchyma was stretched, compressed, or showed an inflammatory reaction to dissected mucin. After 1- to 10-year follow-up (mean, 3.7 years), 3 patients died of metastasis and 1 of amitriptyline toxic effects; 6 were alive without tumor. Combined analysis of our cases and previously reported cases suggests a histologic spectrum from benign cystadenoma to mucinous cystic tumor with atypia to well-differentiated mucinous cystadenocarcinoma.
The histomorphologic criteria derived from this analysis can help distinguish PMCN from other types of primary or metastatic mucinous tumors and predict outcome.PROSTATE CANCER, METASTATIC
The morphologic spectrum of metastatic prostatic adenocarcinoma to the lung: special emphasis on histologic features overlapping with other pulmonary neoplasms.Copeland JN, Amin MB, Humphrey PA, Tamboli P, Ro JY, Gal AA.
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Am J Clin Pathol 2002 Apr;117(4):552-7 Abstract quote We undertook a detailed histologic study to identify specific morphologic features that may aid in distinguishing prostatic adenocarcinoma with lung metastases (PALM) from other pulmonary tumors with similar histologic features.
In 16 cases, we found 3 predominant architectural patterns: microacinar (n = 10), tubulopapillary (ductal; n = 4), and carcinoid-like (n = 2). Characteristic features of PALM included small acinar and/or cribriform growth, frequent lymphangitic permeation, lack of stromal response, uniform round nuclei with prominent nucleoli, intraluminal blue mucin, and prominent cell borders.
By immunohistochemical staining, prostate-specific antigen and prostate-specific acid phosphatase were present in 13 of 14 and 13 of 13 cases, respectively. Metastatic prostatic duct adenocarcinoma exhibited morphologic features similar to metastatic colonic adenocarcinoma. Two cases had a carcinoid-like appearance with nested or solid architecture, parachromatin clearing, and prominent nucleoli, but lacked the finely stippled chromatin pattern of carcinoid tumors. Several features that may result in misinterpretation or lack of association of the neoplasm in the lung with a prostatic primary include lung metastasis preceding the detection of a prostatic primary tumor, solitary pulmonary nodule, tubulopapillary (ductal) or carcinoid-like pattern, scant material in which histologic features of metastatic prostate carcinoma are not fully appreciated, and frequent necrosis.
Attention to specific discriminating histologic features, supported by immunohistochemical staining, may be useful in the differential diagnosis, which is therapeutically and prognostically critical.
SEBACEOUS CARCINOMA, PRIMARY
Sebaceous carcinoma of the lung: histologic and immunohistochemical characterization of an unusual pulmonary neoplasm: report of a case and review of the literature.Borczuk AC, Sha KK, Hisler SE, Mann JM, Hajdu SI.
Department of Pathology, Columbia Presbyterian Medical Center, New York, NY 10032, USA.
Am J Surg Pathol 2002 Jun;26(6):795-8 Abstract quote Sebaceous neoplasms, including carcinomas, are tumors most often seen around the eye and eyelid. Cases of extraorbital sebaceous tumors associated with skin adnexa are less common. The parotid gland may also be a source for sebaceous neoplasms, and cases associated with minor salivary gland tissue have also been reported. Once beyond the oropharynx, individual cases of pharyngeal and laryngeal sebaceous tumors are reported.
The case of a patient with primary sebaceous carcinoma of the bronchus is presented. Our case is that of an endobronchial mass that has histopathologic features of a sebaceous carcinoma, with predominance of areas with morphologically classic sebaceous differentiation, confirmed by oil red O stain for lipid, analyzed by immunohistochemistry and evaluated ultrastructurally.
This unique tumor extends the spectrum of extraocular, extracutaneous neoplasms with sebaceous differentiation from existing single reports in the hypopharyx and larynx to now include bronchus.
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