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pulmonary adenocarcinoma

Thursday 13 November 2003

pulmonary adenocarcinomas

Definition: Adenocarcinoma is the most common type of lung cancer in contemporary series, accounting for approximately one-half of lung cancer cases (about 50%).

The increased incidence of adenocarcinoma is thought to be due to the introduction of low-tar filter cigarettes in the 1960s, although such causality is unproven.

WHO 2015 Classification

The 2015 World Health Organization (WHO) lung tumors classification divides tumours into categories of indolent pre-invasive, minimally invasive and predominantly lepidic and, by examining predominant patterns of invasion, allows for further stratification into intermediate and high-grade tumours.

The most significant changes in the 2015 edition comparing to the 2014 one involve:
(1) use of immunohistochemistry throughout the classification,
(2) a new emphasis on genetic studies, in particular, integration of molecular testing to help personalize treatment strategies for advanced lung cancer patients,
(3) a new classification for small biopsies and cytology similar to that proposed in the 2011 Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification,
(4) a completely different approach to lung adenocarcinoma as proposed by the 2011 Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification,
(5) restricting the diagnosis of large cell carcinoma only to resected tumors that lack any clear morphologic or immunohistochemical differentiation with reclassification of the remaining former large cell carcinoma subtypes into different categories,
(6) reclassifying squamous cell carcinomas into keratinizing, non-keratinizing, and basaloid subtypes with the nonkeratinizing tumors requiring immunohistochemistry proof of squamous differentiation,
(7) grouping of neuroendocrine tumors together in one category,
(8) adding NUT carcinoma,
(9) changing the term " sclerosing hemangioma " to " sclerosing pneumocytoma ",
(10) changing the name " hamartoma " to " pulmonary hamartoma ,"
(11) creating a group of pulmonary PEComatous tumors that include :

(a) " pulmonary lymphangioleiomyomatosis ",
(b) " pulmonary PEComa, benign (with clear cell tumor as a variant) and
(c) PEComa, malignant,

(12) introducing the entity " pulmonary myxoid sarcoma " with an EWSR1-CREB1 translocation,
(13) adding the entities " pulmonary myoepithelioma " and " pulmonary myoepithelial carcinoma ", which can show EWSR1 gene rearrangements,
(14) recognition of usefulness of WWTR1-CAMTA1 fusions in diagnosis of " pulmonary epithelioid hemangioendothelioma ",
(15) adding Erdheim-Chester disease to the lymphoproliferative tumor,
(16) a group of tumors of ectopic origin to include pulmonary germ cell tumors, intrapulmonary thymoma, pulmonary melanoma and pulmonary meningioma.

pre-invasive Lesions

atypical adenomatous hyperplasia
adenocarcinoma in situ (formerly bronchioloalveolar carcinoma )
- Non-mucinous
- Mucinous

minimally invasive pulmonary adenocarcinoma / lepidic predominant pulmonary adenocarcinoma

A lepidic predominant tumor with - 5 mm or - 10% invasion

invasive Adenocarcinoma

Lepidic predominant (formerly nonmucinous bronchioloalveolar carcinoma pattern)
Acinar predominant
Papillary predominant
Micropapillary predominant
Solid predominant

Variants

Mucinous adenocarcinoma with lepidic pattern (formerly mucinous BAC)
Colloid adenocarcinoma
Fetal adenocarcinoma
Enteric adenocarcinoma

Abbreviation: BAC, bronchioloalveolar carcinoma.

Digital slides

pulmonary acinous adenocarcinoma

JRC:1593 : Pulmonary acinous adenocarcinoma arinsing in a sequestred lung (pulmonary sequestration).
JRC:6068 : Pulmonary acinous adenocarcinoma.
JRC:6063 : Pulmonary acinous adenocarcinoma.
JRC:6064 : Liver metastasis of a pulmonary acinous adenocarcinoma.

pulmonary papillary adenocarcinoma

- JRC:6076 : pulmonary papillary adenocarcinoma.

pulmonary clear cell adenocarcinoma

JRC:6198 : Pulmonary clear cell adenocarcinoma.

pulmonary mucinous adenocarcinoma

JRC:6232 : pulmonary mucinous adenocarcinoma.

pulmonary small cell adenocarcinoma

JRC:1594 : Pulmonary small cell adenocarcinoma.

pulmonary compact adenocarcinoma

JRC:1595 : Pulmonary compact adenocarcinoma.

pulmonary adenocarcinoma NOS

JRC:6065 : Pulmonary adenocarcinoma.

Links

The Histologic Reclassification of Adenocarcinoma of the Lung: Implications for Diagnosis and Therapy By Elisabeth Brambilla, MD, PhD (PDF)
International Association for the Study of Lung Cancer/
American Thoracic Society/European Respiratory
Society: International Multidisciplinary Classification of
Lung Adenocarcinoma - 2011 (PDF)

2011 IASLC classification

The 2011 IASLC/ATS/ERS schema stresses the radiographic correlates of this approach to classification.

Examples of this approach include the following:

The preinvasive AAH and non-mucinous AIS characteristically have a ground glass radiographic appearance. Minimally invasive non-mucinous lesions may have a predominantly ground glass appearance with a smaller solid component.

In contrast, mucinous AIS has a solid appearance on imaging.

The radiographic and molecular correlations of the different subtypes are shown in the attached table.

The 2011 IASLC/ATS/ERS document also emphasizes that tissue specimens should be managed not only for pathologic diagnosis, but to preserve tissue for molecular studies.

For patients with advanced lung adenocarcinoma, tissue should be tested for the presence of epidermal growth factor receptor (EGFR) mutation status as well as potentially for other molecular abnormalities that could affect subsequent therapy.

Changes

The 2011 schema from the IASLC/ATS/ERS incorporates a number of changes in the classification of patients with adenocarcinoma. The term "bronchioloalveolar carcinoma" (BAC) is eliminated. Lesions that were formerly classified as BAC are now placed in one of several categories that appear to correlate with the stages of transformation into widely invasive adenocarcinoma.

The early stages of these lesions include the following:

Atypical adenomatous hyperplasia (AAH), an entity that was previously recognized in the WHO system as a "preinvasive lesion for lung adenocarcinoma".

Adenocarcinoma in situ (AIS) is a localized (≤3 cm) adenocarcinoma in which growth is restricted to tumor cells growing along alveolar structures (lepidic growth pattern) and lacks any component of invasion.

Most AIS tumors are nonmucinous.
Mucinous lesions comprise a small subset of such tumors.
Observational studies indicate that AIS has a 100 percent cancer-specific survival if completely resected.
AIS was previously categorized as "bronchioloalveolar carcinoma" in the 2004 WHO system.

Minimally invasive adenocarcinoma is a small, solitary adenocarcinoma (≤3 cm) with a predominantly lepidic growth pattern and less than or equal to 5 mm invasion. Most but not all of these lesions are nonmucinous. The cancer-free survival in these patients should approach 100 percent with complete surgical resection, based upon observational studies.

Invasive adenocarcinomas are classified by their predominant pattern. As an example, invasive non-mucinous bronchioloalveolar lesions are classified as invasive adenocarcinoma, lepidic predominant. Other patterns include acinar, papillary, micropapillary, and solid predominant with mucin production.

Invasive mucinous adenocarcinoma (formerly mucinous bronchioloalveolar pattern) is now classified as a separate variant, the implication being that most of what was formerly called mucinous BAC represented invasive adenocarcinomas.

Other variants of invasive adenocarcinoma include colloid, fetal, and enteric adenocarcinoma.

For lesions without identifiable adenocarcinoma patterns present but in which immunohistochemical stains support the diagnosis of adenocarcinoma, the terminology “Non-small cell carcinoma, favor adenocarcinoma” is used.

Microscopy

Histologic diagnosis requires evidence of either neoplastic gland formation or intracytoplasmic mucin.

There is significant variation in the extent and architecture of neoplastic gland formation, ranging from well-formed acini to more papillary and even cribriform types.

The solid type of adenocarcinoma lacks the architectural characteristics of better differentiated tumors and is indistinguishable from large cell undifferentiated carcinoma except for the presence of intracellular mucin.

The detection of intracellular mucin requires special histochemical stains, such as mucicarmine or Periodic Acid-Schiff (PAS)

malignant glandular structures with central lumina
some of which contain intraluminal mucinous-like material.
extensive areas of necrosis

Types (2004 WHO classification of adenocarcinoma)

In the 2004 World Health Organization schema, adenocarcinoma is divided into a number of subtypes. Although it remains to be seen whether the WHO adopts the new classification scheme for adenocarcinoma, the 2004 classification defined some entities more specifically, and introduced some new entities, most of which are retained in the new proposed classification.

pulmonary acinar adenocarcinoma
pulmonary papillary adenocarcinoma
pulmonary bronchioloalveolar adenocarcinoma
pulmonary solid adenocarcinoma
pulmonary clear cell adenocarcinoma
pulmonary mucinous adenocarcinoma (colloid)
pulmonary mucinous cystadenocarcinoma
pulmonary signet ring adenocarcinoma
pulmonary mixed adenocarcinoma
pulmonary fetal adenocarcinoma

low-grade adenocarcinoma of fetal lung type (L-FLAC)
high-grade adenocarcinoma of fetal lung type (H-FLAC)

Grading systems : 20551825

Variants

pulmonary adenocarcinomas with enteric differentiation (15832091)

Differential diagnosis

Adenocarcinoma from Extrathoracic Origin

Immunohistochemistry positive for TTF-1; keratin 7 would favor lung origin in vast majority of cases

Atypical Adenomatous Hyperplasia (AAH)

Lesion ≤ 0.5 cm in diameter
Shares similar histological features with BAC
Size of lesion will separate carcinoma from AAH: Cases designated as AAH are under 5 mm in diameter

Adenoid Cystic Carcinoma (ACC)

Shows characteristic double layer-forming glands
Immunohistochemical studies show myoepithelial differentiation

Fetal Adenocarcinoma (Monophasic Pulmonary Blastoma)

Presence of morules and embryonic-type glandular structures
Presence of cytoplasmic mucin content in favor of AdenoCa

Papillary Carcinoma of Thyroid Origin

Histologically tumors with papillary pattern may show similar histological features
Positive TTF-1 and negative staining for thyroglobulin favors primary lung cancer

Grading system

G. Sica, A. Yoshizawa, C.S. Sima, et al. A grading system of lung adenocarcinomas based on histologic pattern is predictive of disease recurrence in stage I tumors. Am J Surg Pathol, 34 (2010), pp. 1155–1162.

Comparative genomic hybridization (CGH)

CGH revealed regions on 1q, 2p, 3q, 5p, 5q, 7p, 8q, 11q, 12q, 14q, 16p, 17p, 19q, 20q, 21q, and 22q to be commonly overrepresented and regions on 2q, 3p, 4p, 5q, 7q, 8p, 9p, 13q, 14q, and 17p to be underrepresented.

16p13 gain (50%)

16p13 amplification was associated with relatively poor differentiation and late stage.

Videos

Pulmonary adenocarcinoma by Washington Deceit

http://www.youtube.com/v/ZkvUodBSStQ

Links

The Histologic Reclassification of
Adenocarcinoma of the Lung: Implications
for Diagnosis and Therapy
By Elisabeth Brambilla, MD, PhD (PDF)
International Association for the Study of Lung Cancer/
American Thoracic Society/European Respiratory
Society: International Multidisciplinary Classification of
Lung Adenocarcinoma - 2011 (PDF)

Open references

Pulmonary adenocarcinoma: implications of the recent advances in molecular biology, treatment and the IASLC/ATS/ERS classification.
Revannasiddaiah S, Thakur P, Bhardwaj B, Susheela SP, Madabhavi I.
J Thorac Dis. 2014 Oct;6(Suppl 5):S502-25.
doi : 10.3978/j.issn.2072-1439.2014.05.19
PMID: 25349702 (Free)

Main reference

Clinical relevance of the new IASLC/ERS/ATS adenocarcinoma classification. Keith M Kerr. J Clin Pathol doi : 10 1136/jclinpath-2013-201519

International association for the study of lung cancer/american thoracic society/european respiratory society international multidisciplinary classification of lung adenocarcinoma. Travis WD, Brambilla E, Noguchi M, Nicholson AG, Geisinger KR, Yatabe Y, Beer DG, Powell CA, Riely GJ, Van Schil PE, Garg K, Austin JH, Asamura H, Rusch VW, Hirsch FR, Scagliotti G, Mitsudomi T, Huber RM, Ishikawa Y, Jett J, Sanchez-Cespedes M, Sculier JP, Takahashi T, Tsuboi M, Vansteenkiste J, Wistuba I, Yang PC, Aberle D, Brambilla C, Flieder D, Franklin W, Gazdar A, Gould M, Hasleton P, Henderson D, Johnson B, Johnson D, Kerr K, Kuriyama K, Lee JS, Miller VA, Petersen I, Roggli V, Rosell R, Saijo N, Thunnissen E, Tsao M, Yankelewitz D. J Thorac Oncol. 2011 Feb;6(2):244-85. Review. PMID: 21252716

Links

Pulmonary Adenocarcinomas - Subtyping and differential diagnosis by Dr. med. Arne Warth, Prof. Dr. med. Wilko Weichert. (PDF)

Open references

Prognostic considerations of the new World Health Organization classification of lung adenocarcinoma. Borczuk AC. Eur Respir Rev. 2016 Dec;25(142):364-371. doi : 10.1183/16000617.0089-2016 PMID: 27903658 Free

The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification.
Travis WD, Brambilla E, Nicholson AG, Yatabe Y, Austin JH, Beasley MB, Chirieac LR, Dacic S, Duhig E, Flieder DB, Geisinger K, Hirsch FR, Ishikawa Y, Kerr KM, Noguchi M, Pelosi G, Powell CA, Tsao MS, Wistuba I; WHO Panel..
J Thorac Oncol. 2015 Sep;10(9):1243-60. doi : 10.1097/JTO.0000000000000630
PMID: 26291008

Subtype Classification of Lung Adenocarcinoma Predicts Benefit From Adjuvant Chemotherapy in Patients Undergoing Complete Resection.
Tsao MS, Marguet S, Le Teuff G, Lantuejoul S, Shepherd FA, Seymour L, Kratzke R, Graziano SL, Popper HH, Rosell R, Douillard JY, Le-Chevalier T, Pignon JP, Soria JC, Brambilla EM. J Clin Oncol. 2015 Oct 20;33(30):3439-46. doi : 10.1200/JCO.2014.58.8335 PMID: 25918286 Free

Paywall References

W.D. Travis, E. Brambilla, A.P. Burke, A. Marx, A.G. Nicholson WHO classification of tumours of the lung, pleura, thymus and heart F.T. Bosman, E.S. Jaffe, S.R. Lakhani, H. Ohgaki (Eds.), World Health Organization Classification of Tumors, IARC Press, Lyon (2015)

A. Mansuet-Lupo, A. Bobbio, H. Blons, et al.
The new histologic classification of lung primary adenocarcinoma subtypes is a reliable prognostic marker and identifies tumors with different mutation status: the experience of a French cohort
Chest, 146 (2014), pp. 633–643

J. Gu, C. Lu, J. Guo, et al.
Prognostic significance of the IASLC/ATS/ERS classification in Chinese patients—a single institution retrospective study of 292 lung adenocarcinoma
J Surg Oncol, 107 (2013), pp. 474–480

J.J. Hung, W.J. Jeng, T.Y. Chou, et al.
Prognostic value of the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society lung adenocarcinoma classification on death and recurrence in completely resected stage I lung adenocarcinoma Ann Surg, 258 (2013), pp. 1079–1086

A. Yoshizawa, S. Sumiyoshi, M. Sonobe, et al.
Validation of the IASLC/ATS/ERS lung adenocarcinoma classification for prognosis and association with EGFR and KRAS gene mutations: analysis of 440 Japanese patients
J Thorac Oncol, 8 (2013), pp. 52–61

P.A. Russell, S.A. Barnett, M. Walkiewicz, et al.
Correlation of mutation status and survival with predominant histologic subtype according to the new IASLC/ATS/ERS lung adenocarcinoma classification in stage III (N2) patients
J Thorac Oncol, 8 (2013), pp. 461–468

J.E. Grilley-Olson, D.N. Hayes, D.T. Moore, et al.
Validation of interobserver agreement in lung cancer assessment: hematoxylin-eosin diagnostic reproducibility for non-small cell lung cancer: the 2004 World Health Organization classification and therapeutically relevant subsets
Arch Pathol Lab Med, 137 (2013), pp. 32–40

A. Warth, J. Cortis, L. Fink, et al.
Training increases concordance in classifying pulmonary adenocarcinomas according to the novel IASLC/ATS/ERS classification
Virchows Arch, 461 (2012), pp. 185–193

A. Warth, T. Muley, M. Meister, et al.
The novel histologic International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification system of lung adenocarcinoma is a stage-independent predictor of survival
J Clin Oncol, 30 (2012), pp. 1438–1446

E. Thunnissen, M.B. Beasley, A.C. Borczuk, et al.
Reproducibility of histopathological subtypes and invasion in pulmonary adenocarcinoma. An international interobserver study
Mod Pathol, 25 (2012), pp. 1574–1583

W.D. Travis, E. Brambilla, M. Noguchi, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol, 6 (2011), pp. 244–285.

European respiratory society/american thoracic society/international association for the study of lung cancer international multidisciplinary classification of lung adenocarcinoma: state of the art. Witt C. J Thorac Oncol. 2011 Aug;6(8):1451. PMID: 21847068

Subtyping of non-small cell lung carcinoma: a comparison of small biopsy and cytology specimens. Sigel CS, Moreira AL, Travis WD, Zakowski MF, Thornton RH, Riely GJ, Rekhtman N. J Thorac Oncol. 2011 Nov;6(11):1849-56. PMID: 21841504

A. Yoshizawa, N. Motoi, G.J. Riely, et al. Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. Mod Pathol, 24 (2011), pp. 653–664

P.A. Russell, Z. Wainer, G.M. Wright, M. Daniels, M. Conron, R.A. Williams
Does lung adenocarcinoma subtype predict patient survival?: a clinicopathologic study based on the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary lung adenocarcinoma classification
J Thorac Oncol, 6 (2011), pp. 1496–1504

- The new taxonomy of lung adenocarcinoma stemming from a multidisciplinary integrated approach: novel pathology concepts and perspectives. Pelosi G. J Thorac Oncol. 2011 Feb;6(2):241-3. PMID: 21252715

Sequential molecular changes during multistage pathogenesis of small peripheral adenocarcinomas of the lung. Soh J, Toyooka S, Ichihara S, Asano H, Kobayashi N, Suehisa H, Otani H, Yamamoto H, Ichimura K, Kiura K, Gazdar AF, Date H. J Thorac Oncol. 2008 Apr;3(4):340-7. PMID: 18379350 (free)

A grading system of lung adenocarcinomas based on histologic pattern is predictive of disease recurrence in stage I tumors. Sica G, Yoshizawa A, Sima CS, Azzoli CG, Downey RJ, Rusch VW, Travis WD, Moreira AL. Am J Surg Pathol. 2010 Aug;34(8):1155-62. PMID: 20551825

Shen H, Zhu Y, Wu YJ, Qiu HR, Shu YQ. Genomic alterations in lung adenocarcinomas detected by multicolor fluorescence in situ hybridization and comparative genomic hybridization. Cancer Genet Cytogenet. 2008 Mar;181(2):100-7. PMID: 18295661

Shibata T, Uryu S, Kokubu A, Hosoda F, Ohki M, Sakiyama T, Matsuno Y, Tsuchiya R, Kanai Y, Kondo T, Imoto I, Inazawa J, Hirohashi S. Genetic classification of lung adenocarcinoma based on array-based comparative genomic hybridization analysis: its association with clinicopathologic features. Clin Cancer Res. 2005 Sep 1;11(17):6177-85. PMID: 16144918

Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin;60;277
300. World Health Organization classification of tumors. Pathology and genetics. Tumours of the
lung, pleura, thymus and heart. Lyon:
IARC Press, 2004.

Travis WD, Brambilla E, Noguchi M et al. International association for the study of lung cancer/american thoracic society/european respiratory society international
multidisciplinary classification of lung adenocarcinoma.
J Thorac Oncol
2011;6;244
285

Russell PA, Wainer Z, Wright GM, Daniels M, Conron M, Williams RA (2011) Does lung adenocarcinoma subtype predict patient survival?: A clinicopathologic study based on the new International Association for the Study of Lung Cancer/Amer
ican Thoracic Society/European Respiratory Society international multidisciplinary lung adenocarcinoma
classification.
J Thorac Oncol
6:1496
1504.

— Sica G, Yoshizawa A, Sima CS, Azzoli CG, Downey RJ, Rusch VW, Travis WD, Moreira AL (2010)
A grading system
of lung adenocarcinomas based on histologic pattern is predictive of
disease recurrence in stage I tumors.
Am J Surg Pathol
34:1155
1162.

Yoshizawa A, Motoi N, Riely GJ, Sima CS, Gerald WL, Kris MG, Park BJ, Rusch VW, Travis WD
(2011) Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic
subgroups and implications for further revision of staging based on analysis
of 514 stage I
cases.
Mod Pathol
24:653
664.

Warth A, Muley T, Meister M, Stenzinger A, Thomas M, Schirmacher P, Schnabel PA, Budczies
J, Hoffmann H, Weichert W (2011) The Novel Histologic IASLC/ATS/ERS Classification of
Invasive Pulmonary Adenocarcinom
a is a Stage
Independent Predictor of Survival.
J Clin
Oncol

.
Warth A, Stenzinger A, von Brünneck AC, Goeppert B, Cortis J, Petersen I, Hoffmann H, Schnabel PA, Weichert W: Interobserver Variability in the Application of the Novel IASLC/ATS/ERS Classification. Europ Resp J, in press

A. Warth, T. Muley, E. Herpel, M. Meister, F. J. F. Herth, P. Schirmacher, W. Weichert, H. Hoffmann, P. A. Schnabel: Large Scale Comparative Analyses of Immunomarkers for Diagnostic Subtyping of Non Small Cell Lung Cancer Biopsies, Histopathology, in press

Wahbah M et al: Changing trends in the distribution of the histologic types of lung cancer: a review of 4,439 cases. Ann Diagn Pathol. 11(2):89-96, 2007

Moran CA: Pulmonary adenocarcinoma: the expanding spectrum of histologic variants. Arch Pathol Lab Med. 130(7):958-62, 2006

Prudkin L et al: Epidermal growth factor receptor abnormalities in lung cancer. Pathogenetic and clinical implications. Ann Diagn Pathol. 10(5):306-15, 2006

Moran CA et al: Papillary lung carcinoma with prominent "morular" component. Am J Clin Pathol. 122(1):106-9, 2004

Amin MB et al: Micropapillary component in lung adenocarcinoma: a distinctive histologic feature with possible prognostic significance. Am J Surg Pathol. 26(3):358-64, 2002

Arnould L et al: Hepatoid adenocarcinoma of the lung: report of a case of an unusual alpha-fetoprotein-producing lung tumor. Am J Surg Pathol. 21(9):1113-8, 1997

Silver SA et al: True papillary carcinoma of the lung: a distinct clinicopathologic entity. Am J Surg Pathol. 21(1):43-51, 1997

Rosado-de-Christenson ML et al: Bronchogenic carcinoma: radiologic-pathologic correlation. Radiographics. 14(2):429-46; quiz 447-8, 1994

Haque AK: Pathology of carcinoma of lung: an update on current concepts. J Thorac Imaging. 7(1):9-20, 1991

Ishikura H et al: Hepatoid adenocarcinoma: a distinctive histological subtype of alpha-fetoprotein-producing lung carcinoma. Virchows Arch A Pathol Anat Histopathol. 417(1):73-80, 1990