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2012 — October Case of the Month

Posted October 30, 2012

CLINICAL SUMMARY: Lung  

CAP Foundation Online Case of the Month

Click Slide Image to View Case with DigitalScope

After reading the summary, try answering the three related multiple-choice questions below.

A 70-year-old-man with a 100-pack-per-year history of smoking presented with hemoptysis. Radiologic studies demonstrated a mass in the upper lobe of the left lung which was biopsied and a subsequent lobectomy was performed. The lobectomy was remarkable for a centrally located 2.5 cm partially necrotic mass.

Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2009, case 33, and is squamous cell carcinoma.

Criteria for Diagnosis and Comments:
The tumor present in this case is comprised of large polygonal cells with eosinophilic cytoplasm arranged in sheets and irregularly shaped nests. Depending on the section received, features of keratinization such as intercellular bridge formation, individual cell keratinization or “squamous pearl” formation are present. These are features of squamous cell carcinoma. The diagnosis of squamous cell carcinoma is usually straightforward in a resection specimen; however, a few diagnoses may enter the differential, particularly if the tumor is poorly differentiated. Until relatively recently, accurate discrimination among the various types of non-small cell carcinoma was not overly critical given that all non-small cell carcinomas were treated in a similar fashion. However, given the advent of more specific therapeutic modalities, this distinction has become more important. This is particularly true if a patient is being considered for treatment with bevacizumab (Avastin®) as this drug should not be given to patients with squamous cell carcinoma given the association with severe pulmonary hemorrhage.

The solid variant of adenocarcinoma may occasionally be difficult to distinguish from poorly differentiated squamous cell carcinoma. In any histologically undifferentiated carcinoma, it is important to perform mucin stains to evaluate for the presence of intracytoplasmic mucin. The solid variant of adenocarcinoma is defined in the WHO classification as having intracytoplasmic mucin in at least 5 tumor cells in each of two high power fields. This definition is, however, arbitrary, and there is debate regarding whether tumors that fall short of this definition should be classified as adenocarcinoma or large cell carcinoma. In general, a diagnosis of large cell carcinoma should be made only when a tumor has been more or less entirely sampled and demonstrates no evidence of squamous or glandular differentiation. A definitive diagnosis of large cell carcinoma should therefore not be made on a small biopsy sample. Such biopsies warrant a diagnosis of “poorly differentiated non-small cell carcinoma,” although this has become increasingly less acceptable to clinicians in the age of Avastin® therapy. Immunohistochemical studies may be of assistance in small biopsy specimens to aid in the discrimination of poorly differentiated adenocarcinoma versus squamous cell carcinoma. A panel consisting of TTF1, p63 and CK 5/6 is frequently useful in this regard. In a small biopsy containing an otherwise poorly differentiated non-small cell carcinoma, a TTF1 +, p63 –, CK 5/6 – profile favors adenocarcinoma while a TTF1 –, p63 +, CK 5/6 + profile favors squamous cell carcinoma. Unfortunately, the panel results are not always clear cut and it is currently unclear which morphology is consistently associated with all three markers being either positive or negative, and these should be left as non-small cell carcinoma with an inconclusive immunohistochemical panel. At this point it is also unclear whether a histologically undifferentiated tumor in a thoroughly sampled resection specimen should be definitively sub classified based on this staining panel, but this is under investigation.

Adenosquamous carcinoma is defined in the WHO as “a carcinoma showing components of both squamous cell carcinoma and adenocarcinoma with each comprising at least 10% of the tumor.” Each component should have definitive diagnostic features before assigning this designation.

Basoloid carcinoma of the lung is relatively rare and may occur in a pure form or more commonly exhibit squamous differentiation. As the name implies, the tumor is comprised of basaloid appearing cells arranged in nests with peripheral palisading of tumor cells. The tumor may be purely basaloid or may exhibit overt squamous differentiation towards the center of the tumor nests.

Practice Points
In 2009, the staging of lung carcinoma will undergo several major modifications for the 7th edition of the AJCC staging manual. The new staging system will apply to both non-small cell and small cell lung carcinomas and for carcinoid tumors of the lung. The information below is taken essentially verbatim from the accepted AJCC document; however, as the final publication is still pending at the time of this writing, the reader is advised to re-confirm this information once the staging manual has been published. Major changes are summarized immediately below and updated table summaries of TNM and stage designations follow.

Modifications to the T classifications are as follows:

  • T1 has been sub classified into T1a (2.0 cm in size) and T1b (>2.0 to 3.0 cm in size)
  • T2 has been sub classified into T2a (>3.0 to 5.0 cm in size) and T2b (>5.0 to 7.0 cm in size)
  • T2 (>7 cm in size) has been reclassified as T3
  • Multiple tumor nodules in the same lobe have been reclassified from T4 to T3
  • Multiple tumor nodules in the same lung but a different lobe have been reclassified from M1 to T4

No changes have been made to the N classification; however, a new international lymph node map defining the anatomical boundaries for lymph node stations has been developed.

The M classifications have been redefined as follows.

  • M1 has been subdivided into M1a and M1b
  • Malignant pleural and pericardial effusions have been reclassified from T4 to M1a
  • Separate tumor nodules in the contralateral lung are considered M1a
  • M1b designates distant metastases

The updated TNM definitions are provided in the table below:

T (Primary Tumor)

TX

Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in sputum or bronchial washings but not visualized by imaging or bronchoscopy

T0

No evidence of primary tumor

Tis

Carcinoma in situ

T1

Tumor ≤3.0 cm in greatest dimension, surrounded by lung or visceral pleura, without bronchoscopic evidence of invasion more proximal than the lobar bronchus (i.e., not in the main bronchus)a

T1a

Tumor ≤2.0 cm in greatest dimension

T1b

Tumor > 2.0 cm but ≤3.0 cm in greatest dimension

T2

Tumor >3.0 cm but ≤7.0 cm OR tumor with any of the following features (T2 tumors with these features are classified T2a if ≤ 5.0 cm)
Involves main bronchus, ≥2.0 cm distal to the carina
Invades visceral pleura (PL1 or PL2)
Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung

T2a

>3.0 cm but ≤5.0 cm in greatest dimension

T2b

Tumor >5.0 cm but ≤7.0 cm in greatest dimension

T3

Tumor >7.0 cm or one that directly invades any of the following: parietal pleural (PL3) chest wall (including superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumor in the main bronchus (<2.0 cm distal to the carinaa but without involvement of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe)

T4

Tumor of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, esophagus, vertebral body, carina, separate tumor nodule(s) in a different ipsilateral lobe

N (Regional Lymph Nodes)

NX

Regional lymph nodes cannot be assessed

N0

No regional lymph node metastases

N1

Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension

N2

Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)

N3

Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)

M (Distant Metastasis)

M0

No distant metastasis

M1

Distant metastasis

M1a

Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant pleural (or pericardial) effusionb

M1b

Distant metastasis

a The uncommon superficial spreading tumor of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1a.
b Most pleural (and pericardial) effusions with lung cancer are due to tumor. In a few patients, however, multiple cytopathologic examinations of pleural (pericardial) fluid are negative for tumor, and the fluid is nonbloody and is not an exudate. Where these elements and clinical judgement dictate that the effusion is not related to the tumor, the effusion should be excluded as a staging element and the patient should be classified as M0.

Additionally, in the 7th edition, clearer guidelines are provided for defining invasion of the pleura based on the Hammar classification of visceral pleural invasion. Using this scheme, pleural invasion is divided into PL0, PL1, PL2 and PL3 categories. PLO is defined as tumor located within the lung parenchyma or only superficially invading in the pleural connective tissue, but not beyond the elastic layer of the visceral pleura. PL1 is defined as tumor invading into the visceral pleura beyond the elastic layer, PL2 is defined as tumor invading to the visceral pleural surface and PL3 is defined as tumor invading into the parietal pleura or the chest wall. Using this scheme, PL1 and PL2 upstage a T1 tumor to a T2 tumor, and PL3 equates with a T3 tumor. Additionally, based on a review of published literature, the IASLC Staging Committee recommends that elastic stains be used in cases where it is difficult to identify invasion of the elastic layer by hematoxylin and eosin (H&E) stains. Of note, direct tumor invasion into an adjacent ipsilateral lobe (i.e., invasion across a fissure) is classified as T2a.

Finally, the below table represents the new stage groupings based on the updated 7th edition classification with changes noted in bold/underline:

Sixth Edition

7th Edition

N0

N1

N2

N3

T/M Descriptor

T/M

 

 

 

 

T1 (≤2.0 cm)

T1a

IA

IIA

IIIA

IIIB

T1 (>2.0 – 3.0 cm)

T1b

IA

IIA

IIIA

IIIB

T2 (≤5.0 cm)

T2a

IB

IIA

IIIA

IIIB

T2 (>5.0 – 7.0 cm)

T2b

IIA

IIB

IIIA

IIIB

T2 (>7.0 cm)

T3

IIB

IIIA

IIIA

IIIB

T3 invasion

IIB

IIIA

IIIA

IIIB

T4 (same lobe nodules)

IIB

IIIA

IIIA

IIIB

T4 (extension)

T4

IIIA

IIIA

IIIB

IIIB

M1 (ipsilateral lung)

IIIA

IIIA

IIIB

IIIB

T4 (pleural effusion)

M1a

IV

IV

IV

IV

M1 (contralateral lung)

IV

IV

IV

IV

M1 (distant)

M1b

IV

IV

IV

IV

Supplementary Questions: For each of the following, select the most likely diagnosis from the diagnostic set (an answer may be used once, more than once, or not at all).

Question Diagnostic Set
1. Using the AJCC 7th edition guidelines, a carcinoma measuring 2.5 cm and invading through the elastic lamina of the pleura but not extending to the pleural surface should be classified as: A. T1a
B. T1b
C. T2a
D. T2b
2. Using the AJCC 7th edition guidelines, a lobectomy specimen with two grossly distinct tumors of similar histology should be staged as: A. M1
B. T2a
C. T3
D. T4
3. Using the AJCC 7th edition guidelines, a lung carcinoma with a malignant pleural effusion should be staged as: A. M1a
B. M1b
C. T3
D. T4

References

  1. Goldstraw P, Crowley J, Chansky K, et al. The IASLC lung cancer staging project: Proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol. 2007;2:706-714.
  2. Groome PA, Bolejack V, Crowley JJ, et al. The IASLC lung cancer staging project: Validation of the proposals for revision of the T, N, and M descriptors and consequent stage groupings in the forthcoming (seventh) edition of the TNM classification of malignant tumours. J Thorac Oncol. 2007;2:694-705.
  3. Kargi A, Gurel D, Tuna B. The diagnostic value of TTF-1, CK 5/6, and p63 immunostaining in classification of lung carcinomas. Appl Immunohistochem Mol Morphol. 2007;Dec;15:(4):415-420.
  4. Postmus PE, Brambilla E, Chansky K, et al. The IASLC lung cancer staging project: Proposals for revision of the M descriptors in the forthcoming (seventh) edition of the TNM classification of lung cancer. J Thorac Oncol. 2007;2:686-693.
  5. Rami-Porta R, Ball D, Crowley J et al: The IASLC Lung Cancer Staging Project: Proposals for the revision of the T descriptors in the forthcoming (seventh) edition of the TNM classification for lung cancer. J Thorac Oncol. 2007;2:593-602.
  6. Rusch VW, Crowley J, Giroux DJ et al: The IASLC Lung Cancer Staging Project: Proposals for the revision of the N descriptors in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol. 2007;2:603-612.
  7. Travis WD, Brambilla E, Müller-Hermelink HK et al, eds: WHO Classification of Tumours: Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and heart. Lyon, France: IARC Press; 2004.
  8. Travis WD, Brambilla E, Rami-Porta R, et al. Visceral pleural invasion: Pathologic criteria and use of elastic stains: Proposal for the 7th edition of the TNM classification for lung cancer. J Thorac Oncol. 2008;3:1384-1390.

Author:
2009
Mary Beth Beasley, MD FCAP
Surgical Pathology Committee
Mt. Sinai Medical Center
New York, NY