A 66-year-old woman presents with progressive shortness of breath and chest pain. Cardiac workup is negative, and imaging shows a 10.0-cm spiculated mass at the periphery of the right lung’s upper lobe. At 780 grams, the pneumonectomy specimen is 25.0 x 16.0 x 8.0 cm and shows an indurated, fleshy tan 10.0-cm mass in the upper lobe, puckering the overlying pleura.

Master List of Diagnoses

  • Adenocarcinoma in situ, non-mucinous type
  • Adenocarcinoma, mixed subtype
  • Adenocarcinoma, NOS
  • Bronchioalveolar carcinoma
  • Minimally invasive adenocarcinoma, non-mucinous type
  • Pulmonary adenocarcinoma, predominantly lepidic type
  • Pulmonary adenocarcinoma, predominantly papillary type
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This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2017, Case 11, and is pulmonary adenocarcinoma, predominantly papillary type of the lung.

Criteria for Diagnosis and Comments

Sections show a large mass filling alveolar spaces with papillary-type architecture of glandular cells growing along fibrovascular cores. The lining glandular cells are cuboidal to columnar with finely vacuolated-mucinous cytoplasm and nuclei with vesicular chromatin and prominent nucleoli. The most appropriate histological diagnosis is pulmonary adenocarcinoma, predominantly papillary type.

Pulmonary adenocarcinomas characteristically are heterogeneous and show a mixture of morphological subtypes, including lepidic, papillary, micropapillary, acinar, and solid, among others. According to the World Health Organization (WHO) 2015 of lung tumors, the terminology used for resections containing pulmonary adenocarcinoma should identify the predominant pattern present. Thus, adenocarcinoma, NOS and adenocarcinoma, mixed subtype are not preferred, and neither is the best diagnosis for the current case. In addition to classification of predominant subtype present, WHO 2015 of lung tumors encourages semi-quantitatively reporting of subtypes by estimating the percentage in 5% increments, rather than focusing on a single pattern. In small biopsy and cytology specimens, a description of the identifiable patterns present is suggested. The WHO 2015 of lung tumors recognizes that subtypes present may lie on a morphologic continuum and there is difficulty in distinguishing morphologic patterns, however morphological subtypes correlate with prognostic and molecular alterations in an increasing number of research studies. Furthermore, reporting of the multiple morphologic types present may aid in distinguishing intrapulmonary spread from multiple synchronous primaries.

Pulmonary adenocarcinoma, predominantly papillary type shows central fibrovascular cores lined by malignant glandular cells. Careful examination is required to exclude tangential sectioning of lepidic growth pattern. Myofibroblastic stroma is not needed to diagnose papillary type. Papillary type should be distinguished from micropapillary type adenocarcinoma, which shows epithelial papillary tufts that lack true fibrovascular cores and is comprised of ring-like glandular structure that float in alveolar spaces, with or without presence of psammoma bodies. Micropapillary type pulmonary adenocarcinoma is associated with intrapulmonary and lymph node metastases and has been reported to show worse overall survival.

Pulmonary adenocarcinoma with lepidic growth shows bland pneumocytes growing along alveolar walls. Diagnosis of invasive adenocarcinoma requires an invasive component of greater than 5.0 mm in largest linear dimension, invasion of lymphatics, blood vessels or pleura, demonstration of tumor necrosis, or spread through alveolar spaces. The preferred terminology is pulmonary adenocarcinoma, predominantly lepidic type. In tumors that fall short of 5 mm invasive component, minimally invasive adenocarcinoma should be considered and the term bronchioalveolar carcinoma should be avoided (see discussion below.) Reporting of the size of the invasive component is controversial, though studies suggest the size of the invasive component may predict lymph node metastases and survival better than gross size. Because current staging practices are based upon gross measurement, a note giving both measurements of gross size and invasive size may be useful to treat patients. Lepidic and papillary pattern adenocarcinomas are associated with epidermal growth factor receptor (EGFR) mutations whereas solid pattern and mucinous tumors are most often associated with KRAS mutations.

The term bronchioalveolar carcinoma is obsolete. Current categories that comprise this former entity include non-mucinous adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma, and lepidic predominant adenocarcinoma. Additionally, invasive mucinous carcinoma was formerly referred to as mucinous bronchioalveolar carcinoma; however, these typically have different characteristic morphologic features of columnar-goblet cells with abundant cytoplasmic mucin and basally oriented nuclei and are not discussed further in this review. Both AIS and minimally invasive adenocarcinoma are usually incidental findings, presenting as ground glass lesions on computed tomography imaging or upon microscopic examination of a surgical specimen resected for another reason.

Minimally invasive adenocarcinoma is defined as solitary, discrete adenocarcinoma, smaller than or equal to 3.0 cm, predominantly lepidic growth pattern, and with an invasive component of larger than 5 mm in largest linear measurement. Measurement of the invasive component includes any histologic subtype other than lepidic pattern, including solid, acinar, papillary, micropapillary and mucinous, among others, and tumor cells infiltrating myofibroblastic stroma. If glands are associated with scar or desmoplastic reaction, invasion is present. Minimally invasive adenocarcinoma is excluded if the tumor invades lymphatics, blood vessels, air spaces or pleura or contains tumor necrosis. By cytologic evaluation, it is not possible to differentiate minimally invasive adenocarcinoma from frankly invasive adenocarcinoma from AIS, as minimally invasive adenocarcinoma requires architectural evaluation (ie, these are cytologically identical lesions) and one cannot exclude unsampled higher grade invasive component. Minimally invasive adenocarcinoma is staged as T1a (mi) and has 100% disease-free and recurrence-free survival if the tumor is completely resected.

Like minimally invasive adenocarcinoma, AIS is a small (less than, smaller than, or equal to 3.0 cm), localized, adenocarcinoma; however, in contrast, the diagnosis of AIS requires pure lepidic growth pattern and lack of any stromal, vascular, or pleural invasion as well as lack of spread through air spaces. Papillary and micropapillary patterns are absent. Alveolar walls appear thickened and elastic tissue may be prominent. Distinction of AIS from atypical adenomatous hyperplasia can be difficult. AIS is usually larger (larger than 5.0 mm), with more crowded, homogenous cell population and more abrupt transition to adjacent alveolar lining cells. Upon gross examination, any poorly defined nodule should be completely sampled for microscopic examination to confirm lack of invasive component. Further similarity to minimally invasive adenocarcinoma includes 100% disease-free survival upon complete resection. Of note, if multiple tumors are present and are theorized to be synchronous primaries, rather than intrapulmonary metastases, the term AIS may be used for the multiple lesions, provided the lesions meet currently accepted morphologic and molecular criteria for synchronous primaries as discussed by Schneider et al.

The current case is a large 10.0-cm tumor mass with tumor cells growing on the surface of fibrovascular cores rather than along existing alveolar septae, and focal areas of invasion. Overall, the diagnosis in this case is pulmonary adenocarcinoma, predominantly papillary type.

  1. Which of the following is true regarding adenocarcinoma in situ (AIS)?
    1. AIS can be easily distinguished by size criteria from atypical adenomatous hyperplasia.
    2. AIS has a better prognosis than minimally invasive adenocarcinoma.
    3. AIS may show spread through air spaces.
    4. Morphologically, AIS requires pure lepidic growth pattern.
    5. Presence of thickened alveolar walls eliminates AIS as the diagnosis.
  2. Which of the following is a diagnostic criterion for minimally invasive carcinoma?
    1. Invasion of pleura
    2. Invasive component greater than 1.0 mm
    3. Solid growth pattern
    4. Solitary
    5. Tumor necrosis
  3. Which of the following is true regarding prognosis in pulmonary adenocarcinoma?
    1. AIS has equal disease-free and recurrence-free survival to minimally invasive carcinoma.
    2. Gross size correlates with survival more than presence of lymph node metastasis.
    3. Micropapillary type pulmonary adenocarcinoma has been associated with better survival rates than papillary type adenocarcinoma.
    4. Minimally invasive adenocarcinoma should have 100% disease-free and recurrence-free survival rates regardless of the tumor’s resection status.
    5. Morphologic subtypes (eg, lepidic, papillary, solid, acinar) do not need to be reported as they do not correlate with prognostic information.

References

  1. Borczuk A. Assessment of invasion in lung adenocarcinoma classification, including adenocarcinoma in situ and minimally invasive adenocarcinoma. Mod Path. 2012; 25:S1-S10.
  2. Miyoshi T, Satoh Y, Okumura S, et al. Early-stage lung adenocarcinomas with a micropapillary pattern, a distinct pathologic marker for a significantly poor prognosis. Am J Surg Pathol. 2003;27(1):101-109.
  3. Schneider F, Derrick V, Davison J, Strollo D, Incharoen P, Dacic S. Morphological and molecular approach to synchronous non-small cell lung carcinomas: impact on staging. Mod Path. 2016;29:735-742.
  4. Travis W, Brambilla E, Burke A, Marx A, Nicholson A. WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart. 4th ed. Lyon, FR: IARC; 2015.

Author

Nichole Steidler, MD
Surgical Pathology Committee
Vista Pathology
Medford, OR

Answer Key

  1. Morphologically, AIS requires pure lepidic growth pattern. (d)
  2. Solitary (d)
  3. AIS has equal disease-free and recurrence-free survival to minimally invasive carcinoma. (a)