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2011—March Case of the Month

Posted March 11, 2011


CAP Foundation March 2010 Online Case of the Month

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78-year-old man with a history of prior colonic adenocarcinoma presents with a new left lower lobe lung mass. A lobectomy specimen showed a mass measuring 6.5 cm extending to the visceral pleura. The tumor cells were CK7 (+), CK20 (-), and TTF-1 (+).

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2008, Case 9 and is pulmonary adenocarcinoma, mixed subtype.

Criteria for Diagnosis and Comments: Of the primary malignant pulmonary tumors, adenocarcinoma has displaced squamous cell carcinoma as the most common form of cancer in the lung. The association with tobacco use of all pulmonary carcinomas is well established, but pulmonary adenocarcinoma (PA) is also notable as the most common type to occur in non-smokers, particularly women. Radiographically, PA may take form as a solid mass, ground glass opacification, or combinations of both. PET imaging is an increasingly utilized and relatively sensitive modality in the identification of malignant lung tumors, although less so for pure bronchioloalveolar adenocarcinoma. Hilar adenopathy appears less frequently in typical PA than in other types of epithelial lung tumors. PA is also more likely to involve the pleura and chest wall and may disseminate along pleural surfaces mimicking mesothelioma requiring immunohistochemistry in some cases. The tumors are usually poorly circumscribed by gross examination, may be single or multiple and tend to occur peripherally. Unlike squamous cell carcinoma, PA only rarely cavitates. An association with a scar occurs more frequently in PA for unknown reasons and likely represents a desmoplastic host response to invasion.

PA exhibits a variety of histologic patterns and in the current WHO classification these are divided into acinar, papillary, bronchioloalveolar, mixed subtype and solid adenocarcinomas with mucin production (further subdivided into fetal, mucinous, signet ring cell, and clear cell types). Pure histology is uncommon with the majority or tumors (80%) exhibiting a mixture of patterns (i.e. “mixed subtype”), as seen in this case with fields varying among the different sections. Bronchioloalveolar carcinoma (BAC), which accounts for around 5% of PA, may also present as a single or multiple nodules or in some cases show a diffuse pneumonia-like or lobar pattern, both by imaging and gross examination. These tumors characteristically spread along the alveolar surface (lepidic/aerogenous growth pattern) and by definition, show no evidence of stromal, vascular or pleural invasion. BAC is usually well to moderately differentiated and composed of either atypical columnar/cuboidal cells (non-mucinous BAC) or cells with prominent cytoplasmic mucin (mucinous BAC). The non-mucinous type of BAC is more commonly seen as solitary BAC while the less common mucinous type of BAC shows tendency to multifocality and a comparatively worse prognosis. Although the diagnosis of BAC might be suggested in cytologic or needle specimens, it should be stressed that definitive diagnosis requires thorough histologic examination to exclude the presence of invasion. It is to be also noted that PA may not infrequently show an aerogenous/BAC type growth pattern and even when predominant are currently classified as “well differentiated adenocarcinoma with BAC-like growth pattern” rather than BAC. Microscopic lesions (5 mm or less) with some but not all the features of BAC are currently categorized as atypical adenomatous hyperplasia (AAH), a putative precursor of pulmonary adenocarcinoma. Genetic changes identified in adenocarcinomas include mutations of K-ras (30%) which appears only infrequently in other lung cancer types and also mutations of p53 which has been suggested to be a molecular target of cigarette smoke. Some tumors also demonstrate over-expression of Her2/neu and EGFR which may have therapeutic implications in individual patients.

Lobectomy is the standard treatment for resectable lesions although wedge excision may be sufficient for some patients with small BAC’s or patients with localized disease who cannot withstand pulmonary resection. Localized BAC in general has a good prognosis and tumors with limited invasion (<5 mm) appear to have a 100% 5-year survival similar to localized pure BAC. Unfortunately, the five year survival rate of bronchogenic carcinoma overall continues to be poor (~ 9%).

Mucinous (colloid) carcinomas (MCC) have similar histologic appearance to tumors seen in the GI tract with epithelial cell clusters and abundant pools of dissecting mucin. Two variants have been described: goblet cell and signet ring cell types. Goblet cell MCC is the more common of the two with a better prognosis. Signet ring cell type MCC as elsewhere seems to portend a worse prognosis. The goblet cell type tends to show an intestinal immunophenotype (CK20+, CDX2+), which may be problematic, however, most cases are also CK7(+), TTF-1 (+), in which case a positive TTF-1 stain has been shown to take precedence over CDX-2 in regard to site of origin at this time. Rare cases may be negative for TTF-1, which may require clinical correlation to exclude a gastrointestinal primary. In contrast, the signet ring cell type MCC usually shows a pulmonary phenotype (CK7 (+), CK20 (-) TTF-1(+). Thus far pulmonary signet ring carcinoma has not been reported to be CDX-2 positive.

Fetal adenocarcinoma is a rare variant of PA that is comprised of glandular structures that are non-ciliated and glycogen-rich resembling the fetal lung. The average age of presentation on average is in a somewhat younger age group (~ 40 years). The tumors display sub and supranuclear vacuoles that may impart an endometrioid appearance. Most tumors are well differentiated. When associated with a sarcomatous blastema-like stroma, the tumors are classified as pulmonary blastomas.

Briefly, metastatic adenocarcinoma may be a consideration in patients with a previous history or with tumors of unusual histology. The presence of a tumor with a BAC-like pattern may suggest a primary lung neoplasm, although one must be wary as metastatic disease may also spread in a lepidic fashion. Clinical history including tumor distribution (solitary vs. multiple) and comparison with prior tumor slides, if available, is often helpful. Immunohistochemistry may be informative in cases. Cytokeratin markers are expressed in PA with CK7 (+) more common than CK20 (+). TTF-1 expression is seen in most cases of PA (~ 75%); the exception to this is mucinous BAC which is typically CK 7 (+), CK20 (+) and TTF-1 (-), however CDX2 is usually negative aiding in the differential with metastatic colon/GI carcinoma. In cases with pure papillary histology where TTF-1 positivity overlaps with papillary thyroid carcinoma, thyroglobulin stains can help to discriminate. In patients with prior history of breast or prostate neoplasia, BRST-2 and PSA stains can be of aid. Other immunostains not mentioned here may be utilized depending on the particular differential diagnosis in individual cases.

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. Which malignant lesion is, by definition, non-invasive? A.  Atypical adenomatous hyperplasia
B.  Metastatic adenocarcinoma
C.  Pulmonary adenocarcinoma, bronchioloalveolar type
D.  Pulmonary adenocarcinoma, fetal type
E.  Pulmonary adenocarcinoma, mixed subtype
F.  Pulmonary adenocarcinoma, mucinous type
2. Which lesion above typically shows glycogen rich glands with supranuclear and subnuclear vacuoles imparting an endometrioid appearance? A.  Atypical adenomatous hyperplasia
B.  Metastatic adenocarcinoma
C.  Pulmonary adenocarcinoma, bronchioloalveolar type
D.  Pulmonary adenocarcinoma, fetal type
E.  Pulmonary adenocarcinoma, mixed subtype
F.  Pulmonary adenocarcinoma, mucinous type
3. Which histologic pattern of primary adenocarcinoma of the lung is the most common? A.  Atypical adenomatous hyperplasia
B.  Metastatic adenocarcinoma
C.  Pulmonary adenocarcinoma, bronchioloalveolar type
D.  Pulmonary adenocarcinoma, fetal type
E.  Pulmonary adenocarcinoma, mixed subtype
F.  Pulmonary adenocarcinoma, mucinous type


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  3. Marchevsky AM. Problems in pathologic staging of lung cancer. Arch Pathol Lab Med. 2006; (130); 292-302.
  4. Moran CA. Pulmonary adenocarcinoma: the expanding spectrum of histologic variants. Arch Pathol Lab Med. 2006; 130(7):958-962.
  5. Rosai J. Rosai and Ackerman’s Surgical Pathology. 9th ed. Mosby; St Louis, Mo. 2004; 391-393.
  6. Travis WD, Brambilla E, Müller-Hermelink HK, Harris C. World Health Organization Classification of Tumors: Pathology and Genetics. Tumors of the Lung, Pleura, Thymus and Heart. IARC Press, Lyon, France; 2004; 35-44.
  7. Weydert JA, Cohen MB. Small peripheral pulmonary adenocarcinoma: morphologic and molecular update. Adv Anat Pathol. 2007; 14(2):120-128.

Kevin Wu, MD
Surgical Pathology Committee
Mayo Clinic
Jacksonville, FL