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2008 —July Case of the Month

Updated August 20, 2008


CAP Foundation July 2008 Online Case of the Month

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

A 42-year-old man presented with shortness of breath and a cough productive of copious sputum. CT examination revealed extensive consolidation of the right upper and middle lobes. Following a diagnostic biopsy, a right bilobectomy was performed. The lung parenchyma was firm, tan, and diffusely consolidated. The cut surface had a slightly mucoid consistency.

Archive Case and Diagnosis: This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2005, Case 08 and is a bronchioloalveolar carcinoma, mucinous type.

Criteria for Diagnosis and Comments:
Bronchioloalveolar carcinoma (BAC) is defined in the current World Health Organization (W.H.O.) classification as an adenocarcinoma with a purely lepidic pattern of growth, i.e. growth along pre-existing alveolar structures, without evidence of stromal, vascular or pleural invasion. Tumors that show invasion of stroma, blood vessels or pleura should not be classified as BAC. The W.H.O. classification divides BAC into non-mucinous, mucinous and mixed subtypes.

This case demonstrates typical morphology for a mucinous BAC. The existing alveolar septa are lined, either partially or completely, by a continuous layer of tall columnar cells with abundant apical cytoplasmic mucin. Cytologic atypia is characteristically minimal. The tumor in this case also shows “multifocality”, which is not infrequently encountered in BAC. It is thought that this is secondary to aerogenous spread of tumor rather than true multifocal growth. The mucinous variant of BAC has a propensity to involve entire lobes, mimicking pneumonia grossly and radiographically.

The definition of BAC has undergone considerable evolution in recent years. Prior to the 1999 W.H.O. classification, Clayton, et al, divided BAC into four types: mucinous, non-mucinous, mixed and sclerosing. The sclerosing variant proposed by Clayton does not meet the rigid criteria for the current W.H.O. definition and is not included in the current classification of BAC. The reasoning behind the current strict definition lies primarily in studies of non-mucinous BAC’s, which have shown that solitary small tumors (<3.0 cm) with a pure lepidic growth pattern do not have lymph node metastasis and have a 100% five year survival. Stage 1 tumors with a lepidic growth pattern but with areas of stromal invasion were found to have a five-year survival similar to that of “conventional” adenocarcinomas (approximately 75%). Additionally, tumors with stromal invasion were found to have lymph node metastases in approximately 30% of cases. Similar survival advantages appear to apply to multifocal BAC, particularly if the tumors are in the same lobe, but further study is needed to clarify this issue.

As many conventional pulmonary adenocarcinomas may contain areas of lepidic growth, particularly around the periphery, the diagnosis of BAC should not be made on a small biopsy or cytology specimen, given that invasive areas may be present in the tumor which have not been sampled. A diagnosis of BAC should only be made on a large or resected specimen in order to rule out any areas of invasion. Generally, proper classification of BAC has implications for prognosis but not necessarily for treatment. However, BAC and tumors with a prominent BAC component have recently been shown to respond more readily than conventional adenocarcinomas and other non-small cell lung carcinomas to the tyrosine kinase inhibitor, gefitinib (IressaTM), which targets the epidermal growth factor receptor (EGFR).

The differential diagnosis of mucinous BAC includes a variety of primary pulmonary carcinomas as well as metastatic adenocarcinomas, particularly of gastrointestinal origin. Mucinous, a.k.a. “colloid” carcinoma of the lung, like mucinous carcinoma of the breast or colon, is characterized by dissecting pools of mucin containing islands of neoplastic epithelium, which are often free floating. Unlike mucinous BAC, colloid carcinoma destroys the underlying architecture. Colloid carcinomas may be difficult to diagnose due to the paucity of malignant cells in some cases. The finding of pools of mucin within alveoli in the presence of a radiographic mass should prompt a careful search for malignant cells. Some reports indicate a slightly better prognosis for colloid carcinoma than for conventional adenocarcinomas. Unlike BAC, they do metastasize to lymph nodes and distant sites.

Mucinous cystadenomas are rare benign tumors consisting of a fibrous-walled cyst filled with mucin and lined by well-differentiated columnar mucinous epithelium. Definitive diagnosis usually requires a resected specimen to appreciate the morphologic features. The vanishingly rare cystadenocarcinoma is typically partially circumscribed but shows areas of invasion or lepidic growth of tumor cells along alveolar walls. It is likely that many of these cases are actually colloid carcinomas according to current definitions.

Primary signet ring cell carcinoma and pulmonary adenocarcinoma with goblet cell morphology are relatively recently described variants of pulmonary adenocarcinoma. Signet ring carcinomas have essentially identical morphologic features to those encountered in the more common gastric signet ring carcinomas. Goblet cell carcinoma resembles conventional colonic adenocarcinoma with tall columnar cells and atypical columnar goblet cells. Both of these entities are often associated with dissecting mucin and are currently considered as probable variants of mucinous (colloid) carcinoma, although both are evolving areas of study. The importance of these entities is to recognize that such morphology can be encountered in a pulmonary primary.

Metastatic carcinomas, particularly of gastrointestinal origin, should be considered when a mucinous carcinoma of any type is encountered in the lung. Immunohistochemical studies are frequently used to attempt to establish the primary site of origin, and one should be aware of the potential pitfalls peculiar to mucinous carcinomas of the lung. Cytokeratin 7 (CK7), cytokeratin 20 (CK20), thyroid transcription factor (TTF-1) and CDX2 are antibodies often employed to determine pulmonary vs. gastrointestinal origin. Typically, conventional primary pulmonary adenocarcinomas and the non-mucinous type of BAC are positive for CK7 and negative for CK20. Primary GI tumors, particularly those of colonic origin, characteristically show the opposite staining pattern. Nearly all non-mucinous BAC and most well to moderately differentiated pulmonary adenocarcinomas are positive for TTF-1, a marker which has proven very useful in supporting a primary pulmonary origin for a given tumor. In contrast, while mucinous BAC is positive for CK7, the majority are also positive for CK20 and negative for TTF-1. The recently described goblet cell variant of pulmonary adenocarcinoma is also positive for CK20 as well as CK7 in the majority of cases. Unlike mucinous BAC, goblet cell adenocarcinoma has been positive for TTF-1 in most cases thus far. CDX2 is a homeobox gene encoding a nuclear transcription factor involved in the differentiation of intestinal epithelium. CDX2 has emerged as a sensitive and specific marker for differentiating gastrointestinal carcinomas, particularly of colorectal origin, from primary pulmonary carcinomas. Recent reports have shown that the goblet cell variant of pulmonary adenocarcinoma shows strong staining with CDX2 in nearly all cases. While TTF-1 should also be positive, awareness of this aberrant staining pattern with CDX2 and CK20 in this lung carcinoma variant is important to avoid misclassifying a tumor as a gastrointestinal primary. Mucinous BAC has not shown staining with CDX2 but awareness of the CK20 positive, TTF-1 negative phenotype is important to avoid misclassification. The signet ring cell variant of pulmonary adenocarcinoma has shown a CK7 positive, CK20 negative, TTF-1 positive pattern typical of pulmonary adenocarcinomas.

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 tumor is composed of cytologically bland, tall columnar cells with apical mucin growing in a purely lepidic pattern without areas of stromal, pleural or vascular invasion? A.  Adenocarcinoma, goblet cell type
B. Adenocarcinoma, signet ring type
C. Bronchioloalveolar carcinoma, mucinous type
D. Mucinous (colloid) carcinoma
E. Mucinous cystadenoma
2. Which tumor is a recently described variant of mucinous pulmonary adenocarcinoma which shows positive staining with CK20 and CDX2 in the majority of cases? A.  Adenocarcinoma, goblet cell type
B. Adenocarcinoma, signet ring type
C. Bronchioloalveolar carcinoma, mucinous type
D. Mucinous (colloid) carcinoma
E. Mucinous cystadenoma
3. Which tumor is characterized by a fibrous-walled cyst lined by cytologically bland mucinous epithelium? A.  Adenocarcinoma, goblet cell type
B.  Adenocarcinoma, signet ring type
C.  Bronchioloalveolar carcinoma, mucinous type
D.  Mucinous (colloid) carcinoma
E.  Mucinous cystadenoma


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