Cribriform Adenocarcinoma of the Lung: Clinicopathologic, Immunohistochemical, and Molecular Analysis of 15 Cases of a Distinctive Morphologic Subtype of Lung Adenocarcinoma

Alexander C Mackinnon Jr; Arturo Luevano; Lisley C de Araujo; Nagarjun Rao; Min Le; Saul Suster


Mod Pathol. 2014;27(8):1063-1072. 

In This Article


Clinical Features

The patients' clinical characteristics are summarized in Table 2. The median age at diagnosis was 64 years (range 30–80 years). Eight patients were men and seven were women. All patients, except one (case 14), were heavy cigarette smokers (greater than 40 cigarettes per day). Co-morbidity was present in two patients; one had sickle cell disease and another had chronic myeloid leukemia. Based on initial histologic examination, the majority of cases were initially interpreted as representing metastases from other organs. Thorough clinical and radiographic examination following the initial diagnosis did not reveal evidence of a primary tumor elsewhere. All patients but one underwent surgical resection as treatment; lobectomy was performed in seven patients, wedge resection in six, one patient had a partial pneumonectomy, and one patient had only a liver biopsy for metastatic disease. Follow-up information was available in six patients; two patients died before 1 year with disseminated disease, four patients were alive without evidence of metastases at 4 months after surgery. The remainders of patients have been lost to follow-up.

Gross Features

Fifteen patients had single tumors; tumor size ranged from 1.9 to 7.5 cm. Grossly, the tumors were described as tan-white, well-circumscribed solid masses. Two tumors showed central cavitation. All tumors were peripherally located, with pleural puckering. Six patients had mediastinal lymph node metastases at diagnosis, and one patient had pleural and chest wall metastases.

Histologic Features

On scanning magnification, all tumors showed a predominant cribriform architecture consisting of glandular spaces lined by cuboidal to cylindrical cells with punched-out round to ovoid lumens. Four cases resembled prostatic or breast adenocarcinomas (Figure 1a). The nests of tumor cells were round to ovoid in shape and separated by abundant desmoplastic stroma. On higher magnification, the cells were cuboidal to polygonal, with centrally placed nuclei containing prominent nucleoli and ample cytoplasm. No goblet cells, signet-ring cells, or other evidence of mucin secretion could be identified. The cribriform spaces resembled 'roman bridges' (Figure 1b). Secretion in the lumens varied from amphophilic to basophilic in two cases, and eosinophilic in two other cases. Areas of comedonecrosis were present in all four cases.

Figure 1.

(a) Cribriform adenocarcinoma of lung showing tumor cell islands with punched-out cribriform spaces lined by cuboidal to polygonal epithelial cells. The structures are reminiscent of cribriform ductal carcinoma of the breast (case 1). (b) Higher magnification from the same case shows punched-out lumens with rigid columns of cells resembling roman bridges.

Two cases had abundant mucinous eosinophilic secretion in the glandular lumens. Cribriform structures lined the periphery of cystic spaces in a garland-like pattern, resembling mucinous adenocarcinomas of the pancreas or ovary (Figure 2a). The tumor nests were separated by scant fibrous stroma. Cells varied from cuboidal to cylindrical, their cytoplasm was eosinophilic and the nuclei were oval or elongated with some pseudostratification. Atypia was moderate to severe and there were frequent mitoses (Figure 2b).

Figure 2.

(a) Lung mucinous adenocarcinoma with prominent cribriform spaces are seen arranged in a garland-like distribution at the periphery resembling metastasis from mucinous cystadenocarcinoma of pancreas or ovary (case 5). (b) Higher magnification shows punched-out luminal spaces surrounded by cells with marked nuclear atypia and mitotic figures.

Four cases resembled adenocarcinoma of the endometrium, with tumor islands containing cribriform structures separated by desmoplastic stroma (Figure 3a). The cells were cylindrical, with ovoid nuclei containing two or three small nucleoli and well-defined cell borders. All cases showed, at least focally, subnuclear vacuoles resembling periovulatory-phase endometrium, and dirty necrosis in the lumen (Figure 3b). One of these cases also showed areas that resembled ovarian mucinous cystadenocarcinoma, with cystic spaces rich in mucin, cribriform architecture, and more solid foci with structures resembling morules; however, the solid areas were separate from the cribriform areas and did not show squamoid features as are seen in true morules.

Figure 3.

(a) Cribriform adenocarcinoma of lung showing multiple punched-out cribriform spaces and foci of comedonecrosis resembling endometrioid adenocarcinoma (case 7). (b) Higher magnification of area showing prominent subnuclear vacuoles resembling periovulatory endometrium.

Three cases showed features that simulated intestinal-type colorectal adenocarcinoma (Figure 4a), with extensive areas of necrosis, cystically dilated tumor islands with cribriform structures adopting a garland-like arrangement at their periphery, and adjacent areas with small confluent cribriform nests with necrosis in their lumens. Tumor cells were columnar and showed marked nuclear atypia, with elongated nuclei, increased nuclear chromatin, and ample eosinophilic cytoplasm. Scattered goblet cells were present. Thick mucoid eosinophilic secretions were present in the lumens admixed with inflammatory cells and nuclear debris (ie, 'dirty' necrosis; Figure 4b).

Figure 4.

(a) Intestinal-type adenocarcinoma of lung showing dilated glandular spaces filled with hemorrhage and necrotic debris and showing focal cribriform growth pattern (case 12). (b) Higher magnification shows cribriform glandular structures lined by tall columnar cells admixed with a few goblet cells.

Two cases simulated metastases from thyroid papillary carcinoma and showed a striking cribriform pattern admixed with small papillary tufts (Figure 5a). The tumor cells were round or oval and showed marked clearing of the nuclear chromatin, scattered longitudinal nuclear grooves, and rare intranuclear eosinophilic inclusions as well as overlapping of nuclei (Figure 5b). The lumens in the cribriform areas were filled with an eosinophilic secretion with scalloping and occasional macrophages. Scattered psammoma bodies were also present. Both cases also showed focal areas displaying a lepidic, bronchioloalveolar-type pattern of growth in adjacent alveoli.

Figure 5.

(a) Cribriform adenocarcinoma of lung with focal papillary areas (lower right) showing clearing of the nuclear chromatin in the tumor cells simulating a metastasis of papillary thyroid carcinoma (case 14). (b) Higher magnification showing prominent clearing of the nuclear chromatin and overlapping of nuclei.

Immunohistochemistry Analysis

All cases were positive for TTF-1 and CK7 (Figures 6a and b). None of the cases showed positivity for CK20 or CDX-2. Case 15 showed positive staining of the tumor cells for ALK antibody (Figure 7). Thyroglobulin was negative in both cases that showed a thyroid-like pattern (cases 14 and 15).

Figure 6.

(a) Cribriform adenocarcinoma of lung showing strong nuclear immunoreactivity for TTF-1 (case 1). (b) Cribriform adenocarcinoma of lung showing cytoplasmic immunoreactivity for CK7 (case 1).

Figure 7.

(a) ROS1 translocation indicated by loss of 5' (red) signal with retention of 3' (green) signal in 62.5% of nuclei. (b) RET 5' and 3' probes split in 17.1% of nuclei. (c) EML4-ALK rearrangement in 46.6% of nuclei. Overlapping probes (arrowhead) indicate intact chromosomes. Split probes (arrows) indicate chromosomes in which the target gene is disrupted due to chromosomal translocation. (d) Same case as c demonstrating ALK expression by IHC.

Molecular Studies

No activating EGFR mutations were identified. EGFR exon 20 contains a synonymous single-nucleotide polymorphism (refSNP ID rs1050171) p.Q787Q (c.2361G>A),[26] with the ancestral allele of G. The minor allele frequency of A is 0.418. Four patients were heterozygous G/A (cases 2, 7, 8, 15) and two patients were homozygous A/A (cases 10 and 14) for this SNP. For each case, sequence of paired normal and tumor DNA demonstrated the same genotype indicating this is a germline single-nucleotide polymorphism that does not correlate with either histology or activating EGFR mutation. Dideoxy sequencing demonstrated the activating KRAS mutation c.G35A (p.G12D) in a tumor with endometrioid-like cribriform histology (case 8). Both cases with thyroid-like histology demonstrated gene rearrangements by FISH (Figure 7) with one case harboring a ROS1 rearrangement (case 14) and the other an ALK rearrangement (case 15). Case 7 with endometrioid histology demonstrated a RET gene rearrangement in a small number of malignant nuclei (17.1%).