Moderator: Dr. Celeste N. Powers
Lung FNA: Well differentiated Fetal Adenocarcinoma
Dr. Máire Duggan
A 25 year old woman presented with a 3 to 4 day history of pleuritic type chest pain, shortness of
breath, fever and chills. She had a 6 year history of chronic bronchitis attributed to her 1 pack a day,
10 year smoking habit. Her family medical history was remarkable for premenopausal breast cancer in her
grandmother, 5 maternal grand aunts, and her mother. At presentation, she was noted to be in mild
respiratory distress. Examination revealed reduced air entry and breath sounds in the right lower lobe.
A pleural effusion was also detected. Chest X ray confirmed the presence of a right sided pleural
effusion with consolidation of the right lower lobe. A large, 10 cm mass was identified in the same
lobe. She was initially treated with antibiotics and a right sided chest tube to drain the effusion.
Nine days later she underwent CT guided FNA (fine needle aspiration) of the mass.
Two Thinprep ® (Cytyc Corporation, Boxborough, Massachusetts, U.S.A.) smears and a formalin
fixed, paraffin embedded cell block were prepared from the FNA. The Papanicolaou stained smears were
hypercellular and contained numerous variably sized epithelial fragments, occasional foamy macrophages,
rare small fragments of reactive stroma and collections of neutrophils. The epithelial cells were mostly
columnar and organized into structures resembling glands or tubules. The columnar cells had a small to
moderate amount of pale cytoplasm and round to ovoid nuclei with a homogenous chromatin and a single
small basophilic chromocentre. Between these cells was a second type of columnar cell with an elongated,
twisted hyperchromatic nucleus. Circumscribed 3 dimensional balls of closely packed hyperchromatic
nuclei were also seen in some of the fragments. Necrosis, mitoses and marked nuclear atypia were not
The cell block showed a proliferation of branching and anastomosing tubular glands lined by a
stratified columnar epithelium. The intervening stroma was fibroblastic and contained collections of
macrophages. The columnar cell cytoplasm was vacuolated. The nuclei were round, basal in location and
the chromatin was finely granular with a small chromocentre. Intercalated cells were scattered between
the columnar cells. Between the tubules were solid nests of small uniform polygonal cells. The columnar
cells were focally positive with synaptophysin, but negative with chromogranin.
The FNA was interpreted as malignant and a well differentiated fetal adenocarcinoma (WDFA) was
Management and follow up
Thereafter she had a right pneumonectomy with lymph node sampling. The lung resection had a 10 cm
tumor with characteristic features of a WDFA . It showed a branching and anastomosing
proliferation of tubules and glands lined by glycogen rich columnar cells. Morules of polygonal cells
were present at the margin of these structures. The immunohistochemical profile was supportive of the
diagnosis. In representative sections, there was focal, strong nuclear staining with chromogranin,
cytokeratin 7, cytokeratin 20, AE1/3, Cam 5.2, carcinoembryonic antigen, and actin, focal cytoplasmic
staining with epithelial membrane antigen and diffuse membranous staining with AE1/3 and CAM 5.2.
She did not receive adjuvant therapy and is alive and well without recurrence or metastatic disease, 7
Lung FNA: Well differentiated Fetal Adenocarcinoma
WDFA is currently classified as a rare subtype of lung adenocarcinoma . It forms less
than 1% of all pulmonary neoplasms. The resemblance to the epithelial component of pulmonary blastoma
and its neuroendocrine qualities were underscored by the previous name of pulmonary blastoma with
argyrophil cells and lacking sarcomatous features (pulmonary endodermal tumor resembling fetal lung)
. The tumor morphology recapitulates fetal lung development at 10 to 15 weeks of gestation.
WDFA typically presents in the fourth decade of life as an asymptomatic lung mass that may be central or
peripheral in location. There is an association with smoking. The histopathology resembles secretory
endometrioid carcinoma. Immunohistochemistry highlights the neuroendocrine qualities. It is
chromogranin positive and can be positive with other neuroendocrine markers such as synaptophysin and
somatostatin. Primary treatment is surgical excision. The survival is excellent for early stage tumors,
but the overall mortality is approximately 15%.
The cytopathologic features of WDFA, particularly of specimens prepared using the ThinPrep®
liquid based cytology method are infrequent. Prior to the publication of the current case, there were
only 3 reports of the FNA features of WDFA
There were 2 single case reports, both
prepared by conventional, alcohol fixed direct smears and one, which was part of a larger series of
diagnostic dilemmas in pulmonary cytology prepared by the ThinPrep® method. There have been
no additional reports. The conventional preparations were described as moderately cellular and formed of
small uniform cells present singly and in clusters
The clusters were variable and
described as irregular, spherical, glandular, rosette like and branching. The cells had a small to
medium amount of eosinophilic cytoplasm, round/oval uniform nuclei, distinct nuclear membranes, granular
clumped chromatin, and small eosinophilic nucleoli. Hepatocytoid and multinucleated giant cells were
described in one case .
With the increasing use of liquid based technology in the evaluation of non gyneoclogical material
comes the knowledge that the cytological presentation of tumors may differ from that seen in
conventionally prepared smears . Clusters composed of 2 cell types were described in a brief
report of WDFA prepared by the ThinPrep®
method . One type of cell had a larger
round to oval nucleus, slightly open chromatin, mildly irregular nuclear membranes and a small nucleolus,
and the other had a smaller dark round nucleus and an inconspicuous or absent nucleolus. There was no
reference to hepatocytoid and multinucleated cells.
The current case expands the cytological description of WDFA prepared by the Thinprep®
method . Most of the epithelial fragments were formed of glands and 3 dimensional balls.
The columnar cells with a small to moderate amount of pale cytoplasm corresponded to the vacuolated
columnar cells lining the tubules and were the equivalent of the cells with larger nuclei described by
Crapanzano and Zakowski . The cells contained a single chromocentre rather than a nucleolus,
however. Small overlapping cells with small hyperchromatic nuclei in 3 dimensional balls were
representative of the morules and likely the smaller cell described in the previous Thinprep®
case report . Columnar cells with hyperchromatic nuclei were the cytological counterparts of
the intercalated cells lining the tubules. These cells were not described in any of the previous reports
As hepatocytoid and multinucleated giant cells were not seen in either
Thinprep® prepared case or in one of the conventionally prepared cases, these features were
likely unique to the Lee et al example of WDFA and atypical
The differential diagnosis based on the morphology and patient history included such primary lung
tumors as pulmonary blastoma, carcinoid tumor, and adenocarcinoma, and because of the history of
premenopausal breast cancer in first degree relatives, metastatic, non palpable breast carcinoma
Pulmonary blastoma is a biphasic tumor with a malignant glandular and stromal component
. The epithelial component is similar to WDFA and its exclusion therefore requires
assessment of the stroma. Since the stromal fragment in the FNA was benign, blastoma was a less likely
diagnosis. Carcinoid tumor was excluded mostly because single cells with a plasmacytoid appearance and
nuclei with a finely granular hyperchromasia were lacking
Additionally, carcinoid tumor
has a monotonous cellular composition, which contrasts with the heterogeneity of WDFA.
Pulmonary adenocarcinoma, in particular acinar and bronchioloalveolar types were considered because of
the glandular pattern of growth
Acinar type adenocarcinoma is formed of fragments of
large cells with obvious malignant nuclear features. Single cells also occur. The nuclei are eccentric
and have one or more large irregular nucleoli. The cytoplasm is basophilic and may be vacuolated. The
architectural and nuclear features contrast with the organized and low grade nuclear features of the
WDFA. Bronchioloalveolar carcinoma is characterized by ball like clusters of columnar cells with round
to oval nuclei and bland chromatin. Nucleoli may be present, but are usually small. Useful diagnostic
clues are intranuclear inclusions and psammoma bodies. These features are absent in WDFA.
Metastatic non palpable breast carcinoma is rare . The diagnosis was excluded in this
case by virtue of the tumor's growth pattern and heterogenous cellular composition. Breast carcinoma of
the ductal type is formed of loosly cohesive sheets of malignant cells with enlarged hyperchromatic
nuclei and irregular nuclear membranes . Single malignant cells are also present. Smears
of the lobular type are hypocellular and the solitary malignant cells may show cytoplasmic vacuoles.
In summary, useful diagnostic features of WDFA in Thinprep® preparations include a
glandular and morular like arrangement of epithelial cells. The predominant cell in the glands is
columnar and there is a lesser population of smaller intercalated cells. The morular cells are tightly
packed and uniform epithelioid cells. Malignant stroma is absent.
- Kradin RL, Kirkham SE, Young RH, Mark EJ, Dikersin GR. Pulmonary blastoma with argryophilic cells and lacking sarcomatous features (pulmonary endodermal tumor resembling fetal lung). Am J Surg Pathol 1982;6:165-172.
- Brambilla E, Travis WD, Colby TV, Corrin B, Shimosato Y. The new World Health Organization Classification of Lung Tumors. Eur Respir J 2001;18:1059-1068.
- Kneafsey P, Duggan MA, McFadden S. Fine needle aspiration cytology of pulmonary, well-differentiated fetal adenocarcinoma prepared by the ThinPrep method. Cytopathology. 2003; 14:87-90.
- Lee GL, Cho NH. Fine-needle aspiration cytology of pulmonary fetal adenocarcinoma of fetal type: Report of a case with immunohistochemical and ultrastructural studies. Diagn Cytopathol 1991; 7:409-414.
- Nguyen GK. Fine-needle aspiration cytology of well-differentiated fetal adenocarcinoma (endodermal tumor) of the lung. Acta Cytol 2001; 45:478-81.
- Crapanzano JP, Zakowski MF. Diagnostic dilemmas in pulmonary cytology. Cancer (Cancer Cytopath) 2001; 93:364-375.
- Bavikatty NR, Michael CW. Cytologic features of small-cell carcinoma on ThinPrep. Diagn Cytopathol. 2003; 29:8-12.
- Michael CW, McConnel J, Pecott J, Afify AM, Al-Khafaji B. Comparison of ThinPrep and TriPath PREP liquid-based preparations in non-gynecologic specimens: a pilot study. Diagn Cytopathol 2001; 3:177-84.
- Rana DN, O'Donnell M, Malkin A, Griffin M. A comparative study: conventional preparation and ThinPrep 2000 in respiratory cytology. Cytopathology. 2001; 12:390-8.
- Francis D, Jacobsen M. Pulmonary blastoma: preoperative cytologic and histologic findings. Acta Cytol 1979; 6:437-442.
- Nicholson SA, Ryan MR. A review of cytologic findings in neuroendocrine carcinomas including carcinoid tumors with histologic correlation. Cancer. 2000; 90:148-61.
- Saleh HA, Haapaniemi J, Khatib G, Sakr W. Bronchioloalveolar carcinoma: diagnostic pitfalls and immunocytochemical contribution. Diagn Cytopathol. 1998; 18:301-6.
- Medina-Franco H, Urist MM. Occult breast carcinoma presenting with axillary lymph node metastases. Rev Invest Clin. 2002; 54:204-8.
- Biscotti CV, Shorie JH, Gramlich TL, Easley KA. ThinPrep vs. conventional smear Cytologic preparations in analyzing fine-needle aspiration specimens from palpable breast masses. Diagn Cytopathol 1999 2:137-41.