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Fine needle aspiration cytology of pulmonary papillary adeno-carcinoma mimicking papillary thyroid carcinoma.


Adenocarcinoma is the most common subtype of lung cancer (1,2). Pulmonary adenocarcinoma are histologically heterogeneous, presenting a wide range of histologic features including solid growth with mucin production, acinar, papillary, lepidic, enteric within the current WHO adenocarcinoma classification (2-10). Pulmonary papillary adenocarcinoma is a rare variant accounting for 7-12 % (2). This subtype of invasive non-mucinous adenocarcinoma is composed of true papillary structures in greater than three quarters of the tumour on histopathologic examination (2,3,11).

In this case report, we describe the classical morphologic features of a pulmonary papillary adenocarcinoma which resemble those of papillary thyroid carcinoma and discuss the utility of immunohistochemical staining in distinguishing primary from metastatic tumours.


A 63 year old male presented with a triangular shaped mass within the medial left upper lobe of the lung. On CT imaging the lesion measured 65 mm in maximum dimension. Additionally, there were numerous rounded, solid and ground glass nodules within the left upper lobe and right lung. There was no cavitation, hilar or mediastinal lymphadenopathy or background changes of chronic lung disease. Imaging features suggested the possibility of a primary lung malignancy, organising pneumonia, granulomatosis with polyangiitis, sarcoidosis or lymphoma. A CT guided fine needle aspiration (FNA) and subsequent core biopsy of the left lung mass were performed.


The FNA sample was collected in SurePath preservative (BD Diagnostics TriPath, Burlington, NC) for liquid-based thin-layer preparation. The aspirate sample was spun at 600 rcf for 5 minutes. From the sediment, a SurePath slide was prepared and stained (Papanicolaou stain) using the SurePath prepstain machine. The remainder of the sediment was used to make a cell block, fixed in 10% formalin, embedded in paraffin, routinely processed and stained with Hematoxylin-Eosin (H & E). Immunohistochemical staining were carried out on the cell block and core biopsy sections using antibodies to thyroid transcriptor factor-1 (TTF-1), Napsin-A, Thyroglobulin, CD10, PAX 8, AMACR, CA19-9 and CD57 (Automated Ventana Bench Mark machine, the EnVisionTm System).


Cytologic findings

SurePath and cell block preparations showed numerous fragments from a complex papillary neoplasm demonstrating true fibrovascular cores (Figures 1a 2a). The lining epithelial cells demonstrated prominent nuclear pseudo-inclusions and focal nuclear clefts and grooves (Figure 1b). The differential diagnosis therefore included metastatic papillary thyroid carcinoma, metastatic papillary renal cell carcinoma or primary pulmonary adenocarcinoma with a predominant papillary architecture.

Histologic findings

H & E stained sections of the lung core biopsy showed multiple fragments of a tumour having a complex papillary architecture. The papillae were lined by cuboidal cells with oval nuclei and prominent nuclear pseudo-inclusions (Figure 3a). There were suggestions of cilia on the luminal edge of the epithelial component and admixed lymphocytes. Based on these features and diffuse positive immunostaining for TTF-1 and Napsin A, and negative staining for Thyroglobulin, a diagnosis of primary pulmonary papillary adenocarcinoma was confirmed.

Immunohistochemical findings

Immunohistochemical staining on the cell block showed the tumour cells to be positive for TTF-1 (Figure 2b), Napsin A (Figure 2c) and negative for Thyroglobulin, CD10, PAX8, AMACR, CA19-9 and CD57 (Figure 2d). Immunohistochemical staining on the lung biopsy showed the tumour cells were diffusely positive for TTF-1 (Figure 3b) and Napsin A (Figure 3c), and negative for Thyroglobulin (Figure 3d).

PD-L1 immunohistochemistry was performed on formalin-fixed paraffin-embeded biopsy sections using the Roche clone SP263 (Ventana Optiview DAB detection system). PD-L1 staining by this methodology was negative.

Molecular analysis

EGFR testing was performed by IGENZ, Auckland using Mass Array Multiplex allele-specific PCR analysis (Agena Bioscience). EGFR testing on cell block sections showed no evidence of an activating mutation in EGFR, BRAF or KRAS genes.

Fluorescence in situ hybridisation (FISH) analysis was performed on biopsy sections using ZytoLight SPEC ROS1 and Vysis LSI ALK probe. This showed no evidence of an ALK (2p23) or a ROS1 gene rearrangement. However, loss of one copy of ROS1 was observed in 72 cells out of 100 cells examined.


Papillary carcinoma of the lung is an uncommon form of invasive adenocarcinoma accounting for 7-12% of the lung adenocarcinoma (2). In this subtype papillary structures normally replace the underlying alveolar spaces with complex branching papillae having true fibrovascular cores, lined by single or multiple layers of cuboidal to columnar glandular cells. The tumour cells exhibit moderate nuclear polymorphism, hyperchromatic nuclei and prominent nucleoli. The immunophenotype is similar to usual type pulmonary adenocarcinoma with positive immunostaining for TTF-1, Napsin A and Surfactant Apoprotein A (SPA) (1-5,8).

In a 1997 study papillary adenocarcinoma was classified based on histologic features by Silver and Askin (11). These tumours are composed of >75% papillary growth pattern. The behaviour of primary papillary adenocarcinoma is believed by some investigators to represent a more aggressive disease (1,7), while others have shown a similar 5-year survival between usual type adenocarcinoma [68%] and papillary-predominat adenocarcinoma [71 % 5-year survival]. Micropapillary tumours, as discussed below, are a more aggressive tumour subtype [38% 5-year survival] (12).

The true papillary adenocarcinoma of the lung needs to be distinguished from primary and metastatic micropapillary adenocarcinoma of the other organ including breast, urinary bladder, ovary and salivary glands (2,3,6,8,13). Lung adenocarcinoma with a micropapillary pattern were first reported by Silver and Askin in 1997 (11), then by Amin et al in 2002 (14). This tumour is characterized by small papillary tufts of neoplastic cells without fibrovascular core seen, mostly as detached clusters from the surrounding tumour in comparison to the well -defined true papillae in pulmonary papillary carcinoma (6-8,10,11,14).

Where available, a clinical history of a known extrapulmonary primary, along with the imaging findings and distinctive morphologic features are helpful in identifying a metastatic tumour in this site. Commonly primary lung carcinoma presents as a single nodule while metastases often present as multiple and bilateral nodules. However, as seen in this case, primary lung carcinoma may have intrapulmonary metastasis presenting as multiple nodules and so mimic extrapulmonary metastatic disease. In challenging cases ancillary immunohistochemical studies will be invaluable in defining a likely primary site.

Papillary adenocarcinoma resembling papillary thyroid carcinoma has been described in the lung, breast, kidney, prostate and pancreas (1,13,15,16). The combination of the classic nuclear features includes nuclear pseudo-inclusions, nuclear grooves, ground glass nuclei along with true papillary architecture that are considered standard diagnostic criteria for papillary thyroid carcinoma. A definitive distinction between a primary and metastatic tumour may be difficult on cytomorphology alone.

Positive immunostaining for TTF-1 and Napsin A, and negative staining for Thyroglobulin and PAX8 helped in the differential diagnosis and confirmed the lung primary origin of the tumour. Positive markers for lung primary and negative staining for CD10, PAX8, CA19.9, CD57 and AMACR excluded the renal, pancreas and prostate primary respectively.

Intranuclear pseudoinclusions as a single diagnostic pointer to the likely primary site of origin can be misleading as, in addition to their occurrence in papillary thyroid carcinoma, they are also evident in pulmonary papillary adenocarcinoma, hepatocellular carcinoma, melanoma, meningioma and variants of parenchymal renal cell carcinoma (1,13).

The frequency of EGFR, K-RAS and BRAF mutations varies in different subtypes of pulmonary adenocarcinoma. EGFR mutations are reported to be higher in papillary and micropapillary adenocarcinoma of the lung compared to other variants (7,8). Tumours with EGFR mutation may be more responsive to molecular targeted medicines such as tyrosine kinase inhibitors. Tumours with ALK and ROS1 gene rearrangements are responsive to crizotinib. Tumours with negative EGFR, ALK and ROS1 mutations are further tested for PD-L1. If PD-L1 is positive, pembrolizumab (Keytruda) may be used as first line immunotherapy (17).

In summary, the morphologic characteristics in the present case strongly resemble a papillary thyroid carcinoma. Definitive diagnosis of primary versus metastatic tumour was difficult without immunohistochemical studies. Awareness of the existence of papillary thyroid carcinoma like pulmonary adenocarcinoma will avoid misdiagnosis or unnecessary clinical and radiological investigations.


The authors acknowledge Louise Goossens for her excellent photographic assistance.


Sharda Lallu, BSc CT(FIAC), Cytotechnologist Sarla Naran, BSc CT(FIAC), Cytotechnologist Peter Bethwaite, MB ChB PhD FFSc(RCPA) FRCPA, Cytopathologist

Department of Anatomic Pathology, Wellington Southern Community Laboratories, Wellington Hospital

Author for correspondence: Dr Peter Bethwaite, Anatomic Pathology, Wellington SCL, Wellington. Email:


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Sharda Lallu, Saria Naran and Peter Bethwaite

Department of Anatomic Pathology, Wellington Southern Community Laboratories, Wellington Hospital

Caption: Figure 1a. Surepath preparations from FNA showing numerous complex papillary fragments demonstrating true fibrovascular cores. (Papanicolaou stain X 400).

Caption: Figure 1b. Showing tumour cells with prominent nuclear pseudo-inclusions and occasional nuclear grooves (Papanicolaou stain X 400).

Caption: Figure 2a. Cell block from FNA showing numerous complex papillary fragments demonstrating true fibrovascular cores (H & E stain X 200).

Caption: Figure 2b. Immunohistochemical stain on cell block showing diffuse nuclear positive staining for TTF-1 (TTF-1 stain X 200).

Caption: Figure 2c. Immunohistochemical stain on cell block showing cytoplasmic positive staining for Napsin-A (Napsin A X 200).

Caption: Figure 2d. Immunohistochemical stain on cell block showing negative staining for Thyroglobulin (Thyroglobulin stain X 200).

Caption: Figure 3a. Lung core biopsy showing complex papillary fragments demonstrating true fibrovascular cores predominantly (H & E stain X 200)

Caption: Figure 3b. Immunohistochemical stain on core biopsy showing diffuse nuclear positive staining for TTF-1 (TTF-1 stain X 200).

Caption: Figure 3c. Immunohistochemical stain on core biopsy showing cytoplasmic positive staining for Napsin-A (Napsin A X 200).

Caption: Figure 3d. Immunohistochemical stain on core biopsy showing negative staining for Thyroglobulin (Thyroglobulin stain X 200).
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Title Annotation:CASE STUDY
Author:Lallu, Sharda; Naran, Sarla; Bethwaite, Peter
Publication:New Zealand Journal of Medical Laboratory Science
Date:Nov 1, 2018
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