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Pathology International 2014; 64: 352–357

doi:10.1111/pin.12179

Case Report

Ciliated muconodular papillary tumor of the lung: A newly defined peripheral pulmonary tumor with conspicuous mucin pool mimicking colloid adenocarcinoma: A case report and review of literature

Hao-Wen Chuang,1 Jia-Bin Liao,1 Huang-Chou Chang,2 Jyh-Seng Wang,1 Shong-Ling Lin1 and Pin-Pen Hsieh1 Departments of 1Pathology and Laboratory Medicine and 2Division of Thoracic Surgery, Department of Surgery, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan

We report the case of a 68-year-old man with a newly defined rare entity of a peripheral pulmonary tumor, consisting of a nodular papillary lesion with papillary structures containing ciliated columnar and goblet cells, as well as floating tumor cells in the mucin pool. The conspicuous mucin pool was observed to be mimicking colloid adenocarcinoma in a lowpower view, particularly in a frozen section slide. We originally reported it as an adenocarcinoma during intraoperative consultation. Immunohistochemically, the tumor cells exhibited a similar immunophenotype to pulmonary adenocarcinoma, except for the presence of focal ciliated and basaloid cells, which we found using CK5/6 and P63 immunostaining. No KRAS or EGFR mutation was found. We revised the diagnosis to that of a ciliated muconodular papillary tumor (CMPT). Four years after a wedge resection, the patient remained free of tumors. Although the malignant potential of CMPT cannot be ignored, a wedge resection with a safe margin might be a treatment option for CMPT patients. Key words: ciliated muconodular papillary tumor, colloid adenocarcinoma, glandular papilloma, wedge resection

Lung tumors with ciliated cells are considered benign, and most of these tumors occur in the central airway.1 Ciliated muconodular papillary tumors (CMPTs),2–5 newly defined and distinct peripheral lung neoplasms, are indicated by ciliated columnar epithelial cells and considered low-grade malignant tumors. An extremely well-differentiated adenocarcinoma6 and solitary glandular papilloma of the peripheral lung7,8 have

Correspondence: Pin-Pen Hsieh, MD, Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung City 813, Taiwan. Email: [email protected] Received 19 December 2013. Accepted for publication 5 June 2014. © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd

been reported as peripheral lesions with ciliated cells, with pathological findings similar to CMPTs. These small borderline lesions with ciliated cells can pose diagnostic and therapeutic problems, and may become more frequently detected with the increasing availability of the thin-section computed tomogram (CT). This case study reports a CMPT case, with potential diagnostic pitfalls in the frozen section because of the mucin pool mimicking colloid adenocarcinoma. CLINICAL SUMMARY A 68-year-old man had history of hypertension under medication control. The patient also had smoking history for more than 10 years, but had quit 5 years previously. He felt anterior chest wall discomfort and followed up regularly at the outpatient department (OPD). Other signs and symptoms were not noted. Despite negative findings on the chest X-ray, a chest CT revealed a solitary ground-glass nodule exhibiting a solid part of approximately 7 mm at the superior segment of the peripheral right lower lobe (Fig. 1a). Based on regular follow-ups at OPD for 5 months, the chest CT showed no interval changes in the lesion, and no other findings of interstitial lung disease, such as reticular opacity. Neither lymphadenopathy nor metastatic lesions in other organs were noted during imaging and physical examinations. However, the symptom of the anterior chest wall discomfort still remained. Primary lung cancer was impressed with a differential diagnosis of infectious granuloma and other benign lesions. Hence, he was admitted for surgical intervention. During operation, the frozen section slide was reported as adenocarcinoma due to the histological pictures mimicking colloid adenocarcinoma. Afterward, wedge resection with a safe margin was performed because the surgeon favored it as a benign lesion because of there being no interval change shown in CT scans for 5 months.

CMPT of lung mimicking CA

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PATHOLOGICAL FINDINGS

Figure 1 (a) Chest CT showed a solitary ground glass nodule with solid part about 7 mm at the peripheral region of superior segment of right lower lobe. (b) A well-demarcated whitish tumor in the peripheral region of right lower lobe.

The macroscopic examination of the resected specimen showed a well-demarcated whitish tumor in the peripheral region of the right lower lobe of the lung, 1.2 × 0.9 × 0.8 cm in size (Fig. 1b). The histological examination revealed a nodular papillary tumor, composed of ciliated cells and nonciliated columnar cells, goblet cells, and basaloid cells, in a mucin pool. Nuclear atypia was mild and mitosis was not found. We observed mucin production in this tumor, with the mucin pool in the tumor and surrounding alveolar spaces, and spreading focally to adjacent alveolar spaces. Some tumor cells were floating into the mucin pool. Calcification was noted focally, too (Fig. 2a–d). Immunohistochemically, the tumor cells stained focal positive for carcinoembryonic antigen (CEA; clone CEA, DakoCytomation, Glostrup, Denmark), thyroid transcription factor-1 (TTF-1; clone SPT24, Novocastra Laboratories Ltd, Newcastle Upon Tyne, United Kingdom) (Fig. 3a), epithelial membrane antigen (EMA; clone E29, DakoCytomation), and cytokeratin 7 (CK7; clone OV-TL 12/30, Genemed Biotechnologies, San Francisco, CA, USA) (Fig. 3b). On the other hand, tumor cells stained negative for cytokeratin 20 (CK20; clone Ks20.8, Genemed Biotechnologies). Basaloid cells were also revealed by P63 (clone 4B1E12, Invitrogen Corporation, Camarillo, CA, USA) (Fig. 3c) and cytokeratin 5/6 (CK5/6; clone D5/16B4, Genemed Biotechnologies) (Fig. 3d) in most areas of this papillary tumor. However, the Ki67 (clone MIB-1, DakoCytomation) proliferative index and P53 (clone DO7, Novocastra Laboratories Ltd) both had less than 1% of positively stained cells. The presence of ciliated cells and

Figure 2 (a) An irregular-shaped papillary tumor proliferating along the alveolar walls and surrounded by mucin pool. The adjacent lung parenchyma showed no inflammatory changes, pneumocyte hyperplasia, or fibrosis and no other abnormalities. (hematoxylin and eosin (HE) stain, 10X). (b) Tumor cell nests floating in the mucin pool and spreading to the adjacent alveolar space (HE stain, 40X). (c) The tumor showed papillary structures, lined with ciliated and non-ciliated columnar cells, goblet cells, and basaloid cells (HE stain, 100X). (d) Compared with adjacent normal bronchiole (inset), the epithelium in CMPT was a stratified ciliated epithelium with basaloid cell and goblet cell proliferation (HE stain, 400X). © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd

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Figure 3 The tumor showed TTF1 positive staining in some basaloid cells and negative staining in goblet cells (a; 400X). The epithelium was diffusely positive for CK7 (b; 200X) immunostain. Basaloid cells were shown by P63 (c; 200X) and CK5/6 (d; 200X) immunostains in most areas of this tumor.

Table 1

Primer pairs used in this study

Target

Primer sequences

KRAS

exon 2

EGFR

exon 18 exon 19 exon 20 exon 21

F R F R F R F R F R

5′-CTG AAA ATG ACT GAA TAT AAA CTT GT-3′ 5′-ATA TGC ATA TTA AAA CAA GAT TTA CC-3′ 5′-GGC TGA GGT GAC CCT TGT CTC T-3′ 5′-AGC TTG CAA GGA CTC TGG GCT C-3′ 5′-TGT GGC ACC ATC TCA CAA TTG CC-3′ 5′-AGA GCA GCT GCC AGA CAT GAG A-3′ 5′-TCA CCT GGA AGG GGT CCA TGT G-3′ 5′-AGA CCG CAT GTG AGG ATC CTG G-3′ 5′-CCC TGA ATT CGG ATG CAG AGC TTC-3′ 5′-CTG GTG TCA GGA AAA TGC TGG CTG-3′

EGFR, epidermal growth factor receptor; F, forward primer; KRAS, Kirsten Ras; R, reverse primer.

basaloid cells distinguished this tumor type from invasive adenocarcinoma, such as colloid adenocarcinoma and invasive mucinous adenocarcinoma. However, the possibility of a malignancy cannot be completely excluded because of the presence of an abundant mucin pool with surrounding alveolar wall destruction and floating tumor cells outside the main muconodule, and the loss of TTF-1 staining in goblet cells. The morphology and immunophenotype were identical to those in CMPT. Molecular studies for KRAS and EGFR were performed on this tumor.9,10 The tumor DNA was extracted from parrafin-embedded tissue by using DNA extraction kits (QIAamp DNA Mini kit, QIAGEN, Hilden, Germany), and primer pairs (Table 1) were used to amplify the complete coding sequences of KRAS exon 2 and EGFR exon 18, exon 19, exon 20, and exon 21. Polymerase chain reaction (PCR) was performed in a 25 μL volume containing 100 ng of template DNA, 2 × PCR buffer, 0.25 mM deoxynucleoside triphosphate (dNTP), 10 pmol primers, and 1.25 U Taq DNA polymerase (GenScript, Piscataway, NJ, USA). The PCR

products were electrophoresed on 2% agarose gels, which were purified and directly sequenced using the BigDye Terminator v3.1 cycle sequencing kit, followed by an analysis using an Applied Biosystems 3700 automated sequencer (Applied Biosystems, Foster City, CA, USA). No mutations were shown at KRAS exon 2, including codons 12 and 13, and EGFR exons 18, 19, 20, and 21.10,11 The postoperative course was uneventful, and neither local recurrence nor distant metastasis was found during a 4-year follow-up.

DISCUSSION Ciliated muconodular papillary tumor was first proposed by Ishikawa2 as a new entity, characterized as a papillary tumor of the peripheral lung, consisting of ciliated columnar and goblet cells, and possessing some pathological features suggesting malignant potential, such as destroyed alveolar structures and central fibrosis, proliferation along the alveolar walls and skip lesions as seen in adenocarcinoma in situ, and no encapsulation.2–5 Immunohistochemical studies presented in previously reported cases and ours have shown positive results for CK 7, as well as focal-positive results for CEA and TTF-1 but not for CK 20; these findings are similar to those observed for adenocarcinoma.4 Park et al.12 recently proposed the concept of non-terminal respiratory unit type adenocarcinoma, arising through mucous columnar cell change. Although CMPT does not fulfil the criteria of ciliated adenocarcinoma, it exhibits features of a precursor lesion, as mentioned by Park et al., including goblet (mucous) cell metaplasia and the loss of TTF-1 staining in goblet cells. Based on these findings, the malignant potential of CMPT

© 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd

CMPT of lung mimicking CA

Table 2

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Summary of clinical, immunohistochemical, and molecular findings of previously reported and present cases of CMPT Ishikawa2

Author Age/Gender Smoking Location CT finding

50F + RUL Nodule

Size (mm)

IHC

Mutation status Treatment Follow-UP

CEA TTF-1 Ki67 CK7 CK20 EMA (MUC1) MUC5AC CK5/6 P63 P53 HPV EGFR KRAS

15 + n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a Lobectomy 10 yr NED

Harada3

Sato4

Hata5

Present case

62M + LLL Irregular-shaped nodule 9 + − + + − n/a − n/a n/a n/a − n/a n/a Partial resection 2 yr NED

67M + RUL Nodule with GGO 8 + + + (10%) + − + + n/a n/a n/a n/a n/a n/a Partial resection 10 mo NED

59F − RLL GGO with cavity 5 + + +(3%) + − + − n/a n/a n/a n/a n/a n/a Partial resection 1 yr 6 mo NED

76F n/a LUL Irregular-shaped nodule 7 n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a NM n/a Lobectomy 24 mo NED

68M +† RLL Ground- glass nodule 12 + (focal) +‡ + (

Ciliated muconodular papillary tumor of the lung: a newly defined peripheral pulmonary tumor with conspicuous mucin pool mimicking colloid adenocarcinoma: a case report and review of literature.

We report the case of a 68-year-old man with a newly defined rare entity of a peripheral pulmonary tumor, consisting of a nodular papillary lesion wit...
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