396

The Korean Journal of Pathology2008; 42: 396-400

Malignancies in congenital cystic adenomatoid malformations (CCAMs) of the lung are rare.We report a 41-year-old male patient with a pulmonary cystic lesion suspicious for CCAM,unrecognized until the patient was 40 years of age, and which subsequently became moreconsolidated during the interval between initial presentation and surgery. Microscopic exami-nation of the resected specimen revealed features of type 1 CCAM with a mucinous adeno-carcinoma, metastatic to the mediastinal lymph nodes. This case illustrates the importance ofprompt surgical resection for all suspected CCAMs, especially those discovered in adulthood.

Key Words : Congenital cystic adenomatoid malformation; Adenocarcinoma

Jinyoung Yoo∙∙Sun Mi LeeJi Han Jung∙∙Myeong Im Ahn1

Deog Gon Cho2∙∙Seok Jin KangKyo Young Lee

396

Adenocarcinoma Arising in Type 1 Congenital Cystic Adenomatoid

Malformation: A Case Report and Review of the Literature

396 396

Corresponding AuthorSeok Jin Kang, M.D.Department of Pathology, St. Vincent’s Hospital, TheCatholic University of Korea, 93 Ji-dong, Paldal-gu,Suwon 442-723, KoreaTel: 031-249-7591Fax: 031-244-6786E-mail: sjkang@vincent.cuk.ac.kr

Departments of Pathology, 1DiagnosticRadiology, and 2Thoracic Surgery, St.Vincent’s Hospital, The Catholic University of Korea, Suwon, Korea

Received : July 2, 2008Accepted : September 9, 2008

Malignancies in congenital cystic adenomatoid malformations(CCAM) are rare with a reported incidence of less than 1%.1,2

Bronchioloalveolar carcinoma (BAC) arising in type 1 CCAMwas first described in 1953, and to the best of our knowledge,only 16 cases of CCAM with malignant change have been report-ed since that time in the English literature.3,4 They usually occurin adults whose CCAMs have not been resected in childhood.We report a case of adenocarcinoma in association with a pre-existing type 1 CCAM, probably aggravated during the timeof surgical delay.

CASE REPORT

A 41-year-old man was admitted to the Department of Tho-racic Surgery for surgical excision of a suspected CCAM in thelung. The lesion had first been detected 17 months earlier, whenthe patient had been evaluated for a rib fracture following a traf-fic accident. Computed tomography (CT) at that time showed

a 7.0×4.4×3.2 cm sized lesion in the medial basal segment ofthe right lower lobe. It consisted of multiple small air cysts andexhibited mild enhancement, suggesting an infected cystic lunglesion such as an adult CCAM (Fig. 1A). The patient had beenvisiting a local clinic for copious sputum production for theprevious 2 years, but he was otherwise well. Conservative treat-ment was implemented for his rib fracture, while surgical exci-sion was advised for the lung lesion. However, the patient waslost to follow-up.

Nine months later, he was diagnosed with stomach cancerbased on gastroendoscopic biopsy. Billroth II subtotal gastrec-tomy demonstrated a poorly differentiated tubular adenocarci-noma, limited to the mucosa (T1aN0M0) (Fig. 2). The patientrecovered well and received oral chemotherapy. However, hiscarcinoembryonic antigen (CEA) level remained elevated. On afollow-up CT scan, the lung lesion showed increased size (7.5×5.1×4.0 cm) and greater consolidation (Fig. 1B). The patientunderwent a right lower lobectomy with subsequent dissectionof multiple calcified mediastinal lymph nodes. Grossly, the spec-

Adenocarcinoma in Adult CCAM 397

imen had a relatively solid area (70%) with poorly preservedhemorrhagic cystic spaces (Fig. 3). Cystic changes were foundin the periphery of the lobe. Histologically, the cysts were linedby pseudostratified ciliated columnar cells with underlyingfibrous tissue and smooth muscle, but scant cartilage. This wasconsistent with a type 1 CCAM, based on Stocker’s classifica-tion (Fig. 4A).5 The bulk of the lesion consisted of tall colum-nar mucosecretory epithelial cells in bronchioloalveolar and solidpatterns, with mucin production, consistent with adenocarci-noma, mixed subtype (Fig. 4B, C). Although the transition frombland columnar epithelial cells to atypical cells was indiscernible,

the cysts adjacent to the typical CCAM demonstrated adeno-carcinoma involvement (Fig. 4D). Tumor cells were positive forthyroid transcription factor-1 (TTF-1) and cytokeratin 7 (CK7),but negative for cytokeratin 20 (CK20). However, patients withgastric adenocarcinoma have a TTF-1 negative, CK7 negative,and CK20 negative immunophenotype (Fig. 5). The mediasti-nal lymph nodes showed extensive metastasis. The patient wasdischarged from the hospital after an uneventful post-operativecourse, and he has been on chemotherapy with no recurrenceduring one year of follow-up.

A B

Fig. 1. Coronal reconstruction images of the initial chest CT scans demonstrate air-cysts with internal fluid in the right lower lobe, sugges-tive of an adult form of CCAM with inflammation (A). Seventeen months after the initial scan, the lesion was increased in size and virtuallyreplaced by fluid and consolidation (B).

Fig. 2. Gastric biopsy reveals poorly differentiated tubular adeno-carcinoma in the mucosa.

Fig. 3. Gross photograph shows a large well-circumscribed lesion,composed of hemorrhagic spaces and tan white solid glisteningcomponents.

398 Jinyoung Yoo∙Sun Mi Lee∙Ji Han Jung, et al.

C D

A B

Fig. 4. The cysts are lined by ciliated pseudostratified columnar epithelium with underlying fibrous tissue and smooth muscle, consistentwith type1 CCAM. Notice the interspersed goblet cells (A). The solid area reveals mucinous bronchioloalveolar carcinoma (B) and ade-nocarcinoma with mucin production (C). Malignancy (*) is noted adjacent to the CCAM cysts (**) (D).

Fig. 5. On immunohistochemical staining, the gastric cancer is TTF-1(-)/CK7(-)/CK20(-) (A), while the lung carcinoma is TTF-1(+)/CK7(+)/CK20(-) (B).

TTF-1 CK7 CK20

A

TTF-1 CK7 CK20

B

Adenocarcinoma in Adult CCAM 399

DISCUSSION

CCAM is characterized by anomalous fetal development ofthe small airways and distal lung parenchyma, which leads toan adenomatoid proliferation of terminal respiratory structuresand cyst formation.6 Most CCAMs are diagnosed and managedwithin the first two years of life. In rare instances, however, suchlesions may remain unrecognized until adulthood. Althoughfrequently complicated by recurrent infection,3 adult CCAMsmay be asymptomatic. Hence, they may be detected only inci-dentally on routine chest radiography or during a study of anon-pulmonary lesion, as in the present case. Our patient hadsought medical attention for his copious sputum. However, hehad never undergone a radiologic examination until he sufferedribs fractured in a traffic accident.

A few patients with (or history of) CCAMs have developedcarcinomas, usually mucinous BACs.1,7 This has led to the sus-picion of the potential for malignant transformation in CCAMs.Our case demonstrated mucinous BAC, invasive carcinoma,and features of a type 1 CCAM in the residual cysts. Along withthese histological features, the sequential progression of imag-ing abnormalities provides evidence for tumor development inthe setting of CCAM. Mani et al.3 documented a type 1 CCAMwith a full spectrum of precursor (atypical adenomatous hyper-plasia) and neoplastic lesions (BAC and invasive adenocarcino-ma), suggesting the predisposition of type 1 CCAMs towardmalignancy. Lantuejoul et al.8 recently noted loss of heterozy-gosity on analysis of microsatellite alterations and direct sequenc-ing polymerase chain reaction for molecular studies in sevencases of type 1 CCAM with associated mucinous proliferation.The mucinous cells were found to share the same differentiationprofile with the corresponding mucinous BAC cells, thus justi-fying their consideration as BAC precursors. An earlier study of22 CCAMs also revealed gains in chromosomes 2 and 4 in bothatypical goblet cell hyperplasia and carcinoma, but not in res-piratory-type surface epithelium or surrounding normal lungtissue. This supports the pre-neoplastic status of goblet cell pro-liferation in CCAM.2

All 16 cases of type 1 CCAM-related malignancies previous-ly reported in the medical literature were BACs, exclusivelymucinous type, with or without invasive carcinoma (5 includ-ing the present case vs. 12).1,3,9 Most patients (11/17, 65%) wereadults. Of the five children with available follow-up, one diedof disease at 15 years of age, and four were free of disease for aperiod ranging from 18 months to 16 years. Of the six adultpatients with available follow-up, one died of disease at 4 years,

and five were free of disease for 3 months to 4 years. There aretoo few such cases to characterize the differences in prognosisbetween pediatric and adult patients. However, the age at diag-nosis ranged from 6 months to 60 years, with a mean age of25.2 years, which is much younger compared to the mean ageof BAC diagnosis in the general population (59 years).10 Thissupports the fact that carcinoma associated with type 1 CCAMusually occurs in adults whose CCAMs have not been resectedin childhood. We reported a case of type 1 CCAM that eventu-ally developed metastatic adenocarcinoma during the surgicaldelay, in order to emphasize the importance of prompt surgicaltreatment for adult CCAMs. These lesions should be resectedas soon as possible to prevent malignant change and progres-sion to invasion.

REFERENCES

1. MacSweeney F, Papagiannopoulos K, Goldstraw P, Sheppard MN,

Corrin B, Nicholson AG. An assessment of the expanded classifica-

tion of congenital cystic adenomatoid malformations and their

relationship to malignant transformation. Am J Surg Pathol 2003;

27: 1139-46.

2. Stacher E, Ullmann R, Halbwedl I, et al. Atypical goblet cell hyper-

plasia in congenital cystic adenomatoid malformation as a possible

preneoplasia for pulmonary adenocarcinoma in childhood: a genet-

ic analysis. Hum Pathol 2004; 35: 565-70.

3. Mani H, Shilo K, Galvin JR, Stocker JT, Franks TJ. Spectrum of pre-

cursor and invasive neoplastic lesions in type 1 congenital pul-

monary airway malformation: case report and review of the litera-

ture. Histopathology 2007; 51: 561-5.

4. Korol E. The correlation of carcinoma and congenital cystic emphy-

sema of the lungs: report of ten cases. Dis Chest 1953; 23: 403-11.

5. Stocker JT, Madewell JE, Drake RM. Congenital cystic adenoma-

toid malformation of the lung: classification and morphologic spec-

trum. Hum Pathol 1977; 8: 155-71.

6. Morelli L, Piscioli I, Licci S, Donato S, Catalucci A, Del Nonno F.

Pulmonary congenital cystic adenomatoid malformation, type I,

presenting as a single cyst of the middle lobe in an adult: case report.

Diagn Pathol 2007; 2: 17.

7. Benjamin DR, Cahill JL. Bronchioloalveolar carcinoma of the lung

and congenital cystic adenomatoid malformation. Am J Clin Pathol

1991; 95: 889-92.

8. Lantuejoul S, Nicholson AG, Sartori G, et al. Mucinous cells in type1

pulmonary congenital cystic adenomatoid malformation as muci-

nous bronchioloalveolar carcinoma precursors. Am J Surg Pathol

400 Jinyoung Yoo∙Sun Mi Lee∙Ji Han Jung, et al.

2007; 31: 961-9.

9. West D, Nicholson AG, Colquhoun I, Pollock J. Bronchioloalveolar

carcinoma in congenital cystic adenomatoid malformation of lung.

Ann Thorac Surg 2007; 83: 687-9.

10. Barsky SH, Cameron R, Osann KE, Tomita D, Holmes EC. Rising

incidence of bronchioloalveolar carcinoma and its clinicopatholog-

ic features. Cancer 1994; 73: 1163-70.