Bronchioloalveolar carcinoma (BAC) arising in a type 1 congenital cystic adenomatoid malformation (CCAM) Dr. Andrew G Nicholson Department of Histopathology, Royal Brompton Hospital London, UK

Clinical History: Male patient presented with an infected intrapulmonary cyst in 1995, aged 11, reported as an infected bronchogenic cyst. He subsequently presented, aged 19, with further chest sepsis and underwent lobectomy. Representative slide is from the lobectomy. Patient is alive and symptom free at 3 years after operation. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Diagnosis Bronchioloalveolar carcinoma (BAC) arising in a type 1 congenital cystic adenomatoid malformation (CCAM) Carcinomas complicating cystic disease in the lungs are rare but well described in the literature and, although some such lesions are now thought to be cystic tumours, there are undoubtedly cases of carcinomas reported in relation to pre-existent cysts, mainly type 1 CCAMs. [1, 2, 3] Most of these are adenocarcinomas of mucinous bronchioloalveolar type although other subtypes of lung carcinoma have also been reported. [4] The aetiology of these malignancies is unknown, although goblet cell hyperplasia without evidence of malignant transformation has been reported seen in type 1 adenomatoid malformations in about one third of cases, this 'mucinous hyperplasia' proposed as a possible premalignant phase. [1] Atypical adenomatous hyperplasia is also described in adjacent parenchyma, suggesting there may be a genetic instability within the disordered parenchyma. [3] The incidence of malignant transformation is estimated at 1%. BACs in CCAMs may present with new symptoms on a background of cystic disease, asymptomatic radiographic changes or may be identified at the time of resection as an occult finding. Patients present at a younger age than those with BACs arising 'de novo', [1, 2, 3] although most present in adulthood. There is no association with smoking. Cysts are usually solitary and greater than 2cm in size, although they may be multiloculated. Lung parenchyma affected by carcinoma comprises areas of mucoid consolidation although the tumour is usually first noted microscopically. Type 1 CCAMs, as defined by Stocker, show cystic airspaces lined by respiratory-type epithelium, with the intervening parenchyma often underdeveloped in terms of alveolar density. [5] Mucinous hyperplasia may often be seen within the cysts, but a diagnosis of bronchioloalveolar carcinoma has historically only made when there was extension of the cellular proliferation beyond the wall of the cyst, i.e. when the histologic features are identical to those of bronchioloalveolar carcinoma arising 'de novo'. The tumour cells are usually extremely bland in cases associated with cysts, but there is no statistically significant difference in either proliferation rates or p53 expression between bronchioloalveolar carcinomas arising in cysts and those arising 'de novo'. [3] However, both intracystic and intra-alveolar areas of mucinous proliferation have been shown to contain K-ras mutation and LOH and/or microsatellite instability at the p16 locus, displaying similar molecular abnormalities and differentiation profiles to those in mucinous BAC 'de novo', indicating that the intracystic mucinous proliferations in type 1 CCAM may be precursors to BAC (unpublished data). Gains in chromosomes 2 and 4 have also been reported in areas of intra-alveolar mucinous proliferation and metastatic disease is occasionally seen, [2, 6] indicating that classification as carcinoma is justified. With regard to treatment, any clinical or radiographic changes in a pre-existent cyst should be aggressively investigated and some investigators advocate elective excision of all congenital cysts after two years of age, though this is more related to the risk of infective complications than the likelihood of malignant transformation. [7] Of those cases that have been resected, only occasional cases have shown metastases beyond the lung. [2, 6] There is also one report of a mucinous BAC arising in the left lower lobe of a 19 year-old man, the patient having had an adenomatoid malformation resected from this lobe in infancy, [8] a history not dissimilar to this case. These lesions therefore have an excellent prognosis, although most of these tumors are small and well localized, akin to the types A and B small adenocarcinomas described by Noguchi et al. [9] which have 100% 5-year survival. Therefore, a low incidence of recurrent disease for bronchioloalveolar carcinoma associated with a congenital cystic adenomatoid malformation1 is perhaps to be expected. [3] Finally, it should be noted that, as well as tumours arising in cysts, neoplasms can cause cystic change both as a secondary feature, in both primary (eg MALT lymphoma, sclerosing haemangioma) and secondary low-grade neoplasms (metastatic sarcomas, [10] low-grade stromal sarcoma [11] and metastatic cellular fibrous histiocytoma [12] and benign metastasizing leiomyoma) or as an integral part of the tumour (pleuropulmonary blastoma). These latter cases overlap histologically with type 4 CCAMs and likely represent published cases of sarcomas, in particular rhabdomyosarcomas, arising in pre-existent lung cysts. [3, 5, 13, 14] References Sheffield EA, Addis BJ, Corrin B, McCabe MM. Epithelial hyperplasia and malignant change in congenital lung cysts. J. Clin. Pathol. 1987;40;612-614. Prichard MG, Brown PJ, Sterrett GF. Bronchioloalveolar carcinoma arising in longstanding lung cysts. Thorax 1984;39;545-549. 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