Diverse histologic appearances in pulmonary mucinous cystic neoplasia: A case report
© Wynveen et al; licensee BioMed Central Ltd. 2008
Received: 02 July 2007
Accepted: 29 September 2008
Published: 29 September 2008
Primary pulmonary mucinous cystic neoplasia comprises a group of tumors, from benign cystadenoma to mucinous cystadenocarcinoma.
We report a case of primary pulmonary mucinous cystadenocarcinoma in a 75-year-old woman who was found to have a right hilar mass on a routine chest X-ray. A lobectomy was performed and the resection specimen revealed a multicystic mucinous tumor. Microscopically, the tumor was composed of confluent mucin-filled cystic spaces lined by columnar mucin-secreting cells which ranged from cytologically bland to moderately atypical with 'bronchioloalveolar pattern' invasion into the adjacent parenchyma. Immunohistochemically, tumor cells were positive diffusely for Cytokeratin 7, and focally for Cytokeratin 20 and Thyroid Transcription Factor-1.
This case highlights the continuous spectrum of pulmonary mucinous cystic neoplasia from benign mucinous cystadenoma to malignant mucinous cystadenocarcinoma, and the probable existence of a 'borderline' mucinous cystic tumor. Although molecular data are lacking to substantiate progression from benign to malignant in these neoplasms, the importance of recognizing the morphologic continuum lies in alerting pathologists to thoroughly examine specimens to rule out invasive foci in tumors with 'borderline' morphology.
Primary mucinous cystic tumors of the lung are rare neoplasms with a distinctly different histology from more commonly encountered pulmonary adenocarcinomas. Although these mucinous neoplasms are histologically similar to well recognized mucinous tumors of the ovary, pancreas and appendix, there has been considerable confusion in the literature with the use of various diagnostic terms, including some overlapping ones. These terms include mucinous cyst, mucinous cystadenoma, mucinous multilocular cystic carcinoma, pseudomyxomatous pulmonary adenocarcinoma, mucinous cystic tumor of low malignant potential, mucinous cystic tumor of borderline malignancy, mucinous cystadenocarcinoma, colloid carcinoma and signet ring cell carcinoma . They include diverse entities that span a spectrum of histologic changes and biologic behavior ranging from benign, to borderline and malignant. Using strict diagnostic criteria, pulmonary mucinous cystic neoplasia (PMCN) may be recognized as a distinct entity . Individual variation in tumor behavior occurs, that is not well predicted by histologic features. As a result, cases of 'borderline malignancy' have been reported with recurrence or metastases. Conversely, cases reported with microscopic foci of 'carcinoma' have been free of recurrence or metastases. This case illustrates the spectrum of histologic appearances in PMCN and the importance of recognizing them.
On pathological examination, the specimen consisted of resected right upper lobe of lung with attached superior segment of right lower lobe. The pleural surface showed a retracted, indurated area 4.5 × 3 cm close to the bronchus intermedius of the upper lobe. On sectioning, a 5.5 cm nodular cystic mass with a distinctly mucoid appearance (Figure 1B and 1C) was seen.
Primary mucinous cystic tumors of the lung are very rare. Following their initial description [2, 3], approximately 76 cases have been reported in the English literature [1, 4–10]. Clear-cut criteria for the diagnostic designation of PMCN are lacking, partly owing to the different terminologies that have been used to describe them . For example, the term 'mucinous or colloid' carcinoma has been used for tumors morphologically resembling mucinous cystic tumors [4, 11]. However, PMCN deserve to be a separate entity due to their unique morphology and clinical behavior that is different from other primary lung tumors. In line with this thinking, the World Health Organization (WHO) classifies mucinous cystadenocarcinoma and colloid/mucinous carcinoma separately . Mucinous cystadenocarcinoma is 'a circumscribed tumor that may have a partial fibrous capsule. Centrally there is cystic change with mucin pooling and the neoplastic mucinous epithelium grows along alveolar walls'. Mucinous (colloid) carcinoma, on the other hand, is described as a 'lesion identical to their counterparts in the gastrointestinal tract, with dissecting pools of mucin containing islands of neoplastic epithelium. The epithelium in such cases may be extremely well differentiated and sometimes tumor cells float within the pools of mucin'. Mucinous cystadenoma is defined as 'a localized cystic mass filled with mucin and surrounded by a fibrous wall lined by well-differentiated columnar mucinous epithelium'.
In a recent review , diagnostic criteria of PMCN have been proposed based on well-defined morphologic features including: 1) solitary, well-circumscribed tumors with a cystic gross appearance; 2) no evidence of carcinoma in situ in the bronchial mucosa; 3) mucin comprising greater than 90% of the tumor bulk; 4) neoplastic epithelial cells are mucin-producing and are found lining the fibrous wall or floating within mucin; and 5) no evidence of another primary mucinous malignant neoplasm. In this analysis, the presence of solid invasive areas and marked cytologic atypia, including prominent nuclear stratification, nuclear enlargement or high nuclear/cytoplasmic ratio, prominent nucleoli, and frequent mitoses, indicated malignancy. However, histologic features may not be very accurate in predicting progression. Three separate reports comprising five cases of mucinous cystadenocarcinoma demonstrated no evidence of recurrence or metastasis after a range of 1.5 to 6 years of follow-up [6–8]. Also, in a series of 11 cases of 'borderline' mucinous cystic tumors, all patients were alive and well after a mean follow-up of 4.7 years, despite the presence of microscopic foci of carcinoma in four cases . Conversely, distant metastasis has been reported in a case of a 'multilocular mucous cyst' in which seeding of the parietal pleura was noted at the time of surgery . Additionally, a case of local recurrence of a borderline mucinous cystic tumor after limited resection has also been reported , as has been a patient with late recurrence of mucinous cystadenoma .
The variation in biologic behavior, especially in the 'borderline' category, brings into question the necessity of having such a category for diagnostic purposes. In fact, the WHO classification does not recognize pulmonary borderline mucinous cystic tumor/mucinous cystic tumor with atypia as a distinct entity . However, the borderline category still has its uses as outlined below. First, recognition of borderline features within a tumor ensures adequate sampling of the lesion by pathologists so that histologically malignant foci are not missed. Secondly, clinicians are alerted to the need for close follow-up in such cases. Therefore, until molecular genetic lesions underlying this group of tumors are elucidated, borderline mucinous tumor should not be eliminated as a diagnostic category. In the current case, the existence of the full spectrum of benign, borderline and malignant histology within a single tumor suggests that these tumors may be analogous to type I ovarian tumors according to the model proposed by Shih and Kurman .
The differential diagnosis of PMCN includes mucous gland adenoma, mucoepidermoid carcinoma, mucinous bronchioloalveolar carcinoma and metastatic mucinous carcinoma. Mucous gland adenoma and mucoepidermoid carcinoma are both endobronchial lesions in contrast to the peripheral location of PMCN. Mucous gland adenoma exhibits cystically dilated mucin glands protruding into the bronchial lumen while mucoepidermoid carcinoma is composed of mucin-producing cells admixed with squamous and intermediate cells . A thorough clinical and radiologic evaluation is necessary to exclude a metastasis of mucinous carcinoma from another organ. The immunohistochemical profile in the current case consisted of strong diffuse positivity for CK7 and focal positivity for CK20, whereas TTF-1 was negative. Such an immunoprofile may be a source for diagnostic confusion. It is important to remember that CK20 positivity has been described in some types of primary pulmonary mucinous lesions . Differentiating pulmonary mucinous cystadenocarcinoma from mucinous bronchioloalveolar carcinoma may pose a challenge, especially in those unusual cases where necrosis leads to secondary cavitation or cyst formation in the latter. Necrosis is conspicuously absent in mucinous cystadenocarcinoma. Growth pattern is another differentiating feature. While PMCN are solitary, generally well circumscribed tumors, mucinous bronchioloalveolar carcinoma is diffuse and often bilateral, appearing grossly as an ill-defined lobar consolidation.
The optimal management of PMCN appears to be complete surgical excision by lobectomy. The role of adjuvant therapy is unclear, but likely limited. In our patient, the tumor was resected with clear margins and all 15 lymph nodes submitted for histological examination were negative for metastasis. Although our patient's prognosis is favorable, close long-term follow-up is clearly indicated.
In summary, we have reported a case of pulmonary mucinous cystadenocarcinoma which showed histologic changes extending from the benign to the malignant end of the spectrum. The pathologist's role in such cases lies in recognizing the entity, distinguishing it from other mucinous lesions in the lung and alerting the clinician to the probability of aggressive behavior in the presence of atypical 'borderline' histology and invasive foci.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.
The Institutional Review Board (IRB) has waived its right to grant approval to this study based on this being a single case report where no additional tests were done to enhance the potential academic or educational value of the publication.
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