What caused this patient's cough and mild hemoptysis?

The case

A 64-year-old woman presented with a 6-month history of nonproductive cough and 2 episodes of mild hemoptysis.¹ She denied fever, weight loss, dyspnea, and chest pain. She had no significant medical history and did not take medication. She was a lifelong nonsmoker and denied any occupational exposure or contact with sick persons.

On physical examination, her blood pressure was 129/78 mm Hg, heart rate was 72 beats per minute, respiration rate was 18 breaths per minute, and oxygen saturation measured by pulse oximetry was 97% on room air. She appeared healthy and was in no acute distress.

Examination of the head and neck revealed no lymphadenopathy or jugular venous distention. Cardiac examination revealed normal heart sounds. Decreased breath sounds and dullness to percussion over the left upper hemithorax were noted on lung examination. There was no digital clubbing or peripheral edema. Findings from the rest of the physical examination were unremarkable.

A chest radiograph revealed a large, well-demarcated left upper lobe density (Figure 1). A nonenhanced helical CT scan demonstrated a large left upper lobe heterogeneous mass with no evidence of mediastinal adenopathy (Figure 2). A CT-guided transthoracic core biopsy yielded abundant mucin with rare atypical epithelial cells. Inconclusive biopsy results and the persistence of symptoms warranted surgical resection.

During surgery, significant adhesions were noted; a left pneumonectomy was performed for complete removal of the tumor (Figure 3). This well-circumscribed, spherical tumor, measuring 8 3 8 3 6 cm, was located in the posterior superior segment of the left upper lobe. Surgical margins were free of tumor, and results of lymph node sampling were negative.

Microscopic evaluation revealed large cysts filled with mucin and lined with atypical columnar epithelium with areas of invasion of lung parenchyma (Figure 4). A diagnosis of mucinous cystadenocarcinoma was made.

Discussion

Mucinous pulmonary cysts usually represent degeneration of fairly common tumors, such as mucinous adenocarcinoma and bronchioloalveolar carcinoma. Mucinous cystadenocarcinoma, however, is a rare type of pulmonary cancer that belongs to a group of tumors characterized by copious mucin production (Table).

These lung tumors, first described in 1978, were the subject of debate among pathologists and received various designations in the literature.² Some considered them a spectrum of the same lesion with different degrees of invasiveness; others denied their existence, classifying them as bronchioloalveolar carcinoma.

Mucinous cystadenocarcinoma was first proposed as a distinct entity by Devaney and colleagues³ in 1989. In 1999, the World Health Organization classified these tumors into 3 distinct entities: mucinous adenoma, mucinous carcinoma, and mucinous cystadenocarcinoma. According to this classification, mucinous cystadenocarcinoma is a "cystic adenocarcinoma with copious mucin production resembling tumors of the same name in the ovaries, breast, and pancreas."⁴ Although this definition does not completely resolve the confusion, it provides some guidance for the pathologist.

Symptoms of pulmonary mucinous cystadenocarcinoma are usually mild and include cough, chest pain, and weight loss.⁵ Some patients are asymptomatic. Mucinous cystadenocarcinoma occurs in both smokers and nonsmokers and does not have a gender or lobar predilection.⁵ On radiographs, the tumor is difficult to distinguish from benign cysts of the lung, and its indolent growth and benign behavior further confuse the picture.

The cystic nature of this tumor is usually apparent on a CT scan, which typically reveals a low-attenuation, well-demarcated peripheral cystic mass. The presence of an enhancing wall on a contrast CT scan corresponds pathologically to the fibrous capsule surrounding the tumor and should raise suspicion of the diagnosis.⁶

A contrast CT scan may also reveal enhancing septa within the mass that correlate histologically with mucinous epithelium-lined septa.⁶ A mixed mucinous cystadenocarcinoma-bronchioloalveolar carcinoma tumor may show evidence of ground-glass attenuation that correlates with lepidic tumor growth, the histologic hallmark of bronchioloalveolar carcinoma. This finding is absent in a case of pure mucinous cystadenocarcinoma.

Grossly, mucinous cystadenocarcinoma appears as a well-demarcated cystic gelatinous mucoid mass. Tumors have ranged in diameter from 1 to 13 cm.⁵ Pathologically, this tumor is composed of cysts filled with copious amounts of extracellular mucus and is lined by a few columnar, mucin-producing cancer cells that show various degrees of atypia.

Mucinous cystadenocarcinoma has the distinct feature of containing a single group or sparse groups of cells suspended in pools of mucin or having invasive adenocarcinoma foci. The tumor is characterized by expansive growth resulting from a mucus pool that is secreted by cancer cells.

Mucinous carcinoma, a distinct entity since 1999,⁴ shows cytologic findings similar to those of mucinous cystadenocarcinoma, except that it resembles tumors of the "same name in the gastrointestinal tract."⁴ In addition, mucinous carcinoma usually lacks cystic changes, rarely appears multicystic, and usually does not contain the fi-brous capsule found in mucinous cystadenocarcinoma.⁶

Preoperative pathologic diagnosis of pulmonary mucinous cystadenocarcinoma is challenging and of low yield. Bronchoscopy is not helpful, even when the tumor is located endobronchially and when transbronchial biopsies are performed,⁷ because of the thick gelatinous consistency of the tumor and the scarcity of cancerous cells in an abundant mucinous background. The use of transthoracic fine-needle aspiration for preoperative diagnosis is also unsuccessful.⁷

When feasible, the treatment of choice for pulmonary mucinous cystadenocarcinoma is surgical resection. Although this tumor cytologically resembles mucinous bronchioloalveolar carcinoma, it seems to have a more favorable prognosis; even when the tumor is relatively large, disease-free survival of up to 6 years has been reported.⁶

As noted above, a criterion in the classification of mucinous cystadenocarcinoma is its resemblance to "tumors of the same name in the ovaries, breast, and pancreas." Even in the pancreas, mucin-producing neoplasms have been less clearly delineated than other types of neoplasms. Mucinous cystadenocarcinoma of the pancreas is rare, representing fewer than 1% to 2% of pancreatic neoplasms. It tends to occur in younger female patients; to have a relatively better prognosis; and to be more commonly located in the tail of the pancreas, making it more amenable to surgical resection.⁸

In the breast, mucinous cystadenocarcinoma is much rarer, with fewer than 10 cases reported in the literature.⁹ In the ovary, most malignant tumors are of the epithelial type, with mucinous tumors being a less common subtype.¹⁰

In considering the diagnosis, the most important task for the clinician is excluding an extrapulmonary site of origin. Metastasis seems unlikely in the case of a large, well-encapsulated single mass in the lung without obvious extrapulmonary disease; however, this possibility should always be ruled out.

Many studies have looked at the immunohistochemical profile of pulmonary mucinous cystic neoplasms as a group.² Results of these studies can be extrapolated to mucinous cystadenocarcinoma. Positive results of staining for cytokeratin 7 (CK7) and thyroid transcription factor-1 (TTF-1) further support the pulmonary origin of these tumors. In our patient, results of a workup for metastasis were negative and stain of the tumor was positive for CK7 and negative for TTF-1.

Outcome in this case

The patient showed no clinical evidence of recurrence more than 2 years after her surgery.

References:

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