Unusual Primary Malignant Lung Neoplasms

Introduction

A variety of uncommon or rare tumors develop in the lung, with incidence rates of 1 in 100,000 people or fewer. For this group of neoplasms, most published accounts take the form of case reports and small series. Given the unusual nature of these processes, it is likely that some examples will be classified as other, more common, types of neoplasms due to lack of familiarity with the entity or with its potential to develop in the lungs. This chapter will provide an overview of these tumors, recognizing that more information will undoubtedly become available with the growing availability of genetic and genomic data, which assist in tumor classification and prognostic assessment.

Salivary Glandlike Tumors

These entities represent a rare and distinctive group of neoplasms arising from the seromucinous glands of the trachea and bronchi. The majority of these tumors are of low malignancy, are centrally located, and share similar histologic features with their counterparts arising in the major salivary glands. The most common members of this category to occur as primary neoplasms of the lung are discussed in this chapter. Other histologic types of salivary glandlike tumors can also arise in the lung; case reports and small series of epithelial-myoepithelial carcinomas, acinic cell carcinomas, salivary duct carcinomas, hyalinizing clear cell carcinomas, myoepithelial carcinomas, and other related lesions can be found in the literature.

Mucoepidermoid Carcinoma

Mucoepidermoid Carcinoma—Fact Sheet

Definition

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Mucoepidermoid carcinoma is a malignant neoplasm composed of squamoid cells, mucin-producing cells, and cells of intermediate type

Incidence

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Less than 1% of lung neoplasms

Morbidity and Mortality

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Bronchial obstruction by the tumor can lead to pneumonia, bronchiectasis, and atelectasis
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Low-grade tumors are associated with low mortality
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For high-grade tumors, survival is similar to non-small cell lung carcinomas

Age Distribution

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Occur at any age from childhood to late adulthood

Clinical Features

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Symptoms include cough, hemoptysis, shortness of breath, fever, and pneumonia

Radiologic Features

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Centrally located solitary nodule
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Postobstructive pneumonia or atelectasis distal to the tumor

Prognosis and Therapy

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Sleeve resection or laser therapy is used for low-grade tumors and is usually curative
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Surgical resection and postoperative radiotherapy is used for high-grade tumors
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Low-grade tumors rarely metastasize to the lymph nodes
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High-grade tumors may metastasize to bone, liver, adrenals, and brain

Mucoepidermoid Carcinoma—Pathologic Features

Gross Findings

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Polypoid endobronchial mass usually originating in a lobar or segmental bronchus
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Cystic and/or solid appearance with mucus
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Infiltrative margins with necrosis and hemorrhage in high-grade tumors
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Postobstructive pneumonia, bronchiectasis, and atelectasis may be seen

Microscopic Findings

Low-Grade Carcinomas

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Mucus-filled cysts and solid areas
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The columnar cells lining the cysts show round, basally located nuclei with mild atypia and apical mucin-rich cytoplasm
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Solid areas are composed of squamoid and intermediate cells
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The stroma may be dense or hyalinized with calcification

High-Grade Carcinomas

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A solid squamoid and/or intermediate component usually predominates, with less evidence of cyst or gland formation
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Marked nuclear atypia and pleomorphism and high mitotic activity are typical
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Necrosis and hemorrhage can be present

Ancillary Studies

Immunohistochemical Features

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Tumor cells are positive for pancytokeratins and CK7
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Intermediate cells are positive for CK 34βE12, p63, and p40 (variable)
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Squamoid cells express CK5/6.
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CK20, TTF-1, and napsin A are negative

Genetic Characteristics

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Fusion gene CRTC1-MAML2 in low- and high-grade carcinomas

Pathologic Differential Diagnosis

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Mucous gland adenoma
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Adenosquamous carcinoma, squamous cell carcinoma, adenocarcinoma
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Metastatic mucoepidermoid carcinoma from the head and neck

Clinical Features

Mucoepidermoid carcinoma is an uncommon neoplasm representing less than 1% of lung tumors. These tumors may be observed in any age group, including children, in whom they are one of the more common bronchial tumors. Because most of these tumors occur endobronchially, symptoms are due to bronchial obstruction and include cough, hemoptysis, shortness of breath, fever, and pneumonia, but some patients are asymptomatic. There is no association with smoking.

Radiologic Features

Radiologically, mucoepidermoid carcinoma presents as a centrally located, solitary nodule, which is typically positive on a positron emission tomography (PET) scan. Parenchymal consolidation may be seen distal to the tumor.

Pathologic Features

Gross Findings

Mucoepidermoid carcinomas form endobronchial masses covered by bronchial mucosa that can have a smooth surface or can be focally ulcerated. They generally arise in the proximal bronchi or the trachea. The cut surface of the tumor has a cystic or solid appearance with abundant mucin. High-grade tumors are usually larger, have necrotic and hemorrhagic areas, and tend to infiltrate the lung parenchyma. The pulmonary parenchyma distal to the tumor may show secondary bronchiectasis and postobstructive pneumonia.

Microscopic Findings

Mucoepidermoid carcinomas are divided into low and high grades based on morphologic and cytologic features. Low-grade mucoepidermoid carcinomas show solid and cystic areas filled with mucus ( Fig. 28.1 ). The cysts are lined by columnar cells with small, basally located nuclei with little cytologic atypia and abundant mucin-rich cytoplasm. Mitoses are rare. The lumina are typically filled with mucin, and occasionally mucin spills into the surrounding stroma, stimulating a granulomatous reaction, calcification, and ossification. The solid areas are composed of squamoid and intermediate cells. Squamoid cells have dense cytoplasm and well-defined cell borders. The intermediate cells are smaller than the squamoid cells, round or oval, with eosinophilic cytoplasm and sometimes with perinuclear clearing. The stroma may be myxoid or fibrotic, sometimes with dense hyalinized material and calcification. A prominent lymphoplasmacytic infiltrate may be associated with the tumor. High-grade mucoepidermoid carcinomas show a predominance of solid areas composed of intermingled squamoid and intermediate cells. In addition, they are characterized by increased nuclear pleomorphism, high mitotic counts, and areas of necrosis and hemorrhage.

FIG. 28.1, Mucoepidermoid carcinoma. (A) This tumor forms a subepithelial mass in this bronchus. (B) Tumor cells form glands with microcystic spaces that are lined by cuboidal or columnar cells, and smaller numbers of squamoid cells are seen.

Ancillary Studies

Immunohistochemistry

These tumors stain with pancytokeratins and CK7 and are negative for CK20, thyroid transcription factor 1 (TTF-1), and napsin A. The intermediate cells are positive for cytokeratin 34βE12 and p63, and p40 is variably expressed. Cytokeratin 5/6 is positive in the squamoid component.

Genetic Characteristics

The fusion gene CRTC1-MAML2 is found in many low- and high-grade mucoepidermoid carcinomas and represents a diagnostic marker. It can be evaluated using a fluorescence hybridization in situ (FISH) break-apart probe. EGFR mutation has also been described in some cases.

Differential Diagnosis

Low-grade mucoepidermoid carcinomas differ from mucous gland adenomas by the presence of intermediate cells and squamous differentiation in the former. High-grade mucoepidermoid carcinomas must be differentiated from adenosquamous carcinomas. Features favoring high-grade mucoepidermoid carcinoma include an endobronchial growth pattern, lack of squamous cell carcinoma in situ in the surface epithelium, lack of individual cell keratinization and keratin pearl formation, and areas of low-grade mucoepidermoid carcinoma. TTF-1 and MAML2 rearrangement are also helpful for differentiating mucoepidermoid carcinoma (TTF1-negative, MAML2 rearrangement often present) from adenosquamous or adenocarcinoma of the lung (TTF-1 often positive, MAML2 rearrangement-negative). Metastasis from a mucoepidermoid carcinoma arising in the head and neck should also be excluded before classifying a mucoepidermoid carcinoma as a primary pulmonary neoplasm.

Prognosis and Therapy

The treatment and prognosis of these tumors are related to the histologic grade. Low-grade tumors appear to have an excellent prognosis, particularly in children, and very rarely metastasize to the lymph nodes. Tumors may be treated by sleeve resection or laser therapy, but lobectomy or pneumonectomy may be required. High-grade tumors are treated with surgical resection and may receive postoperative radiotherapy. They behave more aggressively; prognosis is related to the clinical staging at the time of the diagnosis.

Adenoid Cystic Carcinoma

Adenoid Cystic Carcinoma—Fact Sheet

Definition

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Malignant epithelial and myoepithelial cell tumor similar to its counterpart arising in the salivary glands, with characteristic cribriform and tubular arrangements of tumor cells

Incidence

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Less than 1% of malignant tumors of the lung

Morbidity and Mortality

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With advanced disease, death is often due to widespread metastases
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Postobstructive pneumonia is a frequent complication

Age Distribution

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Most frequently diagnosed in the fifth decade

Clinical Features

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Symptoms are usually related to bronchial obstruction (cough, hemoptysis, wheezing)

Radiologic Features

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Solitary, centrally located mass, often with an endobronchial component or a diffuse wall thickening

Prognosis and Therapy

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Prognosis depends on the clinical stage at presentation
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Well-demarcated endobronchial neoplasms have a long survival, up to 15 years
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Recurrences are common, and late metastasis occurs
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Surgical resection is the treatment of choice

Adenoid Cystic Carcinoma—Pathologic Features

Gross Findings

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Well-circumscribed, endobronchial, polypoid masses in large airways
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Less often, annular lesions with thickening of the airway walls

Microscopic Findings

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Uniform epithelial cells with round nuclei and pale eosinophilic cytoplasm arranged in three main patterns: cribriform, tubular, solid
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In the cribriform and tubular patterns, the cells form nests, columns, or tubules around cystic spaces containing mucinous basophilic or eosinophilic PAS–positive basal lamina material
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In the solid pattern, the cells form islands without cystic spaces
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Low mitotic rate
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Perineural invasion and infiltration of the bronchial wall are common

Immunohistochemical Features

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Luminal cells express cytokeratins, CEA, and EMA
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Cells around pseudocysts stain with vimentin, S-100, actin, p63, and calponin
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Extracellular material is immunoreactive for type IV collagen, laminin, heparin sulfonate proteoglycan, and entactin
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Overexpression of C-kit (CD117)

Genetic Characteristics

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Reports of loss of heterozygosity of chromosomes 3p14 and 9p and losses at 3p, 4p, and 15q and gains at 12q15 ( MDM2 site)

Pathologic Differential Diagnosis

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Adenocarcinomas of the lung
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Basaloid carcinoma
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Small cell carcinoma
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Metastatic ACC

Clinical Features

Adenoid cystic carcinoma (ACC) represents less than 1% of all lung tumors. They are most often diagnosed in the fifth decade of life, and there is no apparent gender predilection. The symptomatology is related to bronchial obstruction and its sequelae and consists of cough, hemoptysis, wheezing, and shortness of breath.

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