This chapter describes a group of lung tumors characterized by uncertain histogenesis and very rare occurrence. Despite current advances in immunohistochemistry and molecular biology, definitive conclusions regarding the cellular origins of these neoplasms are still lacking. Although researchers have made progress in correcting erroneous concepts about the histogenesis of some of these tumors, very little information is available on others. The following tumors are discussed:
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Clear cell “sugar” tumor
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Granular cell tumor
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Inflammatory pseudotumor (IPT)
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Sclerosing hemangioma (pneumocytoma)
The most important clinical and immunohistochemical features for these entities are summarized in Tables 11-1 and 11-2 , respectively.
| Location | ||||
|---|---|---|---|---|
| Tumor | Symptoms | Central | Peripheral | Clinical Behavior |
| Clear cell “sugar” tumor | Asymptomatic | Rare | Common | Complete resection curative |
| Granular cell tumor |
| Common | Rare | Complete resection curative |
| Inflammatory pseudotumor | Airway obstruction | Common | Common | Recurrence if not completely resected |
| Sclerosing hemangioma | Asymptomatic | Rare | Common |
|
| Antibody | Clear Cell “Sugar” Tumor | Granular Cell Tumor | Inflammatory Pseudotumor | Sclerosing Hemangioma |
|---|---|---|---|---|
| Cytokeratin | − | − | −, + | −, + |
| Keratin 7 | − | − | − | +, − |
| S-100 protein | + | + | − | − |
| TTF-1 | − | − | − | + |
| HMB-45 | + | − | − | − |
| Surfactant protein | − | − | − | + |
| CD34 | + | − | − | − |
| EMA | − | − | − | + |
| Vimentin | − | −, + | + | + |
| CD1a | +, − | − | − | − |
| HMB-50 | + | − | − | − |
| Factor XIIIa | + | − | − | − |
| NSE | +, − | −, + | − | − |
| Leu7 | − | +, − | − | − |
| ALK-1 | − | − | + | − |
CLEAR CELL “SUGAR” TUMOR OF THE LUNG
Benign clear cell tumors of the lung are unusual neoplasms that have been reported sporadically in the literature. Since its original description, this neoplasm has been described mainly in individual case reports or in small series that emphasize the elucidation of its histogenesis. Although several theories have been advanced, the true histogenesis of this neoplasm is not universally agreed upon.
Historical Aspects
The original description of the clear cell “sugar” tumor of the lung appeared in 1963, when Liebow and Castleman presented this new entity in an abstract. In 1971, the same investigators presented one of the largest series to date, consisting of 12 cases, and outlined most of the currently available information on these tumors. These workers noted that the colloquial name of “sugar tumor” derived from a chemical analysis in one case that demonstrated the presence of glycogen hexose—hence the term sugar . The clinical, macroscopic, and microscopic features presented in these 12 cases have been largely echoed in more recent descriptions of this particular tumor. Although Liebow and Castleman did not offer an explanation for its occurrence, they did acknowledge the possibility of a myoid origin by demonstrating histologic features that were similar to those of clear cell leiomyomas of the stomach and uterus.
A wide array of explanations for the origin of these tumors have been proposed. Becker and Soifer described the tumor’s ultrastructural features in a case in which glycogen was detected, comparing its distribution with that of glycogen in the livers of patients with Pompe’s disease, and noting dense core neurosecretory granules in 2% to 5% of the cells. They suggested that these tumors derived from Kulschitzky cells. Andrion and colleagues presented a case in which the tumor cells did not react with neuroendocrine markers and suggested a possible origin from epithelial nonciliated bronchiolar (Clara) cells or epithelial serous cells. In a series of nine cases, Gaffey and associates documented melanogenesis by showing positive staining in tumor cells for HMB-45 and HMB-50, and demonstrating premelanosomes by electron microscopy. Lantuejoul and coworkers reported two cases in which the tumor cells showed positive staining not only for HMB-45 but also for CD34, which they interpreted as pericytic differentiation.
More recently, a group of tumors sharing some of the histologic and immunohistochemical features of clear cell sugar tumors have been introduced into the literature under the designation PEComas . Clear cell tumors with histopathologic features similar to those of tumors found in the lung also have been described in extrathoracic locations. It has been stated that clear cell tumors, angiomyolipoma, and lymphangioleiomyomatosis may belong to the family of lesions known as PEComas.
Clinical Features
The clear cell sugar tumor does not appear to have any gender or age predilection. Although a majority of cases have been described in adults, the tumor also has been reported in children. A majority of patients are asymptomatic, and the tumor is discovered during a routine chest radiographic examination. Clinical and laboratory signs and symptoms, if present, may include fever, anemia, elevated erythrocyte sedimentation rate, presence of C-reactive protein, elevated platelet count, pneumonia, and chest or back pain. Rarely, the tumor may be associated with unusual manifestations such as hemoptysis or other pathologic conditions such as lymphangioleiomyomatosis and tuberous sclerosis. The anatomic location of the tumor generally is in the periphery of the lung.
Macroscopic Features
In the vast majority of cases, tumor size ranges from 1 to 7 cm in greatest dimension, but larger sizes up to 12 cm also have been reported. The tumors usually are well circumscribed but not encapsulated and of solid consistency, with variable color ranging from pink to red, gray, or brown ( Fig. 11-1 ). Rarely, tumors have been described as cystic. The cut surface may be slightly granular or glistening and smooth in appearance.
Histopathologic Features
The low-power view shows a cellular proliferation replacing normal lung parenchyma, which appears to be composed of cells with predominantly clear cytoplasm ( Figs. 11-2 and 11-3 ). The cells may be arranged in cords or sheets, with minimal intervening connective tissue and prominent ectatic blood vessels with thin walls ( Figs. 11-4 and 11-5 ). Higher magnification reveals oval to polygonal cells with distinct cell borders, clear cytoplasm, small nuclei, and inconspicuous nucleoli ( Figs. 11-6 to 11-8 ). In other areas, histologic features may consist of a mixture of clear cells and spindle cells characterized by an elongated nucleus, inconspicuous nucleoli, and rather light eosinophilic cytoplasm ( Fig. 11-9 ). The spindle cell component may be prominent in some areas of the tumor. One important characteristic of this tumor is the presence of “spider cells,” larger cells with granules in a linear arrangement that radiate from the nucleus (see Fig. 11-9B ). In some areas, ectatic vessels with pools of red cells may be present ( Fig. 11-10A ), whereas in others, the presence of ectatic vessels and spindle cells imparts a hemangiopericytic pattern ( Fig. 11-10B ). In unusual cases, Touton-type giant cells or otherwise multinucleated giant cells may be present ( Fig. 11-11 ). Neuroid cells also may be prominent ( Fig. 11-12 ), and focal areas may show a neurotization-like process ( Fig. 11-13 ). The clear cell component may show an inflammatory infiltrate ( Fig. 11-14 ). The tumor does not characteristically show increased mitotic activity; and although rare mitotic figures may be seen, in most cases mitotic activity, cellular pleomorphism, and necrosis and hemorrhage are lacking. Although most of these features are more readily seen in resected specimens, the diagnosis of sugar tumor of the lung also can be accomplished by cytologic analysis and examination of core biopsy material.
Histochemical-Immunohistochemical and Ultrastructural Features
The use of periodic acid–Schiff reagent (PAS) is helpful in identifying glycogen in the clear cells, whereas stains for mucin are negative. The tumor characteristically shows negative staining for epithelial markers such as keratin and epithelial membrane antigen (EMA), as well as neuroendocrine markers including chromogranin. Tumor cells have shown positive staining for S-100 protein, synaptophysin, CD34, CD1a, HMB-45, HMB-50, NKIC3, HAM-56, cathepsin B, factor XIIIa, and neuron-specific enolase. At the ultrastructural level, various findings have been reported, including neurosecretory granules, pericytic differentiation, and premelanosomes.
Differential Diagnosis
The most important considerations in the differential diagnosis are primary lung carcinoma and metastatic carcinomas (such as carcinomas of the kidney and thyroid), both with clear cell features. In this setting, the use of immunohistochemical stains, especially keratin, may lead to a correct interpretation. Clinical history of a kidney tumor is strongly suggestive of metastatic disease.
Treatment and Clinical Behavior
The treatment of choice for these tumors is complete surgical resection, accomplished with a wedge resection or lobectomy. In some unusual circumstances involving large tumors, pneumonectomy has been performed. The clinical course typically is uneventful, with an excellent outcome; in one reported case, however, metastatic disease developed and the patient died 10 years after initial diagnosis. The tumor was described as a “sugar tumor” of the lung with necrosis and an unusual histologic feature of columnar cells with clear cytoplasm, raising the possibility that it may have represented a different neoplasm.
GRANULAR CELL TUMOR
Granular cell tumors are neoplasms of rare occurrence and ubiquitous distribution that appear to be more common in the head and neck area (accounting for approximately 50% of all tumors of this type). These neoplasms have been described in multiple anatomic locations, however, including soft tissues, the breast, and the gastrointestinal, biliary, genitourinary, and lower respiratory tracts. The vast majority of these tumors are benign; however, a malignant counterpart has been described. Despite the well-known occurrence of these tumors, their histogenesis remains unsettled.
Historical Aspects
Abrikossoff is credited with the initial description of this tumor in 1926. He initially argued that it represented degenerative skeletal muscle and later modified his opinion, suggesting an origin from myoblasts and referring to the tumor as “myoblastoma.” With the development of techniques such as ultrastructural and immunohistochemical studies, different theories have been proposed to explain the histogenesis of these tumors, including origins from histiocytes, fibroblasts, and Schwann cells. Although some researchers have argued in favor of the Schwann cell as the cell of origin, granular cell tumors and schwannomas do not necessarily share similar ultrastructural, immunohistochemical, and karyotypic features. Currently, the granular cell tumor is regarded as a “specific” clinicopathologic entity without a known histogenetic mechanism.
Kramer published the initial description of the granular cell tumor in the bronchus. By the late 1960s, the occurrence of this tumor in the lower respiratory tract was noted mostly in case reports, as a mere curiosity.
Clinical Aspects
Like granular cell tumors appearing outside of the thoracic cavity, the bronchial tumor has been described mainly in adult patients, with a median age of 47 years, who may present with a history of cough, hemoptysis, wheezing, obstructive pneumonia, or weight loss. In unusual cases, the patient is completely asymptomatic and the tumor is discovered during a routine radiographic examination. Bronchial granular cell tumors also have been described in children, who exhibit symptoms similar to those in adults. Although in a majority of patients a single bronchial tumor is present, the presence of multiple, multifocal tumors within the bronchial tree has been reported. In their study of 20 patients with granular cell tumor of the lung, Deavers and coworkers documented that multifocal tumors were present in approximately 25% of the cases. In contrast with these findings, a study of 31 tumors of the lower respiratory tract reported by van der Maten and associates found that 19 of the tumors originated from the bronchus; in approximately 61% of the patients, the tumor was found incidentally during the workup for lung carcinoma. This association has been reported in cases in which granular cell tumor coexists with bronchogenic carcinoma.
Macroscopic Features
The tumors generally are centrally located and involve the airway. Size is variable and ranges from less than 1 cm up to 5 cm in greatest dimension. The tumor has a firm consistency and ranges in color from tan to whitish to yellowish ( Fig. 11-15 ). It may take on the appearance of a polypoid tumor obstructing the airway or of a coin lesion. In a case described by Schulster and colleagues, the tumor had a coin lesion appearance and was found to involve the wall of a segmental bronchus. In general, the cut surface does not show evidence of necrosis or hemorrhage, so documentation of these features, when present, is important, because they indicate more aggressive behavior.
Histopathologic Features
The low-power view shows a tumor cell proliferation growing underneath the bronchial epithelium in sheets, replacing or growing around the normal bronchial structures ( Fig. 11-16 ). In some cases, the epithelium may display squamous metaplasia or ulceration ( Fig. 11-17 ). At higher magnification, the tumor is seen to be composed of medium-sized, round to polygonal cells with ample light eosinophilic and granular cytoplasm. The nuclei may be centrally or peripherally located, with inconspicuous nucleoli ( Fig. 11-18 ). High-power examination should provide definitive evidence of the granular nature of the cytoplasm. The tumors are not encapsulated and often show infiltrative borders ( Fig. 11-19 ). Perineural invasion is common ( Fig. 11-20 ). Some tumors may have a prominent spindle cell component ( Fig. 11-21 ) with cytologic features similar to those of the round or polygonal cell component; however, when the spindle cell component is prominent, areas with a desmoplastic-like reaction may be visible. In some unusual cases, the tumor extends into lymph nodes ( Fig. 11-22 ), may show cystic changes ( Fig. 11-23 ), or displays metaplastic bone formation ( Fig. 11-24 ). When the tumor is not endobronchially located, it may appear well circumscribed, replacing the lung parenchyma.
Mitotic activity, necrosis, and hemorrhage are absent in benign tumors. Although the great majority of granular cell tumors of the lung are benign, malignant tumors have been reported. The histologic features of malignant tumors are similar, with the addition of nuclear pleomorphism, mitotic activity ( Fig. 11-25 ), and necrosis. When a single biopsy specimen is available for review, the presence of these features should alert the pathologist to the possibility of a malignant granular cell tumor.
Histochemical, Immunohistochemical, and Ultrastructural Features
The granules present in the cytoplasm of granular cell tumors react positively with PAS. On immunohistochemical studies, the most consistent marker is S-100 protein. Researchers also have reported positive staining for neuron-specific enolase, vimentin, actin, myelin basic protein, Leu7, cathepsin B, and antichymotrypsin. Granular cell tumors demonstrate negative staining for keratin, EMA, glial fibrillary acidic protein (GFAP), chromogranin, lysozyme, neurofilament protein, HMB-45, desmin, myoglobin, and carcinoembryonic antigen (CEA). One case of a granular cell tumor arising in soft tissue with DNA ploidy has been reported.
Differential Diagnosis
Although the histologic features of granular cell tumors allow for a light microscopic diagnosis, in some cases the tumor can be confused with other entities, such as melanoma or sarcoma. Both granular cell tumors and melanoma may show positive staining for S-100 protein, but granular cell tumors will not display positive staining for HMB-45 or Melan-A. Some mesenchymal neoplasms also may show positive staining for S-100 protein; however, in doubtful cases, the use of a wider panel of immunohistochemical studies may provide better evidence for a specific diagnosis. In addition, the use of PAS histochemical stains may prove to be useful. Malignant granular cell tumors of extrathoracic origin may metastasize to the lungs, so reliable clinical information is required for accurate designation as primary or metastatic.
Treatment and Prognosis
The treatment of choice for granular cell tumors of the lung is complete surgical resection. Bronchoscopic extirpation, laser therapy, sleeve resection, lobectomy, or transbronchoscopic surgical resection all have been used. The choice of a particular procedure will depend on the location, size, and other features of the tumor. Reported instances of recurrence may be related to incomplete resection of the tumor. If the tumor is completely resected and the histologic picture is benign, the treatment is curative. When the tumor is malignant, an aggressive clinical course, with development of metastatic disease, is likely.
INFLAMMATORY PSEUDOTUMOR
Inflammatory pseudotumor of the lung is a controversial term for a pulmonary growth that destroys normal lung parenchyma and is believed in many cases to follow an inflammatory process. This neoplasm has the potential to recur and invade adjacent structures, such as the pleura, mediastinum, and diaphragm, and it may not necessarily display an inflammatory component (i.e., a pneumonic process). The term inflammatory myofibroblastic tumor has been used as an alternative designation for these lesions but does not completely explain their true nature in that some tumors are composed almost exclusively of plasma cells. Accordingly, the more accurate term inflammatory pseudotumor is retained here.
Historical Aspect
In the view of many investigators, IPT may represent an inflammatory response to a previous insult. In some cases, the clinical history includes an upper respiratory infection or a resolving pneumonic process. This possibility is potentially supported by the finding that in some cases, IPT has expressed human herpesvirus-8 genes. Some workers, however, have argued that IPT may be a true tumor and have demonstrated cytogenetic evidence supporting a clonal origin. In addition, the fact that many of these lesions recur also indicates that it may be a true tumor, rather than a postinflammatory response. This neoplasm may originate from pulmonary myofibroblasts, however, and the presence of myofibroblasts in conditions such as diffuse alveolar damage may indicate that IPT does in fact follow an inflammatory response. Regardless of the histologic type encountered, no known etiology for these lesions has been recognized.
Clinical Features
IPT has been estimated to represent less than 1% of all pulmonary tumors. The true incidence is uncertain, however, because a wide variety of lesions have been included under this designation. Other conditions that have been mistakenly identified as IPT include organizing pneumonia, sclerosing hemangioma, and pseudolymphoma, among others. In most cases IPT manifests as a solitary “coin lesion” in a relatively young patient, usually before the age of 40 years. IPT is not restricted to younger patients, however, and also has been described in patients older than 40 years.
Although a history of cough, chest pain, and fever is common, IPT also has been described in patients who have been completely asymptomatic, in whom the lung abnormality has been discovered during a routine radiographic study. Patients also may present in a more acute state with massive hemoptysis. Agrons and colleagues analyzed data for 61 patients ranging in age from 17 to 61 years, with a slight male predominance (male-to-female ratio of 36:25). In 52 patients, the tumor manifested as a peripheral solitary nodule or mass, and in 11 of these, extrapulmonary involvement was evident in the hilum, mediastinum, and airway. Thus, these workers concluded that IPT typically is a solitary pulmonary lesion that can involve extrapulmonary structures. Ishida and associates documented pleural involvement in three of seven patients with IPT. Kim and coworkers described the radiographic features of IPT in ten patients, in three of whom the lesion was endobronchial in location.
Classification
Although most pathologists would not categorize organizing pneumonia as IPT, Matsubara and colleagues described 32 cases of IPT of the lung in which they alluded to the possible progression of organizing pneumonia to fibrous histiocytoma or to plasma cell granuloma. They stated that most or all of the cases of IPT are believed to originate as organizing pneumonia and noted a considerable overlap of histopathologic features among organizing pneumonia, fibrous histiocytoma, and plasma cell granuloma. In this report, 44% of the cases corresponded to organizing pneumonia.
One of the problems in classifying organizing pneumonia as IPT is that in bronchiolitis obliterans, findings may include radiologic evidence of an intrapulmonary nodule with airspace consolidation, similar to that in some of the cases referred to as IPT. If cases of bronchiolitis obliterans are included in this category of lesions, then any “benign” mass lesion in the lung that is unclassified will automatically be labeled as an IPT. Because of these problems, some investigators have determined this entity as a whole to be etiologically enigmatic, nosologically confusing, and histologically unpredictable and have recommended restricting the use of this designation to pulmonary lesions. Bahadori and Liebow preferred the term plasma cell granuloma for this entity; use of this nomenclature, however, denies the existence of lesions that are composed almost entirely of a fibrohistiocytic proliferation. In a description of an endobronchial case of IPT, Buell and associates documented the presence of plasma cells and spindle cells, which on electron microscopy resembled those of fibrocytic derivation. Spencer documented 27 cases of IPT, finding that all of the lesions incorporated features of both plasma cell granuloma and histiocytoma; he proposed the pulmonary plasma cell–histiocytoma complex. Two cases in these series were categorized as tumors that had undergone malignant transformation. Pettinato and colleagues, however, described 20 cases of “inflammatory myofibroblastic tumor (plasma cell granuloma)” in which the lesions were seen to be composed of variable proportions of plasma cells, histiocytes, and spindle cells. Of interest, the investigators documented that in 5% of the cases, more than one lesion was present in the lung. Also, in 5% of the cases, the inflammatory process had involved the mediastinum and thoracic wall.
Other workers have focused their attention on lesions with fibrohistiocytic histology. Gal and coworkers analyzed the prognostic factors for fibrohistiocytic lesions of the lung, classifying them as IPT, fibrohistiocytic type; borderline fibrohistiocytic lesions; or malignant fibrous histiocytoma. In this study, 15 lesions were identified as IPT and 3 as borderline lesions. Only 2 of the patients with IPT experienced recurrence. In a study of 23 patients with IPT, Cerfolio and associates concluded that regardless of the histologic findings, the most important prognostic factor is whether the tumors are circumscribed or locally invasive.
Based on the many descriptions of IPT in the lung, two distinct histopathologic subtypes generally are accepted: fibrohistiocytic type and plasma cell type. It is important for prognostic purposes to determine whether these tumors are invasive. Painstaking analysis of the radiologic features and careful sectioning of the tumor are important aspects of the evaluation and final classification of these lesions.
Macroscopic Features
As with other intrapulmonary neoplasms, the lesion may be either centrally or peripherally located ( Fig. 11-26 ), which in turn may determine symptomatology. With peripheral lesions, tumor size may range from 1 cm to more than 10 cm in diameter. The lesions are well circumscribed but not encapsulated. Cut surface is rather homogeneous in appearance and may have a yellowish color. Endobronchial tumors may show similar features; however, they may not be as large as those occurring in the periphery of the lung parenchyma. Centrally located tumors may show some ulceration of the overlying epithelial surface and appear to have infiltrative borders. Rare cases of cystic lesions also have been described.
