Tumors derived from presumed ectopic tissue constitute a family of tumors that are rarely encountered as primary intrapulmonary neoplasms. This is a diverse group in terms of not only histology and presentation but also clinical behavior. Nevertheless, the diagnostic criteria are essentially the same as those for such tumors occurring in the usual anatomic site. In view of their rarity as primary lung neoplasms, it is important to rule out a possible metastatic lesion before a definitive diagnosis of primary pulmonary neoplasm is rendered. Thus, careful clinicopathologic correlation, including information from appropriate radiologic investigations, is essential in the evaluation and diagnosis of these tumors.
The tumors and conditions described in this chapter, which by themselves have no particular clinical or histologic associations, can be categorized as follows:
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Glomangioma/glomangiosarcoma
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Melanoma
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Meningioma/meningothelial-like nodules/diffuse meningotheliomatosis
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Teratoma
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Thymoma
The most important clinical and immunohistochemical features are presented in Tables 9-1 and 9-2 , respectively.
| Tumor | Age Group | Anatomic Site | Prognosis |
|---|---|---|---|
| Glomangioma | Young and older adults | Central or peripheral location | Good |
| Glomangiosarcoma | Young and older adults | Central or peripheral location | Aggressive behavior |
| Melanoma | Young and older adults | Central or peripheral location | Variable aggressiveness |
| Meningioma | Young and older adults | Intraparenchymal | Good |
| Meningothelial-like nodule | Any age | Intraparenchymal | Good |
| Diffuse meningotheliomatosis | Young and older adults | Intraparenchymal | Good |
| Teratoma | Any age | Central or peripheral location | |
| Mature | Good | ||
| Malignant component | Aggressive behavior | ||
| Thymoma | Young and older adults | Intraparenchymal | Good |
| Tumor | Actin | Vimentin | S-100 | EMA | Keratin | LCA | TdT | CEA | CD34 |
|---|---|---|---|---|---|---|---|---|---|
| Glomangioma/ glomangiosarcoma | + | + | − | − | − | − | − | − | ± |
| Melanoma | − | + | + | − | − | − | − | ± | − |
| Meningioma | − | + | ± | + | ± | − | − | − | ± |
| Thymoma | − | ± | − | ± | + | + | + | − | − |
* The immunohistochemical results for a teratoma will vary depending on the tissues present.
GLOMANGIOMA AND GLOMANGIOSARCOMA
Of glomangioma and glomangiosarcoma, the former is by far the more common. Glomangiomas occur more often in the nail bed and in superficial and deep soft tissues but also have been described in a more ubiquitous distribution that includes the gastrointestinal and gynecologic systems and the head and neck. The tumors are assumed to originate from the glomus body, which is a specialized arteriovenous anastomosis made up of Suquet-Hoyer canals and is more commonly seen in the deep dermis and subungual area. Over the years, considerable debate has arisen regarding whether glomangioma represents a true tumor or a hyperplasia. Of note, however, the existence of glomangiosarcoma, an entity with aggressive clinical behavior, indicates that glomangioma may be a true neoplasm as well.
Although glomus tumors occurring in the respiratory system have been reported, they are exceedingly rare. The trachea is the most common location, and although most of the reported cases are of the benign type (glomangioma), cases of glomangiosarcoma also have been described. This chapter focuses only on tumors of the lower respiratory tract, occurring in the bronchus and lung.
Primary pulmonary or bronchial glomangiomas and glomangiosarcomas are, for the most part, reported as curiosities or in small series of cases. Tang and coworkers are given credit for the first description of a glomangioma in the lung. This case was in a 67-year-old woman in whom radiographic evaluation revealed a mass in the left lung, suggesting a possible diagnosis of glomus tumor. The patient had two distinct intrapulmonary nodules, indicating the possibility of multicentric disease. Mackay and associates described a 19-year-old patient with a coin lesion in the lung. A more detailed history disclosed that the patient also had a soft tissue tumor with similar histologic features; therefore, in this case, it is most likely that the lesion in the lung represented metastatic disease from an extrapulmonary origin.
Alt and colleagues reported the case of a 34-year-old asymptomatic man with a coin lesion in the lung. These workers proposed that the term glomus tumor be reserved for those tumors composed of endothelium-lined vascular spaces surrounded by smooth muscle. Koss and associates reported two additional cases of intrapulmonary glomangiomas in two asymptomatic patients who were 40 and 51 years of age, respectively. Gaertner and coworkers collected five cases; in one of these, however, the tumor originated in the mediastinum, and one case was that of a glomangiosarcoma. The three patients with glomangiomas were adults, and the intrapulmonary lesion was discovered incidentally during follow-up for different reasons. The patient diagnosed with glomangiosarcoma appeared to have tumor-related signs and symptoms, such as hemoptysis. More recently, three additional reports of glomangiomas have been presented, and in contrast with previous cases in which the tumor occurred in the lung parenchyma, the tumors were located within the bronchus, obstructing the lumen.
Clinical Features
No specific clinical features can be assigned to glomangioma or glomangiosarcoma. In the reported cases many patients have been asymptomatic, and the tumor was discovered during either a routine radiographic evaluation or an investigation for a different problem. When these tumors occur in a central location, however, the patient is more likely to present with some symptomatology related to bronchial obstruction—namely, cough, chest pain, or hemoptysis. Because glomangiomas are very unusual tumors, the clinical impression tends to be that of a different, more common bronchial neoplasm. Glomangiomas can occur in young adults or in older patients, between the ages of approximately 20 to 65 years, and have been described in both men and women and in white, black, and Asian patients.
Macroscopic Features
Glomangiomas may manifest as either central or peripheral tumors. In a majority of the cases, the tumor arises within the lung proper. These neoplasms may appear as well-circumscribed tumor nodules that range in size from 1 to 6 cm in greatest dimension. In a few cases, two separate nodules have been described. The tumors are of soft consistency and tan in color, with a smooth, homogeneous-appearing surface. In a few cases, “encapsulated” tumor nodules with dilated spaces seen on the cut surface have been described. Glomangiomas characteristically do not show areas of necrosis or hemorrhage. By contrast, glomangiosarcomas tend to be larger tumors with areas of hemorrhage or necrosis.
Microscopic Features
The spectrum of histopathologic features is broader for glomangiomas occurring in the soft tissue than for those observed in the lung, which tend to be of the solid mucohyaline type. The low-power view is that of a well-demarcated tumor nodule surrounded by normal lung parenchyma ( Fig. 9-1 ). Even at low magnification, the tumor is characterized by a fairly homogeneous cellular proliferation in which tumor cells are admixed with ectatic vascular spaces ( Fig. 9-2 ). Those arising in a central location will show partial obstruction of the bronchial lumen, with histopathologic features similar to those of tumors arising within the lung parenchyma. Higher magnification reveals a homogeneous cellular proliferation composed of medium-sized cells, with round to oval nuclei, clear to lightly eosinophilic cytoplasm, and ectatic vascular spaces ( Figs. 9-3 to 9-8 ). The cellular proliferation is characterized by clear cytoplasm, giving a “fried egg” appearance, whereas the vascular spaces show perivascular hyalinization ( Figs. 9-9 to 9-11 ). Glomangiomas characteristically do not display evidence of necrosis or mitotic activity.
Glomangiosarcoma will display areas reminiscent of glomangiomas; at low magnification, however, it is possible to observe areas of necrosis, which may not necessarily be extensive. The higher-power view reveals areas of nuclear atypia and mitotic activity ( Figs. 9-12 to 9-14 ). Areas demonstrating transition from conventional glomangioma to glomangiosarcoma may be observed and are helpful in arriving at a correct interpretation ( Fig. 9-15 ).
Immunohistochemical Features
The most consistent finding on immunohistochemical studies is positive staining for vimentin and muscle-specific actin ( Fig. 9-16 ). Glomangiomas may show positive staining for other markers as well, including smooth muscle actin, desmin, neuron-specific enolase, and Leu-7. These tumors characteristically show negative staining for keratins, epithelial membrane antigen (EMA), myoglobin, chromogranin, S-100 protein, and HMB-45. Although in some cases of intrapulmonary glomangiomas, the tumors have displayed negative staining for CD34, Hatori and coworkers reported a study of six cases of glomus tumor (subungual in location) in which positive staining for CD34 was observed in vascular endothelial cells and tumor cells.
Differential Diagnosis
The differential diagnosis for glomangiomas in the lung may be challenging, owing to their rarity as primary lung neoplasms. Tumors that may have some macroscopic and histopathologic features in common include clear cell “sugar” tumor and well-differentiated neuroendocrine carcinoma (carcinoid tumor). Histologic findings in both of these entities may include dilated vascular spaces, lack of mitotic activity and necrosis, and a cellular proliferation composed of medium-sized cells with clear or lightly eosinophilic cytoplasm. The use of immunohistochemical studies, especially that showing positive staining of tumor cells for muscle-specific actin, will lead to the correct interpretation, because sugar tumors and neuroendocrine carcinomas demonstrate negative reactivity for muscle markers. Sugar tumors also may show positive staining for CD34, S-100 protein, and HMB-45, whereas neuroendocrine carcinomas will show positive staining for keratin, EMA, and neuroendocrine markers such as chromogranin or synaptophysin. In cases of glomangiosarcoma, the main issue will be the identification of more conventional areas of glomangioma and positive staining for muscle-specific actin. Leiomyosarcoma is a valid differential diagnostic possibility, however, because this tumor may have a similar immunophenotype. In this clinical scenario, the identification of more conventional areas of glomangioma is crucial to arriving at a more specific diagnosis.
Treatment and Prognosis
With glomangioma, complete surgical resection of the tumor is curative. Either wedge resection or lobectomy may be performed, depending on the clinical and radiologic findings. With glomangiosarcoma, surgical resection followed by chemotherapy appears to be a reasonable approach; however, because the rate of occurrence in the lung is exceedingly low, cumulative information is insufficient to determine the exact nature of these tumors. Nevertheless, it is likely that they follow an aggressive course, with widespread metastasis.
MELANOMA
Primary melanomas of the lung are rare, and the criteria for diagnosis as primary lung neoplasms are rather controversial. The lung is not an unusual site for metastatic disease from melanomas, however. In a study of 324 patients with malignant melanoma over a follow-up period of 24 months from diagnosis, Gromet and colleagues found that the thorax was the initial site of relapse in 13 patients, 12 of whom were asymptomatic. The investigators concluded that the thorax is a common site for relapse, and that early detection of resectable metastases correlates with longer survival. Panagopoulos and Murray evaluated 30 patients with metastatic melanoma of unknown primary origin and determined that 5 patients (16%) presented with lung metastases. These findings suggest that it is essential to obtain a detailed history, especially concerning previous cutaneous tumors, before any attempt at making the diagnosis of a primary pulmonary malignant melanoma.
The existence of primary melanomas of the lung is well known; however, most of the literature consists of case reports. Some of the older reports do not present enough clinical, radiologic, or histologic information for proper definition of the entities described as primary lung tumors, whereas others cite a history of cutaneous tumor. It is possible that the first description of primary melanoma in the lung was reported by Reid and Metha. Although these investigators presented two cases, one of the tumors was a tracheal melanoma. The other, described as “bronchial melanoma,” was diagnosed in a 60-year-old woman who was found at bronchoscopy to have a mass in the posterior basal bronchus. The patient had no previous history of tumor and was treated with pneumonectomy. No other malignancy was found.
Most of the historically accepted criteria for the diagnosis of primary pulmonary melanoma were originally presented by Jensen and Egedorf, as follows: (1) no history of cutaneous lesion; (2) no history of ocular tumor; (3) single tumor in the lung; (4) morphology of the lung tumor compatible with primary neoplasm; (5) no spread of melanoma in other organs at the time of diagnosis; and (6) autopsy proven. Allen and Drash reiterated the diagnostic criteria for melanomas in other areas and suggested that for a confident diagnosis of melanoma as a primary lung neoplasm, three additional findings should be documented: (1) junctional change with “dropping off” or “nesting” of malignant cells just beneath the bronchial epithelium; (2) invasion of the bronchial epithelium in an area in which the bronchial epithelium is not ulcerated; and (3) obvious melanoma beneath the epithelium. In numerous reports, the likelihood that the neoplasm was in fact a primary pulmonary melanoma has been diminished, because a previous cutaneous melanoma may have undergone spontaneous regression. Thus, the diagnosis of primary malignant melanoma of the lung is very difficult, if not impossible, to make convincingly.
In one of the largest series of primary lung melanomas, Wilson and Moran noted that not all of the diagnostic criteria will necessarily be met in a single case. In this study, the incidence of primary malignant melanoma of the lung was assessed at 0.01% over a period of 45 years. Even though the eight cases described mirrored previous case reports to some extent, not all of the parameters were identified in each individual case. For instance, one of the strongest criteria for the diagnosis of pulmonary melanoma is the presence of in situ melanoma; however, some metastatic melanomas to the lung will display histopathologic features of in situ melanoma, despite manifesting as a single pulmonary mass.
When the clinical and histologic criteria for the diagnosis of pulmonary melanoma are examined in more detail, it is apparent that some of the 1967 criteria may not necessarily apply in current practice. For instance, the use of autopsy to confirm the diagnosis is less relevant today than it may have been some years ago, because it is now possible to evaluate a patient for an occult tumor in the eye or elsewhere. It also is possible to evaluate the possibility of widespread metatatic disease at the time of diagnosis. More recently, in a study of 15 patients presenting with lung melanomas who had no history of melanoma, de Wilt and colleagues analyzed the findings on which a diagnosis of metastatic or primary lung neoplasm was based. As acknowledged by the investigators, this group of patients may represent approximately 5% of those in whom the primary site is unknown. Eleven of the 15 patients presented with a single tumor, and in 7 cases, the diagnosis of primary pulmonary melanoma was very likely. These workers concluded that the distinction between primary and metastatic melanoma of the lung is best accomplished on the basis of clinical behavior (pattern of spread), rather than on histopathologic criteria. De Wilt and co-investigators, like Wilson and Moran, were not able to apply the entire set of criteria to any individual case. They argued that although the dilemma over primary and metastatic disease is of considerable interest, it may be irrelevant to the optimal management of these patients, and recommended that each case be evaluated on an individual basis.
Clinical Features
The clinical signs and symptoms of primary melanomas of the lung are nonspecific and are similar to those of primary lung carcinomas: cough, dyspnea, fever, chest pain, hemoptysis, and other signs of bronchial obstruction. Bronchoscopic findings may suggest melanoma if the lesion is pigmented; however, such pigmentation is not always present. The tumor does not have any predilection for a particular gender and usually is diagnosed in adult patients with a mean age of 51 years. Past or present cutaneous or ocular tumor must be excluded by history or physical and radiologic evaluations.
Macroscopic Features
The presence of a single tumor has been proposed as an important parameter for diagnosis; however, it should be kept in mind that a single tumor may also occur in metastatic disease. These tumors appear well defined, with or without obvious pigment ( Fig. 9-17 ). The cut surface may be tan in color with a homogeneous surface, with or without areas of hemorrhage or necrosis. Tumor size may range from 1 cm to larger than 5 cm in greatest dimension, and the presentation may be one of polypoid bronchial lesions partially obstructing the lumen or as an intraparenchymal mass.
Microscopic Features
The spectrum of histopathologic features is similar to that seen in melanomas of the skin. The tumor may show in situ changes of the bronchial epithelium in many cases, but not in all ( Figs. 9-18 to 9-20 ). These in situ changes may mimic those of carcinomas. Underneath the bronchial epithelium, the tumor may grow in an organoid, nested, diffuse, or spindle cell pattern ( Figs. 9-21 to 9-26 ). The neoplastic cellular proliferation may be composed of medium-sized cells with moderate amounts of eosinophilic cytoplasm, round to oval nuclei, prominent nucleoli, and easily identified mitotic activity. The cellular proliferation may be composed of rather smaller cells with round nuclei and inconspicuous nucleoli, mimicking the growth pattern of a small cell carcinoma. In spindle cell melanomas, the tumor may be composed of fusiform cells with elongated nuclei and inconspicuous nucleoli. Pseudonuclear inclusion and mitotic activity can be easily identified. Areas of necrosis or hemorrhage may be observed, regardless of the growth pattern. Melanin pigment is present in a majority of cases; less commonly, however, it may appear only in focal areas.
Immunohistochemical Features
Immunohistochemical stains may be of great value in the diagnosis of pulmonary melanoma. Since these tumors are very unusual as primary lung neoplasms, and since melanomas may also share some immonophenotypic features with lung carcinomas, it is important to perform a panel of immunohistochemical stains that may allow for a proper designation of these tumors. Melanomas react positively with S-100 protein, HMB-45, and Melan A; thus, these stains should be part of the panel. They may also be positive for carcinoembryonic antigen (CEA), and some spindle cell melanomas may be negative for HMB-45. Therefore, it is important to add other putative epithelial markers, such as keratins and EMA, to the panel.
Differential Diagnosis
Any attempt at a differential diagnosis is rather impractical because melanoma can mimic any primary tumor in the lung, including carcinomas that do not show the conventional squamous or adenocarcinomatous features. The histopathologic picture observed in some pleomorphic or sarcomatoid carcinomas of the lung is readily applicable to certain cases of melanoma. Some neuroendocrine tumors also may share histopathologic features with melanoma, including the presence of melanin pigment. Therefore, an immunohistochemical panel is essential in cases in which a nonepithelial malignancy is strongly suspected. A thorough clinical and radiologic evaluation is necessary to make the distinction between primary and metastatic disease.
Treatment and Prognosis
The treatment of choice for primary melanomas of the lung is complete surgical resection, and the prognosis is variable. Some tumors behave aggressively, whereas others exhibit a protracted course. In the series of 8 patients reported by Wilson and Moran, five patients died of their disease between 4 and 32 months after initial diagnosis; two patients were alive with metastasis between 4 and 30 months after initial diagnosis; and one patient was alive without evidence of metastatic disease at 108 months after initial diagnosis. In the cases described by de Wilt and associates, the 5-year survival rate was 42%, and the investigators concluded that resection in patients with pulmonary melanoma without a known primary can result in long-term survival.
MENINGIOMA
Meningiomas occur predominantly in the central nervous system; however, they also commonly occur in ectopic locations such as the scalp, orbital fossa, maxillary antrum, and frontal sinus. When pulmonary meningiomas manifest in conjunction with a central nervous system tumor with otherwise “benign” histology, they have been regarded by some investigators as “benign metastasizing meningioma” or as late metastasis in patients with a previous history of central nervous system tumors. Metastases detected up to 19 years later have been reported in some patients. In 1960, Hoye and colleagues suggested a set of four diagnostic criteria for extracranial meningiomas: (1) direct extension from an intracranial tumor; (2) extracranial growth from arachnoid cell rests along cranial nerve sheaths; (3) proliferation of ectopic embryonic rests of arachnoid cells; and (4) extracranial metastases from intracranial tumors. The appearance of meningiomas in the lung may be best explained by the proliferation of ectopic embryonic rests of arachnoid cells.
The occurrence of ectopic primary pulmonary meningiomas is well documented. Because they are rare, most of the literature consists of case reports. Kemnitz and colleagues are given credit for the first description of a primary pulmonary meningioma, in a 59-year-old woman. Since then, numerous case reports describing similar findings have been presented. Based on these cases, patients tend to be adults and are predominantly female. A majority of tumors were discovered incidentally during routine physical examination. Related symptoms were recorded in only a few cases. In the only large series published, the study authors reported 10 cases of primary pulmonary meningioma. Their findings are similar to those from previous reported cases. The patients were adults between the ages of 30 and 72 years (mean, 51 years), and their tumors were discovered incidentally. Only one patient in this series had symptoms (cough) related to the intrapulmonary tumor. The female predominance previously reported was not apparent in this study. Although the investigators argued that the occurrence of intrapulmonary meningiomas remains speculative, they acknowledged that meningothelial-like nodules arising in the lung were a possible and more logical origin for pulmonary meningiomas. Associated meningothelial-like nodules were not found in any of the 10 cases of pulmonary meningioma in this series; however, in some more recent cases this association has been reported. An explanation still needs to be provided for the origin of the meningothelial-like nodules themselves, however, indicating that the theory concerning ectopic embryonic rests may have some merit. Although the great majority of intrapulmonary meningiomas are benign, malignant intrapulmonary meningiomas have been reported.
The diagnosis of malignancy can be problematic. Prayson and Farver assigned a malignant classification to one case on the basis of histologic features, including nuclear pleomorphism and increased mitotic activity (15 mitotic figures per 10 high-power fields). In a case described by van der Meij, however, it appears that the authors designated the tumor as malignant based on invasiveness (tumor invaded pleura, esophagus, intrapulmonary vessels, hilar lymph nodes, and peribronchial fat) and destruction of bronchial cartilage, rather than the histologic features of the meningioma, which showed 0 to 1 mitotic figures per square millimeter. Both features should be taken into account in order to accurately predict behavior.
Macroscopic Features
Pulmonary meningiomas are well-circumscribed tumors and often are found in a subpleural location. They are solid and whitish in color with a homogeneous-appearing cut surface ( Fig. 9-27 ). Areas of necrosis and hemorrhage are not common, except in cases in which malignant features are present. Tumor size ranges from 1 cm to larger than 5 cm; in a majority of cases, however, average sizes range between 3 and 4 cm.
