102 - Present Concepts in the Molecular Biology of Lung Cancer
Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.
Title: General Thoracic Surgery, 6th Edition
Copyright 2005 Lippincott Williams & Wilkins
> Table of Contents > Volume II > Section XVII - Other Tumors of the Lung > Chapter 119 - Uncommon Primary Malignant Tumors of the Lung
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Chapter 119
Uncommon Primary Malignant Tumors of the Lung
Philip G. Robinson
Thomas W. Shields
Most of the uncommon primary malignant tumors of the lungs are sarcomas, but they also include pulmonary blastomas, carcinosarcomas, primary pulmonary lymphomas (PPLs), and various other malignancies, including the rare primary malignant melanoma, primary teratoma, and malignant ependymoma (Table 119-1). In an 11-year review (1980 1990) of 80 rare pulmonary neoplasms seen at the Mayo Clinic, Miller and Allen (1993) reported that 41% were non-Hodgkin's lymphomas, 20% were carcinosarcomas, 15% were mucoepidermoid carcinomas (these tumors are discussed in Chapter 117), and 18% were sarcomas; the remainder were either malignant melanomas or blastomas. The patients had a median age of 60 years. In contrast, Hancock and colleagues (1993) described the distribution of lung tumors in children. They added nine cases to the literature and summarized a total of 383 cases. Most of the tumors (76%) were malignant. Of these, 40.5% were bronchial adenoma, and 16.8% were bronchial carcinomas. The remaining malignant tumors were pulmonary blastomas (15.5%), lymphomas or plasmacytomas (2.4%), and malignant teratomas (1%). Benign tumors made up 24% of the cases, with the majority of these being inflammatory pseudotumors.
SOFT TISSUE SARCOMAS
Primitive mesenchymal cells are present in every organ of the human body. In the lung, tumors of mesenchymal origin may arise from the stromal elements of the bronchial or vascular wall or from the interstices of lung parenchyma. These tumors usually expand toward the lung parenchyma; occasionally they extend into the lumen of a bronchus. Only rarely do they invade and break through the bronchial epithelium. As a result, these tumors do not exfoliate cells, and diagnosis by cytologic examination of expectorations or of tracheobronchial washings is uncommon. Grossly, the tumor usually appears as a well-circumscribed and encapsulated mass in the lung parenchyma (Fig. 119-1). They generally spread by local invasion. Peripheral lesions may invade the adjacent pleura and chest wall; only rarely do they cavitate. They can metastasize by way of the circulation and rarely by lymphatic invasion. As Watson and Anlyan (1954) noted, metastases to distant organs are usually late manifestations of the disease process. Microscopically, these tumors present a wide range of cellular differentiation.
Primary pulmonary sarcomas occur at almost any age, with equal frequency in either sex. Fadhli and colleagues (1965) reported an age range of 4 to 83 years. The tumors occur with equal frequency in either lung. Many patients are asymptomatic, and lesions are detected only on a routine radiograph of the chest. Symptomatic patients most commonly experience chest pain, cough, dyspnea, and hemoptysis. Fever, fatigue, anorexia, and weight loss usually are late manifestations. On radiographs of the chest, the tumor usually appears as a sharply demarcated mass density within the lung substance at the hilus or in the lung periphery. The lesions are usually solitary. Martini and associates (1971) reported that these tumors vary in diameter from 1 to 15 cm or more, with an average diameter of 6 to 7 cm. Peripheral tumors invading the chest wall may be associated with varying degrees of pleural effusion. Tumors obstructing a bronchus (~15%) may result in distal parenchymal changes (Fig. 119-2).
Keel and co-workers (1999) reported a study of 26 primary pulmonary sarcomas. The tumors were distributed as follows: seven malignant fibrous histiocytomas (27%), six synovial sarcomas (23%), three malignant peripheral nerve sheath tumors (12%), three leiomyosarcomas (12%), two angiosarcomas (8%), two intimal sarcomas (8%), two fibrosarcomas (8%), and one epithelioid hemangioendothelioma (4%). The patients ranged in age from 18 to 75 years, with a mean age of 48 years. The tumors ranged in size from 0.9 cm to filling the entire hemithorax. The tumors
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were distributed almost equally between the two lungs, with one being bilateral, two in the pulmonary artery, and one in a location that was not stated. In a follow-up study of 23 of these patients by Bacha and colleagues (1999), it was recorded that three patients were unresectable; 13 patients were treated by surgical resections that included lobectomies, bilobectomies, sleeve resections, a carinal resection, and a chest wall resection; four patients had radical pneumonectomies; and three patients with vascular or cardiac invasion underwent extended resection with the use of cardiopulmonary bypass. Eleven patients received postoperative chemotherapy and eight had radiation therapy. The follow-up on 22 of the patients ranged from 2 to 183 months, with a mean of 48 months. Fourteen patients were free of disease, six died of disease, one died of surgical complications, and two were alive with disease. The size and grade did not correlate with the survival, but the completeness of the resection did. Thus, these authors concluded that patients with pulmonary sarcomas may have an acceptable survival rate if the resection is complete.
Table 119-1. Less Common Malignant Tumors of the Lung | |
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In another study of primary lung sarcomas, Magne and colleagues (2001) reported on nine patients. Five patients were women and four were men. The patients ranged in age from 35 to 73 years, with a median of 63 years. They complained of chest pain (four patients) and dyspnea (four patients). All of the patients underwent surgery, with three having incomplete resections. The tumors ranged in size from 2 to 15 cm, and they consisted of four malignant fibrous histiocytomas, three leiomyosarcomas, one fibrosarcoma, and one myxoid liposarcoma. Five patients received adjuvant chemotherapy (anthracyclin-ifosfamide-containing regimens) and three patients received adjuvant radiation therapy. The median overall survival was 36 months. In the three patients with an incomplete resection, the median survival was 47 months. Two patients underwent a second procedure for the management of a recurrence, and each had a satisfactory long-term survival (58 and 83 months, respectively). This good long-term survival for patients with resected recurrence stresses the importance of close follow-up for these patients. The important prognostic factors are low grade of the malignancy, small size of the tumor, and initial complete resection.
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Fig. 119-1. Posteroanterior chest radiograph reveals recurrent fibrosarcoma of the right lung after previous wedge resection of a fibromatous tumor from the middle lobe. |
Dail (1988) categorized the soft tissue sarcomas arising within the lung into three groups: (a) parenchymal and bronchial-endobronchial sarcomas, (b) sarcomas of large vessel origin, and (c) sarcomas of small vessel origin.
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Fig. 119-2. Malignant endobronchial sarcoma. |
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Parenchymal and Bronchial-Endobronchial Sarcomas
Fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma, neurogenic sarcoma, chondrosarcoma, osteosarcoma, synovial sarcoma, malignant mesenchymoma, liposarcoma, and malignant fibrous histiocytoma are included in this category. These sarcomas may occur in either an endobronchial or a parenchymal location; however, the occurrence of any of these sarcomas as primary lesions in the lung is rare. Table 119-2 is a list of the distribution of some of these lesions in adults and children in the series reported by Hartman and Shochat (1983), McCormack and Martini (1988), as well as Nascimento (1982) and Janssen (1994) and their associates.
Pulmonary Fibrosarcoma
Combining the patients in the series of Guccion and Rosen (1972) and Nascimento and colleagues (1982) yields a total of 22 cases of primary pulmonary fibrosarcomas. The patients ranged in age from 23 to 69 years, with an average age of 47 years. There were 16 (72%) men and 6 (27%) women. This bias might exist because one of the studies is from the Armed Forces Institute of Pathology. These fibrosarcomas may occur in either an endobronchial or a parenchymal location. The endobronchial tumors were almost always symptomatic. The symptoms ranged from none to chest pain, cough, hemoptysis, and shortness of breath. McLigeyo and associates (1995) reported a pulmonary fibrosarcoma in a 50-year-old woman who presented with hypoglycemia and hypertrophic pulmonary osteoarthropathy. Most patients were treated mainly by surgical excision. A few patients received radiation therapy and chemotherapy. In Guccion and Rosen's (1972) series, several patients were lost to follow-up, but the majority of the followed patients died of their disease. Those patients with endobronchial lesions seemed to survive longer. In the nine cases of Nascimento and colleagues (1982), seven died from their disease within 3 months to 18 years after treatment. Two were alive at 7 and 18 years following treatment. The patient who survived 18 years had an endobronchial lesion. The one who survived 7 years had a parenchymal tumor.
Pulmonary fibrosarcoma is rare in children. Kuhnen and associates (2001) described a pulmonary spindle-cell tumor in a newborn that they believed to be an infantile fibrosarcoma. Prognosis is thought to be excellent after resection of such a lesion. Picard and colleagues (1999) resected a bronchial fibrosarcoma by a sleeve resection of the left upper lobe in an 8-year-old boy; the patient was alive and well 2 years after resection. Goldthorn and colleagues (1986) described a cavitating fibrosarcoma in an 11-year-old girl who underwent a resection followed by chemotherapy. She had a 36-month disease-free survival. Picard and associates (1999) in their review of bronchopulmonary fibrosarcomas noted that at least 28 cases have been recorded in children; six were newborns and the others ranged in age from 1 month to 19 years. Each gender was approximately equally affected, as were the two lungs. According to Hancock and colleagues (1993), these tumors account for 9.6% of the cases of pediatric lung tumors. In children, the tumor is low grade and the prognosis is relatively satisfactory with an early survival rate of approximately 78%. Complete surgical resection is the procedure of choice. The roles of radiation therapy and chemotherapy are unknown.
Pulmonary Leiomyosarcoma
Guccion and Rosen (1972), as well as Nascimento (1982), and Moran (1997a) and their colleagues have reported a total of 41 cases of pulmonary leiomyosarcomas. These patients ranged in age from a newborn to 91 years, with an average of 51 years. There were 29 men and 12 women, for a gender ratio of 2.4:1.0. The symptoms ranged from none to cough, chest pain, dyspnea, and hemoptysis.
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The chest radiographs usually showed a solitary homogeneous density with sharply lobulated borders. Cavitation was observed in some of the leiomyosarcomas, as noted by Lillo-Gil and associates (1985). The tumors were randomly distributed in all the lobes of both lungs. On gross examination, the leiomyosarcoma may be in an endobronchial, parenchymal, or subpleural location and is usually well circumscribed, firm, and gray-white. Areas of necrosis or hemorrhage may exist. Microscopically, the tumor comprises spindle cells with broad fascicles that intersect at right angles. Distant metastases may occur to the lung and not infrequently to the adrenal glands according to Ramanathan (1974).
Table 119-2. Distribution of Soft Tissue Sarcomas | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Moran and colleagues (1997a) divided the pulmonary leiomyosarcomas into low-grade malignancy, intermediate-grade malignancy, and high-grade malignancy. The low-grade neoplasms have a well-developed fascicular pattern. The cells have cigar-shaped nuclei without much atypia, eosinophilic cytoplasm, and 1 to 3 mitoses per 10 high power fields (HPFs). The intermediate-grade tumors have a fairly well-preserved fascicular pattern but are more cellular. The cells have slightly more atypical hyperchromatic nuclei. Mitoses are slightly increased to 3 to 8 per 10 HPFs. Areas of hemorrhage and necrosis are not apparent. High-grade tumors show a more solid cellular proliferation with less of a fascicular pattern. The cells are markedly pleomorphic with large hyperchromatic nuclei and prominent nucleoli. Mitoses are increased to 8 to 12 per 10 HPFs, and areas of hemorrhage and necrosis are present. Immunostaining shows that most of the tumors (75%) stain for smooth muscle actin.
Treatment is surgical removal of the tumor. Shimizu and associates (1997) resected a primary pulmonary leiomyosarcoma and a hepatic metastasis in a single-stage procedure. Whether such aggressive intervention is appropriate is questionable. The prognosis is poor, with the majority of the patients dying of the disease, although a few patients have survived for 15 to 20 years. Muscolino and associates (2000) reported the successful resections and long-term survivals (7 years) in two patients with low-grade bronchial leiomyosarcoma. This report supports the conclusion of Moran and colleagues (1997a) that the grade of the tumor was one of the more important factors in determining the patient's prognosis.
Pulmonary Rhabdomyosarcoma
Rhabdomyosarcomas are malignant tumors of skeletal muscle and can occur in various age groups and in either sex. The majority of the cases occur in infants and children from the ages of 1.5 years to 14 years, but Przygodzki and associates (1995) described three cases in men ranging in age from 57 to 78 years. Comin and colleagues (2001) reported a primary pulmonary rhabdomyosarcoma in a 62-year-old patient. The symptoms depend on whether the lesion is endobronchial or parenchymal. According to d'Agostino and colleagues (1997) many of the rhabdomyosarcomas that arise in children are associated with cystic adenomatoid malformations. The chest radiographs usually show a mass that may contain cysts. The computed tomographic (CT) scan shows a soft tissue mass that may be cystic. Pathologically, the tumors have reddish gray surfaces with hemorrhagic and necrotic areas. On microscopic examination, the cells may be arranged in fascicles or may be randomly organized. The nuclei are hyperchromatic with a nucleolus and eosinophilic cytoplasm. Cross striations within the cytoplasm can be demonstrated with a phosphotungstic acid hematoxylin stain. The cells will usually immunostain for desmin, actin (HHF-35), sarcomeric actin, troponin-T, and vimentin. Treatment is surgical resection, and according to Schiavetti and colleagues (1996), it is usually combined with chemotherapy and radiation therapy. McDermott and colleagues (1993) pointed out that these patients were predisposed to develop cerebral metastases. The patient of Comin and colleagues (2001) underwent a left pneumonectomy followed by radiation. He is alive and free of disease at 9 months. In the younger age group, approximately one third of the patients died or were living with disease, and approximately two thirds were alive with no evidence of disease at varying periods of follow-up. Noda and co-workers (1995) noted that serum neuron-specific enolase was helpful in detecting metastasis and disease recurrence in a patient with alveolar rhabdomyosarcoma of the lung.
Malignant Fibrous Histiocytoma
A malignant fibrous histiocytoma is usually found in the extremities or retroperitoneum in adults. It occurs infrequently in the lung and is less common than pulmonary fibrosarcomas and leiomyosarcomas. Yousem and Hochholzer (1987a) reviewed 22 cases that they identified from the files of the Armed Forces Institute of Pathology. McDonnell and colleagues (1988) reported one case of pulmonary malignant fibrous histiocytoma and reviewed 15 other cases they found in the literature. Halyard and colleagues (1996) reported 4 cases and reviewed 49 cases that have appeared in the English-language literature. The patients in these three reports ranged in age from 18 to 80 years, with an average age of 55 years. There was a slight preponderance of men to women (30:23). The most common clinical symptoms were cough, chest pain, weight loss, and hemoptysis. Hypoglycemia and hypertrophic pulmonary osteoarthropathy also were observed in a few patients. Hermann and associates (2000) reported on a 57-year-old man with spontaneous hypoglycemia associated with this tumor, with a markedly high level of insulin growth factor-2 (IGF-2) and suppressed levels of insulin and C-peptide associated with low levels of growth hormone and IGF-1. Following resection of the tumor, insulin and C-peptide both returned to normal and the IGF-1/IGF-2 ratio increased
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to the normal reference range. In most instances, the chest radiograph showed a mass lesion, usually a large solid noncavitary mass. Calcification in the mass is rarely seen. The tumors appear to be distributed randomly between both lungs. Microscopically, most of the tumors were storiform (pleomorphic), and a few were of the myxoid or inflammatory type. Tian and associates (1997) reported seven cases seen in 11 years in their thoracic unit in Shanyang, China. The findings were similar in all respects to those in the aforementioned reports.
The primary therapeutic approach to these tumors is complete surgical excision followed by radiation therapy or chemotherapy, if either is clinically indicated. Saga and colleagues (2001) suggest the neoadjuvant as well as the postoperative use of chemotherapy (i.e., cisplatin with vindesine) in patients with large bulky lesions. Poor prognostic indicators are an advanced stage at the time of diagnosis, extension of the tumor into the chest wall or mediastinum, metastasis beyond the thorax, or incomplete excision. Halyard and associates (1996) reported that eight patients in their report had survived more than 5 years after surgical excision with or without adjuvant therapy, for a survival rate of 15%. Tian and colleagues (1997) reported a similar survival rate; 14% (one patient) at 48 months in seven patients after surgical resection of the tumor.
Pulmonary Chondrosarcoma
Morgan and Salama (1972) reported a case of pulmonary chondrosarcoma, an extremely rare tumor, and reviewed the literature. The eight patients identified with primary pulmonary chondrosarcoma ranged in age from 23 to 73 years, with an average age of 46 years. The lesions were distributed equally between the sexes. Colby and coinvestigators (1995) noted that fewer than 20 chondrosarcomas of the lung have been reported. The clinical symptoms in the order of frequency were cough, chest pain, and dyspnea. The tumor seemed to be more common in the left lung. Radiologically, these tumors have shown areas of calcification or ossification. These tumors were solid masses, but Parker and co-workers (1996) described a patient in whom the CT scan and magnetic resonance (MR) imaging mimicked a bronchogenic cyst. Grossly, these tumors had a gray surface, were circumscribed, and appeared to have a capsule. Microscopically, the tumors contained areas of malignant cartilage with calcification or ossification. These tumors are classified histologically as: (a) conventional (hyaline and/or myxoid), (b) clear cell, (c) dedifferentiated, and (d) mesenchymal. In the lung, most of these tumors have been of the conventional type. The occurrence of the other types is infrequent. The mesenchymal variant is composed of well-differentiated cartilage that may undergo calcification or even ossification, surrounded by sheets of hyperchromatic malignant small cells (blue cells) with evident staghorn vascular spaces. The mesenchymal type tends to have a more aggressive course than the other histologic types. Nonetheless, the outlook is poor in most patients. Local recurrence and distant metastases commonly occur as noted by Morgenroth (1989) and Hayashi (1993) and their colleagues, respectively. Huang and associates (2002) reported the successful surgical resection of mesenchymal chondrosarcoma of the lung and noted the immunohistochemical features of diffuse positivity against vimentin for all components and reaction to S-100 limited to the cartilaginous areas. The tumor was negative to cytokeratins, epithelial membrane antigen (EMA), leukocyte common antigen, and a panel of neuroendocrine markers. The only other case of mesenchymal chondrosarcoma of the lung in the literature that we could find was that reported by Kurotaki and colleagues (1992).
Pulmonary Osteosarcoma
Primary pulmonary osteosarcoma is rare. Loose and colleagues (1990) reported two cases and found nine other cases in the literature. For the lesion to be considered an extraosseous osteosarcoma, they adhered to the following criteria: (a) the tumor must be composed of a uniform pattern of sarcomatous tissue that excludes the possibility of a malignant mixed mesenchymal tumor, (b) osteoid or bone must be formed by the sarcoma, and (c) a primary osseous tumor must be excluded. The patients ranged in age from 35 to 83 years, with a mean of 61 years. The tumors were seen equally in men and women. The most common clinical symptom was chest pain. The sarcomas were distributed approximately equally in the right and left lungs. When possible, the tumor should be resected. The prognosis is poor. Seven patients in the collected series died of their disease, two patients died of other diseases, and three patients were alive within 2 to 14 months of follow-up. Several additional case reports of osteosarcomas have appeared in the literature in the early 1990s. Petersen (1990) reported on a 70-year-old man with a large lung mass. A technetium 99m methylene diphosphonate bone scan revealed an abnormal area in the region of the left lower lung, but not in the skeleton. After lobectomy, the lesion was diagnosed as an osteosarcoma. Connolly and associates (1991) described a 93-year-old man whose chest radiograph showed a densely calcified lung lesion. On needle biopsy it was an osteosarcoma. The patient died at home, and the family refused an autopsy. Bhalla and colleagues (1992) described a 58-year-old man with a cavitary lesion that was thought to be an abscess. The CT scan showed an irregular cavity with a partially calcified thick wall. A repeat scan 3 weeks later showed increasing calcifications and a marked increase in size. The patient was treated with drainage and antibiotics but without improvement. At autopsy, the mass was a pulmonary osteosarcoma. Chapman and co-workers (2001) reported a case of pulmonary osteosarcoma in a 33-year-old woman. She survived for 42 months after pneumonectomy, adjuvant chemotherapy, and irradiation, but she developed widespread metastatic disease. Her tumor showed an overexpression
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of bcl-2, which is an antiapoptotic protein, and cyclin D1, which drives cells from the G1 phase of the cell cycle to the S phase. Both markers have been associated with resistance to chemotherapy. In addition, the tumor showed a higher level of genomic aberrations than do skeletal osteosarcomas.
Pulmonary Liposarcoma
A primary liposarcoma is one of the rarer sarcomas that occur in the lung. Krygier and associates (1997) described a patient with a pleomorphic liposarcoma whose disease ran a rapidly fatal course despite aggressive treatment. These investigators also noted 11 other cases of primary liposarcomas of the lung that had been reported in the literature. The most common type of liposarcoma was the myxomatous variety as reported by Hochberg and Crastnopol (1956) and others. The most successful treatment is complete surgical resection when possible.
Synovial Sarcoma
Zeren (1995) and Essary (2002) and their associates reported a study of 25 and 12 cases, respectively, of primary pulmonary sarcomas with features of monophasic synovial sarcoma. In both studies, these tumors were seen slightly more often in women than in men. The majority of patients in Zeren and colleagues' (1995) study were middle-aged adults (30 to 50 years of age), but in Essary and associates' (2002) study the patients ranged in age from 20 to 72 years, with a median age of 31 years. The tumors varied in size, with a median of 4.2 cm. The clinical symptomatology consisted of chest pain, cough, dyspnea, and hemoptysis.
The tumors were either peripheral or central in location and appeared to be well circumscribed but were not encapsulated. The tumors had histologic and ultrastructural features of monophasic synovial sarcoma. Immunohistochemical studies revealed the tumor cells to react positively to vimentin, cytokeratins, and EMA. Tornkvist and colleagues (2002) discussed the unique chromosomal translocation in synovial sarcoma. The translocation is t(X;18)(p 11.2;q 11.2) resulting from the fusion of the SYT gene on chromosome 18 with the SSX gene on chromosome X. The fusion is known as the SYT-SSX fusion. Kaplan and colleagues (1996) presented two similar cases. In each (one a 12-year-old girl and the other a 40-year-old woman), the researchers also described the presence of the specific chromosome translocation t(X; 18), the SYT-SSX fusion. More recently Terasaki (2001) and Hisaoka (1999) and their co-workers reported three cases of primary synovial sarcoma of the lung that were confirmed by finding SYT-SSX fusion gene transcripts. In all patients surgical removal is suggested as the treatment of choice. The prognosis of the patients with this rare tumor is undetermined but is suspected to be poor.
Neurogenic Sarcoma
A neurogenic sarcoma is a malignant proliferation of Schwann cells. Other synonyms for this lesion include malignant schwannoma and neurofibrosarcoma. Roviaro and colleagues (1983) described an example of a primary pulmonary malignant schwannoma in a 27-year-old man. The patient was symptomatic with weight loss and chest pain. A large well-defined mass in the right lower lung field was identified on radiographic studies of the chest. Histologically the tumor consisted of immature fusiform cells in sheets and cords. Mitotic figures were common. Some of the cells tended to form fascioles with a reticular pattern resembling that of a neurofibroma. The final diagnosis was that of a malignant schwannoma. Recurrence of the tumor occurred shortly after resection, and the patient died of the malignant process 4 months after the surgical resection. A second patient was reported by Rowlands and associates (1987). A primary malignant melanotic schwannoma of the right upper lobe bronchus was identified in a 27-year-old man. A sleeve lobectomy was performed, and on histologic examination the morphology of the tumor was characteristic of a melanotic schwannoma. Areas of both Antoni A and B pattern were present, and varying numbers of melanosomes at different levels of maturation were readily demonstrated. Mitotic figures were scanty. The patient developed a cerebral metastasis and was terminal 14 months after the initial diagnosis.
McCluggage and Bharucha (1995) subsequently reported two additional cases and reviewed the literature. Their patients were 34 and 45 years of age; one was a man and the other a woman. Both presented with dyspnea and chest pain. On gross examination, one tumor was 8 cm and the other 10 cm in diameter. One was a white, circumscribed mass that had a whirled appearance on cut section. The other was also white but contained necrotic areas. On microscopic examination, the smaller tumor had a benign appearance with a fibrous capsule and spindle cells with irregular wavy nuclei. The larger tumor was highly cellular with necrosis. It had pleomorphic cells and multinucleated giant cells with easily identified mitotic figures. Immunostaining revealed that both tumors were focally positive for S-100 protein and diffusely positive for vimentin. They were negative for desmin, carcinoembryonic antigen, and CAM 5.2, a keratin. The tumor was resected in both patients, but each patient subsequently developed metastatic disease.
Primary Pulmonary Ganglioneuroblastoma
Primary ganglioneuroblastoma of the lung is rare. Only three cases have been reported in the English-language literature. Cooney (1981) reported the first case, which occurred in a 47-year-old man. The patient presented with cough and was found to have a 5-cm mass in the right lower
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lobe on radiographs of the chest. The tumor was removed by a bilobectomy of the middle and right lower lobes. On examination of the specimen, the tumor abutted the segmental bronchi, but no intrabronchial tumor was noted. Microscopically the tumor had a fibrous capsule that enclosed a rim of mature ganglioneuromatous tissue containing mature and immature ganglion cells that surrounded a central core composed of primitive neuroblastoma. Vascular invasion of the tumor was evident. Cooney suggested that the tumor arose within a sympathetic component of the posterior pulmonary plexus. The patient was living and well 2 years after the surgical resection.
The second and third cases of primary pulmonary ganglioneuroblastoma were recorded by Hochholzer and colleagues (1998). Both patients were adult women, and in each the tumor extended from an adjacent bronchus. The first patient was 38 years old and had the signs and symptoms of an advanced multiple endocrine neoplasia (MEN) type 1 syndrome. Blood chemistries supported the diagnosis. There were also radiographic findings of a 3-cm infrahilar mass and two small peripheral nodules in the right lung. The patient died within several days of admission, and the autopsy revealed the perihilar mass to be a typical ganglioneuroblastoma with direct invasion of two adjacent hilar lymph nodes but no intrabronchial extension. One of the peripheral masses was a carcinoid tumorlet and the other was a metastatic islet cell tumor of the pancreas. An islet cell tumor of the tail of the pancreas, a tumor of a parathyroid gland, and a cystic tumor of the pituitary gland were also present. The thyroid gland was normal. The second patient was 20 years old and essentially asymptomatic, but radiographs of the chest revealed a mass in the left upper lobe. A left upper lobectomy was performed and the mass, 5 5 cm in size, histologically was a typical ganglioneuroblastoma abutting and invading the bronchial lumen. No lymph node involvement was seen. Immunohistochemical studies revealed focal staining for neurofilament protein and S-100 protein and diffuse staining for neuron-specific enolase. The staining for chromogranin, keratin, and glial fibrillary acid protein was negative. The patient was alive without metastatic or locally recurrent disease 1 year after the surgical resection.
Although the eventual prognosis has yet to be determined, the primary pulmonary neuroblastomas to date appear to have a low malignant potential, and surgical resection is the treatment of choice.
Primary Malignant Triton Tumor of the Lung
A malignant neurogenic tumor with rhabdomyoblastic differentiation is known as a Triton tumor (ectomesenchymoma). These are more common in the soft tissues, and their occurrence in the lung is rare. Moran and colleagues (1997b) have described two such tumors that originated in the lung. One patient was a 3-year-old child and the other a 53-year-old man. Both patients had a large intrapulmonary mass, and each presented with marked dyspnea. Both lesions were removed by pneumonectomy. The tumors were characterized by atypical spindle cell proliferation in an abundant myxoid stroma. Areas of focal rhabdomyoblastic differentiation were present and were characterized by large cells with occasional cytoplasmic cross striations. Immunohistochemically, focal reaction to S-100 protein was present in the atypical spindle cells and a strong reaction to desmin and myoglobin was present in the rhabdomyoblastic areas. The course of the tumor was rapidly fatal in the child, and the fate of the older man is unknown as a result of no follow-up information.
Malignant Mesenchymoma
Malignant mesenchymoma is a sarcoma composed of two or more cellular elements, excluding fibrous tissue. Domizio and colleagues (1990) reported a case arising from a cyst in a 4-year-old boy. The boy had a history of pulmonary cyst in the right lower lobe diagnosed when he was 6 months old by chest radiograph, and he had a clinical history of anorexia, recurrent dry cough, and night sweats. He was anemic with an elevated sedimentation rate. At the time of admission, the chest radiograph showed an opaque right hemithorax with an air fluid level in the right midlung field and the mediastinum shifted to the left. He underwent a right lower lobectomy. On gross examination, the lobe was replaced by a necrotic tumor. The viable outer rim was composed of yellowish gray gelatinous nodules with an area of central necrosis. Microscopically, the tumor was composed of large anaplastic cells with numerous multinucleate giant cells. There were areas of rhabdomyosarcoma and chondrosarcoma. A cystic lesion was also present with multiple cystic spaces lined by epithelial cells. The patient was treated with chemotherapy and radiation therapy and was free of disease at short-term follow-up.
Sarcomas of Large Vessel Origin
A pulmonary trunk sarcoma is a primary lesion arising within the pulmonary artery or, as Mandelstramm (1923) described, from the pulmonary valve of the heart. In reviews by Wackers and colleagues (1969), Bleisch and Kraus (1980), Baker and Goodwin (1985), and Goldblum and Rice (1995), as well as by Emmert-Buck (1994) and Nonomura (1988) and their associates, undifferentiated sarcoma, leiomyosarcoma, and fibrosarcoma make up the majority of the cell types of these intravascular tumors but also include pleomorphic rhabdomyosarcoma and epithelioid angiosarcoma. Burke and Virmani (1993), after doing immunohistochemistry, concluded that most pulmonary artery sarcomas were derived from intimal cells with myofibroblastic differentiation. Ko (1996) and Leone (1996) and their co-workers both described leiomyosarcomas in the
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pulmonary vein. In the past several years, additional case reports of large vessel sarcomas have been published (see Reading References).
The large vessel sarcomas may spread distally within the vascular tree or extend outside the vessel to invade the lung tissue. The patients may be of any age. In reported cases, the age range was 21 to 81 years, with an average age of 50 years. There is a slight predominance of these large vessel sarcomas in women. The patients present with chest pain and dyspnea, and one third may also have cough, hemoptysis, and palpitations. A systolic heart murmur may be present. Pulmonary hypertension with proximal dilatation of the vessels is a constant feature. A late manifestation is right-sided heart decompensation. Moffat and colleagues (1972) reported the radiographic features, as did Britton (1990). The lesion manifests most often as a lobulated perihilar mass. Angiography may reveal multiple defects within the pulmonary artery. CT scanning and MR imaging may help to determine the extent of the disease. Mader and colleagues (1997) believe that MR imaging is the imaging modality of choice for these lesions because it is noninvasive and gives an excellent definition of the heart, pericardium, mediastinum, and lungs. MR imaging can also delineate both the extent and location of the lesion. Cox and colleagues (1997) agree with this assessment and believe the imaging findings are quite specific. Parish and associates (1996), in addition to discussing the MR imaging and CT scan features of nine cases, suggested that transesophageal echocardiography might also be useful in evaluating pulmonary trunk sarcomas. Simpson and Mendelson (2000) agree that the new imaging modalities, including helical CT and MR imaging are useful in making premortem diagnosis. They describe three cases. Treatment is resection. Head (1992) and Redmond (1990) and their co-workers, among others, reported cases in which these tumors were successfully resected. Kruger and associates (1990) reported prolonging survival with resection followed by adjuvant therapy; however, the prognosis for long-term survival is poor. Genoni and colleagues (2001) describe four patients who underwent resection for pulmonary trunk sarcomas. One had a thromboendarterectomy of the pulmonary trunk with adjuvant radiation therapy and remains disease free after 3 years. One tumor was resected, but the patient developed metastases. After chemotherapy, the metastases disappeared and the patient was alive and well 1 year later. The other two patients died within 2 months of surgery. One died as the result of a tumor mass in the inferior vena cava and the other died of cerebral metastases. Mayer and co-workers (2001) reported the results of resection in seven patients with pulmonary artery sarcomas. None of the patients died in the perioperative period. Four patients were dead after 19 months due to metastatic disease or recurrent tumor; two patients were alive after 21 and 35 months despite the presence of metastatic pulmonary disease. However, one patient was alive at 62 months with no evidence of recurrent disease.
Sarcomas of Small Vessel Origin
Angiosarcoma, epithelioid hemangioendothelioma, and hemangiopericytoma are malignant vascular tumors that occasionally may occur in the lung but are rare in this location. Kaposi's sarcoma, a vascular neoplasm, is not discussed here because it has not been described as having a primary pulmonary origin. Lastly, according to Enzinger and Weiss (1983), the term hemangioendothelioma should be used only to designate a group of vascular tumors that cannot be accurately classified histologically as to their ultimate biological behavior.
Angiosarcoma
An angiosarcoma is a malignant neoplasm of endothelial cells. They have also been called malignant hemangiomas or malignant hemangioendotheliomas. When the neoplastic endothelial cells have an epithelial appearance, the sarcomas are referred to as epithelioid angiosarcomas. Spragg and associates (1983) reviewed the literature and presented 10 possible cases of angiosarcoma arising in the lung, but some doubts exist about whether these cases were all true pulmonary angiosarcomas. Yousem (1986) believes that these tumors are most likely metastases from an angiosarcoma of the right ventricle, pulmonary arterial trunk, or an extrathoracic site. Patel and Ryu (1993) reviewed the files of the Mayo Clinic from 1950 to 1990, and they could not identify any primary pulmonary angiosarcomas. They identified 15 patients with metastatic angiosarcoma and discussed the single case reports of so-called primary angiosarcoma. Sheppard and colleagues (1997) described an epithelioid angiosarcoma of the lung in a 65-year-old man who presented with pulmonary hemorrhage. At autopsy, the lungs were hemorrhagic with multiple nodules of tumor. An angiosarcoma can be associated with a hemothorax, hypertrophic pulmonary osteoarthropathy, or both. Atasoy and co-workers (2001) reported a primary pulmonary angiosarcoma. In their report, they pointed out that the MR images showed a heterogeneous pattern consisting of hyperintense areas scattered throughout a background of intermediate signal intensity. These findings gave the lesion a cauliflower-like appearance, especially on T2-weighted images. The prognosis for patients with angiosarcoma is poor.
Epithelioid Hemangioendothelioma
Epithelioid hemangioendothelioma is a low-grade sclerosing angiosarcoma that occurs in the lung as well as the liver, bone, soft tissue, and other sites. This vascular lesion was first described by Dail and Liebow in 1975. Dail and colleagues (1983) reviewed an additional 19 cases. They initially called this tumor an intravascular bronchioloalveolar tumor (IVBAT), but they now prefer the term sclerosing endothelial tumor. Weiss and Enzinger (1982) described 41 cases of an identical tumor occurring in soft tissue and proposed
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the name epithelioid hemangioendothelioma, which has become widely accepted. Weiss and colleagues (1986) published a combined review of lesions in soft tissue, lung, liver, and bone. Since then, individual case reports have appeared in the literature (see Reading References). Wenisch and Lulay (1980) reported that, in the lung, these tumors occur in patients who are 4 to 70 years of age, with one third of the patients less than 30 years of age. The tumor occurs four times more frequently in women than in men. Most of the patients are asymptomatic or complain of a nonproductive cough. Ross and associates (1989) note that the chest radiographs and CT scans reveal many small (<1 cm in diameter) nodular densities in both lung fields. According to Moran and Suster (2000), the tumors are characterized by proliferation of round-to-oval epithelial endothelioid cells. These cells contain abundant cytoplasm with oval nuclei embedded in a hyaline matrix. The tumor has a tendency to fill the alveoli in a polypoid fashion. The cells are immunohistochemically positive for endothelial markers (factor VIII related antigen, Ulex europucus lectin, CD31, and CD34). Weibel-Palade bodies may be seen infrequently on electron microscopic examination. The average survival after diagnosis is 4.6 years, but Miettinen and associates (1987) reported a patient who survived for 24 years with repeated surgical excisions. Kitaichi and co-workers (1998) reviewed 21 patients with epithelioid hemangioendothelioma. They found three subsets of patients who had a poor prognosis. These patients had either pleural effusions, tumors with a spindle cell component, or fibrinofibrous pleuritis with the presence of extrapleural tumor cells. Kawashima and colleagues (1995) reported a case and suggested that aggressive surgical intervention is the treatment of choice for these lesions. Death from pulmonary insufficiency is the usual course of this disease.
Hemangiopericytomas
Hemangiopericytomas are unusual sarcomas derived from the ubiquitous capillary pericytic cell and are commonly located in the soft tissues of the thigh and retroperitoneum. Yousem and Hochholzer (1987b) found that pulmonary hemangiopericytomas occurred with equal frequency in men and women; the average age of patients was 46.1 years. Approximately one third of the patients were asymptomatic. Those with symptoms complained of chest pain, hemoptysis, dyspnea, and cough. One patient had pulmonary osteoarthropathy. Radiographs of the chest usually show a lobulated, well-circumscribed, homogeneous soft tissue density, but other findings may be present (Fig. 119-3). Rusch and colleagues (1989) found that MR imaging was critical in the preoperative evaluation of these patients because of its ability to delineate the anatomic extent of the lesion. Treatment is surgical excision. Prognosis is variable. Indicators of a poor prognosis are chest symptoms, tumor greater than 8 cm in diameter, pleural and bronchial wall invasion, tumor giant cells, more than three mitoses per 10 HPFs, and tumor necrosis. Shin and Ho (1979) noted that 33% of patients with tumors 5 cm or larger had metastasis and 66% of those with tumors 10 cm or larger had metastasis. Davis and co-workers (1972) demonstrated that most recurrences took place within 2 years of diagnosis. Enzinger and Smith (1976) and Feldman and Seaman (1964) reported that chemotherapy and radiation therapy do not consistently help the patient. In separate case reports, Wu (1997), Shimizu (1993), Kiefer (1997), Van Damme (1990), Rusch (1989), and Hansen (1990) and Brega Massone (2002) and their colleagues described their experience with pulmonary hemangiopericytomas. The patients described by Van Damme and co-workers (1990) died
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within several months of their operation. In contrast, the patient of Rusch and associates (1989) was disease free 28 months after surgical excision. Wu and colleagues (1997) described a patient who had an associated coagulopathy that recurred when the tumor recurred.
 |
Fig. 119-3. A. Posteroanterior radiograph of the chest reveals a 5-cm mass in the right lower lobe. Suggestion of additional masses evident on the levels of the second and third anterior interspaces. B. CT scan reveals a mass in the right lower lobe with multiple satellite lesions. Histologic examination of the resected specimen revealed a poorly differentiated hemangiopericytoma. |
CARCINOSARCOMA
The terminology of carcinosarcoma has been changing as pathologists examine these neoplasms more closely. A carcinosarcoma is defined as a malignant neoplasm composed of both malignant epithelial and mesenchymal elements. The mesenchymal component should show differentiation into specific heterologous mesenchymal tissues, such as bone, cartilage, or striated muscle, but not fibroblasts. The purpose of this definition was to separate carcinosarcoma from spindle cell carcinoma. A spindle cell carcinoma is a type of squamous cell carcinoma with spindling of the squamous cells and the presence of squamous islands. Heterologous sarcomatous elements, such as osteosarcoma, are not identified in these spindle cell carcinomas. Nappi and associates (1994) reviewed 21 cases of carcinosarcomas and spindle cell carcinomas. They believed
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these two neoplasms were merely part of a spectrum and suggested adopting the names biphasic sarcomatoid carcinoma for carcinosarcoma and monophasic sarcomatoid carcinoma for spindle cell carcinoma. They noted that both of these tumors tended to behave in an aggressive fashion, with 20 of their patients dying within 2 years and only 1 patient alive with no evidence of disease at 21 months. Ishida and colleagues (1990) described five cases of carcinosarcoma and three cases of spindle cell carcinoma. Kimino and co-workers (1996) described a case in which the sarcomatous component was positively stained by the EMA, suggesting a sarcomatous transformation of the carcinomatous component of the tumor. Grahmann and co-workers (1993) reported three cases of carcinosarcoma and reviewed the literature, as did Berho (1995) and Wick (1997) and their colleagues. Wick and colleagues (1997) went on to place both these tumors under the designation sarcomatoid carcinoma.
 |
Fig. 119-4. Posteroanterior (A) and left lateral (B) chest radiographs of a 75-year-old man with suspected myocardial infarction. An asymptomatic 3 3 2 cm mass is identified just below the aortic arch. CT scan (C) demonstrates a solitary parenchymal lung mass. Photomicrograph (D) shows the lesion is a carcinosarcoma of the lung after its removal by a left upper lobectomy. |
Carcinosarcomas (sarcomatoid carcinomas) frequently have a slow rate of growth. Much of the growth can be endobronchial with little propensity to infiltrate the bronchial wall, but extensive invasion into the surrounding lung does occur. Metastases to the regional lymph nodes and to distant organs, especially to the brain, are common. The more common symptoms are cough and hemoptysis. Chest pain, fever, and malaise may occur. Meade and co-workers (1991) described a patient with associated pulmonary osteoarthropathy. Patients with a peripheral tumor may be asymptomatic. Bronchial biopsy may be followed by excessive hemorrhage but is nonetheless indicated for the preoperative evaluation of an endobronchial lesion. Surgical resection, when possible, is the indicated treatment. In most series, however, most of the patients die within the first year of resection. Approximately 16% to 23% of patients may survive 5 years or longer. However, in the series reported by Miller and Allen (1993), a 5-year survival rate of only 6% was recorded. Koss and co-workers (1999) studied 66 cases of carcinosarcomas. The patients had a mean age of 65 years with a ratio of men to women of 7.25:1. The tumors usually presented in the upper lobes and many measured 7 cm in greatest dimension. The majority (62%) were endobronchial or central, with 38% being peripheral in location (Fig. 119-4). The 5-year survival rate was 21.3%. Only the tumor size (<6 cm) appeared to be adversely related to survival.
Recently, several single case reports by Shah and Sabanathan (2002) as well as those by Kim (2002) and Saha (2002) have been published, but no new essential information was added to our understanding of these interesting tumors.
PULMONARY BLASTOMA
Barnard (1952) first reported a pulmonary blastoma but called it an embryoma. Spencer (1961) reviewed Barnard's case, added three cases of his own, and renamed the tumor a pulmonary blastoma. These tumors comprise both malignant mesenchymal stroma and epithelial components that resemble the lung at 3 months' gestation (primitive blastoma and epithelial tubules). The two malignant components make the pulmonary blastoma conceptually similar to the carcinosarcoma.
Kradin and associates (1982) reported a histologic variant that contained malignant fetal-type glands but not a malignant stroma. They called this neoplasm a pulmonary endodermal tumor resembling fetal lung. It later came to be known as a well-differentiated fetal adenocarcinoma (WDFA). Manivel and co-workers (1988) described a neoplasm in children that they termed the pleuropulmonary blastoma. In contrast to the WDFA, this neoplasm comprises malignant mesenchyme and blastema but no malignant glands. In summary, a pulmonary blastoma has both malignant mesenchymal and epithelial tissue, the pleuropulmonary blastoma has malignant mesenchyme and blastema, and the WDFA has only malignant epithelial cells.
Pulmonary Blastoma and Well-Differentiated Fetal Adenocarcinoma
Larsen and Sorensen (1996) reviewed the subject of pulmonary blastomas, and they estimated their incidence to be only 0.5% of all pulmonary neoplasms. Francis and Jacobsen (1983) reviewed 72 cases and added another 11 of their own. Koss and associates (1991) reviewed 52 cases and divided them into WDFAs and pulmonary blastomas. In the review of Larsen and Sorensen (1996), the researchers described 156 cases of pulmonary blastoma with a median age of 40 years and an age range of newborn to 80 years. The ratio of men to women was approximately 2:1. They described 23 cases of WDFA with a median age of 40 years and an age range of 12 to 73 years, with this tumor being approximately divided evenly between men and women. In Koss and associates' (1991) study, the average age at the time of diagnosis was 35 years, although the range was from less than 1 year to 72 years of age. The tumor occurred slightly more frequently in women than in men. Twenty-one of 52 patients (41%) were asymptomatic, and the tumors were discovered on routine chest radiographs. They did not separate the WDFA from the pulmonary blastomas when they described the patient demographics. The most common clinical complaints were cough, hemoptysis, and dyspnea. In a large percentage of cases, the chest radiographs revealed a unilateral pulmonary mass randomly located in the lung. The tumors were peripheral or hilar, and some involved both regions. Results of clinical laboratory tests were nonspecific. Sputum cytology was negative in the six patients from whom it was obtained. Bronchoscopy and fine-needle aspiration (FNA) were variably helpful in the diagnosis of the tumor.
Twenty-eight of the 52 tumors (54%) were classified as WDFA; the other 24 (46%) were biphasic blastomas. The WDFAs ranged in size from 1 to 10 cm, with a mean of
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4.5 cm. Histologically, they were malignant glands composed of pseudostratified columnar epithelium and benign stroma. The biphasic blastomas ranged in size from 2 to 27 cm, with a mean of 10.2 cm. Histologically, these were malignant glands and either an adult sarcomatous or embryonic mesenchyme. Bodner and Koss (1996) studied nine pulmonary blastomas and 12 WDFAs for mutations in the p53 gene. They found a mutation in five of nine (42%) pulmonary blastomas but none in the WDFAs. In the pulmonary blastomas, both the epithelial and mesenchymal components showed the mutation, suggesting they both came from a single clone of cells. Nakatani and colleagues (1998) further differentiated fetal adenocarcinomas of the lung into high-grade and low-grade forms. They described seven cases of the high-grade form. The patients ranged in age from 46 to 70 years, with most patients in their sixties. There were four men and three women. Several were discovered on a routine chest radiograph, but most were symptomatic with a cough, dyspnea, or chest discomfort. In five patients, the lesions were on the left side and in two patients they were on the right side. The resected tumors ranged in size from 3 to 9.5 cm in greatest dimension. Microscopically, the tumors were composed of complex glandular structures whose cells had large atypical nuclei. Several cases also showed a stroma of spindle cells (biphasic pattern). Five of the seven patients were dead of disease, with the survival ranging from 1 month to 7 years and with all of these patients being smokers. Two patients were alive at 1 and 2 years with these two patients being nonsmokers.
The group of patients with low-grade fetal adenocarcinoma of the lung consisted of nine patients who ranged in age from 19 to 55 years, with most of the patients being in their thirties. The patients were almost equally divided between men and women. Only one patient had pulmonary symptoms (cough and hemoptysis). The lesions were almost equally divided between the left and right lungs. The resected tumors ranged in size from 1.4 to 5 cm. Microscopically, the tumors were only composed of glands. The cells had small nuclei with clear cytoplasm. One patient died of disease at 2 years, one was lost to follow-up, and seven were alive and well at intervals ranging from 2 to 10 years. Most of the patients were light smokers. The treatment of choice is surgical resection. Occasionally, adjuvant chemotherapy has been used. Postoperatively, the patients with the WDFA type of pulmonary blastoma have better survival rates than those with the biphasic type. Nakatani and associates (1990, 1998) also noted that those patients with a low-grade malignant fetal adenocarcinomatous type of tumor had a better prognosis than those with high-grade malignant features. In the series by Koss and colleagues (1991), tumor metastases and recurrence were poor prognostic signs. In patients with biphasic pulmonary blastoma, tumors less than 5 cm in greatest dimension carried a prognosis that was more favorable than that noted with the larger tumors.
Pleuropulmonary Blastoma
Priest and colleagues (1997) reported 50 cases of pleuropulmonary blastomas. Their report included the 11 cases previously reported by Manivel and co-workers (1988). They classified the lesions as types I, II, and III based on whether the lesions were cystic (type I), cystic and solid (type II), or solid (type III). Their patients ranged in age from a newborn to 12 years. They found that each type tended to occur at a different age. Type I (seven patients) presented at an average age of 10 months. Type II (24 patients) presented at an average age of 34 months. Type III (19 patients) presented at an average age of 44 months. There were 24 boys and 26 girls. Their symptoms included respiratory distress, fever, chest or abdominal pain, and malaise. The chest radiographs showed densities, sometimes with cystic formation. On gross examination, the tumors ranged in size from 2 to 28 cm and weighed up to 1,100 g. The appearance ranged from cystic to solid, with gray, soft surfaces. On microscopic examination, the type I tumors had multiloculated cysts separated by thin septa and lined by respiratory mucosa. Beneath the epithelium, there were round to spindle-shaped immature cells. Some of these cells had the appearance of rhabdomyoblasts. The type II and III tumors had mixed sarcomatous and blastomatous elements. Rhabdomyoblasts and chondroblasts could be identified in the sarcomatous areas. The immunohistochemical studies showed the rhabdomyoblasts to stain for muscle-specific actin and desmin. Electron microscopy studies also supported the presence of skeletal muscle and cartilage. In addition to case reports (see Reading References), Indolfi and co-workers (2000) recently described another 11 cases of pleuropulmonary blastoma. The patients had a median age of 32 months, with seven boys and four girls. The most common presenting symptom was respiratory distress. Hill and colleagues (1999) reported a case of pleuropulmonary blastoma in a 36-year-old man, which is unusual since most of these patients are children under 5 years of age. The patient died less than 1 year after diagnosis. The treatment for these lesions is surgical excision followed by chemotherapy and rarely by radiation therapy. The thorax was a common site of recurrence. The central nervous system and bone were also common metastatic sites.
At the last follow-up in Priest and colleagues' (1997) study of 50 patients, 26 of the patients were disease free, 23 had died of their disease, and 1 was alive with disease. Although statistically there did not seem to be a survival advantage of one type over another, the data seemed to suggest that patients with the type I tumor may have a survival advantage over those with a type II or III tumor. The 2-year survival rate was 80% for type I, 73% for type II, and 48% for type III. Overall, 2-year survival was 72%. This tumor remains an aggressive neoplasm of early childhood, despite advances in adjuvant therapy.
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OTHER UNCOMMON PRIMARY MALIGNANT TUMORS OF THE LUNG
Mucinous Cystic Tumor of Borderline Malignancy
As noted in Chapter 118, pulmonary cystic mucinous tumors are rare. This tumor was first reported by Kragel and associates (1990) and subsequently by Roux and colleagues (1995). These were believed to be benign, but in 1991 Graeme-Cook and Mark suggested that some of the tumors were of borderline malignancy. Other investigators, including Davison (1992) and Higashiyama (1992) and their associates, reported frank adenocarcinoma arising in pulmonary cystic mucinous tumors. The histopathologic findings in these tumors with borderline malignancy are subtle. The tumor nuclei tend to be hyperchromatic, with mild to moderate atypia and occasional mitotic figures. Tumor cells may occasionally be found floating in mucin within the cyst. When any such findings are present, Mann and colleagues (2001) strongly suggest the lesion be treated as a malignant tumor and a standard lobectomy rather than a local excision be performed. The prognosis should be satisfactory with the appropriate excision of the lesion, although too few cases have been reported to state this unequivocally.
Basaloid Carcinoma of the Lung
Basaloid carcinoma of the lung may be considered as one variety of the non small cell, nonneuroendocrine lung carcinomas. It was initially described by Brambilla and associates in 1992 as a separate entity from a group of poorly differentiated squamous cell and undifferentiated large cell carcinomas. Grossly these tumors are located in the lobar or segmented bronchi in 85% of the cases; 15% are located more distally. The tumor is usually exophytic but is associated with bronchial wall invasion. Foroulis and colleagues (2002) described a basaloid carcinoma that was originally misdiagnosed as a small cell carcinoma. Brambilla (1997) and associates (1992) have described the histologic features of this tumor: small moderately pleomorphic cuboidal to fusiform cells with hyperchromatic nuclei with granular dense chromatin and a scanty amount of cytoplasm. The mitotic index is high. Immunohistochemically, the basaloid carcinomas express low-molecular-weight cytokeratins, and in 90% of cases neuroendocrine markers are absent. Genetic studies have shown p53 is stabilized in 85% of these tumors. The origin of the tumor is thought to be from the basal, pluripotent reserve cells of the bronchial mucosa.
The basaloid carcinomas of the lung are highly aggressive, and despite resection of even early-stage lesions, with or without subsequent irradiation, the 5-year survival rate has been reported to be zero by Moro and colleagues (1994).
Primary Pulmonary Choriocarcinoma
Primary pulmonary choriocarcinoma is a rare tumor first described by Hayakawa and colleagues in 1977. This tumor is discovered almost exclusively in men. Only one of the small number of the reported cases has been in a woman. Uwatoko and Kajita (1997) reported one case in a man and reviewed five other cases that were reported in the Japanese literature. The two cases reported by Hayakawa and colleagues (1977) have been included in most reviews. Two other cases reported by Nakamura (1982) and Endo (1988) and their associates, as well as that of Uwatoko and Kajita (1997) and the Russian report by Uspenski and colleagues (1982), have been missed in most English-language reviews. More recently, Tsai and co-workers (2002) reported a case. The total number of reported cases is probably 25.
The tumor may present as a peripheral nodule, as in the case reported by Canver and Voytovich (1996), but in most of the patients the tumor is far advanced locally and accompanied by distant metastases at the time of diagnosis. The serum -human chorionic gonadotropin ( -HCG) level is elevated well above normal in most cases. Tsai and colleagues (2002) suggested the use of a urine pregnancy test as a rapid technique to suggest the diagnosis of this tumor. Gynecomastia is a common finding in these men.
Histologically the tumor has the appearance of a typical choriocarcinoma (an admixture of anaplastic cytotrophoblastic cells and syncytiotrophoblastic cells). Recently, Chen and associates (2001) described a combined choriocarcinoma and adenocarcinoma in the lung of a 61-year-old man. The anaplastic cytotrophoblastic cells exhibit immunohistochemical reactivity to HCG antigen. Most patients have been managed by a combination of radiation therapy and chemotherapy, as noted by Sridhar (1989) and Tanimura (1985) and their associates. The recommended chemotherapy of a choriocarcinoma at the present time as suggested by Ghosn (1988) and Garris (1995) and their co-workers is a combination of etoposide, ifosfamide, and cisplatin. Uwatoko and Kajita (1997) added surgical resection of the primary tumor in addition to chemotherapy. With rare exception, however, survival is recorded in months despite aggressive therapy, and long-lasting control of the tumor remains elusive.
Lymphoepitheliomalike Carcinoma of the Lung
The first patient with a lymphoepitheliomalike carcinoma of the lung was described by Begin and associates (1987). To date there have been 50 case reports in the literature. Most of the reported lymphoepitheliomalike carcinomas of the lung have occurred in patients of Asian descent, especially those from Southeastern China. Previous exposure to Epstein-Barr virus (EBV) has been documented in these Asian patients. Han and co-workers (2000) reviewed 3,663 consecutive cases of lung carcinoma in southern China and found 32
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cases that met the criteria for lymphoepitheliomalike carcinoma. They tested these 32 cases as well as 19 non-lymphoepitheliomalike carcinoma by in situ hybridization and immunohistochemistry for EBV-encoded small nonpolyadenylated RNA (EBER). Of the 32 cases, 30 (94%) were positive for EBER, but none of the 19 control cases were positive. They concluded that EBV infection may have an essential role in the tumorigenesis of pulmonary lymphoepitheliomalike carcinoma. Chang and associates (2002) found similar results in 23 patients and also thought that EBV probably played a role in the tumorigenesis of these malignancies. These authors also found that the tumors expressed bcl-2, which probably gave the infected cells a growth advantage. Latent membrane protein-1 expression as well as p53 and C-erb-B-2 expression were extremely low in these tumors. In the small number of non-Asian patients in whom this tumor has occurred, previous exposure to EBV has not been documented. The histologic features of the tumor in both Asians and non-Asians are typical of the lymphoepitheliomalike carcinomas seen in the nasopharynx and those occasionally seen in the thymus (see Chapter 173). Most of the lung lesions are solitary masses; occasionally, lymph node metastases may be present, as in the patient reported by Frank and colleagues (1997) of our group. These researchers, as well as Curcio and associates (1997), have reviewed the literature on this subject.
The usual therapy for these unusual tumors has been surgical resection. Curcio (1997), Frank (1997), and Chang (2002) and their co-workers added intensive chemotherapy after the initial resection. The rationale of adding adjuvant chemotherapy is based on the study of Al-Sarraf and associates (1996), who reported the superiority of chemotherapy versus radiation therapy with locally advanced nasopharyngeal lymphoepitheliomalike carcinoma. Chang and associates (2002) recommended the use of gemcitabine and cisplatin. With surgery alone, in early-stage pulmonary disease the short-term survival rate has been satisfactory, but the long-term prognosis is yet unknown. Likewise, the value of chemotherapy as an adjunct in patients with resected pulmonary lymphoepitheliomalike carcinoma remains unknown. Han and colleagues (2001) subsequently compared the long-term survival of their 32 cases of pulmonary lymphoepitheliomalike carcinoma with 84 cases of pulmonary non-lymphoepitheliomalike carcinoma. They found that a pulmonary lymphoepitheliomalike carcinoma had a better prognosis in stages II, III, and IV than did a typical non small cell carcinoma of the lung.
Malignant Melanoma of the Bronchus
Miller and Allen (1993) reviewed 80 patients over a 10-year span with rare pulmonary neoplasms at the Mayo Clinic. Only three patients had pulmonary melanoma, which represents 0.03% of their 10,134 patients with lung cancer. Jennings and colleagues (1990) described a primary malignant melanoma of the lower respiratory tract and summarized another 19 cases in the literature. They used the following criteria to exclude other possible primary sites: (a) no previously removed skin lesion, particularly pigmented; (b) no ocular tumors removed and no enucleation; (c) solitary tumor; (d) morphologic tumor characteristics compatible with a primary tumor; (e) no demonstrable melanoma in other organs at the time of removal; and (f) autopsy without primary melanoma demonstrated elsewhere, especially the skin or the eyes. The differentiation of a primary melanoma from a melanin-containing carcinoid tumor is necessary in all cases. The immunohistochemical and ultrastructural differences between these two tumors (Table 119-3) may be helpful in this regard. In the 20 reported cases reviewed by Jennings and colleagues (1990), the patients ranged in age from 29 to 80 years, with almost equal distribution between men and women. In 4 patients, the melanoma arose in either the trachea or the tracheal carina, whereas in the remaining 16 patients, the melanoma arose in bronchial sites involving any one of the lobes of the lungs. The clinical symptoms, physical findings, and radiographic features were not described for many of these patients, although melanomas
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arising in the bronchus behave clinically like a primary lung carcinoma with resulting bronchial obstruction. Marchevsky (1995) pointed out that bronchial melanomas are morphologically similar to those of the skin and mucosa. These melanomas, as noted in Table 119-3, also immunostain for S-100 protein and HMB-45 but not for neuroendocrine markers, which helps separate them from carcinoids. Wilson and Moran (1997) also described the immunohistochemistry for seven primary pulmonary melanomas. They found the seven tumors to be positive for S-100, HMB-45, and vimentin, but negative for cytokeratin, CAM 5.2 (a keratin), and chromogranin. If a melanoma is encountered and no history or evidence of a simultaneous or previous primary lesion can be elicited, resection should be performed if possible. Treatment instituted in the cases reported in the literature ranged from no therapy to resection of the entire lung. Eight patients died of their disease, six were free of disease for as long as 11 years, and two other patients were free of disease at 12 and 19 months. Ost and colleagues (1999) described an additional case of pulmonary melanoma and concluded that aggressive surgical resection, regardless of lymph node involvement, offered the best long-term survival.
Table 119-3. Differentiation of a Primary Melanoma of the Lung and a Melanin-Containing Carcinoid | |||||||||||||||||||||||||||||||||||||||||||||
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Malignant Teratomas
Intrapulmonary teratomas are uncommon; half of these tumors may be malignant. Day and Taylor (1975) reviewed the available literature and noted that for some unexplained reason, most malignant teratomas occurred in the left upper lobe. In the past, some malignant lesions have been confused with the pulmonary blastomas. The prognosis of a malignant teratoma is poor. Kakkar and associates (1996) described a pulmonary teratoma with a yolk sac tumor. The patient was a 20-year-old man who presented with a history of fever, chest pain, dry cough, and a recent onset of hemoptysis. The chest radiograph showed a consolidation in the right middle lobe. He died 4 days after admission. Grossly, the right middle and upper lobes were involved with a tumor that showed necrosis and hemorrhage. Microscopically, the tumor showed benign elements from all the germ layers. It also contained malignant glands and areas of yolk sac tumor. The immunostain for -fetoprotein was focally positive. In addition, this patient had myeloid metaplasia with atypical megakaryocytes in the liver, spleen, hilar lymph nodes, and the left adrenal gland, as well as myelofibrosis in the marrow. Kakkar and associates (1996) note this is the first described malignant teratoma of the lung associated with a hematologic malignancy.
Malignant Meningioma
The two cases of malignant meningioma have been described in Chapter 118, along with the more common benign primary pulmonary meningiomas.
Malignant Ependymoma
A case report of a possible primary malignant ependymoma of the lung was reported by Crotty and associates (1992). This heretofore unreported pulmonary lesion occurred in a patient previously treated for small cell lung cancer (SCLC). The ultrastructural and immunohistochemical features of the solitary peripheral ependymoma and the original small cell tumor were remarkably dissimilar. It was hypothesized that a metaplastic event related to therapy may have caused an unexplained alteration of the original tumor phenotype. The importance of this observation remains to be determined.
Sebaceous Carcinoma of the Lung
Borczuk and associates (2002) described the occurrence of what they believe to be the first case of a sebaceous carcinoma of the lung. These lesions are normally found in the skin around the eye and the eyelids and have been described rarely as occurring in the parotid gland and in the larynx. The lesion, just over 2 cm in size, originated in a left lower lobe bronchus of an adult. The tumor was located endobronchially but invaded the bronchial wall. The tumor was removed by a standard lobectomy. Histologically, the tumor cells were diffusely located throughout the tumor as sebaceous foci of cells with vacuolated cytoplasm. Numerous mitotic figures were seen. The vacuolated cells were negative for mucicarmine but were positive for sebaceous differentiation by the oil red O stain for lipid. Ultrastructure investigation revealed lipid-filled cells stained by toluidine blue. Immunohistochemical studies revealed cytokeratin reactivity (positive CAM 5.2, K903, and AE1/AE3), as well as positivity to EMA and polyclonal carcinoembryonic antigen. The patient remains well without evidence of disease 3 years postsurgery.
PULMONARY LYMPHOMA
Lymphomas of the lung can be divided into Hodgkin's lymphoma and non-Hodgkin's lymphoma. Primary pulmonary lymphomas (PPLs) are rare. L'Hoste and colleagues (1984) reported that these tumors represented 0.5% of all lung tumors, and Miller and Allen (1993) recorded a 0.33% incidence. Secondary involvement of the lung by lymphoma, however, is common and is the result of spread of original mediastinal disease, especially Hodgkin's lymphoma (disease).
Secondary Pulmonary Lymphomas
Kern and associates (1961) reported secondary involvement to be as high as 40%, but Fisher and associates (1962) believed it was less. Berkman and associates (1996) noted
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that pulmonary parenchymal involvement occurred in 38% of Hodgkin's lymphoma and 24% of non-Hodgkin's lymphoma. In a review of 108 patients with newly diagnosed Hodgkin's disease, in whom the extent of the thoracic disease was evaluated by CT scans, Diehl and co-workers (1991) found thoracic involvement in 77. In these patients, they observed a pattern of contiguous spread from the anterior mediastinal or paratracheal areas, to adjacent mediastinal lymph node groups, to the hilar nodes, and lastly into the lungs. The pulmonary involvement was present as either direct extension or discrete nodules. Only when bulk disease (with an anterior mediastinal or paratracheal mass <30% of the thoracic diameter) was present was involvement noted in the pleura, pericardium, or chest wall. Any exception to these patterns suggests the presence of a disease process other than Hodgkin's disease. In non-Hodgkin's lymphoma, Risdall and associates (1979) found lung involvement at autopsy in 39 of 72 patients. Most of these lymphomas that involved the lung were of the large cell type.
After treatment of an initial thoracic lymphoma, recurrent or secondary involvement of the lungs and thorax may have manifestations entirely different from those seen with original disease. Lewis and colleagues (1991) reported that in 31 patients with recurrent or secondary lymphoma of the lungs (15 with Hodgkin's disease and 16 with non-Hodgkin's lymphoma), CT scans identified the following findings: (a) pulmonary nodules of less than 1 cm; (b) mass or masslike consolidations of more than 1 cm, with or without cavitation; (c) alveolar or interstitial infiltrates; (d) masses of pleural origin; (e) peribronchial or perivascular thickening, with or without atelectasis; (f) pleural effusions; and (g) hilar or mediastinal adenopathy. In most patients (68%), three or more of these CT abnormalities were present simultaneously. Unfortunately, whether these CT findings, especially multiple simultaneous findings, can effectively differentiate secondary pulmonary parenchymal lymphoma from other pathologic processes without invasive confirmation remains to be seen. Of note is the observation that the prognosis of primary lymphoma of the lung is better than that of secondary involvement of the lung (Fig. 119-5).
Primary Pulmonary Lymphoma
Non-Hodgkin's Lymphoma
The multiple classification schemes for non-Hodgkin's lymphoma have confused clinicians and pathologists alike. These schemes are those of Jackson and Parker (1947), Rappaport (1966), Lukes and Collins (1975), the Kiel classification reported by Lennert (1978), and the Working Formulation of the Non-Hodgkin's Lymphoma Pathologic Classification Project (1982). Costa and Martin's (1985) classification of pulmonary lymphoid disorders is both practical and useful. However, several new entities, such as the mucosa-associated lymphoid tissue (MALT) lymphoma, have been described in recent years, and a new classification system has been proposed: the Revised European-American Lymphoma (REAL) classification. Chan and colleagues (1995), as well as Harris and associates (1994), described this new classification. Since then, Harris and co-workers (2000a,b) and Chan (2001) have both described the new World Health Organization (WHO) classification of lymphomas. Travis and Galvin (2001) classified the nonneoplastic lymphoid lesions as follicular bronchiolitis (diffuse lymphoid or MALT hyperplasia), lymphocytic interstitial pneumonia (LIP), and nodular lymphoid hyperplasia (pseudolymphoma, or PSL). It is listed and compared with the Rappaport classification and the Working Formulation in Table 119-4. The REAL classification is the basis for the WHO classification. Unlike previous classifications, it does not group lymphomas into prognostic categories (Table 119-5). Table 119-6 shows the clinical stage grouping of primary
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pulmonary non-Hodgkin's lymphoma as modified from the original Ann Arbor classification.
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Fig. 119-5. Survival curves of patients with primary and secondary lymphoma of the lung. SLP, survival curve of patients with small lymphocytic proliferation including those with small cell lymphocytic lymphoma as well as pseudolymphoma or lymphocytic interstitial pneumonia; PL, survival curve of patients with presumed primary lymphoma of the lung, limited to one or both lungs, exclusive of primary Hodgkin's disease; DL, Survival curve of patients with disseminated lymphoma of extrapulmonary origin involving the lungs. From Kennedy JL, et al: Pulmonary lymphomas and other pulmonary lymphoid lesions: a clinicopathologic and immunologic study of 64 patients. Cancer 56:539, 1985. With permission. |
Table 119-4. Pulmonary Lymphoreticular Disorders | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Table 119-5. World Health Organization Lymphoma Classification | ||
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The rare PPL may occur in any of the deposits of lymphoid elements normally present in the lung: (a) in the bronchial-associated lymphoid tissue (BALT), which represents MALT (MALT is becoming the preferred term, although both are used in the literature); (b) in the interstices of the lung parenchyma; or (c) in the intrapulmonary and subpleural lymph nodes (intrapulmonary and subpleural lymph nodes are normally present, particularly in persons <25 years of age). Using pulmonary lymphangiography, Trapnell (1964) demonstrated that 18% of normal persons had intrapulmonary nodes within the lung parenchyma (see Chapter 6).
Table 119-6. Clinical Staging Grouping of Pulmonary Non-Hodgkin's Lymphoma | ||||||
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Primary non-Hodgkin's pulmonary lymphoma develops from B lymphocytes predominantly. Husband and Gowans (1978) reported that the primary lymphoma develops from centrocytelike cells, which in turn develop from parafollicular B lymphocytes. These B lymphocytes express either - or -immunoglobulin light chains (so-called light chain restriction) and imply a clonal proliferation derived from a single B cell. Although the tumor is often referred to as a B-cell lymphoma, as in the report of Uppal and Goldstraw (1992), these tumors more frequently are referred to as small cell lymphocytic lymphomas or as large cell (histiocytic) lymphomas.
The pathologist may have difficulty in separating benign lymphoid lesions, such as LIP and nodular lymphoid hyperplasia, formerly known as PSL of the lung, from primary pulmonary lymphocytic lymphomas. Addis and co-workers (1988) studied 15 cases of pulmonary lymphoid lesions with immunohistochemical staining for various B-cell markers. They concluded that cases of nodular lymphoid hyperplasia and LIP required careful evaluation because many of them are really PPLs. Bragg and colleagues (1994) emphasized that with monoclonal antibodies and molecular biology, it is possible to establish whether a group of lymphocytes is monoclonal or polyclonal in origin. This distinction is important because monoclonal proliferations are considered malignant and polyclonal ones are considered benign. Kradin and Mark (1983) applied the term diffuse lymphoid hyperplasia to LIP. This term may be better for describing this lesion, but now it serves to confuse clinicians.
Saltzstein (1963) addressed the problem of separating benign from malignant lymphoid lesions by proposing three criteria for PPLs. His criteria were (a) immature lymphocytes, (b) absence of germinal centers, and (c) involvement of hilar lymph nodes. Despite these criteria for differentiating benign from malignant lymphoid lesions, there are reports of LIP and nodular lymphoid hyperplasia
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progressing to PPL. Turner and associates (1984) tried to clarify the situation with regard to pulmonary lymphoid lesions by proposing that a pattern of lymphangitic spread and a monomorphic cell population could be used to separate the malignant and benign lesions. With regard to Saltzstein's criteria, they pointed out that germinal centers could be seen with lymphomas and that hilar lymph nodes are not always involved when a lymphoma is present. Hence, the lack of hilar lymph node involvement should not be used to support the diagnosis of a benign lymphoid process. In conclusion, truly benign lymphoid lesions of the lung (LIP and nodular lymphoid hyperplasia) probably exist, but they must be viewed with caution.
Recently, Abbondanzo and colleagues (2000) examined 14 cases of pulmonary nodular lymphoid hyperplasia collected from the files of the Armed Forces Institute of Pathology from 1974 to 1998. They performed state-of-the-art immunohistochemistry on 12 of the 14 cases and gene rearrangement studies on 10 of 14 cases. In none of the cases did they find evidence of a lymphoma. Their study supports the concept that benign pulmonary lymphoid lesions exist.
Follicular Bronchiolitis
Follicular bronchiolitis or diffuse lymphoid hyperplasia or MALT hyperplasia is described by Travis and Galvin (2001). MALT, or as some authors call it, BALT, is found along the lymphatic routes and occurs as lymphoid aggregates along the bronchioles. Follicular bronchiolitis occurs in different clinical settings that include collagen vascular disease (especially rheumatoid arthritis), immunodeficiency, hypersensitivity disorders, and a variety of nonspecific airway-centered inflammatory conditions. The disease is seen mostly in adults, but may occur in children. Patients with collagen vascular diseases have a mean age of 44 years (range 6 to 69 years), those with immunodeficiency diseases 16 years (range 1.5 to 32 years), and those with hypersensitivity syndromes 55 years (range 38 to 77 years). The patients typically present with progressive shortness of breath and cough, but they may have fever, recurrent pneumonia, or weight loss. The chest radiograph shows reticular or reticulonodular infiltrates. High-resolution CT scans show bilateral centrilobular nodules in all cases and peribronchial nodules in half of the cases. Histologically, the disease shows abundant peribronchiolar lymphoid follicles. These follicles are situated between the arteries and the bronchioles, causing airway compression. The bronchial epithelium is often infiltrated with lymphocytes. In general, these patients have a favorable prognosis, but patients under 30 years of age may develop a progressive disease.
Lymphocytic Interstitial Pneumonia
Carrington and Liebow (1966) first described LIP, and Liebow and Carrington (1973) further defined LIP as widespread pulmonary interstitial infiltrates composed of lymphocytes, plasma cells, and histiocytes. In some cases, germinal centers are present, and the term diffuse lymphoid hyperplasia has been applied to this condition. Colby and Carrington (1983) and Turner and colleagues (1984) believed that some cases reported in the past actually represented diffuse, well-differentiated lymphocytic lymphomas arising in the lung. Saldana and Mones (1992) believe that LIP is best considered a prelymphomatous state frequently associated with other immune dysfunction, such as dysgammaglobulinemia. Most patients with LIP are adult women, usually in their fifth through seventh decades of life. These patients have nonspecific symptoms, such as dry cough, dyspnea, weight loss, and fever. Typical radiographic features are diffuse bilateral lower lobe reticular infiltrates. Small (1 cm) or large (1 to 3 cm) nodules or patchy consolidations may be present on the chest radiograph. Koss (1995) described the lung as showing angiocentric and bronchocentric lymphoid nodules with germinal centers. Travis and Galvin (2001) describe the histology as dense lymphoid infiltrates extensively involving the alveolar septa. They stress that a silver stain should be used to detect Pneumocystis carinii because this organism can produce a similar pattern of inflammation. The interstitium may show granulomas and giant cells. The cells should be polyclonal in origin. Patients with LIP can have diseases with immunologic abnormalities such as Sj gren's syndrome (one-third of cases), collagen vascular diseases, autoimmune diseases, and immunodeficiency diseases, including acquired immunodeficiency syndrome (AIDS). Whether LIP in AIDS patients is a prelymphomatous lesion remains to be demonstrated. Pitt (1991) noted that LIP is more common in the pediatric AIDS population than in the adult counterpart. The course of LIP varies. Patients have been treated with corticosteroids and immunosuppressive drugs, but the response is difficult to judge because of the occurrence of spontaneous remissions. Fishback and Koss (1996) pointed out that LIP sometimes evolves into lymphoma, but the frequency of this transformation is difficult to assess because low-grade lymphomas may mimic LIP. Travis and Galvin (2001) do not believe that LIP progresses to MALT lymphoma. They believe that most of the lesions reported as LIP progressing to lymphoma were lymphomas from the onset.
Nodular Lymphoid Hyperplasia (Pseudolymphoma)
As noted, Saltzstein (1963) attempted to establish histologic criteria to separate malignant from benign lymphocytic pulmonary infiltrates. He termed the benign lymphocytic proliferations PSLs, or, as they are now called, nodular lymphoid hyperplasias of the lung. Koss (1983), Herbert (1984), and Weiss (1985) and their colleagues, as well as others, reinterpreted many of the lesions that were called nodular lymphoid hyperplasia as well-differentiated lymphocytic lymphoma (PPL). True nodular lymphoid hyperplasias are reactive lymphoid proliferations that manifest in
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the lung as one or several masses or as localized infiltrates, as noted by Holland and co-workers (1991). Koss and associates (1983) reviewed 23 PSLs and found that the lesions were usually discovered in asymptomatic patients on routine radiographs of the chest. The patients ranged in age from the third to the eighth decade of life, with a mean age of 51 years. Many of the few symptomatic patients had fever. Microscopically, it is a lymphoid lesion with well-defined germinal centers separated by plasma cells. Koss (1995) reemphasized that the cells should be polyclonal and not monoclonal. Shiota and colleagues (1993) described two cases of PSL that showed monoclonality by gene rearrangement studies. Monoclonality indicates these lesions are lymphomas. Resection of a true PSL is both diagnostic and curative. The lesion has a low rate of recurrence at the original surgical site. The prognosis is excellent, provided the pathologist has made the correct diagnosis. As mentioned earlier, a recent study by Abbondanzo and colleagues (2000) reiterates the histologic criteria for these lesions and confirms through immunohistochemistry and gene rearrangement studies that the lesions exist and that they are not low-grade lymphomas.
Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue (Small Cell Lymphocytic Lymphoma)
Harris and colleagues (2000b), in the WHO Classification of neoplasms of lymphoid tissues, placed and consequently renamed the small cell lymphocytic lymphoma of the lung as extranodal marginal zone B-cell lymphoma of MALT. In the literature, the neoplasm may also be referred to as a marginal zone lymphoma or a MALT lymphoma. The more accepted term is MALT rather than BALT.
According to Koss (1995), the majority of the non-Hodgkin's lymphomas that originate in the lung are low grade and are derived from B cells. They are thought to be derived from MALT, which is composed of lymphoid tissue within the bronchial mucosa. This system is thought to have a role in dealing with inhaled antigens. In various series, the low-grade lymphomas constitute the majority (50% to 70%) of the PPLs. In Fiche and associates' (1995) study, 61 of the 69 (88%) PPLs were low grade. Of the low-grade lymphomas, 54 (88%) were MALT lymphomas. These lesions are proliferations of small lymphocytes or lymphocytes with plasmacytoid features. Table 119-7 notes the differentiating features between nodular lymphoid lymphoma and MALT lesions. Cavalli and associates (2001) reviewed the characteristics of MALT lymphoma. The tumors are composed of mature B-cells that express CD5 or CD10. Cytogenetically, the most common finding is a translocation t(11;18)(q21; q21) that is present in about one third of cases. A second rarely encountered translocation is t(1;14)(p22; q32). These tumors may have a heavy chain gene rearrangement.
Kurtin (2001) and B gueret (2002) and their associates reviewed the clinical and pathologic features of pulmonary MALT lymphomas, each group of investigators reporting 50 and 16 patients, respectively. Combining the two studies, the patients ranged in age from 34 to 88 years, with median age of 68 years for one study and a mean age of 65.2 years for the other study. One study noted a slight predominance in men and the other noted a slight predominance in women, but older studies reported an equal distribution between the sexes. Most patients are asymptomatic and are found through routine chest radiographs. The symptomatic patients complain of cough, dyspnea, fatigue, or chest pain, but some patients only had B symptoms, such as fever, weight loss, and night sweats. B gueret and associates (2002) found no autoimmune diseases, but they did find one patient infected with hepatitis C virus and two infected with Helicobacter pylori. In contrast, Kurtin and colleagues (2001) found 29% of their patients to have autoimmune diseases. Additionally, they tested 28 of their 50 patients for a
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monoclonal gammopathy and found it in 12 patients (43%). The chest radiographs showed randomly distributed single pulmonary nodules or masses with some showing multiple nodules. A rare patient just showed a pulmonary infiltrate. King and co-workers (2000) described the imaging studies in 24 patients with pulmonary MALT lymphoma. They found multiple lesions in 19 of 24 patients (79%) and solitary lesions in 4 of 24 patients (17%) with a diffuse infiltrate in 1 patient (4%). Associated high-resolution computed tomography (HRCT) revealed air bronchograms, airway dilatation, a positive angiogram sign, and a halo of ground-glass shadowing at the margins of the lesion. Other observations included peribronchovascular thickening, hilar and mediastinal lymph node enlargement, and pleural effusions or thickening. The differentiating clinical, pathologic, and radiographic features of LIP, nodular lymphoid hyperplasia, and MALT lymphoma are presented in Table 119-8.
Table 119-7. Nodular Lymphoid Hyperplasia Versus MALT Lymphoma | |||||||||||||||||||||||||||
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Histologically, the tumors were composed of dense lymphoid infiltrates with germinal centers. The infiltrates were composed of small lymphocytes, plasma cells, and monocytoid cells. The infiltrates had a lymphangitic pattern that was accentuated along the bronchovascular bundles, interlobular septa, and visceral pleura. Another histologic feature is the invasion of malignant lymphocytes into the bronchial epithelium. These findings are present in all cases and are known as lymphoepithelial lesions. Lim and colleagues (2001) described amyloid deposits in a MALT lymphoma. This finding emphasizes the need for close follow-up in patients with amyloid nodules. The immunophenotypic and molecular characteristics were discussed earlier.
Treatment may be limited to surgical removal of the mass or additional radiation therapy, chemotherapy, or both, if other factors suggest the need. The prognosis of primary MALT lymphomas is good. Koss and associates (1983) reported a 5-year survival rate of 70%, and L'Hoste and co-workers (1984) cited a survival rate of 83%. Miller and Allen (1993) recorded a similar 86% 5-year survival rate in their series of 22 patients with small cell lymphomas of the lung. Kennedy and colleagues (1985) reported 9.75-year median survival for a group of 12 patients, and Turner and associates (1984) reported a median 4-year survival for a group of 33 patients of whom only one died of lymphoma. In the series of Fiche and co-workers (1995), the patients with small cell lymphomas had a 93.6% survival rate at 5 years and a 60% survival rate at 10 years. Ferraro and associates (2000) at Mayo Clinic reported actuarial survival rates at 1, 5, and 10 years in the MALT lymphomas to be 91%, 68%, and 53%, respectively, regardless of therapy (complete resection having been performed when possible). B gueret and colleagues (2002) had five patients treated with surgery alone, eight patients treated with chemotherapy alone, two patients not treated, and one patient lost to follow-up. The follow-up period ranged from 1 to 13 years. Half the patients had a complete remission, one had a partial remission, two had local recurrence, four were stable, and one died after 13 years. Kurtin and associates (2001)
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had survival rates at 1, 3, 5, and 10 years of 95%, 87.4%, 84.5%, and 71.7%, respectively.
Table 119-8. Differentiation of MALT Lymphoma (Small Lymphocytes), Lymphocytic Interstitial Pneumonia, and Nodular Lymphoid Hyperplasia (Pseudolymphoma) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Large Cell Lymphoma
A primary large cell lymphoma, which used to be called histiocytic lymphoma, of the lung is extremely uncommon. In the series of PPL reported by Toh and Ang (1997), 2 of 11 patients (18%) had a large cell lymphoma. Tamura and co-workers (1995), reporting a similar study, found 3 of 24 (12.5%) were large cell lymphomas. Kurtin and associates (2001) described nine patients with both large cell lymphoma and MALT lymphoma. All of their cases of large cell lymphoma were of the B-cell type. Polish (1989), Poelzleitner (1989), and Ray (1998) and their co-workers have described large cell lymphoma originating in the lungs of patients with AIDS.
Patients with large cell lymphoma are usually in their fifth and sixth decades of life, and men and women are affected almost equally. Symptoms include cough, chest pain, dyspnea, fever, and weight loss. The tumors tend to occur in the upper lobes but also may be found in the other lobes, and even the entire lung may be involved. The chest radiographs show an infiltrate or nodules similar to those seen in patients with MALT lymphoma. On histologic examination, the tumors are composed of cells with large nuclei and prominent nucleoli. Hilar lymph nodes are always involved. Chest wall and pleural involvement have been noted. Cavitation may occur with the mixed (large and small) cell types. After establishing the diagnosis, the treatment of choice is chemotherapy possibly combined with radiation therapy. In the report of Kurtin and colleagues (2001), eight of the nine patients received various regimens of chemotherapy. These large cell tumors are more aggressive than MALT lymphomas, and the prognosis is correspondingly poorer, although the survival data for large cell lymphomas of the lung are less clear because fewer cases have been reported (see Fig. 119-5). L'Hoste and colleagues (1984) reported late recurrence in 53% of their patients. Recurrences can occur within months or many years after the initial treatment. Cordier and associates (1993) reported no survivors out of nine patients by the end of 4 years. In general, these patients do not survive as long as patients with MALT lymphomas. Kurtin and colleagues (2001) estimated an overall survival rate at 1, 3, and 5 years of 77.8% for patients with large cell lymphomas; at 10 years, the survival rate was 51.9%.
Patients with AIDS and primary large cell lymphoma have a poor prognostic outlook, despite an initial response to appropriate therapy. The presence of prior or concurrent opportunistic infection is particularly harmful in these patients. Ray and associates (1998) described 12 cases of AIDS-related PPL occurring between 1986 and 1996. Their patients ranged in age from 32 to 56 years, with an average age of 38 years. The ratio of men to women was 11:1. The symptoms were cough, dyspnea, and chest pain, with most of the patients having B symptoms, such as fever, weight loss, or night sweats. The mean time from human immunodeficiency virus (HIV) seropositive to the discovery of the lymphoma was 5 years. The risk factors for HIV included blood transfusions, intravenous drug abuse, and homosexuality. The CD4 counts ranged from 4 to 50 per microliter. On imaging studies, most patients had a well-defined, progressively enlarging nodule or mass in the subpleural area on their chest radiographs. Histologically, all of the patients showed infiltrates with large cells that invaded the alveolar septa. All of the large cell lymphomas were of the B-cell variety except for one, which was a null cell type. Interestingly, latent EBV infection was detected in every case. The patients were treated with various regimens of chemotherapy. The median survival was 4 months, with all 12 patients dying by 17 months. This report implicates EBV in the pathogenesis of these lymphomas.
Angiocentric Immunoproliferative Lesions (Lymphomatoid Granulomatosis)
The term angiocentric immunoproliferative lesions was coined to encompass a variety of lesions that include benign lymphocytic angiitis and granulomatosis, lymphomatoid granulomatosis, polymorphic reticulosis, and angiocentric lymphoma. The focus of this section is lymphomatoid granulomatosis (LYG). Liebow and colleagues (1972) described LYG as an atypical lymphoreticular infiltrate that involves the vessels of the lung and other organs (skin and brain). The lesion had certain histologic features of lymphoma and Wegener's granulomatosis, hence the name lymphomatoid granulomatosis. Since the original description, the knowledge of extranodal lymphomas has increased considerably. When Weis and associates (1986) examined LYG, they thought it was an example of a peripheral T-cell lymphoma. In 1994, Guinee and associates (1994) analyzed 10 cases of LYG and found a mixed population of small T cells with large atypical B cells. They detected EBV in all 10 cases, with the virus being in the nuclei of the large B cells, but not the small T cells. In a similar study, Myers and co-workers (1995) examined 17 cases of LYG. In 11 cases, they found a population of large B cells, and 10 of these cases contained EBV RNA in their nuclei. Both groups concluded that LYG was a proliferation of EBV-infected B cells with a prominent T-cell reaction and vasculitis (a lesion now known as T cell rich B-cell lymphoma). Koss (1995) also thought that LYG was related to infection by EBV. He postulated that LYG might represent a T-cell reaction to B cells infected with EBV or it could be a T cell rich analogue of the EBV-associated B-cell lymphoproliferative disorders that occur in immunosuppressed individuals.
LYG usually affects middle-aged adults, with a slight predominance in men. Patients present with cough, shortness of breath, chest pain, fever, malaise, and weight loss. The disease also involves the skin, central nervous system, and sometimes upper respiratory tract. Staples (1991) described
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the radiographic findings as multiple small pulmonary nodules ranging from 0.6 to 0.8 cm in size. These nodules tend to be ill defined and are usually present in the lower lung fields. On microscopic examination, there is an atypical polymorphous lymphoid infiltrate around pulmonary blood vessels with necrosis. In a study of 15 patients, Fauci and colleagues (1982) found that cyclophosphamide and prednisone could be beneficial in these patients. However, Katzenstein and co-workers (1979) reported that two thirds of patients died despite treatment with corticosteroids, chemotherapy, or both; the median survival was 14 months. Koss and colleagues (1986) reported that 38% of patients with LYG died within 1 year of diagnosis. Pisani and DeRemee (1990) found that 16 of 28 patients with LYG had an average survival of 23.8 months. Fassas and associates (1999) described a case of LYG in a 60-year-old woman who had a bone marrow transplant for multiple myeloma. Posttransplantation, she developed right lung infiltrates. Seventeen days following transplantation, she had an open lung biopsy that showed LYG. She was treated with ganciclovir and granulocyte-macrophage colony-stimulating factor, and her subsequent chest CTs demonstrated a resolution of the nodules. In summary, this disease should be viewed as a form of malignant lymphoma that primarily involves the lung and has a poor prognosis.
Intravascular Lymphomatosis
Intravascular lymphomatosis is a neoplastic proliferation of lymphoid cells within vascular spaces. The lymphocytes are usually of B-cell origin, but a few cases have been reported to be of T-cell origin. This entity was originally described by Pfleger and Tappeiner (1959), who called it angioendotheliomatosis proliferans systemisata. Other names include malignant angioendotheliomatosis and angiotropic lymphoma. This entity usually presents with cutaneous infiltrates and central nervous system symptoms. Gabor (1997), Demirer (1994), and Stroup (1990) and their colleagues, as well as Yousem and Colby (1990), have all described pulmonary presentations of this type of lymphoma. Combining all of these reports, seven patients have been recorded with a primary pulmonary presentation. The patients were between 40 and 71 years of age, with an average age of 56 years. One patient had a past history of a lymphoma in the breast. The presenting symptoms included fever, cough, night sweats, and progressive shortness of breath. The chest radiographs showed bilateral reticular and reticulonodular infiltrates. Some patients showed hypoxia on analysis of their blood gases. The biopsy specimens showed dilated vessels filled with aggregates of large atypical lymphoid cells. The immunohistochemical staining of these cells showed they were positive for leukocyte common antigen. A biopsy is necessary to establish the diagnosis. The treatment is chemotherapy and possibly radiation therapy. Of the seven patients with primary pulmonary presentation, three died from their disease, one is alive with disease, and three are alive without disease at 8 months, 8 years, and 9 years, respectively, after diagnosis. Evert and colleagues (2000) described a case where the patient had right heart failure secondary to the occlusion of pulmonary blood vessels.
Plasma Cell Disorders
Waldenstr m's macroglobulinemia, plasmacytoma, and multiple myeloma originate in the lung in rare instances. Noach (1956) first reported Waldenstr m's macroglobulinemia involving the lung. Systemic manifestations, such as lymphadenopathy, splenomegaly, and weight loss, may be present in these patients. Plasmacytomas rarely occur in the lung. Roikjaer and Thomsen (1986) described a patient with pulmonary plasmacytoma that recurred after surgical removal. The patient was well 4 years after the second removal of recurrent tumor. The plasma cells immunostained for light chains in both resected specimens. Kazzaz and colleagues (1992) described a multifocal plasmacytoma in the lung of a 60-year-old man. The plasmacytoma demonstrated light chain on immunostaining, but there was no paraprotein in either the serum or urine. Nine years after surgery, the patient was well with no evidence of multiple myeloma. In 1993, Joseph and colleagues described an additional case of primary pulmonary plasmacytoma; they reviewed the literature and found a total of 19 cases. The patients ranged in age from 3 to 72 years, with a median age of 42.3 years. Men and women were equally affected. Koss and associates (1998) described five cases of primary pulmonary plasmacytomas. The cases consisted of four men and one woman whose ages ranged from 50 to 79 years, with a mean age of 57 years. Two patients presented with cough, dyspnea, and hemoptysis. On microscopic examination, these tumors comprised sheets of plasma cells. The cells in the case reported by Joseph and colleagues (1993) immunostained for but not light chains. This is in contrast to the cases reported by Roikjaer and Thomsen (1986) and Kazzaz and associates (1992), in which light chains were found. The cases of Koss and co-workers (1998) had tumors that ranged in size from 2.5 to 8 cm (mean 4.4 cm) and consisted of sheets of well to moderately differentiated plasma cells. They were either peribronchial or involved a major bronchus. These lesions are usually treated surgically, and radiation therapy may be added. Chemotherapy is not indicated. In the follow-up period, these patients must be evaluated for multiple myeloma. When Koss and colleagues (1998) combined their cases with 14 previously published cases, the 2- and 5-year survival rates of pulmonary plasmacytomas were 66% and 40%, respectively. Two of their patients survived more than 20 years. Of the cases reviewed, three of eight patients developed myeloma within 2 years, and they all died of the disease. Thus, the pulmonary lesion may be a forerunner of disseminated disease. Excision of a solitary extrapulmonary lesion is recommended when possible, however, in most instances, chemotherapy is the therapeutic
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method of choice for patients with disseminated disease. Occasionally, multiple myeloma may involve the lung as a solitary mass or as part of a systemic disease process. Shin and colleagues (1992) described two patients with rare secondary pulmonary involvement by myeloma.
Primary Pulmonary Hodgkin's Disease
Primary Hodgkin's disease of the lung is infrequent. No cases were observed in the Mayo Clinic series recorded by Miller and Allen (1993). Radin (1990) reported one case of primary pulmonary Hodgkin's disease and summarized an additional 60 cases in the literature. Chetty and colleagues (1995) added three cases; two of Chetty and colleagues' patients had very aggressive disease and died within 6 to 21 months of presentation.
The patients with primary pulmonary Hodgkin's disease have an average age of 42.5 years, with an age range from 12 to 82 years. The peak occurrence of the disease is bimodal, with the first peak between 21 and 30 years of age and the second between 60 and 80 years of age. Women are affected slightly more frequently than men (1.4:1.0). The most common symptoms are cough, weight loss, chest pain, dyspnea, hemoptysis, fatigue, and rash. Physical examination of the chest usually reveals signs of pulmonary consolidation, but abnormal physical findings may be absent. Other findings include paradoxic movement of the thorax, rash, edema, and lymphadenopathy. Radiographically, most patients show nodular or mass lesions in their lungs, as well as cystic lesions, infiltrates, atelectasis, and effusions. Carter and colleagues (1999) described the radiologic findings in three patients with primary pulmonary Hodgkin's disease. Two patients had unilateral, upper lobe cavitated masses, and one patient had bilateral lower lobe nodules. Boshnakova and associates (2000) reported two cases of primary pulmonary Hodgkin's disease. Results of bronchoscopic examination in most patients are normal, and rarely does it yield the diagnosis. This lack of bronchoscopic specificity indicates that most patients require an open lung biopsy for diagnosis. The histologic types most commonly seen are the nodular sclerosing and the mixed cellularity forms of Hodgkin's disease. Chetty and colleagues (1995) pointed out the importance of separating Hodgkin's disease from pleomorphic T-cell, large B-cell, and anaplastic large cell lymphomas. They stressed the immunohistochemical staining of Reed-Sternberg cells for CD15 and CD30. Patients are treated with a variety of regimens that include surgery, chemotherapy, and radiation therapy. Patients with the poorest outcomes are those with involvement of more than one lobe or of a single lung, those with bilateral lung disease, and those with a high clinical stage. Other factors indicative of a poor prognosis are the presence of B symptoms (fever, night sweats, loss of 10% or more body weight, penetration of the pleura, and cavitary disease).
Summary of Lymphoid Lesions of the Lung
Pulmonary lymphoid lesions can be either primary or secondary. Primary lesions are rare, but they include both non-Hodgkin's lymphoma and Hodgkin's disease. LIP, nodular lymphoid hyperplasia, follicular bronchiolitis, and MALT lymphoma are difficult to evaluate, but with immunophenotyping and gene arrangement studies the task has become easier. Studies suggest that cases of LIP and nodular lymphoid hyperplasia are low-grade lymphomas by immunohistochemical staining and gene rearrangement studies. The study by Abbondanzo and colleagues (2000) reaffirms that not all pulmonary lymphoid lesions are lymphomas and that some represent hyperplasias. The primary large cell lymphoma is easier to diagnose because it resembles its nodal counterparts. LYG has the appearance of a vasculitis with pulmonary necrosis. The current evidence indicates that LYG is a large B-cell lymphoma with a prominent T-cell reaction. The B cells are infected with EBV. Intravascular lymphomatosis does not usually present in the lung, but when it does, diagnosis may be difficult. It does not present as a mass but rather as an intravascular proliferation of lymphoid cells. Primary pulmonary plasmacytomas are extremely rare. They are easy to diagnose since they are composed of plasma cells.
In view of the pathologist's difficulty in interpreting lymphoid lesions of the lung, the surgeon should take extra steps if a lymphoid tumor is suspected. Part of the tumor should be fixed in B-5 solution or some equivalent solution that provides better nuclear detail than formalin. The hilar lymph nodes should be sampled for both diagnosis and staging, and some of the tumor should be frozen for immunologic markers and gene rearrangement studies. Fresh tissue should be submitted for cytogenetic and flow cytometric immunophenotyping studies. The tissue may be submitted in RPMI medium. Marker studies on true nodular lymphoid hyperplasia and LIP demonstrate polyclonal staining for heavy chains (immunoglobulins G, A, and M) and light chains ( , ) of immunoglobulins; B-cell lymphomas show monoclonal staining. Flow cytometric studies will produce information about the cell cycle, the DNA content of the cells, and immunologic markers. The S phases of the cell cycle reveal how rapidly the cells are proliferating. The DNA content differentiates diploid from aneuploid cell populations. Aneuploid tumors have an increased or decreased amount of DNA, and they generally are more aggressive than diploid tumors. Flow cytometry can give a percentage distribution of immunologic markers, whereas frozen sections give only an architectural distribution of the markers. Many of the immunologic markers that once could only be identified on frozen tissue can now be identified on paraffin-embedded tissue. These two methods of performing immunologic markers complement each other. The flow cytometry is helpful in establishing the presence of a monoclonal population of cells. Gene rearrangement
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studies can also demonstrate a monoclonal population of B and T cells. In conclusion, new scientific techniques are offering more ways for the surgeon and the oncologist to evaluate pulmonary lymphoid lesions of the lung. The crucial step is to consider the possibility of a lymphoid lesion and then collect the appropriate fresh, frozen, B-5, and formalin-fixed tissue.
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