A wide range of conditions may manifest as tumors or tumor-like lesions in the lung parenchyma. Although space limitations prevent the inclusion of every single clinical entity that may manifest as a pulmonary growth, this chapter covers some of the most common lesions that may require the expertise of the pathologist for accurate diagnosis. As a simple classification scheme, they have been separated into histiocytic and nonhistiocytic lesions.
Nonhistiocytic lesions comprise a wide range of rare conditions that may pose some difficulty in diagnosis, especially when only a small biopsy specimen is available for histologic analysis. Although these conditions are unusual, it is important to be able to properly diagnose and classify them. The following conditions are addressed in this section:
Mucous gland adenoma
Pulmonary alveolar microlithiasis
Pulmonary metastatic calcification
Alveolar adenoma is a benign tumor of unusual occurrence in the lung parenchyma. Although the tumor may have been reported earlier under a different designation, Yousem and Hochholzer coined the term alveolar adenoma in their report of six cases, which included four women and two men between the ages of 45 and 74 years. All of the patients were asymptomatic or displayed clinical signs and symptoms unrelated to the pulmonary tumor. All of the lesions were solitary pulmonary nodules, and all of the patients underwent surgical resection of the tumor.
On gross inspection, these tumors generally are seen to be solitary coin lesions within the lung parenchyma. Size ranges from 1 to 3 cm in greatest dimension; they may be cystic and hemorrhagic.
On histologic examination, at low magnification the tumors appear to be well circumscribed, with prominent large cystic spaces that contain a clear acellular fluid ( Fig. 12-1 ). At the periphery of the lesion, the tumor appears to be more cellular and glandular, with a microcystic-like pattern ( Fig. 12-2 ). Higher magnification reveals a discrete inflammatory infiltrate composed of lymphocytes and plasma cells in the septa separating cystic glandular areas. These cystic spaces are lined by medium-sized cuboidal cells with a hobnail appearance resembling that of pneumocytes, whereas in the peripheral areas with a more glandular appearance, the cells lining the alveolar spaces constitute a pneumocyte type II proliferation ( Fig. 12-3 ). Mitotic activity is rare or nonexistent in these lesions, and necrosis is not a feature ( Fig. 12-4 ). Periodic acid–Schiff (PAS) histochemical stain shows a positive reaction in the fluid contained in the cystic spaces.
Immunohistochemical studies have been performed in these lesions, and as might be expected, use of epithelial markers such as keratin and EMA gives a positive reaction. Surfactant apoprotein staining also has been found to be positive. The tumor demonstrates negative staining for vascular markers including CD31, CD34, and factor VIII.
Inadequate biopsy specimens constitute the biggest obstacle to a correct diagnosis. Because of the glandular proliferation with prominent type II pneumocytes, the most important consideration in the differential diagnosis is adenocarcinoma with a bronchioloalveolar pattern. Both adenocarcinoma and bronchioloalveolar carcinoma may show positive staining for conventional markers including thyroid transcription factor 1 (TTF-1), surfactant, and epithelial markers. Thus, an unequivocal diagnosis of alveolar adenoma cannot be achieved with use of a small biopsy specimen but will require analysis of material obtained at complete resection of the tumor. Because of the large cystic spaces present in these lesions, one other possibility to be considered is lymphangioma. In this instance, however, the epithelial lining of type II pneumocytes and the negative staining for vascular markers would indicate the correct interpretation.
Treatment and Prognosis
Surgical resection is the treatment of choice for alveolar adenomas and is curative. Procedures used have ranged in extent from wedge resection to lobectomy, although a more conservative approach may be warranted in some cases. Nevertheless, when it is difficult to assess the true nature of this tumor from limited biopsy material, resection is indicated. The available follow-up data have indicated that this is an indolent benign process.
Mucous Gland Adenoma
Mucous gland adenomas are benign tumors that have been recognized for some time but formerly were classified with other so-called adenomas, not of this type, that corresponded to different types of tumors. Thus, it is difficult to determine the exact incidence of mucous gland adenomas. The tumor has been suggested to originate from the submucosal seromucous glands and ducts of the proximal airways and may represent an overdilatation of the normal structures. England and Hochholzer in 1995 presented 10 cases, summarizing the previous names for this tumor and identifying only 41 previous cases.
The tumor appears to affect men and women equally, without any gender predilection, and has been documented to occur in adults between the ages of 25 and 67. The patients may be asymptomatic or may present with clinical signs and symptoms of bronchial obstruction such as cough, dyspnea, chest pain, or hemoptysis, reflecting the central location of the tumor.
Mucous gland adenomas may manifest as polypoid, exophytic endobronchial tumors obstructing the pulmonary lumen. Size ranges from less than 1 cm to more than 5 cm in greatest dimension. These lesions are well circumscribed with a soft consistency and a mucoid appearance, with cystic changes. Areas of hemorrhage and necrosis are not common in these tumors.
The hallmark histopathologic feature of mucous gland adenoma is the limitation of tumor growth between the bronchial epithelium and the bronchial cartilaginous plate ( Fig. 12-5 ). The tumor is circumscribed within that particular space, without invasion into adjacent lung parenchyma or beyond the bronchial cartilage ( Fig. 12-6 ). The low-power view shows an exuberant dilatation of the normal submucosal seromucinous glands of the lung, with areas of inflammatory reaction, and mucoid material filling the dilated glandular structures ( Figs. 12-7 to 12-9 ). The tumor also may show a prominent papillary growth pattern. A higher-power view reveals a gamut of histopathologic change ranging from a glandular component with predominantly mucous epithelium, with little intervening stromal tissue, to compact glandular proliferation of seromucinous glands ( Figs. 12-10 to 12-13 ). In other areas, the tumor may display cystically dilated glands of different sizes lined by squamous epithelium and separated by fibrocollagenous stroma ( Fig. 12-14 ). In most cases, it is possible to identify an admixture of patterns that range from cystic to solid. Areas of cholesterol cleft granulomas, an inflammatory process composed predominantly of plasma cells, and areas of squamous metaplasia are commonly seen ( Fig. 12-15 ). The glandular proliferation does not involve the adjacent lung parenchyma.
Although the diagnosis of mucous gland adenoma is essentially a morphologic diagnosis, immunohistochemical studies have been performed in some reported cases. As might be expected, the tumor shows positive staining for epithelial markers including keratins, epithelial membrane antigen (EMA), and carcinoembryonic antigen (CEA). Proliferative markers such as Ki-67 will label only scattered cells.
The most important considerations in the differential diagnosis are low-grade mucoepidermoid carcinoma and adenocarcinoma. In small biopsy specimens, an unequivocal diagnosis may prove difficult to obtain; however, the presence of an exuberant dilatation of normal endobronchial glands should alert the pathologist to the possibility of a mucous gland adenoma. If the biopsy tissue is from an area of glandular proliferation, the diagnosis may be very difficult, if not impossible. In a resected specimen, the presence of a process limited to the space between surface respiratory epithelium and the bronchial cartilage indicates an adenoma, rather than a mucoepidermoid carcinoma. Abnormal dilatation of glands with acellular mucoid material within the glandular lumen also should point to the correct interpretation; in adenocarcinoma, an atypical glandular proliferation not limited to the bronchial cartilage, and showing nuclear pleomorphism or mitotic activity, or both, may be observed.
Treatment and Prognosis
The treatment of choice is complete surgical resection, and the prognosis is excellent. The choice of surgical procedure will depend on the anatomic distribution of the tumor, the surgeon’s level of confidence in the initial biopsy results, and radiologic findings. Therefore, even though the tumor is completely benign, the surgical approach may entail a more radical procedure such as lobectomy.
Amyloid Tumor (Amyloidoma)
Amyloid deposition within the lung parenchyma is a well-known phenomenon, recognized for many decades. The deposition may be secondary to systemic amyloidosis or to various other conditions. Several studies analyzing the presence of amyloid in the respiratory tract, including the tracheobronchial area and lung parenchyma, have been reported. Celli and associates described 22 autopsy cases of patients with systemic amyloidosis; 12 of the patients had primary systemic amyloidosis, 3 patients had amyloidosis secondary to myeloma or Waldenström’s macroglobulinemia, and 7 patients had secondary amyloidosis. Cordier and colleagues reported their findings in 21 patients with systemic amyloidosis involving the lower respiratory tract. In this series, the lung and tracheobronchial tree manifested different patterns of involvement, including diffuse, nodular, interstitial, and plaque-like. The investigators emphasized that the lung may show amyloid deposition in conditions such as myeloma, Waldenström’s macroglobulinemia, familial neuropathy, and Niemann-Pick or Gaucher’s disease; senile cardiac forms of this condition also have been documented. Although these conditions are important, the focus of the following discussion is solely on the presence of amyloid in the respiratory tract without evidence of systemic disease, because in some cases the pulmonary nodules may raise the clinical possibility of a pulmonary malignancy.
Nodular deposits of amyloid in the lung parenchyma, also known as amyloidomas, are well known to occur, and their presence has been reported in the literature. Possible etiologic factors such as light chain immunoglobulin or the presence of abundant plasma cells often seen adjacent to amyloid tumors have been suggested as the cause of amyloid deposition. The potassium permanganate oxidation technique, which appears to separate amyloid type AA from other forms of amyloid, has provided results that may support the immunoglobulin-derived amyloid by excluding the protein A-amyloid. The etiology is still unknown, however. In some cases, the amyloid tumor has been associated with other conditions such as Sjögren’s syndrome and pulmonary lymphoma, mucosa-associated lymphoid tissue (MALT) type, whereas other cases have been characterized by extensive lung involvement or presence of a solitary nodule. In 1986, Hui and coworkers presented 48 cases of amyloidosis restricted to the lower respiratory tract. These workers encountered 14 cases involving the tracheobronchial tree, 24 cases with solitary or multiple pulmonary nodules, and 6 cases with diffuse interstitial parenchymal pattern. Patients with tracheobronchial involvement are most likely to present with symptoms such as dyspnea, whereas those with nodular parenchymal involvement usually are asymptomatic.
Pulmonary amyloid may be present in different forms. The tracheobronchial involvement may be diffuse or localized, whereas parenchymal amyloidosis may manifest as single or multiple nodules ( Fig. 12-16 ), ranging in size from 1 cm to more than 10 cm in diameter. These tumors may be unilateral or bilateral and have been described as of soft consistency, well circumscribed, and grayish in color. Those in the tracheobronchial tree have been described as plaque-like or polypoid.
The low-power view of lung involved in nodular amyloidosis (amyloidoma) shows a well-circumscribed but unencapsulated amorphous eosinophilic tumor nodule replacing lung parenchyma ( Fig. 12-17 ). Higher magnification reveals this nodule to be composed of an acellular amorphous material; however, in the periphery of the nodule, an inflammatory infiltrate rich in plasma cells and numerous multinucleated giant cells can be seen ( Figs. 12-18 to 12-22 ). In some cases, the process is diffuse, with some preservation of the normal architecture. The amyloid is deposited in an interstitial pattern ( Fig. 12-23 ), with widening of the interstitium, and involving the pulmonary vasculature. In this pattern, the inflammatory infiltrate is not as prominent as in the nodular pattern, and multinucleated giant cells may be only scattered or absent.
Even though the morphologic presence of amyloid is rather characteristic, histochemical staining studies using Congo red may be of help in small biopsy specimens, or in cases with subtle changes suggesting presence of amyloid in the lung parenchyma. Congo red displays a birefringent apple-green color under polarized light microscopy. Amyloid may show a λ light chain immunohistochemical reaction and serum amyloid P. Immunohistochemical studies in the plasma cells present in amyloid tumors have shown a polytypical cellular proliferation. Recently, Rodriguez and colleagues performed spectrometric studies in proteinaceous deposits in neural tissue and concluded that liquid chromatography-electrospray tandem mass spectrometry is a novel application for characterization of proteinaceous deposits, including amyloid.
One important non-neoplastic condition that may be confused with amyloid tumor is the so-called hyalinizing granuloma of lung. In this condition, extensive areas of hyalinization with inflammatory reaction may closely mimic amyloid. Hyalinizing granuloma of the lung is a rare condition, probably related to sclerosing mediastinitis, retroperitoneal fibrosis, sclerosing cholangitis, and other similar lesions. It usually occurs in adults and may manifest as a pulmonary mass, potentially giving rise to signs and symptoms of pulmonary obstruction. On histologic examination, this lesion is seen to be a well-demarcated tumor mass with extensive fibrosis and thick collagen bundles admixed with an inflammatory reaction ( Figs. 12-24 to 12-26 ). Histochemical staining with Congo red is negative in these cases. Another diagnostic possibility is intrapulmonary solitary fibrous tumor, especially with lesions showing extensive areas of collagenization. Once again, Congo red or immunohistochemical studies for CD34 and Bcl-2 should lead to the correct interpretation.
Treatment and Prognosis
The treatment of choice for amyloidosis manifesting as a pulmonary mass is surgical resection. The prognosis appears to be good for patients with this form of the disease, in contrast to patients with diffuse pulmonary involvement, in whom surgical resection may not be possible. The pattern of diffuse involvement appears to be associated with progression to respiratory insufficiency eventuating in death.
Rosen and coworkers are credited for describing this condition in 27 patients, in whom the alveoli were filled by a PAS-positive proteinaceous material rich in lipid. The investigators speculated that the alveolar proteinaceous material was produced by the lining cells, which slough into the lumen, ultimately becoming necrotic and yielding granules and variably laminated bodies to the alveolar content. In addition, the investigators noted the resemblance of this condition to the changes seen with Pneumocystis jiroveci (carinii) infection in the lung.
Alveolar proteinosis also has been associated with immunosuppression. Bedrossian and colleagues reported eight cases of alveolar proteinosis associated with hematologic malignancies and acknowledged that all of the cases reported in the literature were associated with either infectious processes or with hematologic malignancies. Three radiologic patterns of involvement with alveolar proteinosis have been documented: reticulonodular, small acinar nodules mimicking miliary disease, and coalescence of various-sized acinar nodules leading to focal consolidation. A majority of patients will present with clinical signs and symptoms of cough, dyspnea, chest pain, or fever.
The histopathologic hallmark of alveolar proteinosis is filling of the alveoli by a proteinaceous acellular material, which characteristically demonstrates reactivity with periodic acid–Schiff (PAS) histochemical stain. The pulmonary architecture is preserved, with only minimal changes in the interstitium ( Figs. 12-27 to 12-29 ). By electron microscopy, annular inclusions, lamellar osmiophilic inclusions, dense granules, and myeloid bodies have been identified.
The most important consideration in the differential diagnosis is Pneumocystis carinii pneumonia (PCP; P. jiroveci ) ( Figs. 12-30 to 12-32 ). Given that both of these processes may take place in immunocompromised persons, staining with PAS or Gomori-methenamine silver (GMS) may help to confirm the diagnosis. Lung involved in alveolar proteinosis will show positive staining with PAS and negative staining with GMS, which is contrary to what would occur in Pneumocystis pneumonia. Another condition that may be considered is pulmonary edema; however, the use of PAS histochemical stain will lead to the correct interpretation.
Treatment and Prognosis
Pulmonary lavage has been used with some success. Kariman and associates studied 28 patients with alveolar proteinosis and divided them into two groups in accordance with their clinical course. Approximately 24% of the patients exhibited spontaneous remission with no treatment, whereas the remaining 76% underwent pulmonary lavage. In this latter group of patients, 21% did not respond to treatment.
Placental Transmogrification of the Lung
The term transmogrify means “to change into a different form or shape, especially one that is fantastic or bizarre.” This definition clearly indicates the grotesque nature of the process that takes place within the lung parenchyma during placental transmogrification of the lung. Since the original description by McChesney, presented in abstract form, only a few additional cases have appeared in the literature, using different names or designating variants of the condition. Careful analysis of these descriptions reveals that all of them represent the same condition, with a spectrum of histopathologic features. Mark and associates described this condition under the designation placentoid bullous lesion of the lung in four adult patients with “unilateral multicystic lung disease.” Two of the patients had a history of repeated childhood pneumonias. Almost simultaneously, Flider and colleagues reported the cases of three patients, ranging in ages from 24 to 33 years, with cystic lesions of the lung. These workers’ interpretation of this process was as a variant of giant bullous emphysema. In a more recent case report, this condition was interpreted as pulmonary lipomatosis, a variant of placental transmogrification, in an adult patient with history of bronchopneumonia and a cystic intrapulmonary lesion.
On the basis of those reports, it is evident that this process should be classified as a single lesion with variable histopathologic features. The best terminology for these extremely rare lesions is placental transmogrification of the lung . Despite the broad spectrum of histopathologic features that may be seen in these lesions, it is apparent that, in previous reports, different designations refer to the same entity.
The process appears to affect adult patients, especially young adults, with a history of pneumonic process. History of tobacco use also has been recorded in some cases. In all cases, the chest radiograph displayed a unilateral intrapulmonary cystic lesion, which may appear as a bulla or an enlarging cystic lesion.
Invariably, the gross descriptions of the resected lesions are similar, including degenerated intrapulmonary lesions with cystic degeneration, papillary-like areas, or grape-like structures resembling molar placental tissue. The normal lung parenchyma appears collapsed, with total destruction of the normal macroscopic features of lung tissue ( Fig. 12-33 ).
The spectrum of histopathologic features encountered in placental transmogrification of the lung includes variable features. The lung parenchyma is replaced by a proliferation of papillary-like structures lined by cuboidal epithelial cells ( Figs. 12-34 and 12-35 ). The core of these papillary structures may contain variable amounts of inflammatory cells—namely, lymphocytes. They may appear edematous, and in some cells, degeneration of these papillary structures may take place, giving the impression of degenerated placental villi ( Figs. 12-36 to 12-40 ). In other areas, the papillary structures may contain smooth muscle or may be replaced by mature adipose tissue or a mixture of both. In focal areas, airway structures are preserved and may constitute the only visible normal anatomic architecture.
Treatment and Prognosis
The treatment for these unusual lesions is surgical resection, which has been performed in all cases described; the final diagnosis also is made at the time of surgery. Diagnosis on limited biopsy material or cytology may be difficult, and in such cases, findings are of limited value. No recurrences have been reported in any of the reported cases. Thus, complete surgical resection appears to be curative.
Pulmonary Alveolar Microlithiasis
The etiology of pulmonary alveolar microlithiasis, an unusual condition in the lung, is unknown, and although the composition of the microliths points to an abnormal chemical process, none of the patients described has had a primary metabolic abnormality. The process does not seem to have a predilection for either gender and may follow a protracted clinical course. Owing to the rarity of this condition, most of the information in the literature is presented in case reports, with only a couple of short series.
As indicated by findings in the larger series, pulmonary alveolar microlithiasis displays no gender predilection and can affect anyone at any age, having been documented in small children and older adults. A familial pattern has been observed in approximately one half of the cases described. Patients may present with shortness of breath or complaints of gradual decrease in respiratory performance. On radiographic evaluation, a diffuse bilateral pulmonary infiltrate that resembles a “sand storm” typically is seen on the chest film ( Fig. 12-41 ). No metabolic abnormality related to disturbances of phosphorus or calcium has been associated with this condition; however, chemical analysis of the microliths shows that they are composed of calcium and phosphorus salts. Macroscopically, the lung may show features mimicking pulmonary fibrosis ( Fig. 12-42 ).
Alveolar microlithiasis typically is characterized by numerous spherical bodies filling the alveolar spaces ( Figs. 12-43 and 12-44 ). Each of these calcospherites measures approximately 250 to 750 μm in diameter. Morphologically, they appear to be laminated bodies with an onion layer–like appearance ( Figs. 12-45 and 12-46 ). In some cases, focal ossification may be present ( Fig. 12-47 ).
Although the histopathologic features of pulmonary alveolar microlithiasis are fairly straightforward, there are a few lesions that may enter into the differential diagnosis. Pulmonary “blue bodies” may have a similar shape and composition; however, they do not fill the alveolar spaces and are few in number. In addition, blue bodies are commonly associated with inflammatory lesions, pneumoconiosis, or interstitial pneumonitis. Diffuse pulmonary ossification and heterotopic ossification also may enter into the differential diagnosis. Both of these conditions cause lamellar bone formation, and the distribution is interstitial. In addition, light microscopy shows round calcospherites, in sharp contrast with the irregular bone formation present in pulmonary ossification. If multiple corpora amylacea are present, their round shape may erroneously suggest the presence of microliths. Diffuse corpora amylacea filling alveolar spaces would be a highly unusual finding, however. Pulmonary metastatic calcification also may be considered; this entity is discussed further on.
Treatment and Prognosis
No specific treatment for pulmonary alveolar microlithiasis is available. The condition may follow a protracted course, but eventually most patients succumb to respiratory failure. Some patients may live with this condition for long periods, from 5 to 40 years.
Pulmonary Metastatic Calcification
Pulmonary metastatic calcification is an unusual phenomenon that may pose a diagnostic problem because the clinical presentation may mimic that of a neoplastic process. Metastatic calcification may be seen in patients with various disorders and conditions including patients who have undergone treatment for malignancies such as parathyroid carcinoma, those with lymphoproliferative disorders, transplant recipients, and patients with abnormal renal function. Metastatic calcification may occur in any age group and in both male and female patients. Conventional chest radiographs may not be as accurate as CT scans ( Fig. 12-48 ). On radiologic examination, the process is seen to be bilateral, dense, and asymmetrical. Some researchers have suggested that dual-energy digital radiography is a more sensitive modality than conventional chest radiography for the diagnosis of metastatic calcification.
The exact mechanism for metastatic calcification is not known; however, it may be influenced by serum calcium and phosphate concentrations, alkaline phosphatase activity, and local physicochemical conditions such as pH. In contrast to the process of dystrophic calcification, metastatic calcification does not require a previous tissue injury.
On gross examination, the lung may appear congested, with a gritty-looking cut surface ( Fig. 12-49 ). Unlike alveolar microlithiasis, in which the calcospherites fill the alveolar spaces, metastatic calcification follows a more haphazard pattern, in which the calcified material is deposited in the interstitum, bronchial wall, and airways. In many cases, the pattern of calcification follows the outlines of the alveoli ( Figs. 12-50 to 12-52 ).
Treatment and Prognosis
The treatment and prognosis of metastatic calcification will be determined by the underlying condition. In some patients, the pathologic process may end in respiratory failure and death.
Lymphangioleiomyomatosis (LAM) is an unusual disorder of unknown etiology that predominantly affects premenopausal women but also has been described, albeit rarely, in children, men, and postmenopausal women. This disorder may occur without evidence of another disease process or in association with tuberous sclerosis complex (TSC). LAM has been estimated to occur at a rate of 1 to 2 cases per 1 million women; however, it may be underreported. Although the pathogenesis of the disorder has not yet been elucidated, LAM and TSC may share a genetic relationship. The TSC2 tumor suppressor gene at chromosomal locus 16p13 has been implicated in the pathogenesis of LAM. This particular abnormality also has been identified in approximately one half of renal angiomyolipomas in patients with LAM or tuberous sclerosis. Although these are two distinct disorders, the pulmonary changes in TSC, which may occur in less than 5% of these patients, are difficult to distinguish from those in LAM, not only histologically but also clinically and radiologically. TSC affects both genders, however. Some researchers also have argued that tuberous sclerosis has a relatively increased frequency in families, whereas LAM does not. In addition, tuberous sclerosis has an autosomal dominant transmission, with neurologic and cutaneous manifestations. Other investigators have suggested, however, that pulmonary LAM and Bourneville’s tuberous sclerosis may represent two forms of the same process.
Presenting clinical signs and symptoms of LAM may include recurrent pneumothorax, chylous effusion, dyspnea, cough, and hemoptysis. Characteristic radiologic findings consist of multiple bilateral nodular and cystic changes in the lung parenchyma seen on CT scans. Cases of unilateral pulmonary involvement have been described, however. The mean age at onset of symptoms was estimated in one study to be 32 years. Open lung biopsy used to be the procedure of choice to establish the diagnosis, but more recently, transbronchial biopsies have yielded some satisfactory results.
Grossly, the lungs of patients with LAM are characterized by multiple cysts with a honeycomb appearance ( Fig. 12-53 ). The cysts are of different sizes with variable wall thickness. On microscopic examination, the low-power view shows numerous cysts, which may appear as emphysematous changes and may be filled with pools of blood or with pigmented macrophages ( Figs. 12-54 and 12-55 ). At higher magnification, it is possible to identify a cellular proliferation composed of spindle cells with elongated nuclei, inconspicuous nucleoli, and scanty cytoplasm and areas of more ovoid cells with clear cytoplasm ( Figs. 12-56 and 12-57 ). This cellular proliferation appears to partially line some of the cystic structures and also may be visible in the interstitium of the lung parenchyma. It does not show evidence of nuclear atypia or mitotic activity. In adjacent areas, the lung parenchyma also may show hyperplasia with type II pneumocytes, which may be arranged in a micronodular pattern. Some workers have divided LAM into two separate histologic groups, one predominantly cystic and the other predominantly muscular, and have argued that this classification has prognostic importance.