Understanding Secondary Pulmonary Sarcomas: A Comprehensive Overview

Part 1: Leiomyosarcoma

Leiomyosarcoma is a malignant tumor with pure smooth muscle differentiation, occurring in elderly individuals, typically originating from the retroperitoneum and large vessels. In immunocompromised patients (those with HIV/AIDS and transplant recipients), multifocal leiomyosarcoma involving solid organs also occurs, often associated with EB virus infection. Most pulmonary leiomyosarcomas are metastatic, but rare cases of primary tumors can occur. Generally, they appear grayish-white, fleshy, whorled, and are usually lobulated, with bleeding, necrosis, and cyst formation occasionally seen in large tumors.

Cellular Characteristics

· Highly cellular bundles of round to spindle-shaped cells with mitotic activity.

Histological Features

· Well-differentiated leiomyosarcomas exhibit distinctly interlacing bundles of spindle cells with eosinophilic cytoplasm, round-ended cell nuclei, and occasionally transparent or myxoid stroma, necrosis, and hemorrhage.

· Poorly differentiated leiomyosarcomas show significant pleomorphism with abnormal mitotic figures.

Auxiliary Tests

· Immunohistochemistry is usually positive for desmin, SMA, and h-caldesmon in most cases.

· Poorly differentiated tumors may lose SMA and desmin immunoreactivity.

· No specific genetic molecular abnormalities are identified. Functional loss mutations of P53 and RB1 may be observed.

Figure 20.1. A gross photograph showing a well-defined, fleshy, brownish-white mass with focal hemorrhage.

Figure 20.2. Cytological smear showing pleomorphism with spindle cells (round to oval shapes being the most characteristic), along with slender cytoplasmic protrusions.

Figure 20.3. A well-defined mass located in the submucosa of the respiratory tract composed of spindle cell bundles with eosinophilic cytoplasm.

Figure 20.4. Spindle cell bundles with round, oval, and moderate eosinophilic cytoplasm. Few mitotic figures and apoptotic fragments are occasionally seen.

Part 2: Vascular Sarcoma

Pulmonary vascular sarcoma typically manifests as metastatic lesions from other sites. They have a broad age distribution, with a peak incidence in older adults and a slight male predominance. When they involve the lungs, vascular sarcomas are associated with hemoptysis and generally present as ill-defined, multi-nodular, hemorrhagic lesions with cystic degeneration and necrosis.

Cellular Characteristics

· Typically dispersed atypical, pleomorphic cells with epithelial, spindle, or plasmacytoid morphology and angiogenic features (cytoplasmic lumina/vacuoles and endothelial wrapping).

Histological Features

· Various histological patterns may be observed within the same tumor.

· Well to moderately differentiated vascular sarcomas display irregularly anastomosing vascular lumina lined by markedly atypical endothelial cells with deep-staining nuclei and high mitotic activity.

· Poorly differentiated vascular sarcomas may show high-grade pleomorphic spindle cells with rudimentary lumen formation and prominent mitotic activity.

· “Epithelioid” vascular sarcomas describe tumors with solid areas composed of pleomorphic epithelial cells with prominent eosinophilic cytoplasm, large vesicular nuclei, and prominent nucleoli, which may be misclassified as carcinoma (they may be keratin positive).

Auxiliary Tests

· Ultrastructurally, vascular sarcomas may show tight junctions, pinocytic vesicles, and Weibel-Palade bodies.

· Immunoreactivity for CD34, CD31, ERG, and FLI1.

· Specific genetic abnormalities are rarely identified. MYC overexpression is often seen and is frequently associated with radiation-induced vascular sarcomas.

Figure 20.5. A gross photograph of a vascular sarcoma showing multiple areas of hemorrhage (arrows). (Courtesy of Dr. Akihiko Yoshida).

Figure 20.6. Blood smear showing epithelial-like cells and rare intracytoplasmic inclusions (newly formed lumina that may contain red blood cells) may be discerned.

Figure 20.7. A low-power view shows high cellularity of inert cell proliferation, with blood-filled alveolar spaces in the background.

Figure 20.8. A high-power view showing spindle and atypical epithelial cells arranged in blood-filled lumina. Occasionally, tumor cells may contain red blood cells in the cytoplasm. Prominent mitotic figures and apoptotic bodies may be observed.

Part 3: Osteosarcoma

Classic osteosarcoma is the most common primary sarcoma of the skeleton, mostly arising in the metaphyses of long bones in children and young adults around puberty, as well as in soft tissues of the trunk and femur in elderly individuals. Although primary pulmonary osteosarcoma is extremely rare, the lung is the most common site for metastatic osteosarcoma. Generally, these lesions appear grayish-white, with varying degrees of mineralization, hemorrhage, necrosis, and cystic changes. If found near the pulmonary artery, the osteosarcoma component of pulmonary artery intimal sarcoma must be distinguished from metastasis.

Cellular Characteristics

· Nonspecific but often contains high-grade pleomorphic cells, with spindle to epithelial morphology, multinucleated cells, fragments of osteoid, cartilage, and necrosis.

Histological Features

· Osteogenic sarcomas have a highly variable morphology of tumor cells, including spindle, epithelial, plasmacytoid, small and round, transparent, or multinucleated.

· Pulmonary metastases are usually high-grade pleomorphic, with a high mitotic index, and may have occasional chondroid components.

Auxiliary Tests

· SATB immunohistochemistry is usually positive. S100, SMA, CD99, EMA, and keratin show varying degrees of immunopositivity.

· No recurrent molecular abnormalities can define classic osteosarcoma, but MYC amplification and P53 and RB1 inactivation are common.

Figure 20.9.A. A gross photograph of a metastatic osteosarcoma to the lung showing a white-brownish, infiltrative mass with areas of hemorrhage.

Figure 20.10. Cytological smear showing abundant plasmacytoid cells and scattered osteoclasts; osteoid may be sparse or only observed in cell clusters.

Figure 20.11. Pleomorphic spindle proliferation of cells; bone-forming areas are seen (left side of image).

Figure 20.12. Pleomorphic spindle and epithelial cells with eccentrically located nuclei and deeply stained nuclei forming woven bone.

Part 4: Chondrosarcoma

Chondrosarcoma is a malignant cartilage-producing tumor, mostly arising in the pelvis, proximal femur, and proximal humerus of middle-aged and elderly individuals, with a slight male predilection. Low-grade lesions can occasionally give rise to high-grade dedifferentiated chondrosarcoma. In the lung, chondrosarcoma most commonly presents as metastatic tumors. Generally, they are lobulated, grayish-white, glistening masses, with occasional hemorrhage and necrosis.

Cellular Characteristics

· Malignant chondrocytes with abundant vacuolated cytoplasm, large irregular nuclei, and small to prominent nucleoli, set against a background of chondroid myxoid stroma.

Histological Features

· Lobules of gray-blue chondroid mucinous stroma covered by atypical chondrocytes arranged in various loose cell clusters, rows, and nests.

· Lobules are usually separated by fibrous bands.

· High-grade lesions are more cellular, with more pronounced pleomorphism and more mitotic figures.

· Dedifferentiated chondrosarcoma is characterized by undifferentiated spindle to pleomorphic sarcoma that suddenly arises from low-grade chondrosarcoma and may show osteosarcomatous differentiation.

Auxiliary Tests

· The unique morphology of chondrosarcoma typically does not require immunohistochemical staining.

· Using mutation-specific antibodies (IDH1 R132H) may show reactivity and may assist in identifying origin and dedifferentiated components of chondrosarcoma.

· Many chondrosarcomas have isocitrate dehydrogenase gene (IDH-1 or IDH-2) mutations; high-grade tumors also have RB1, P53, or activating mutations of several receptor tyrosine kinases.

Figure 20.13. Cytological smear showing low-grade appearing chondrocytes, accompanied by chondroid to myxoid stroma.

Figure 20.14. A low-power view of a high-grade chondrosarcoma showing a tumor with varied cellularity and gray-blue chondroid stroma.

Figure 20.15. A low-grade chondrosarcoma contains a low-density of epithelial-like cells, with amphiphilic cytoplasm, small round to oval cell nuclei, dense chromatin without prominent nucleoli, and rare binucleation.

Figure 20.16. A high-grade chondrosarcoma contains moderate to high-density pleomorphic cells, with amphiphilic cytoplasm, nucleoli, binucleation, and mitotic figures.

Part 5: Liposarcoma

Liposarcoma is a malignant adipocytic tumor that usually arises in deep soft tissue areas (thigh, retroperitoneum, omentum, breast, mediastinum, and axilla) of elderly individuals. Pulmonary liposarcoma typically presents as metastatic tumors; however, in rare cases, primary pulmonary liposarcoma can also occur. Metastatic liposarcoma is typically a higher-grade tumor with varying histologies, including myxoid liposarcomas, dedifferentiated liposarcomas, and pleomorphic liposarcomas. Generally, metastatic pulmonary dedifferentiated liposarcoma typically appears grayish-white, nodular, fleshy to soft masses with areas of cystic change, hemorrhage, or necrosis.

Cellular Characteristics

· Myxoid liposarcoma may show a delicate capillary network, foamy extracellular stroma, and lipoblasts.

· Dedifferentiated liposarcoma may consist solely of malignant undifferentiated spindle cells, with nuclear pleomorphism, deeply stained chromatin, and mitotic figures.

Histological Features

· Myxoid liposarcoma contains small homogeneous cells (ringed lipoblasts) with cytoplasmic vacuoles and small homogeneous non-adipocyte cells, situated in myxoid stroma containing delicate branching blood vessels.

· Dedifferentiated liposarcoma consists of non-adipocyte high-grade sarcoma. Establishing a diagnosis requires identifying a high-grade liposarcoma component.

· Pleomorphic liposarcoma contains pleomorphic to spindle-shaped cells, with clustered pleomorphic lipoblasts, containing multiple cytoplasmic vacuoles. These tumors lack high-grade liposarcoma components.

Auxiliary Tests

· Myxoid liposarcoma contains characteristic FUS-DDIT3 or EWSR1-DDIT3 rearrangements. Immunohistochemistry is not necessary for diagnosis.

· Dedifferentiated liposarcoma usually shows immunohistochemical staining for MDM2 and CDK4, along with fluorescence in situ hybridization showing MDM2 amplification. Karyotype analysis usually reveals ring and giant marker chromosomes.

· Pleomorphic liposarcoma typically exhibits a complex karyotype, with no MDM2 or CDK4 staining or reproducible genetic changes.

Figure 20.17. Cytological smear showing delicate branching “chicken wire” vascular structures, myxoid stroma, and scattered ringed lipoblasts (inset).

Figure 20.18. A case of myxoid liposarcoma showing lipoblasts in a myxoid background.

Figure 20.19. A case of dedifferentiated liposarcoma showing a large-volume, pleomorphic cell population with deeply stained nuclei.

Figure 20.20. MDM2 immunohistochemistry shows nuclear staining within tumor cells.

Part 6: Malignant Peripheral Nerve Sheath Tumors

Malignant peripheral nerve sheath tumors (MPNSTs) most often arise in patients with neurofibromatosis type 1 (NF1) and may occasionally arise after radiation exposure or from previously existing schwannomas (typically neurofibromas). They most commonly occur in young and middle-aged individuals in the extremities, trunk, and head/neck (especially in NF1). Pulmonary MPNSTs are primarily metastatic and generally appear as nodular, white-brownish, fleshy masses with areas of necrosis and hemorrhage.

Cellular Characteristics

· Typically, clustered bundles of spindle cells are mixed with isolated spindle cells, possessing round nuclei, prominent nucleoli, varying degrees of pleomorphism, and frequent mitosis, set against a myxoid or fibrillary background.

Histological Features

· Diverse appearance, but typically consists of dense cellular bundles with branching vascular structures and map-like areas of necrosis, with viable cells usually surrounding blood vessels.

· Cells are typically fusiform/spindle-shaped, with wavy/comma-shaped nuclei and faintly staining cytoplasm but may exhibit significant pleomorphism.

· Heterogeneous components are uncommon but may include skeletal muscle (malignant triton tumor), bone, and cartilage.

· Epithelioid MPNST is a rare variant that contains plump, epithelial-like cells with abundant cytoplasm, lobular growth, and myxoid stroma, usually associated with previously existing superficial schwannomas.

Auxiliary Tests

· S100 focal positivity is present in about 50% of MPNSTs, but higher-grade lesions may completely lack S100 expression. Immunohistochemistry may show loss of histone H3 lysine 27 trimethylation.

· Molecular alterations have been reported in NF1 and CDKN2A.

· Epithelioid MPNST is diffusely S100 positive and usually shows SMARCB1 (INI) loss in two-thirds of cases.

Figure 20.21. A gross photograph of a malignant peripheral nerve sheath tumor showing a large, lobulated, brownish-white, fleshy mass with necrotic and hemorrhagic areas invading the chest wall (courtesy of the Department of Pathology, Massachusetts General Hospital).

Figure 20.22. Cytological smear showing high-grade spindle cells with deeply stained chromatin, pleomorphism, active mitosis, and necrosis.

Figure 20.23. Moderate cellularity spindle cell proliferation arranged in whorled bundles, inserted into sparse collagen bands.

Figure 20.24. High-power view showing spindle cells with wavy, conical nuclei, and occasionally enlarged nuclei, pleomorphism, and deeply stained chromatin. Mitosis and necrosis (not shown) may be prominent.

Part 7: Rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is a group of tumors showing skeletal muscle differentiation, with various clinical-pathological subtypes, including embryonal, alveolar, pleomorphic, and spindle cell/sclerosing. In the lung, RMS is typically metastatic. RMS is the most common soft tissue sarcoma in young children, usually arising in the head and neck or urogenital systems (embryonal and spindle cell RMS) and limbs (alveolar). Pleomorphic RMS typically arises in the limbs of adults. Generally, pulmonary metastases of RMS are nodular and expansile, with a fleshy white appearance, with varying degrees of hemorrhage and/or necrosis.

Cellular Characteristics

· Primitive-appearing small to medium-sized round blue cells with deeply staining nuclei, scant or inconspicuous cytoplasm, occasional rhabdomyoblasts, rare multinucleation, and varying degrees of myogenic differentiation (tadpole, strap, or spider cell morphology).

Histological Features

· Embryonal RMS contains primitive small round blue cells at various stages of myogenesis and a few rhabdomyoblasts. The stroma is often loose and myxoid, with occasional fibrosis. The “botryoid” variant of embryonal RMS has tumor cells tightly associated with epithelial surfaces, growing as polypoid or pedunculated nodules.

· Alveolar RMS is a high-grade sarcoma composed of dense cellular nests of primitive small round blue cells separated by fibrous septa, with non-adherent cells pointing towards the center of the nests, leading to an alveolar-like morphology.

· Pleomorphic RMS contains undifferentiated, large cells often with multiple nuclei, along with scattered pleomorphic tumor cells showing skeletal muscle differentiation.

· Spindle cell RMS displays a growth pattern of spindle tumor cells with rare rhabdomyoblasts.

Auxiliary Tests

· Typically, RMS is immunohistochemically positive for desmin, actin, MyoD, and myogenin.

· Alveolar RMS has characteristic PAX3 or PAX7 fusions with FOXO1, t(2;13) or t(1;13).

· Embryonal RMS has complex genetic alterations, usually with loss of heterozygosity of ch11q15.5, but PAX-FOXO1 fusions are absent.

· Pleomorphic and spindle cell subtypes show complex genetic alterations.

Figure 20.25. Cytology of alveolar rhabdomyosarcoma shows numerous tumor giant cells arranged in a peripheral flower-like pattern and atypical rhabdomyoblasts with prominent nucleoli; intracytoplasmic inclusions may also be observed.

Figure 20.26. A low-power image of a metastatic pleomorphic rhabdomyosarcoma showing a highly cellular cell sheet composed of spindle cells.

Figure 20.27. A high-power view of pleomorphic rhabdomyosarcoma shows pleomorphic cell sheets, some with rhabdomyoblast characteristics, containing eccentrically located, deeply stained nuclei and prominent eosinophilic cytoplasm.

Part 8: Undifferentiated Soft Tissue Sarcoma

Undifferentiated sarcomas do not show identifiable differentiation based on morphology and auxiliary examinations, while when present in the lung, they are usually metastatic. They account for about 20% of all sarcomas and generally arise in older individuals, with no sex predilection. Generally, their appearance may vary, but undifferentiated sarcomas typically present as a necrotic grayish-brownish nodular mass.

Cellular Characteristics

· A mixture of malignant spindle cells and a few giant cells, with myxoid stroma and necrotic background.

Histological Features

· High-grade sarcomas exhibit various growth patterns, clear mitotic figures, few multinucleated tumor cells, necrosis, and hemorrhage.

· Morphological subtypes include undifferentiated spindle cell sarcoma, undifferentiated pleomorphic sarcoma, undifferentiated round cell sarcoma, undifferentiated epithelioid sarcoma, and undifferentiated sarcoma, not otherwise specified, named for the predominant morphological appearance of sarcoma cells.

Auxiliary Tests

· No reproducible immunohistochemical patterns. Keratin, actin, desmin, CD34, EMA, and CD99 show non-specific or focal staining.

· No reproducible genetic abnormalities are observed.

Figure 20.29. A gross photograph of an undifferentiated pleomorphic sarcoma showing a brownish-white mass with central necrosis.

Figure 20.30. Cytological smear showing pleomorphism, highly atypical epithelial-like cells, and spindle cells, lacking other specific differentiation lines.

Figure 20.31. A low-power image characterized by a highly cellular, whorled spindle tumor replacing lung parenchyma.

Figure 20.32. The tumor contains atypical, pleomorphic spindle cells with numerous mitotic figures and apoptotic bodies.

Part 9: Ewing Sarcoma

Ewing sarcoma is a primitive small round cell tumor that shows variable neuroectodermal differentiation, mostly arising in the metaphyseal/diaphyseal regions of long bones, pelvis, and ribs of children and young adults aged 10 to 30. In a few cases, they arise from extraskeletal sites; when seen in the lung, the most common cause is metastatic spread. Generally, these tumors are usually brownish-gray, with prominent necrosis and hemorrhage.

Cellular Characteristics

· Primitive-appearing small to medium-sized round blue cells with granular to fine chromatin and scant or inconspicuous cytoplasm.

Histological Features

· Most commonly composed of small to medium-sized round cells arranged in a sheet-like pattern, with fine chromatin, scant cytoplasm, and occasional neuroectodermal differentiation, including pseudorosettes.

· When neuroectodermal differentiation is prominent, Ewing sarcoma is sometimes designated as primitive neuroectodermal tumor.

· Although histologically non-specific, Ewing sarcoma is defined by recurrent gene translocations (see below).

Auxiliary Tests

· Immunohistochemistry usually shows diffuse CD99 membrane staining and nuclear FLI1 staining, and may show focal neuroendocrine differentiation (synaptophysin, chromogranin, CD56 positive).

· 85% of Ewing sarcomas carry EWSR1-FLI1 translocation, although EWSR1 (along with less common FUS) can also occur with many other translocations involving the ETS transcription factor family (ERG, ETV1, ETV4, FEV).

· Diagnosis is established by detecting EWSR1 rearrangements through FISH or molecular testing.

A small subset of small round blue cell tumors resembling Ewing sarcoma, when this subset lacks EWSR1 translocation, is designated as Ewing-like sarcomas and has been identified with other translocations, including CIC-DUX4 and BCOR-CCNB3.

Figure 20.33. Cytological smear showing poorly adhesive monomorphic small round blue cells with scant cytoplasm.

Figure 20.34. A low-power image showing round cells loosely adhering to each other, with areas of necrosis and fibrous vascular separations between cells.

Figure 20.35. The tumor contains homogeneous cells with round to angular nuclear profiles, scant cytoplasm, and scattered mitoses.