Abstract
The mediastinum is a complex thoracic region containing numerous vital structures of different cell differentiation (ectoderm, mesoderm, and endoderm) and possibly generating benign and malignant lesions leading to life-threatening conditions. Facing with mediastinal masses often represents a diagnostic challenge for generalist pathologist. A morphology-based approach consisting of six main pattern recognitions, namely, (1) epithelioid cell, (2) spindle cell, (3) small-cell, (4) clear-cell, (5) fibroinflammatory-looking, and(6) cystic patterns, is here proposed as a practical approach to mediastinal masses.
Introduction
The thoracic region, and particularly the mediastinum , contains several structures representing all types of cell differentiation, including epithelial organs (e.g., thymus), various mesenchymal tissues (e.g., nerves, vessels), lymphoid component (e.g., thymus and lymph nodes), and many ectopic tissues (e.g., salivary gland). Apart from tumors arising in specific mediastinal organs (e.g., thymus), the wide spectrum of tissues intuitively leads to imagine that virtually all sort of neoplasms may occur in the mediastinum, including metastatic malignancies .
While neurogenic tumors are predominantly located in the posterior mediastinum, the great majority of mediastinal growths develop in the anterior or middle compartments [1,2,3].
Indeed, the majority of publications have previously subdivided the tumors of the mediastinum based on “geographic”-involved regions, namely, anterior, middle, and posterior mediastinum [1,2,3]. On the other hand, the classification of the World Health Organization (WHO) of the lung, pleura, thymus, and heart [4] commonly distinguishes the tumors in mediastinum on cell differentiation (epithelial, mesenchymal, lymphoproliferative, germ cell tumors, etc.). However, one of the most difficult tasks for surgical pathologists is represented by frozen section examination of mediastinal masses , basically due to the small size of pieces obtained from the thoracic surgeon, tissue fragmentation and artifacts related to intraoperative procedure, and the great range of benign and malignant lesions that one should consider at the microscope during intraoperative analysis [5,6,7].
The alternative design of this chapter is then mainly organized considering the different morphologic patterns with which mediastinal masses may appear on frozen sections and at definitive formalin-fixed and paraffin-embedded sections.
Six main patterns have been arbitrarily identified to discuss this histopathologic approach to mediastinal lesions, as follows: (1) epithelioid cell pattern, (2) spindle cell pattern, (3) small-cell pattern, (4) clear-cell pattern, (5) fibroinflammatory-looking pattern, and (6) cystic pattern.
Provided that this kind of structural classification may be helpful in organizing an initial and logic list of differential diagnoses, pathologists should be aware that overlapping features are frequently seen in lesions involving the mediastinum (e.g., a thymoma with cystic changes, a combined small and large cell neuroendocrine carcinoma, a sarcomatoid carcinoma with bland spindle cell cytology, and a fibroinflammatory background) [8, 9].
Since the pathologic diagnosis of these lesions is made using a variety of techniques including radiologically guided core-needle biopsy or cytology and surgical biopsy through a variety of approaches, the morphology-based scheme here proposed may be likely adopted in different types of samples.
Although small biopsies and cytology from fine-needle aspiration may reach up to 80% of diagnostic adequacy in the hands of expert pathologists, the broad spectrum of tissue types in this region and the variety of cell morphology (even within the same neoplasm) are critical issues recommending an adequate and representative sampling of mediastinal masses [10, 11].
Since the incidence of primary mediastinal tumors is far less common than metastatic neoplasms from other sites, this fact should always be kept in mind when analyzing a tumor growth in this site. Of note, the diagnosis of a mediastinal mass always requires a close integration with clinical data (e.g., age, gender, past medical history, smoking habit) and radiologic features (e.g., solid, cystic, necrotic appearance, location, relationship with neighboring structures), and even laboratory tests (e.g., serum tumor markers) are always mandatory [2, 7].
Finally, the diagnosis of mediastinal mass often requires a surgical approach and then frozen section examination. The most important point to discuss with the thoracic surgeon is whether the mass is completely resectable or not. If resectable, the value of the intraoperative examination is critical, and a rapid, correct diagnosis is mandatory.
If unresectable, the main target to reach by pathologist is to assure an adequate quantity of tissue for definitive diagnosis and appropriately manage the tissue to carry out complementary techniques (e.g., fresh tissue for microbiology and/or frozen tissue for molecular determinations).
Epithelioid Cell Pattern
The differential diagnosis concerning the main lesions with epithelioid cell pattern is concisely summarized in Table 6.1.
Thymomas are rare malignancies overall, but they are the most common mediastinal tumors in adulthood (35%) and exceptional in children. Anterior and superior mediastinum are the most common site of occurrence, even if primary pleural or intrapulmonary thymomas may be uncommonly observed. Type B1 (lymphocyte-rich thymoma) is composed of dispersed epithelial cells, in a dense background of immature T cells, mimicking the non-involuted thymic cortex [4, 8, 12, 13]. Areas of medullary differentiation are always present. It accounts for 17.5% of thymomas, and it occurs most commonly in the fifth and sixth decades of life. Grossly it appears as a nodular encapsulated tumor, ranging in diameter from 5.1 to 7.5 cm. The cut surface is soft, smooth, and tan-pink, with vague lobules delineated by fibrous septa. Necrosis and cystic change may be present. Histologically the tumor could show lobulation or not. Lobules are often larger than those of the normal thymus and traversed by collagenous septa. The neoplastic cells may be difficult to detect on low-power examination, because they are individually interspersed within nonneoplastic immature lymphocytes (Fig. 6.1). They have poorly defined eosinophilic cytoplasm and oval to rounded monomorphic nuclei with vesicular chromatin and small but prominent central nucleoli. Medullary islands appear as pale nodular areas and are characterized by an increased numbers of B cells and mature T lymphocytes; it may contain Hassall corpuscles and myoid cells. Perivascular spaces are often present. Differential diagnosis mainly includes hyperplastic thymus and lymphomas. Type B1 thymoma shows a thicker fibrous capsule and, if present, larger lobules with fibrous septa. In contrast to hyperplastic thymus, type B1 thymoma has a prevalence of cortical areas over medullary islands, which show fewer or absent Hassall corpuscles, and autoimmune regulator (AIRE)-positive epithelial cells [14].
Type B1 (organoid type) thymoma with few, scattered epithelial cells in a background of immature T cells
Neoplastic cells of lymphoma are monotonous and atypical, with frequent necrosis and a diffuse pattern of growth, which effaces corticomedullary architecture. Blasts typically infiltrate mediastinal fat, and rearrangement of T-cell receptor is mostly monoclonal. A panel of epithelial markers including keratins and p63 could be useful to exclude the presence of a preserved network of epithelial cells and to definitely exclude type B1 thymoma [15, 16].
Type B2 (lymphocyte-rich thymoma) is a lymphocyte-rich tumor with a content of epithelial cells higher than that seen in type B1 thymoma (clusters of ≥3 cells). It accounts for 26% of all thymoma, with a mean age at presentation of 49 years. Macroscopically a capsule may or may not be present, and invasion of the mediastinal fat or adjacent organs can occur. The cut surface is gray white and soft to firm, with lobules delineated by white fibrous septa. Cystic changes, necrosis, and/or hemorrhage can be observed. Histologically the tumor shows a lobular architecture with a prevalence of immature nonneoplastic T cells and clusters of neoplastic polygonal epithelial cells, which have the same cytological features described in type B1 thymoma (Fig. 6.2). Rare cases can focally show anaplasia. Perivascular spaces composed of a central venule surrounded by a clear space containing proteinaceous fluid or variable numbers of lymphocytes are typically present. Medullary islands are usually inconspicuous [4, 8, 12,13,14,15].
Type B2 (cortical-type) thymoma with clusters of epithelial cells intermingled with immature T cells
Type B3 (lymphocyte-poor thymoma , well-differentiated thymic carcinoma) is characterized by a predominance of polygonal epithelial cells, which form solid sheets, and paucity of admixed nonneoplastic immature T cells, resulting in a pink appearance on H&E stains at low magnification. It accounts for 16% of all thymoma and the mean age at diagnosis is 55 years. Macroscopically it is usually poorly circumscribed with invasion of the mediastinal fat and adjacent organs. The diameter ranges from 5.1 to 6.8 cm. The cut surface is firm and gray or yellow, with multinodular appearance. Necrosis and hemorrhage may be present. Histologically, typical findings include lobular architecture, pushing borders at the invasion front, prominent perivascular spaces with epithelial palisading, absence of intercellular bridge between tumor cells, and epithelial whorls resembling squamous eddies or abortive Hassall corpuscles. Tumor cells are mildly to moderately atypical, with round or oval nuclei of variable sizes and sometimes grooved (Fig. 6.3). Association with type B2 component is very frequent [4, 8, 12, 13, 16]. Differential diagnosis with thymic squamous cell carcinoma may be challenging, particularly on small biopsy. Thymic squamous carcinoma lacks lobular growth and perivascular spaces and shows infiltrative rather than pushing borders, desmoplasia, more prominent cytological atypia, and presence of intercellular bridges or overt keratinization. Immunohistochemical stains show CD5 and CD117 positivity in 80% of cases of squamous cell carcinoma (Fig. 6.4) together with the absence of TdT + Tcells. Focal expression of CD5 and CD117 in tumors with an otherwise B3 thymoma morphology has been reported [17, 18].
Type B3 thymoma (well-differentiated thymic carcinoma ) with a prevalence of squamoid cells and scattered immature T lymphocytes
Type B2/B3 thymoma with coexistence of both tumor types
Thymic carcinoma (type C thymic epithelial tumor) accounts for nearly 22% of all thymic epithelial neoplasms and about 10% of mediastinal tumor in adults. Several lung cancer-like variants have been reported, such as squamous cell carcinoma, basaloid carcinoma, clear-cell carcinoma, adenocarcinoma, undifferentiated large cell carcinoma, nuclear protein in testis (NUT)-midline carcinoma, and salivary gland-derived carcinomas (mucoepidermoid and adenoid cystic carcinoma, adenosquamous carcinoma, sarcomatoid carcinoma, lymphoepithelioma-like carcinoma) [4, 8, 12, 13, 18,19,20,21,22,23,24].
Squamous cells carcinoma (SqCC) shows morphological features of SqCC occurring in other organs (Fig. 6.5). Unlike thymoma, it generally lacks resemblance to the normal thymic cytoarchitecture: discrete lobulation, perivascular spaces, and intermingled immature T lymphocytes. It accounts for approximately 70% of all thymic carcinomas. Macroscopically it is a frankly invasive tumor with frequent foci of necrosis and hemorrhage and a mean maximum diameter of 7.2 cm. Histologically, it grows predominantly in the form of anastomosing smooth-contoured islands, but it can show jagged invasion in some cases. SqCC can show a range of differentiation from well to moderate to poor, based on the presence or absence of keratinization, nuclear pleomorphism, and the extent of squamous cell maturation. The relevance of grading is controversial, and there is currently no generally accepted tumor grading system. At immunohistochemical level, neoplastic cells are positive for keratins, p63 (83% of cases), PAX8 (75% of cases), CD5 (74% of cases), CD117 (84% of cases), FOXN1 (68–76% of cases), and CD205 (10–59% of cases) [17,18,19, 25, 26]. Basaloid carcinoma is characterized by solid and cystic papillary nests of medium- to small-sized cells with a high nuclear-to-cytoplasmic ratio and peripheral palisading. It accounts for <5% of all thymic carcinomas (less than 40 cases reported in English-language literature), with a median age of 60 years and a male predominance (male-to-female ratio, 2.5:1) [20]. Interestingly multilocular thymic cysts were observed in about 50% of the cases and may represent a precursor lesion. Grossly it is generally a well-circumscribed grayish tumor with solid and cystic areas and a mean size of 8 cm. Histologically it shows an admixture of cystic papillary and nesting growth patterns. Foci of comedo-type necrosis are common, and focal squamous differentiation can be observed in up to 40% of cases (Fig. 6.6). Small glands associated with deposits of amorphous basement membrane-like material may be present. Rarely sarcomatoid transformation can occur. Cystic changes can result from pre-existing multilocular thymic cysts, lined by benign-looking squamous cells, or they represent cystic degeneration of the tumor and are lined by neoplastic basaloid cells. At immunohistochemical level, BC cells are positive for p63/p40, CD117, and CD5 (<50% of cases). TTF1, chromogranin, and synaptophysin are negative.
Type C thymic carcinoma , squamous cell carcinoma variant
Type C thymic carcinoma , basaloid carcinoma variant
Mucoepidermoid carcinoma represents a particularly unusual type of thymic carcinoma, morphologically similar to the salivary gland counterpart. It is composed of a combination of squamous cells, mucinous cells, and intermediate-type cells [4, 8, 12, 13, 20, 25]. The average age is 49 years. Some cases are associated with multilocular thymic cysts. Grossly tumor size ranges from 4 to 11 cm. The tumor is well demarcated, but infiltration of pericardium can occur. The cut surface shows a variable amount of cystic areas containing mucoid substance. Histologically there are variable combination of epidermoid cells forming sheets or solid islands, goblet cells (positive with mucicarmine or periodic acid-Schiff stain) forming nests or occurring as single cells, and intermediate cells forming nests or lobules or intermingled with squamous or mucus-secreting cells. The majority of cases show low-grade histology, but high-grade cases showing atypia and high mitotic activity (>7 mitosis per 2 mm2) are on record, and they can mimic adenosquamous carcinoma or mucinous adenocarcinoma. Immunohistochemistry shows positivity for pan-cytokeratin and EMA. CK5/CK6 and p63 are often positive. Unlike MEC of salivary gland, CK7 is rarely positive. CD5 e CD117 are negative in most cases. A useful diagnostic feature is the identification of the translocation t(11;19)(q21;p13), of the MAML2 gene, using FISH [27,28,29]. This is the same chromosomal rearrangement already described in almost all low-grade MECs and many high-grade MECs of the salivary glands, bronchi, and lung. Lymphoepithelioma-like carcinoma (LELC) is a primary thymic poorly differentiated squamous cell carcinoma associated with a prominent lymphoplasmacytic infiltrate and morphologically similar to nasopharyngeal carcinoma. It accounts for 6–32% of all thymic carcinomas with a median age of 41 years and a bimodal peak at 14 years and 48 years. A male predominance has been reported (male-to-female ratio 2:1). Grossly it is an invasive mass with a solid cut surface yellow-white, with areas of necrosis. Histologically it consists of anastomosing sheets, nests, and cords of carcinoma cells, with indistinct borders, large vesicular nuclei, and distinct nucleoli, accompanied by abundant lymphocytes and plasma cells. Generally, there is no striking anaplasia. Focal squamous differentiation can be present. Germinal centers, eosinophils, and granuloma may be present. Coagulative necrosis is common. Half of cases are associated with EBV, which is almost always positive in children and young adults, while it is uncommon in adults aged >30 years. The most reliable way to demonstrate EBV is in situ hybridization for EBV-encoded small RNA. Immunohistochemically, tumor cells are positive for pan-cytokeratin and frequently for p63. CK7 and CK20 are negative. There is variable positivity for CD5 and frequent immunoreactivity for CD117. The lymphocytes are mostly CD3+/TdT-mature T cells admixed with B cells and polytypic plasma cells [20, 23, 24, 30].
Adenocarcinomas represent a heterogeneous group of malignant thymic epithelial tumors showing glandular differentiation and/or mucin production. They are very rare with only single reports or small series described [31,32,33,34,35,36].
Papillary type. It shows an architectural resemblance to papillary thyroid carcinoma or malignant mesothelioma. It consists of tubulopapillary structures lined by cuboidal to polygonal cells with distinct nucleoli and eosinophilic or clear cytoplasm. Complex glomeruloid structures can also be formed. Psammoma bodies may be numerous. Coagulative necrosis can be sometimes massive. This carcinoma is often associated with type A or AB thymoma and is therefore assumed to represent a malignant transformation of thymoma. Another associated lesion is multilocular thymic cyst. Neoplastic cells are positive for epithelial markers (keratins, EMA, BerEp4) and can show focal positivity for CD5.
Adenoid cystic carcinoma-like tumor. It is morphologically similar to its salivary gland counterpart, but does not exhibit the full range of characteristics seen in salivary gland-type ACCs. In particular, there is no tubular growth pattern, no myoepithelial component, and no obvious neurotropism. It is composed of nests of basaloid cells with variable number of pseudocysts filled with homogeneous or granular basophilic membrane material with cribriform structures formation. Nuclear atypia and necrosis are rare. Tumor cells are positive for keratins and p63 but negative for other myoepithelial markers (e.g., smooth muscle actin, S100). The pseudocyst content is positive for collagen IV, laminin, and stromal mucin. Occasional CD5-positive cells could be present, but CD117 is negative. Mitotic activity is low (ki67 < 10%).
Mucinous adenocarcinoma . It resembles the counterpart that occurs in other organs. The carcinoma cells can show goblet cell or signet-ring cell morphology due to cytoplasmic mucin accumulation, or there could be abundant extracellular mucin, in which neoplastic glands or single tumor cells float. This tumor is often associated with thymic cyst supporting a primary thymic origin rather than metastasis. Tumor cells could express an intestinal immunophenotype (CK20 +, CDX2 +, MUC2 +) and show variable positivity for CD5.
Adenocarcinoma , not otherwise specified (NOS). It encompasses adenocarcinoma not conforming to any of the above three subtypes. Nuclear pleomorphism is significant and necrosis is common.
Tumor cells show positivity for keratins and sometimes for CD5.
In general, the finding of an adenocarcinoma in the mediastinum should consistently raise the possibility of a metastasis from other sites. Organ-specific markers (e.g., TTF1, GCDFP-15, thyroglobulin, PSA) may be helpful to confirm extrathymic origin. Search for associated thymic cyst or thymoma areas could be helpful since their presence favors a thymic primary [37].
NUT-midline carcinoma is a poorly differentiated carcinoma genetically defined by the presence of NUT gene translocation [38, 39]. Originally thought to be a disease of children and young adults, NUT carcinoma can occur at any age (from birth to 78 years). Thoracic/mediastinal primary accounts for 57% of all cases of NUT carcinoma, with the contemporary involvement of both the lung and mediastinum at presentation. It characteristically presents as a rapidly growing mass with rapid dissemination. Histologically it is composed of monomorphic poorly differentiated carcinomatous cells that show focal abrupt keratinization. Glandular and mesenchymal differentiation are typically absent. At immunohistochemical level, it is consistently positive for nuclear protein in testis (NUT, aka NUTM1). Pan-cytokeratins and p63/p40 are positive in the majority of cases. Occasionally it expresses chromogranin, synaptophysin, or TTF1. Tumor cells often stain for CD34, which may lead to a misdiagnosis of acute leukemia. Germ cell and lymphoid and myeloid markers are negative. Molecular determination of NUT rearrangement, t(15;19) in 70% of cases, is diagnostic.
Undifferentiated carcinoma is a diagnosis of exclusion: it is a primary carcinoma of the thymus showing no morphological or immunohistochemical feature other than epithelial differentiation (Fig. 6.6). The tumor cells are positive for pan-cytokeratin, CD117 (60%), and PAX8 (40%). Unlike in poorly differentiated thymic squamous cell carcinoma, there is no expression of CK5/CK6, P63, or CD5 [40]. Malignant germ cell tumor markers (such as OCT3/OCT4 and SALL4) and neuroendocrine markers are negative.
Undifferentiated carcinoma should not be confused with a recent entity of large-sized and rapidly progressive undifferentiated sarcomas of the thoracic region characterized by SMARCA4-deficiency [40], mainly occurring in men and appearing as solid growth of mildly discohesive and relatively monotonous epithelioid cells with prominent nucleoli. At histology, these sarcomas show complete/partial absence of SMARCA4 and variable expression of cytokeratins, CD34, SOX2, SALL4, and p53 together with inactivating SMARCA4 mutation.
Thymic neuroendocrine tumors are classified using the same nomenclature and criteria as for lung tumors. The definition of “neuroendocrine differentiation” in both carcinoids or large cell neuroendocrine carcinomas is based on strong and diffuse expression of usually more than one of the four neuroendocrine markers (chromogranin A, synaptophysin, CD56, and NSE) in >50% of tumor cells [41,42,43,44,45,46,47,48,49,50,51,52]. There are currently no immune-histological markers that can unequivocally distinguish between thymic and pulmonary primaries, although a TTF1-/PAX8 + profile appears to be more common in thymic carcinoids. Clinical and radiological correlation remains the mainstay for the distinction between thymic and lung origin.
Typical carcinoid is a low-grade neuroendocrine epithelial neoplasm of thymic origin with <2 mitoses per 2 mm2 and lacking necrosis. Grossly it is unencapsulated and it could be invasive. The mean size is 8–10 cm, smaller in Cushing syndrome due to earlier detection. Cut surface is gray white and firm, without the characteristic lobulated growth pattern of thymoma. Oncocytic variant may show a tan or brown cut surface. Calcifications are present in 30% of cases, more often than in extrathymic neuroendocrine tumors. At histology, it shows a solid and trabecular growth pattern with delicate vasculature between tumor masses and rosette-like formation (Fig. 6.7). Tumor variants include spindle cell, pigmented, with amyloid, oncocytic, mucinous, and angiomatoid. Therefore, the major differential diagnoses include spindle cell thymoma and paraganglioma, medullary thyroid carcinoma, metastatic mucinous carcinoma, and hemangioma.
Type C thymic carcinoma , undifferentiated type (a) strongly expressing CD117 (b)
Atypical carcinoid is an intermediate-grade neuroendocrine epithelial neoplasm, presenting 2–10 mitoses per 2 mm2 and/or foci of necrosis. It is far more common than typical carcinoid, and it affects mainly adult with a mean age of 48–55 years and a male predominance. In a half of cases, lymph node metastases and invasion into adjacent organ are already present at diagnosis. Histologically, all architectural features of typical carcinoid can occur; a more diffuse growth pattern can be observed (Fig. 6.8).
Thymic typical carcinoid
Large cell neuroendocrine carcinoma is a high-grade neuroendocrine epithelial neoplasm composed of large cells with >10 mitoses per 2 mm2 and frequent necrosis (Fig. 6.9).
Thymic atypical carcinoid
Differently from the lung counterpart, recent evidences suggested that LCNEC of the thymus may developed from pre-existing CTNNB1-mutated AC upon loss-of-function TP53 and gain-of-function JAK3 mutations or through an epithelial-mesenchymal transition [53].
It is important to keep in mind that neuroendocrine tumors, particularly typical and atypical carcinoids, may rarely originate from teratomas [54] and enter in differentials diagnosis with other mimicking entities, such as paragangliomas (negative with cytokeratins) and glomus tumors (expressing collagen IV, smooth muscle actin but not cytokeratins) [55] (Fig. 6.10).
Thymic large cell neuroendocrine carcinoma
Germ cell tumors of the mediastinum represent the 15% of mediastinal tumors in adults and nearly 19% in children [4, 21, 56,57,58,59,60,61,62]. In prepubertal children they consist only of teratomas and yolk sac tumors, either pure or mixed, while in postpubertal they can be almost any of the histological types of germ cell tumors seen in the gonads, apart from spermatocytic seminoma. The most common histological types are mature teratoma and seminoma.
Seminoma occurs almost exclusively in men, with exceptional cases of dysgerminoma reported in women. The peak age distribution is between 33 and 39 years. It is composed of large monomorphic cells with nonoverlapping nuclei and one or more central nucleoli, growing in multinodular clusters, sheets, cords, or irregular lobules. A lymphoid infiltrate with or without granulomatous inflammation is frequently present. Scattered syncytiotrophoblastic cells (βhCG-positive) could be seen close to capillaries and/or focal hemorrhage. Immunohistochemistry shows positivity for OCT4, SALL4, SOX17, CD117 in a cell membrane or paranuclear Golgi pattern (70% of cases), and D2-40. Keratins can be positive but in a dot-like pattern. Tumor cells are negative for CD30, βhCG, AFP, SOX2, and glypican 3.
Embryonal carcinoma affects predominantly young male, with a mean age at presentation of 27 years. It is composed of large cells with indistinct borders, crowded nuclei, and large eosinophilic nucleoli, with a solid growth, complex glandular array or papillae. Mitoses are frequent and atypical. Scattered syncytiotrophoblastic cells (βhCG-positive) are present in nearly 30% of cases. Neoplastic cells stain for low-molecular-weight keratins, CD30, SOX2, OCT4, and SALL4. AFP can be focally positive in 30% of cases, while EMA and SOX17 are usually negative.
Yolk sac tumor before the puberty represents the second most common mediastinal germ cell tumor, after teratoma. After puberty, it occurs almost exclusively in males, with a peak incidence in the third decade. Choriocarcinoma is a wide spectrum of histological pattern, often coexisting; microcystic or reticular, glandular-alveolar, and pseudopapillary with Schiller-Duval bodies; and myxomatous, hepatoid, enteric, polyvescicular-vitelline, solid, and spindle (Figs. 6.11 and 6.12 ). Tumor cells are consistently immunoreactive for cytokeratins, glypican 3, SALL4, and LIN28. They may express also AFP, PLAP (70%), CD117 (40%), CD30 (25%), and EMA (focally in <25% of cases). They are negative for OCT4, NANOG, SOX2, and D2-40.
Mediastinal glomus tumor
Mediastinal yolk sac tumor with microcystic (a) and hepatoid (b) patterns
Choriocarcinoma is a highly aggressive neoplasm, mainly affecting adult male patient. Histologically it appears as a highly polymorphic tumor intimately associated with dilated sinusoids filled with blood. It is composed of multinucleated syncytiotrophoblastic cells, mononuclear cytotrophoblastic cells, and variably intermediate trophoblast. Vast areas of hemorrhage and necrosis are often observed. At immunohistochemical level, it is positive for keratin. Syncytiotrophoblastic cells express βhCG and glypican 3, while cytotrophoblastic cells are positive for SALL4. Tumor cells are negative for OCT4, PLAP, AFP, CEA, and CD30.
A brief summary of immunostains in germ cell tumors is reported in Table 6.2.
Lymphomas of the mediastinum account for the 23% of mediastinal tumors in adults and about 12% in children.
Primary mediastinal large B-cell lymphoma is an aggressive large B-cell lymphoma of putative thymic B-cell origin [63,64,65,66,67,68,69]. It mainly occurs in the third and fourth decade, with a female predominance. It presents as a tumor mass in the thymic area. Histologically it is composed of clusters or sheets of large neoplastic cells, often compartmentalized in areas of varying sizes by a distinctive fibrosis made up of irregular collagen bands (Fig. 6.13). At the periphery of the mass, reactive cells such as lymphocytes, macrophages, and granulocytes may be present. Lymph nodes are involved with a typical carcinoma-like pattern, starting from marginal sinus, with gradual replacement of lymph nodal parenchyma. Some cases may contain cells with pleomorphic nuclei and may resemble Hodgkin lymphoma or not lymphoid tumors. Immunostaining shows positivity for B-cell markers such as CD19, CD20, CD22, and CD79a, but typically immunoglobulin, PAX5, BOB1, and OCT2 are negative. CD30 is positive (80% of cases) but weak and heterogeneous. Tumor cells also express IRF4/MUM1 (75%) and CD23 (70%) and show a variable positivity for Bcl2 and Bcl6. CD10 is almost always negative. Interestingly positivity for p63 can be present in >90% of cases, while p40 is absent. This is helpful in the differential diagnosis with Hodgkin lymphoma, but it could represent a caveat, since p63 is also expressed in normal and neoplastic thymic epithelial cells, although it is typically accompanied by p40 expression.
Primary mediastinal large B-cell lymphoma
Anaplastic large cell lymphoma is a mature T-cell lymphoma characterized by strong expression of CD30 and the presence of a variable proportion of hallmark cells with abundant cytoplasm, a kidney-shaped nucleus, and a prominent Golgi region. Translocation of ALK with a variety of other genes, most commonly with NPM1, typically occurs in more than 90% of cases in children and in nearly 50% of adult cases. Thymus and mediastinum involvement is most commonly present in the context of advanced-stage disease. At morphology, anaplastic large cell lymphoma is composed of large cells, including hallmark cells, with a cohesive pattern and sometimes an intrasinusoidal growth in lymph nodes. Tumor cells are positive for CD30 (membranous and Golgi pattern) and EMA. The expression of cytotoxic molecules and the loss of several pan-T-cell antigens are frequently observed. ALK positivity is nuclear and cytoplasmic in case of nucleophosmin-ALK fusion protein, but the subcellular stain distribution depends on the gene involved in the chromosomal translocation.
Langerhans cell histiocytosis and its malignant counterpart, Langerhans cell sarcoma, can rarely involve thymus or mediastinal lymph node, usually in the setting of disseminated disease [70]. On hematoxylin-eosin stain, they are composed of a diffuse infiltrate of Langerhans cells, characterized by grooved or markedly contorted nuclei, fine chromatin, and eosinophilic cytoplasm. Multinucleated giant cells and eosinophils are frequently present. Necrosis can be observed. The Langerhans cells are characterized by immunoreactivity for S100, CD1a, and langerin (CD207), as well as ultrastructural presence of Birbeck granules.
Histiocytic sarcoma is a malignant proliferation of cells with morphological and immunophenotypic features of mature histiocytes. A subset of cases is associated with mediastinal non-seminomatous germ cell neoplasm, most commonly malignant teratoma with yolk sac component. Histologically it is composed of pleomorphic large cells with abundant eosinophilic cytoplasm and a diffuse pattern of growth. The nuclei are typically large, irregularly folded, and eccentrically placed with a dispersed chromatin. Immunohistochemically there is positivity of one or more histiocytic markers (CD163, CD68/PGM1 or KP1, and lysozyme) and negativity of Langerhans cell markers (CD1a and langerin), follicular dendritic cell markers (CD21 and CD35), and myeloid cell markers (myeloperoxidase). Positivity for CD33 and CD13, other myeloid markers, has been described. CD45 is positive too, and weak expression of CD15 can rarely occur. S100 may be expressed but it is typically weak or focal.
Epithelioid hemangioendothelioma (EHE) i s a malignant intermediate-grade vascular tumor mainly affecting young adult females [71,72,73]. Multiple involvement of the lung, skin, bone, and liver occurs in about 20% of cases. The tumor often shows a multinodular appearance with expansive margins, hypocellular chondromyxoid or hyalinized sclerotic stroma, and epithelioid cells with eosinophilic cytoplasm, intracytoplasmic vacuoles, and intranuclear inclusions. At least one vascular marker at immunostains is positive (CD31, CD34, ERG, CAMPTA1, factor VIII), and cytokeratins are expressed in up to 30% of cases. The presence of prominent cellular atypia, spindle cell features, and necrosis and high mitotic rate more often characterize an epithelioid angiosarcoma. Nevertheless, EHE, particularly when myxoid/hyalinized stroma occurs, may enter in differential diagnosis with granulomatous lesions, infarcts, amyloidosis, mesothelioma, and carcinomas (Fig. 6.14).
Epithelioid hemangioendothelioma with prominent sclerotic stroma and scattered epithelioid tumor cells
Even epithelioid angiosarcomas [74] may be present in the mediastinum as aggressive neoplasms mimicking carcinomas (Fig. 6.15). Since cytokeratins are frequently positive in angiosarcoma, careful search for intratumor vessel formation together with consistent expression with at least one vascular marker (it is a good practice to test for all available endothelial stains, namely, CD31, CD34, ERG) is mandatory to achieve the correct diagnosis.
Epithelioid angiosarcoma with atypical epithelioid cells and a vascular hemorrhagic network
Metastatic tumors to mediastinum are mainly located in lymph nodes, so they are usually in the middle mediastinum, where most mediastinal lymph nodes are situated. Residual nodal component at their periphery could be detected and useful for diagnosis. However, tumors can spread to the thymus or anterior mediastinum too either from adjacent organs or by lymphatic or hematogenous route. Tumors that more often can be confused with primary mediastinal tumors are testicular germ cell tumors, prostatic carcinoma, and melanoma. Many carcinomas can metastasize to the mediastinum, such as the lung, breast, thyroid, kidney, ovary, and nasopharynx. Direct mediastinal extension can also occur from the esophagus, pleura, chest wall, and trachea. Immunostains for organ-specific markers can be useful, but differential diagnosis is mainly based on clinical and radiological features [4, 21].
Some benign mediastinal lesions with epithelioid cell pattern include thyroid nodular hyperplasia, parathyroid adenomas, and thymic hyperplasia.
Spindle Cell Pattern
The differential diagnosis concerning the main lesions with spindle cell pattern is concisely summarized in Table 6.3.
Type A thymoma is a relatively uncommon subtype, accounting for 12% of all thymomas. Patient ages range from 8 to 88 years, with a mean age of 64 years, which is higher than the mean age for all thymomas. A slight female predominance has been reported in most studies [4, 21]. It is generally a well-circumscribed or encapsulated tumor ranging in size from 5.9 to 7.4 cm. The cut surface is homogeneous and light tan to white, with vague lobulation. Focal cystic change can be present. Histologically, it is characterized by a high content of bland spindly and oval epithelial cells and paucity or absence of immature TdT+ T cells (Fig. 6.16). Spindle tumor cells show bland nuclear features with no or minimal nuclear pleomorphism, fine nuclear chromatin, inconspicuous nucleoli, and absent or low mitotic activity. Pattern of growth encompasses a wide morphological spectrum that can cause misdiagnosis above all when dealing with small mediastinoscopic biopsies [75,76,77]. In addition to the diffuse pattern, with spindle cells either arranged in solid sheets without any particular architecture or in a storiform or fascicular pattern, neuroendocrine array can be seen, with cords, ribbons, or rosette-like structures with or without central lumina. Neural pattern, with whorled configuration reminiscent of those typically seen in meningothelial type meningiomas, or schwannoma-like pattern can be present. Adenomatoid pattern with short-spindled epithelial cells alternating with microcystic areas and storiform or hemangiopericytic growth patterns has been described too. Interestingly, in this pattern the spindle cells can have prominent cytoplasmic vacuolation imparting a signet-ring cell-like appearance. These features can be reminiscent of metastatic carcinoma or yolk sac tumor.
Type A (medullary type) thymoma with rosette-like formation pattern
Papillary and pseudopapillary growth patterns usually do not comprise more than 50% of the tumor mass and can mimic papillary thyroid carcinoma or papillary thymic carcinoma. They are characterized by a solid pattern with papillary projections, composed of fibrovascular cores, or pseudopapillary proliferation, composed of larger villous-like stromal projections with central edematous or hyalinized changes and areas of calcification with occasional psammoma body formation. Angiomatoid areas with prominent cavernous blood-filled spaces separating spindled epithelial cells have to be differentiated from hemangioma or angiosarcoma.
Eventually, hemangiopericytoma-like pattern can be encountered, with neoplastic spindled epithelial cells with prominent staghorn-like vasculature reminiscent of solitary fibrous tumor. The clues for the diagnosis of type A thymoma are the coexistence of more histological patterns in a monophasic spindle cell tumor with bland cytological features. Immunohistochemical profile may be useful in selected cases for differential diagnosis: thymic epithelial markers (keratins, p63, PAX8, FOXN1, CD205) are positive, while carcinomatous markers (CD5 and CD117) are negative. Moreover, an ectopic expression of CD20 is frequently present, even if focal. TdT+ T cells are completely absent or represent a minority of the CD3+ T lymphocytes, and CD20+ B cells are usually absent.
An atypical variant of spindle cell thymoma is also on record: rarely type A thymomas can show hypercellularity, increased mitotic activity (>4 mitosis/2 mm2), and focal necrosis, but the clinical significance of these features is still unknown [78].
Type A thymomas with any lymphocyte-dense areas (TdT+ T cells impossible to count), or with moderate infiltrate of TdT+ T cells in >10% of the tumor area, are classified as type AB thymoma (Fig. 6.17). It accounts for 27.5% of thymomas, with an average patient age of 57 years. Macroscopically the tumors are usually encapsulated, and the cut surface shows multiple nodules of various sizes, separated by white fibrous bands. Histologically, it is a well-circumscribed tumor composed of a lymphocyte-poor spindle cell (type A) component and a lymphocyte-rich (type B-like) component in highly variable proportion, either intermingled or forming separate nodules. All histological patterns of type A thymomas can be present. Type A components may also consist of spindle cell fascicles encircling lymphocyte-rich nodules like cellular fibrous septa. Medullary islands are very rare and Hassall corpuscles are generally absent. Type AB thymoma may enter in differential diagnosis with micronodular thymoma with lymphoid stroma [4, 12, 13, 21]. This rare type of thymoma consists of multiple small tumor nodules of bland spindle or oval epithelial cells surrounded by an epithelial cell-free lymphoid stroma. It accounts for about 1% of all thymomas with an average age at diagnosis of 64.5 years. Macroscopically it is well circumscribed and well encapsulated. The cut surface is often soft and friable and light tan, with occasional cystic spaces. The nodules are composed of neoplastic epithelial spindle cells with elongated nuclei and inconspicuous nucleoli. Mitotic activity or cytological atypia is not observed. The stroma separating the tumor islands is composed of a dense proliferation of small lymphocytes, which may contain lymphoid follicles and germinal centers. Occasional plasma cells may be part of this lymphoid component. Initially thought to be primarily of B-cell lineage, this lymphoid infiltrate is a mixed B- and T-cell population, including occasional immature T cells, as commonly seen in the conventional types of thymoma. Areas corresponding to type A thymoma occur in up to 30% of micronodular thymomas with lymphoid stroma. At immunohistochemical level, the epithelial cells of micronodular thymomas with lymphoid stroma typically lack the expression of CD20. Moreover, the lymphoid stroma is devoid of keratin-positive epithelial cells [4, 21].
Type AB (mixed type) thymoma with medullary/type A (left) and cortical/type B2 (right) components
Metaplastic thymoma is a biphasic tumor composed of solid areas of epithelial cells and bland-looking spindle cells, with gradual or abrupt transition between the two components (Fig. 6.18) [4, 21]. It is extremely rare with fewer than 40 cases reported in literature. Median age at presentation is 50 years. At histology, a lobular growth pattern is absent. The epithelial cells show squamoid or whorled appearance and form islands or trabeculae. Sometimes they could have enlarged pleomorphic nuclei, but mitotic activity is usually low (ki67 < 5%). Fibroblast-like spindle cells are present in the background, forming short fascicle or storiform arrays. Immature TdT + Tcells are typically absent. At immunohistochemical level, the epithelial component expresses both keratins and p63, whereas fibroblast-like spindle cells are negative for p63 but show at least focal positivity for epithelial markers (e.g., keratins and epithelial membrane antigen) supporting its metaplastic nature. Both components are negative for CD5, CD20, CD34, and CD117. The differential diagnoses include sarcomatoid carcinoma (spindle cell component is of high grade, with necrosis and high proliferative index), solitary fibrous tumor (distinctive immunoprofile CD34 +, CD99 +, BCL2 +, STAT6 +, CK −), and type A thymoma.
Metaplastic thymoma with clear-cut separated biphasic components
Thymic sarcomatoid carcinoma (TSC) consists partly or completely of spindle sarcomatoid cells. In some tumors, heterologous mesenchymal elements could be present (the so-called carcinosarcoma ) [4, 21]. It accounts for 5–10% of all thymic carcinomas, and it occurs mostly in the fourth to eight decades. Grossly it is often large with infiltrative borders. The cut surface is fleshy white or gray with areas of hemorrhage, necrosis, and cystic degeneration. Histologically, sarcomatoid cells have pleomorphic nuclei, prominent nucleoli, and high mitotic activity and show fascicles and storiform arrays. A carcinomatous component may coexist, consisting of TSCC, ADC, adenosquamous carcinoma, or TUC. Mesenchymal component is more frequently rhabdomyosarcomatous, but chondrosarcoma or osteosarcoma could be also present. Immunohistochemically sarcomatous cells show variable positivity for keratins and EMA, while CD5 may or may not be positive.
Histiocytic and dendritic cell tumors (follicular dendritic cell sarcoma, interdigitating dendritic cell sarcoma, fibroblastic reticular cell tumor) represent a heterogeneous group of neoplasms with similar morphology consisting of proliferations of spindle cells with indistinct borders, vesicular nuclei with evident nucleoli, and a variable growth pattern: storiform, whorled, fascicular, nodular, diffuse, or even trabecular. Cytological atypia is variable and foci of necrosis may be present. Immunohistochemical profile is mandatory for a correct diagnosis.
Follicular dendritic cell sarcoma is uncommon, and nearly 12% of reported cases involve the thymus or mediastinal lymph nodes, as a localized disease [79, 80]. It shows an average age of 50 years at presentation. It can occur in the anterior or posterior mediastinum, and it may be associated with a hyaline vascular Castleman disease. The neoplastic cells show positive immunostaining for one or more follicular dendritic cell markers (CD21, CD35, and CD23), while they are negative for CD1a and CD30. CD68 and S100 may be weekly express. Keratin is negative, but EMA is positive in 40–80% of cases, and D2-40 is frequently positive too. This subset of EMA-positive and/or D2-40-positive follicular dendritic cell sarcomas has to be differentiated from cytokeratin-deficient thymomas, meningioma, and mesothelioma (Fig. 6.19).
Follicular dendritic cell sarcoma showing a characteristic mixture of spindle cell proliferation and lymphocytes
Interdigitating dendritic cell sarcoma is very rare and mediastinal involvement is even rarer. It almost always affects mediastinal lymph nodes as a component of disseminated disease. The neoplastic cells are strongly positive for S100 and show variable weak staining for CD68, lysozyme, CD4, CD11c, CD14, and CD45. They are always negative for CD1a, langerin, follicular dendritic cell markers, myeloperoxidase, and T-cell and B-cell lineage-specific markers. All other melanocytic markers (such as HMB45, melan-A, SOX10) are negative, and this is useful for the differential diagnosis with metastatic melanoma, which is much more common.
Fibroblastic reticular cell tumor is very rare and involves mediastinum and/or mediastinal lymph node, with median patient age of 61 years old. Tumor cells express vimentin and show variable immunoreactivity for keratin, actin, and desmin. There can be also positivity for CD68, while the tumor should not express markers of follicular or interdigitating dendritic cells. The cytokeratin-positive subsets of fibroblastic reticular cell tumors need to be distinguished from spindle cell epithelial tumors (e.g., atypical type A thymomas, sarcomatoid carcinomas), while the main differential diagnosis for actin-positive or desmin-positive fibroblastic reticular cell tumors is smooth muscle and myofibroblastic tumors.
Several soft tissue neoplasms occur in the mediastinum [81,82,83,84,85,86,87,88], such as liposarcoma with their variants, benign and malignant solitary fibrous tumor, synovial sarcoma, and even angiomatoid fibrous histiocytoma. In the mediastinum synovial sarcoma is rare, accounting for 10% of intrathoracic synovial sarcoma, and it is more commonly monophasic or poorly differentiated [4, 21, 83]. It can occur both in the anterior or posterior mediastina, and the median age of patient at presentation is 35 years. Monophasic synovial sarcoma is composed of uniform spindle cells with hyperchromatic nuclei that tend to overlap, arranged in dense cellular sheets or vague fascicles (Fig. 6.20). Most cases show a focal hemangiopericytoma-like vascular pattern, reminiscent of solitary fibrous tumor. Biphasic subtype is characterized by the presence of epithelial areas, usually in the form of gland-like structures lining by cuboidal or columnar cells in a background of neoplastic spindle cells with a fibroblast-like appearance. The main differential diagnoses are with metaplastic thymoma (squamous features in the epithelial component of synovial sarcoma are exceptional), sarcomatoid carcinoma, and type A thymoma with glandular structures. Immunohistochemically, the neoplastic cells are generally positive for CD99 and show focal positivity for EMA and variable positivity for keratins. S100 expression can be detected, while CD34 positivity is very rare. Nuclear positivity for TLE1 is not specific, as it may also occur in malignant peripheral nerve sheet tumor and solitary fibrous tumor. At molecular level, synovial sarcoma is characterized by the t(x;18) (p11; q11) translocation, which is specific of this tumor. The fusion gene includes SS18 gene (SYT or SSXT) on chromosome 18 and one of the SSX genes on chromosome x, more often SSX1.
Monophasic synovial sarcoma with intersected fascicles of uniform spindle cells
Tumors of the peripheral nerves occur in the posterior mediastinum and mainly include schwannoma, neurofibroma, and malignant peripheral nerve sheet tumor. Morphologic features are the same as described for the other sites [4, 21, 84]. Schwannoma and neurofibroma are benign neoplasms composed of bland-looking spindle cells, which express S100 at immunohistochemistry. The distinction between the two entities is mainly based on morphology. Schwannomas are encapsulated biphasic tumors with cellular areas (the so-called Antoni A) showing focal palisading (Verocay bodies) alternating with loosely arranged foci (the so-called Antoni B). The presence of thick-walled, hyalinized blood vessels is characterized. Neurofibroma, which is typically unencapsulated, in the mediastinum tends to reach larger size and therefore is frequently surrounded by a fibrous capsule. Spindle cells are smaller than schwannoma, with indistinct cellular borders and comma-shaped nuclei dispersed in a loosely arrangement of collagen fibers and myxoid material. Malignant peripheral nerve sheet tumor is an aggressive neoplasm with poor prognosis, which, in up to 50% of cases, affects individuals with the hereditary syndrome NF1 and is associated with neurofibroma. Histologically, typical cases are composed of mitotically active spindle cells with a fascicular array, branching hemangiopericytoma-like vascular pattern, and alternating hypercellular and hypocellular areas, closely mimicking synovial sarcoma. Immunophenotype shows a focal positivity for S100 in <50% of cases and positivity for GFAP in 20–30%.
Small and Round Cell Pattern
The term small-round-blue-cell tumor broadly indicates a category of tumors descriptively composed of cells with high nuclear-to-cytoplasmic ratio, then including several tumor entities with various cell differentiations. The differential diagnosis concerning the main lesions with small and round cell pattern is concisely summarized in Table 6.4.
Among epithelial tumors, types B1/B2 thymomas, undifferentiated and basaloid thymic carcinomas, and neuroendocrine tumors may enter into this definition.
B1 and B2 thymomas are characterized by a large number of small round monomorphic, resting lymphocytes and scattered larger epithelial cells [4, 12, 13, 21]. The lymphoid population may show different sizes, but it consists of lymphocytes with dark nuclei lacking a significant mitotic rate, and necrosis is absent. The recognition of a dual population of lymphocytes and epithelial cells and the presence of a peripheral fibrotic capsule with septa of dense collagen are helpful features in discriminating type B1/B2 thymomas from a lymphoproliferative process. These thymomas generally have a cleavage plane and then resulting resectable for the thoracic surgeon. This clinical information together with the radiologic findings may be very helpful to rule out lymphoma.
Thymic carcinomas usually appear as overt malignancies with large cells, enlarged nuclei with evident nucleoli, and moderate amount of cytoplasm, but a subset of these tumors are poorly differentiated or, if preferred, undifferentiated neoplasms lacking any keratinization and consisting of a solid proliferation of small-to-intermediate round cells with scant cytoplasm and coarse nuclei with single macronucleoli (Fig. 6.21). These undifferentiated carcinomas have a squamous cell differentiation at immunohistochemistry (expression of p63 and p40) with positive staining for CD5 and CD117. Even undifferentiated carcinomas harboring t(15;19) leading to fusion of the NUT (nuclear protein in testis ) gene to BRD4, BRD3, NSD3, or other unknown genes may enter in this category. Indeed, this unusual and highly aggressive malignancy, often occurring in children or young adults without gender predilection, is characterized by a solid growth of small-to-intermediate, round monomorphic cells with scant cytoplasm and coarse chromatin with small nucleoli. The abrupt presence of keratinized squamous/squamoid cell component is very characteristic of this tumor. Differential diagnoses commonly include poorly differentiated squamous cell carcinoma and several other undifferentiated small-round-blue-cell malignancies (small-cell neuroendocrine carcinoma, lymphomas or leukemia, Ewing’s sarcoma). The tumor cells generally express pan-cytokeratins, p63 or p40, and variably EMA and carcinoembryonic antigen (CEA). However, demonstration of immunohistochemical nuclear expression of NUT protein or NUT rearrangement by RT-PCR or FISH is diagnostic of NUT carcinoma.
Undifferentiated thymic carcinoma with intermediate-sized, monomorphic tumor cells with evident nucleoli
Among neuroendocrine tumors, small-cell carcinoma (SCC ) properly enters into the small-round-blue-cell category [4, 21, 41]. Most commonly, SCC arises from the central bronchi of the lung invading the lymph nodes and the tissues of the mediastinum; then in some cases, it is quite difficult, if not impossible, to define the exact origin of SCC. By the way, thymic SCC is a highly aggressive tumor mainly occurring in the anterior mediastinum of adults without gender prevalence. High serum levels of adrenocorticotropic hormone (ACTH) leading to Cushing syndrome are well-described. As in the pulmonary counterpart, tumor consists of cells with high nuclear-to-cytoplasmic ratio, scant cytoplasm, finely dispersed chromatin (“salt-and-pepper” chromatin), and inconspicuous nucleoli (Fig. 6.22). Apoptotic debris, necrosis, and high mitotic rate (>50 × 10 HPF) are consistent features in SCC. Tumor cells may be round, oval, or even spindled. Crush artifacts associated with SCC commonly seen on biopsies are generally not seen on frozen section. Thymic SCCs are basically unresectable, and the differential diagnosis may require some immunostains demonstrating pan-cytokeratin (low-molecular-weight cytokeratins CK8, CK18, and CK19 or cocktails such as CAM5.2 are the most useful, and the staining pattern is usually dot-like) expression and positivity for neuroendocrine markers (chromogranin, synaptophysin, CD56). TTF-1 may be expressed in pulmonary and extra-pulmonary SCC, while pan-lymphoid markers (e.g., CD45, CD20, CD3), TdT, p63, p40, and CD5 are negative. CD99 expression may be specific and misleading, since SCCs, some small round cell sarcomas (e.g., Ewing’s sarcoma, desmoplastic small round cell tumor, poorly differentiated synovial sarcoma) and T-lymphoblastic leukemia/lymphoma, are also positive.
Small-cell carcinoma with high nuclear-to-cytoplasmic ratio and dispersed nuclear chromatin and high mitotic rate
By definition, lymphomas are the prototype of small round cell proliferations, and several different types of lymphoma may occur in the mediastinum. However, lymphoproliferative disorders with this morphologic pattern mainly include extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT-type lymphoma) of the thymus and T-lymphoblastic leukemia/lymphoma. MALT-type lymphoma is a peripheral B-cell lymphoma mainly occurring in adults with autoimmune disorders (e.g., Sjogren syndrome) and often appearing as an encapsulated mass with solid and cystic areas. It consists of a dense proliferation of small, centrocyte-like lymphocytes with plasma cells and scattered centroblast-like cells. Lymphoepithelial lesions around residual Hassall corpuscles and aggregates of plasma cells (with Russell’s bodies) are helpful features in the differential diagnosis with type B thymomas. Crystal-storing histiocytes accumulating immunoglobulins into the cytoplasm (Fig. 6.23) may be observed. Immunostaining with CD45, CD20, CD79a, PAX5, IRTA-1 and negativity with cytokeratins (highlighting lymphoepithelial lesions), CD3, CD5, CD23, and cyclin D1 is quite characteristic as well as demonstration of light chain restriction of immunoglobulins with K and lambda stains. Differential diagnosis with benign lymphoproliferative (e.g., follicular lymphoid hyperplasia) and epithelial (e.g., thymic cysts, cystic thymoma) thymic processes may be challenging on frozen section, and closing diagnosis generally requires examination of definitive sections with a panel of immunostains.
Marginal zone, extranodal MALT-type lymphoma with immunoglobulin-engulfed histiocytes leading to crystal-storing histiocytosis
T-lymphoblastic leukemia/lymphoma (Fig. 6.24) is another small round cell lymphoproliferative disorder involving the anterior mediastinum rapidly invading the thoracic organs. It occurs in childhood or young adult, with a male prevalence. The patient generally presents very sick, since a mediastinal mass occurs in up to 80% of cases provoking dyspnea and chest pain or even life-threatening compression of the superior vena cava and tracheobronchial respiratory tract. Tumor cells are small-to-intermediate blasts with scant cytoplasm, round-to-oval or convoluted nuclei with dispersed nuclear chromatin, and indistinct/small nucleoli. Mitotic rate is very high and starry sky is not infrequently observed. The main differential diagnosis is with SCC, type B thymomas, and Ewing’s sarcoma. The infiltrative growth of T-lymphoblastic leukemia/lymphoma coupled to the clinical presentation and patient’s age are generally sufficient to rule out type B thymomas. Nevertheless, pathologists should be aware that immature TdT-positive T cells are present in B-type lymphomas. Purely on morphology, it could be very hard to discriminate T-lymphoblastic lymphoma from SCC. Although patients with SCC are generally older and tumor growth pattern is more discohesive in lymphoblastic lymphoma, definitive sections with ancillary tests are required. A panel of markers including TdT, T-cell lineage markers, CD34, CD1a, CD4, CD8, and CD10 is highly suggestive of this lymphoma. Of note, a subset of T-lymphoblastic lymphoma express CD56, CD79a, CD13, and CD33, while TdT may be negative. Rearrangement of T-cell receptor and NOTCH mutations are helpful genetic findings.
T-lymphoblastic leukemia/lymphoma showing a monomorphic proliferation of round cells
Among sarcomas showing a small round cell pattern and developing from mediastinal region, the main concern is with Ewing’s sarcoma/PNET, desmoplastic small round cell tumor, and alveolar rhabdomyosarcoma.
All these mesenchymal malignancies rarely occur as primary tumor in the mediastinum . However, Ewing’s sarcoma /primitive neuroectodermal tumors (PNET) represent a specific family of tumors with t(11;22) involving EWS-FLI-1 fusion gene [89]. More than 80% of these tumors occur in the skeletal system of children or young adult. Primary EWS/PNET of the mediastinum is quite rare and involves the anterior/middle regions. The tumor consists of a solid growth of small round monomorphic blue cells with hyperchromatic nuclei and scant eosinophilic cytoplasm with rosette-like formation (Fig. 6.25). The diagnosis requires confirmation with expression of CD99 and FLI-1, but molecular identification of t(11;22) using RT-PCR or FISH analysis.
Ewing sarcoma/PNET with a solid growth of monomorphic round blue cells with some rosette-like formations
Desmoplastic small round cell tumor (DSRCT) is an exceedingly rare sarcoma affecting young males in their second/third decade of life and characterized by a very dismal outcome [90]. The tumor may arise from the pleura and mediastinum and appears as a proliferation of small round cell islands into desmoplastic stroma. This sort of biphasic appearance in a young patient is very suggestive, but definitive diagnosis requires the presence of coordinated expression of cytokeratins, desmin, and WT1 in the small round cells. The stromal component is usually positive with smooth muscle actin. Confirmation of EWS/WT-1 fusion gene is the most important diagnostic marker.
Alveolar rhabdomyosarcoma is another sarcoma of childhood and adolescents rarely occurring in the anterior mediastinum [91]. Histology is quite similar to other small round cell tumors with a solid architecture of monomorphic cells with vesicular nuclei, small nucleoli, and brightly fibrillar eosinophilic cytoplasm. Diagnosis requires demonstration of expression of myogenic markers (desmin, myogenin) and t(2;13) or t(1;13) leading to PAX3-FOXO1 and PAX7-FOXO1 gene fusion, respectively.
Neuroblastoma is a tumor of neural crest cells arising in the sympathetic nervous system commonly occurring in children, but even cases of adult neuroblastoma have been reported in the anterior and posterior mediastinum [92]. Neuroblastoma histologically consists of small, round, blue, uniform cells with scant cytoplasm and hyperchromatic nuclei arranged in solid nests in a fibrovascular matrix and Homer-Wright pseudorosettes (up to 50%). The presence of a neuritic process, also called neuropil, is a pathognomonic feature of neuroblastoma cells. Immunostaining reveals positivity with NSE, chromogranin, synaptophysin, CD56, and S100 protein. MYCN overexpression due to gene amplification of the distal arm of chromosome 2 is an important biologic marker.
Mesothelioma may predominantly involve the mediastinal pleura, then appearing as a mass of the anterior-to-posterior mediastinum, and several variants of mesothelioma have been described in literature. Small-cell mesothelioma is a rare form of epithelioid mesothelioma [93, 94]. At histology, the neoplasm is generally associated with a conventional malignant epithelial mesothelioma, and the proportion of the small-cell component is variable, even representing the entire surface in small biopsy. It appears as a solid growth of closely packed monotonous small- to medium-sized cells with open nuclear chromatin, evident nucleoli, and high mitotic activity. Trabecular or papillary arrangement and clear-cell change of the cytoplasm have been described. Immunohistochemically, small-cell mesothelioma is usually positive for cytokeratins (AE1/AE3, CAM 5.2), EMA, calretinin, WT-1, and D2-40, while neuroendocrine markers, CD99, TTF1, CEA, MOC-31, and desmin are negative.
Since thoracic region is the most common visceral site of synovial sarcoma, several examples of this sarcoma have been reported in the mediastinum. The tumor may show a very aggressive small-cell variant poorly differentiated type [95, 96] and generally affects young adults without gender prevalence. Poorly differentiated synovial sarcoma may appear as a monomorphic round cell malignancy, although large cell epithelioid and spindle cell areas may be present. The tumor is highly vascularized with hemangiopericytoma-like dilated thin-walled vessels. Rhabdoid cells may be observed. Differential diagnosis may be very challenging since the tumor co-expresses markers of epithelial (EMA, cytokeratins), mesothelial (calretinin, D2-40), and mesenchymal differentiation. Despite not entirely specific, expression of TLE1 is a helpful marker for synovial sarcoma. Nevertheless, identification of t(X;18) leading to SYT/SSX gene fusion by RT-PCR or FISH is the most important diagnostic test, being reported in nearly all cases.
Clear-Cell Pattern
The finding of a proliferation of cells with clear cytoplasm should raise the suspicion of different neoplasms, mainly thymic tumors (e.g., thymic carcinoma, clear-cell variant), germ cell tumors (e.g., seminoma), lymphomas (e.g., large B-cell lymphoma), sarcoma (e.g., clear-cell sarcoma), and metastatic tumors (e.g., renal cell carcinoma), among others. The differential diagnosis concerning the main lesions with clear-cell pattern is concisely summarized in Table 6.5.
Germ cell tumors , including seminoma, mainly occur in children, but virtually all ages may be involved, and a primary gonadal location should be ruled out. GCT tends to involve the anterior mediastinum, and knowledge of serologic markers (alpha-fetoprotein, beta-human chorionic gonadotropin) may be of diagnostic help. Among GCT, clear-cell growth mainly characterizes seminoma. The tumor generally shows solid sheets and nests of monotonous round-to-polygonal cells with distinct cell membrane, abundant clear-to-pale cytoplasm containing glycogen, and nuclei with unique prominent eosinophilic nucleoli. Tumor cell proliferation is surrounded by delicate or abundant septa of connective tissue and characterized by infiltrates of reactive lymphocytes. Multinucleated syncytiotrophoblastic cells, lymphoid follicles, granulomas, and dense sclerosis may be observed in seminoma and differential diagnosis with lymphomas (Hodgkin or non-Hodgkin) and granulomatous processes (sarcoidosis and infectious diseases). The tumor may also show cystic changes.
Thymic carcinomas most commonly occur in adult population, and the morphologic details are quite similar to the pulmonary counterpart. Several variants of thymic carcinoma (squamous, basaloid, mucoepidermoid, sarcomatoid, adenocarcinoma, undifferentiated with/without NUT rearrangement, lymphoepithelioma-like) are recognized in the last WHO classification, including the clear-cell type (Fig. 6.26) [97]. This rare malignancy is generally widely invasive at diagnosis (not resectable) and consists of a solid and cohesive growth of overtly malignant cells with large cells exhibiting abundant clear cytoplasm and irregular and enlarged nuclei with evident nucleoli. At least focally, areas of keratinization leading to squamoid/squamous cell differentiation are present, and careful search for this finding is very helpful on small biopsies and at intraoperative examination.
Clear-cell-type thymic carcinoma as an undifferentiated, solid carcinoma with large cells with clear cytoplasm
Indeed, thymic clear-cell carcinoma is generally a variant of squamous cell carcinoma. The tumor may be surrounded and intersected by large areas of desmoplastic stroma. The differential diagnoses include a metastasis from renal cell carcinoma and other clear-cell malignancies.
Although rare, even thymoma may partly show a clear-cell component, but nuclear atypia is lacking and mitotic rate very low [98] (Fig. 6.27). Curiously, a couple of cases of sebaceous lymphadenoma characterized by tumor cells with clear cytoplasm with micro-vacuolization have been reported [99].
Type A thymoma with clear-cell cytoplasm
Among mesenchymal tumors with clear-cell changes involving the mediastinum, clear-cell sarcoma has been rarely described (Fig. 6.28) [100]. The tumor consists of epithelioid cells with vesicular nuclei with a single prominent eosinophilic nucleolus and clear-to-eosinophilic cytoplasm. It derives from neural crest cells with melanocytic differentiation and shows an aggressive clinical behavior. The differential diagnoses include primary or metastatic melanoma, thymic carcinoma, lymphoma, and germ cell tumors. Expressions of melanocytic markers (S-100, HMB-45, and/or Melan-A) and identification of t(12;22) involving EWSR1 gene are diagnostic tools.
Clear-cell sarcoma consisting of monomorphic cells with clear-to-eosinophilic cytoplasm and nuclei with an evident single nucleolus
Clear-cell morphology is not a common feature of lymphoproliferative disorders, but primary mediastinal large B-cell lymphoma represents a variant of diffuse large B-cell lymphoma characterized by the presence of large atypical lymphoid cells with pale-to-clear cytoplasm and round or multilobulated nuclei with evident nucleoli [65, 66]. The presence of intermediate-sized lymphocytes, immunoblasts, and pleomorphic/bizarre cells is often observed. Broad or delicate strands of dense sclerosis may be often observed. Since this lymphoma is thought to originate from thymic B cells, epithelial cysts, Hassall corpuscles, and/or atrophic thymic tissue may be present. Primary mediastinal large B-cell lymphoma primarily affects young adults with a female prevalence. As expected, the lesion is positive for CD45 and pan B-cell markers (CD19, CD20, CD79a, PAX5) and negative for CD5, CD10, and T-cell markers. CD30 is variably expressed, but CD15 and ALK are lacking.
Other uncommon neoplasms that may occur in the mediastinum and showing a clear-cell pattern include salivary gland-type tumor with prominent myoepithelial component (e.g., myoepithelial carcinoma) (Fig. 6.29), perivascular epithelioid cell-derived tumor (PEComa or angiomyolipoma) (Fig. 6.30), and clear-cell mesothelioma. PEComa generally shows spindle myoid and epithelioid cells surrounded by prominent hemangiopericytoma-like vascular channels and mature adipose tissue with thick-walled vessels, but monomorphic variants do exist. Negative staining with keratins but expression of melanocytic markers (HMB45) and cathepsin K in perivascular cells and smooth muscle actin in spindle and epithelioid cells are the characteristics.
Myoepithelial tumor with deposits of basal membrane collagen and clear tumor cells
PEComa appears as a bland epithelioid- to spindle-shaped clear-cell proliferation with a rich, hemangiopericytoma-like vascular network
Among metastatic tumor with clear-cell appearance presenting as mediastinal mass , renal cell carcinoma is by far the most common. Metastatic clear-cell renal cell carcinoma typically shows a delicate and rich network of vessels, and nuclei of neoplastic cells have small nuclei with a single nucleolus. Tumor cells react with keratins, CD10, and PAX8.
Accumulation of foamy macrophages in the mediastinum may create some diagnostic problems simulating clear-cell neoplasms on frozen section. Some thymomas may show prominent regressive features with solid accumulation of foamy histiocytes. Cholesterol granuloma (cholesteroloma) [101] is a benign, tumor-like mass of the anterior mediastinum consisting of aggregates of cholesterol cleft granuloma with foamy macrophages and foreign body giant cell reaction in response to the presence of cholesterol crystals (often after cardiac surgical procedures), chronic inflammatory infiltrates, and remnants of normal/atrophic thymic tissue.
Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis involving the long bones, retroperitoneum, central nervous system, heart, orbit, lungs, and other organs [102]. However, cases of ECD have been described in the posterior mediastinum, and the pathology is characterized by accumulation of foamy-to-pale histiocytes intermingled by bland fibrotic tissue (Fig. 6.31).
Erdheim-Chester disease with aggregates of foamy histiocytes among inflammatory cells and fibrotic tissue
Fibroinflammatory-Looking Pattern
Several lesions of the mediastinum are characterized by a combination of fibrous tissue and inflammatory infiltrates leading to a fibroinflammatory-looking pattern. The differential diagnosis concerning the main lesions with fibroinflammatory-looking pattern is concisely summarized in Table 6.6.
Sclerosing mediastinitis (Fig. 6.32) is the paradigmatic entity among these lesions, and differential diagnosis may be posed with inflammatory myofibroblastic tumor, calcifying fibrous tumor, desmoid tumor, sclerosing lymphomas, IgG4-related sclerosing disease, sarcomatoid carcinomas, desmoplastic and histiocytic mesothelioma, inflammatory-sclerosing liposarcoma, and some histiocytic disorders (e.g., Rosai-Dorfman disease, Erdheim-Chester disease) [103,104,105,106].
Sclerosing mediastinitis is a hypocellular mass with abundant collagen-rich tissue
This group of lesions represents the most difficult diagnostic challenge, particularly on small biopsy. Sclerosing mediastinitis involves the anterior mediastinum and may clinically manifest with symptoms secondary to vessel compression (superior vena cava syndrome) or cardiopulmonary involvement. It may occur at any age and radiologically appearing as an invasive mass. Grossly, the lesion is characterized by dense, collagenized, firm, whitish fibrotic tissue, histologically demonstrating deposition of hyalinized hypocellular tissue and sparse inflammatory infiltrates of mature lymphocytes and plasma cells. Scattered granulomas may be noted. Its pathogenesis is unknown, but cases of sclerosing mediastinitis seem to represent a response to Histoplasma capsulatum infection or other fungal (aspergillosis, cryptococcosis, and mucormycosis) or bacterial (nocardiosis, actinomycosis, syphilis) infections [107]. Sarcoidosis, drug toxicity (methysergide), and chronic thoracic trauma are other involved etiologies. Half of cases are idiopathic.
Sclerosing mediastinitis may also represent the mediastinal involvement of IgG4-related disease. Serum and/or tissutal demonstration of elevated levels of IgG4-positive plasma cells is a diagnostic hallmark [108].
Inflammatory myofibroblastic tumor (IMT) [109] is regarded as a true neoplastic process characterized by a more cellular lesion than sclerosing mediastinitis that may rarely occur in the mediastinum. IMT is composed of bland spindled elements arranged in a patternless pattern admixed with a variable collection of lymphocytes, plasma cells, eosinophils, and histiocytes (Fig. 6.33). The fusiform cells consistently express smooth muscle actin and ALK1 in about half of cases. ALK expression is related to the presence of ALK rearrangement, and this genetic alteration is a useful molecular target for specific inhibitors in malignant or unresectable IMT.
Inflammatory myofibroblastic tumor with spindle cell proliferation of myofibroblast intermingled with a mixed inflammatory infiltrate
Calcifying fibrous tumor is a benign/reactive, densely hyalinized collagenous lesion with bland spindle cells and scattered psammoma-like calcification of unknown etiology.
A fibrotic tissue similar to that observed in sclerosing mediastinitis may be observed in poorly sampled malignancies, such as Hodgkin and sclerosing mediastinal large B-cell lymphomas, desmoplastic mesotheliomas, inflammatory-like sarcomatoid carcinoma, and sclerosing inflammatory liposarcoma. Serial sections, specific immunohistochemical stains, and/or molecular analyses are often mandatory to identify the scarce amount of diagnostic neoplastic cells avoiding misdiagnosis.
Nodular sclerosis classic Hodgkin lymphoma [68] is the most common lymphoma in the mediastinum with a predilection for the anterior region. The sclerotic tissue can be prominent, producing large areas of acellular collagenous stroma. The neoplastic process may show nodular compartmentalization of cellular nodules with small cellular nodules containing characteristic “lacunar” Hodgkin Reed-Sternberg cells completely or partially surrounded by broad bands of fibrous tissue. The cellular nodules are composed of an admixture of small lymphocytes, plasma cells, eosinophils, and macrophages with the presence of a variable amount of large “lacunar” and “mummified” Hodgkin cells that are characteristically membranous and Golgi pattern expression for CD15 (50–60%), MUM1/IRF4 (multiple myeloma oncogene 1/interferon regulatory factor 4), and CD30 (up to 90%) coupled with negative staining for CD45, CD3, ALK1, OCT2 (octamer transcription factor 2), and BOB1 (B-cell-specific octamer-binding protein-1). CD20 and EMA may be focally positive. The cellular background infiltrate is significantly dominated by small CD3+ T cells with a high CD4:CD8 ratio, and entrapped thymic tissue may be highlighted by pan-cytokeratins and p63.
Primary mediastinal (thymic) large B-cell lymphoma also occurs in the anterior mediastinum, with a predilection for young females. This lymphoma also shows a nodular growth with fibrous bands compartmentalizing the cellular component with neoplastic cells. These cells show intermediate to large centroblast-like nuclei and express B markers (CD19, CD20, CD22, CD79a, PAX5, OCT2, BOB1), CD45, MUM1, and variably CD30 and p63. CD10, CD15, and EBV are negative. Residual thymic tissue may be appreciated even in small biopsy using pan-cytokeratins and p63, while the background infiltrate mainly consists of small T lymphocytes without the polymorphous appearance of Hodgkin disease.
Rosai-Dorfman disease (RDD) and Erdheim-Chester disease (ECD) are non-Langerhans cell histiocytic disorders that may rarely occur in the posterior paravertebral mediastinum. RDD is characterized by histiocytes (macrophages with large and pale cytoplasm with emperipolesis phenomenon, expression of S100 protein and CD68 with negativity for CD1a, factor XIIIa and CD163) intermingled with a mixed inflammatory infiltrate and dense fibrosis [110]. Histology of ECD shows scattered xanthomatous/foamy histiocytes variably expressing CD68, S100, and factor XIIIa, surrounded by dense fibrosis and a lymphoplasmacytic inflammatory infiltrate. BRAF V600E mutation is reported in up to 60% of patients with ECD.
Among liposarcomas occurring in the mediastinum [111], well-differentiated sclerosing-inflammatory type is the most challenging, particularly in small biopsy/cytology. Histology shows irregularly shaped large and small adipocytes, accompanied by fibrous septa with disperse oval- to spindle-shaped or polygonal atypical cells with hyperchromatic nuclei (Fig. 6.34) expressing S100 and MDM2, arranged in a vaguely fascicular or haphazard pattern with fibro-collagenous stroma and lymphocytic inflammation.
Sclerosing-type liposarcoma with irregular adipocytes intersected by fibrous bands
Inflammatory spindle cell sarcomatoid carcinoma and lymphohistiocytoid or desmoplastic mesothelioma may rarely occur and more frequently involve the mediastinum. These malignancies [112,113,114] closely mimic fibroinflammatory processes, and their recognition requires a careful search for cellular atypia and demonstration of epithelial/mesothelial cell differentiation using a specific panel of stains (pan-cytokeratins, mesothelial markers).
Cystic Pattern
The differential diagnosis concerning the main lesions with cystic pattern is concisely summarized in Table 6.7.
Cystic masses in the mediastinum are relatively uncommon (10–15%) and may characterize benign and malignant lesions. Nevertheless, the vast majority of these lesions are benign, with most being discovered incidentally [115].
When symptoms are present, these are usually the result of compression of adjacent structures. The most common are pericardial and foregut duplication cysts. While in some occasions the origin of a cyst is unclear, location plays a major role in determining the organ from which it may be arising. For example, a cystic lesion in the region of the thymic bed is most likely compatible with a thymic cyst.
Pericardial cyst is a simple cyst with a fibrous wall lined by a single layer of bland-looking mesothelial cells. The cyst is generally located in the cardiophrenic angle, and all mediastinum regions may be involved.
Parathyroid cysts are rare lesions grossly measuring up to 10 cm with thin-walled and containing clear fluid showing a high level of PTH without hypercalcemia. The internal surface is lined by regular parathyroid epithelium.
Thymic cysts are uncommon and represent only 1–3% of mediastinal masses. They are either congenital (usually unilocular) or acquired (often multilocular). They are most commonly encountered in the anterior mediastinum. Congenital thymic cysts are less common than acquired cysts and arise from a remnant of the thymo-pharyngeal duct. They are usually unilocular, thin-walled, and filled with clear fluid (Fig. 6.35). Thymic tissue must be present at least focally within the wall of the cyst. They are rarely inflamed and usually asymptomatic and incidentally detected, but thymic cyst may be considerably large (up to 20 cm). The internal surface consists of bland squamoid cells with a fibrous wall containing inflammatory cells, cholesterol granulomas, and/or hemorrhagic areas. Multilocular thymic cysts have a multilayered lining of squamous cells, columnar cells, and/or cuboidal cells. Hassall corpuscles and parathyroid and/or salivary gland tissue may be observed. Malignant transformation in a thymic cyst is a rare phenomenon, but a proliferating type of multilocular thymic cyst has been described. This latter is characterized by pseudoepitheliomatous hyperplasia of the squamoid epithelium and should not be confused with squamous cell carcinoma [116].
Thymic cyst with single-layer lining epithelium and cystic wall consisting of adipose tissue and lymphocytes
Enteric cysts are confined to the posterior mediastinum and occur in childhood. They may arise from the esophagus or stomach and histologically recapitulate the normal gut. Historically, cysts of foregut origin have been classified into bronchogenic cyst, esophageal duplication cyst, and enteric cyst.
Bronchogenic cysts result from abnormal budding of the ventral foregut, and most are located in the middle mediastinum. They are occasionally associated with other congenital pulmonary malformations, and half of patients present with clinical symptoms (usually related to mass effect). Histology consists of a uni- or multilocular lesion with an internal surface lined by normal respiratory epithelium, and the cystic wall may contain cartilage and smooth muscle (Fig. 6.36).
Bronchogenic cyst with regular respiratory epithelium and smooth muscle in the cystic wall
Mediastinal cystic meningocele is an abnormal herniation of the meninges through a bony defect in a vertebral body rarely presenting as a posterior mediastinal mass. The cyst has a thick fibrous wall lined by mature arachnoidal cells. These frequently occur as a complication of neurofibromatosis type 1 (NF1), Marfan syndrome, and Ehlers-Danlos disease.
Mediastinal paravertebral mullerian cyst (cyst of Hattori) is an asymptomatic ciliated cyst in the posterior mediastinum lined by fallopian epithelium staining positive with estrogen and progesterone receptors, possibly secondary to misplaced mullerian tissues (Fig. 6.37). Patients with mullerian cysts are women generally between the ages of 40 and 60 years [117].
Cyst of Hattori with single layer of fallopian-type ciliated epithelium
Lymphangiomas (cystic hygroma) are malformations of the lymphatic system, representing embryological remnants of lymphatic tissue. The vast majority of these lesions (90%) present before 2 years of age, with most of these presenting as a cervical mass with extension into the thoracic region. Lymphangiomas are generally asymptomatic and may occur in the anterior, middle, and posterior mediastinum. Grossly, these lesions appear as multilobulated and edematous mass with interanastomosing channels lined by a bland, flat endothelial cells and a collagenous stroma. Eosinophilic, proteinaceous lymphatic fluid is noted into vascular channels.
Thoracic duct cysts are rare cystic lesions of the middle or posterior mediastinum communicating with the lymphatic system and the thoracic duct. They contain chylous fluid and histologically show a single layer of flat endothelial cells, smooth muscle, and a fibrous wall with inflammatory infiltrate.
Teratomas are neoplasms derived from endodermal, mesodermal, and ectodermal origin in different combinations (Fig. 6.38). The lesion may be entirely cystic and most commonly seen in the anterior mediastinum of children or young adults. Most patients are asymptomatic, and symptoms may be related to compression of adjacent structures. Given their origin, these lesions are usually filled with sebaceous material, but may also contain adipose tissue, bone, hairs, cartilage, and many other epithelial (squamous, foregut), mesenchymal, and/or neural tissues. Virtually, all tissues may be represented in teratomas. Immature neuroepithelial tissue may be present leading to the diagnosis of “immature teratoma,” but neoplasms may arise from all represented tissues. Teratoma may also represent one of the components of mixed malignant germ cell tumor.
Cystic teratoma predominantly composed of ectodermal tissue
Cystic degeneration may characterize thymomas, seminoma, neuroendocrine tumor, sarcomas, and lymphomas [118,119,120,121,122,123,124,125,126]. Cystic thymoma is a relatively frequent event (up to 40%), but rarely thymomas have extensive cystic changes. Cystic thymoma should show residual solid islands of conventional thymoma, and the prognosis is identical to the solid counterpart.
Cystic change in seminoma is generally due to degenerative processes, such as necrosis and hemorrhage.
Mediastinal Hodgkin lymphoma coexisting with thymic cyst has been reported, but cystic changes may be more often secondary to surgical biopsy or chemoradiotherapy.
Careful examination of mural nodules or solid areas in the cystic wall is mandatory when examining cystic lesions of the mediastinum so that diagnosis of malignancy will not be missed.
Unusual Lesions Appearing as Mediastinal Mass
Ectopic pancreatic tissue of the anterior mediastinum is a rare occurrence possibly derived from enteric cyst or congenital displacement of pancreatic tissue. Differential diagnosis with teratoma is almost impossible in small biopsy, and malignant transformation leading to adenocarcinoma has been well-described. Occurrence of adenocarcinomas into ectopic pancreatic tissue is well-described [127].
Mediastinal masses may often be derived from benign inflammatory processes or infections leading to important lymphadenopathy. Among infections, mycobacteria and fungi (primarily histoplasmosis and coccidioidomycosis) are the most common cause of mediastinal masses. Inflammatory lesions, such as sarcoidosis, silicosis, drug reactions, amyloidosis, heart failure and chronic obstructive pulmonary disease, and Castleman disease may present with mediastinal lesions [128].
Castleman disease [129] is a rare and idiopathic lymphoproliferative disorder of unknown etiology that often involves the thorax, but rarely associated with autoimmune processes, within POEMS syndrome or in association with non-Hodgkin lymphomas, particularly in HIV-positive patients. The disease is often localized and resectable, but a multicentric variant leading to systemic symptoms (fatigue, fever, night sweats, weight loss) and recurrences is described. At histology, the hyaline vascular type is the more frequent (85%) and characterized by lymph nodal tissue with follicular hyperplasia and hyalinized capillaries resulting in the so-called lollipop follicles.
Sarcoidosis [130] commonly involves the mediastinal lymph nodes, possibly leading to mediastinal mass of the middle compartment. The process is characterized by granulomatous inflammation with/without tiny foci of necrosis. Granulomas tend to coalesce, and dense fibrosis replaces granulomatous inflammation with time (Fig. 6.39). Differential diagnosis with infections (particularly mycobacteria and fungi) may be challenging. The use of special stains on serial sections and different paraffin blocks is a useful practice.
Sarcoidosis of mediastinal lymph nodes leading to mass-forming coalescent granulomas with dense fibrosis
On conventional hematoxylin-eosin stain, it is difficult to distinguish dense fibrotic tissue from amyloid deposits, but rare cases of amyloidoma have been reported in the mediastinum [131]. This solitary localized tumor-like deposit of amyloid in the absence of systemic amyloidosis is generally associated with reactive giant cells or granulomatous inflammation, calcification, and, secondary to plasmacytoma, multiple myeloma or other lymphoplasmacytic disorders (e.g., MALT-type lymphoma). A positive Congo red stain with the classic apple green birefringence at polarized light and demonstration of monotypic kappa or lambda expression even in scattered plasma cells are helpful diagnostic features (Fig. 6.40).
Amyloidoma with abundant amorphic eosinophilic amyloid tissue surrounded by reactive giant cells
The main diagnostic immunohistochemical markers and molecular analyses in the differential diagnosis of neoplastic mediastinal masses are listed in Tables 6.8 and 6.9, respectively.
Final Remarks
-
(a)
The mediastinum is a limited anatomic region, but benign and malignant lesions from the epithelial, lymphoid, mesenchymal, and germ cell organs as well as mesothelioma and metastasis may occur in this site.
-
(b)
Knowledge of clinical and radiologic features may be very helpful in guiding pathologists to a correct differential diagnosis [132]. Some specific symptoms may be related to specific pathologies, such as myasthenia gravis (thymic lesions), weight loss, fever and night sweats (lymphoproliferative lesions), autoimmune diseases (thymomas), syndromes due to hormonal production (Cushing, inappropriate secretion of antidiuretic hormone, Eaton-Lambert, type I multiple endocrine neoplasia syndrome in neuroendocrine growths), or hypercalcemia (parathyroid lesions). Even radiologic data are closely related to specific pathologic lesions (thymomas, germ cell tumors, carcinomas, lymphoproliferative lesions and non-neurogenic soft tissue growths in the anterior mediastinum, benign cysts and lymphomas in the middle mediastinum, cysts and neurogenic soft tissue neoplasms in the posterior region).
-
(c)
Although infiltrative gross pattern is associated with malignant processes (lymphomas, carcinomas), even benign lesions (fibrosing mediastinitis, desmoid tumor) may show invasive growth. In general, the presence of an encapsulated lesion is related to a benign entity (cystic lesions) and thymoma. The presence of a lobulated mass with fibrous bands favors thymomas or sclerosing lymphomas. Large necrosis and hemorrhage favor germ cell tumors or metastasis.
-
(d)
Since different vital organs (the heart, large vessels, lungs) reside in the mediastinum, all space-occupying masse may determine compression and displacement leading to general symptoms. Then, all mediastinal lesions may be considered a medical urgency requiring high-priority diagnosis.
-
(e)
Diagnosis of mediastinal masses requires a careful and smart examination of conventional morphology on H&E-stained slides, but special stains, immunohistochemical markers, and molecular biology play an essential role. Continuous update and adequate choice of ancillary techniques should be integrated into clinicopathologic features to obtain the correct diagnosis.
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Rossi, G., Ragazzi, M., Cavazza, A. (2018). Diagnostic Histopathology Approach. In: Franco, R., Zito Marino, F., Giordano, A. (eds) The Mediastinal Mass. Current Clinical Pathology. Humana, Cham. https://doi.org/10.1007/978-3-319-90368-2_6
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