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Immunohistology of the Mediastinum


Introduction

In general, mediastinal pathology is rich in terms of the diversity of neoplasms that may occur primarily in the mediastinal cavity. However, in the context of occurrence, mediastinal tumors are rare. In addition, over the last decades some of the most common tumors of the thymus have generated controversy regarding proper classification and staging. It is important, however, to state that the normal thymus is also a rather enigmatic gland as its presence is more prominent in childhood than it is in adulthood. Needless to say, the normal histology and immunohistochemistry of the normal thymus is to some extent unusual and rather obscure for most practicing pathologists. It is, therefore, important to recognize that knowing the normal histologic and immunohistochemical characteristics of the normal thymus is of great importance in the understanding and interpretation of many of the tumors that involve the thymus. Once the normal histologic and immunohistochemical characteristics of the normal thymus are understood, it becomes easier to analyze and understand the immunohistochemical features that thymic tumors may exhibit.

It is also important to highlight that for practical purposes, even though, anatomically speaking, the mediastinum contains others organs such as the heart, great vessels, esophagus, and diaphragm, tumors in these structures are not discussed in this chapter as they represent a specific tumor pathology. Fig. 11.1 shows a schematic view of the mediastinum with the structures that make up this anatomical area.

Fig. 11.1, (A) Diagram of the mediastinal structures, which include the thymus, heart, and portion of the esophagus encased by the lungs and diaphragm. (B) Thymic depiction of the different components (epitheliocytes and thymocytes) with the respective positive staining for different lymphoid markers.

The Normal Thymus

Although knowledge on the thymic gland extends more than two millennia, it is important to highlight that it is still a work in progress. However, a good amount of important information has been discovered on its histologic features and its immunohistochemical characteristics. Traditionally, the thymic gland has been divided into two main components: the cortex and the medulla ( Fig. 11.2A–E ), and two main cell types have been recognized: thymocytes (lymphocytes) and epitheliocytes (epithelial cells). Furthermore, those main types of cells can be further separated into subcapsular, cortical, and medullary thymocytes and epitheliocytes. Its distribution and immunohistochemical characteristics also varies.

Fig. 11.2, (A) Low power view of a normal thymus showing clear cut areas of cortex and medulla; (B) high power of the thymic cortex showing predominantly immature lymphocytes and fewer epithelial cells; (C) closer view of the thymic medulla showing a mixture of lymphocytes and epithelial cells; also note the presence of Hassall corpuscles; (D) higher magnification of the thymic medulla showing a mixed population of lymphocytes, epithelial cells, and Hassall corpuscles.

In addition to the basic components of the thymic gland, thymocytes and epitheliocytes, the thymic gland also shows a number of other cellular components that are important to recognize. Their presence may at times be prominent in some tumoral conditions. Table 11.1 depicts the main components of the thymic gland and additional cellular components that may be normally present.

TABLE 11.1
Histologic and Immunohistochemical Characteristics of the Normal Thymus
Cell Type Immunohistochemical Markers
Thymocytes
Subcapsular
Cortical
Medullary		 CD3, CD8, CD4, CD45, CD99, Tdt
Epitheliocytes
Subcapsular
Inner cortical
Medullary
Hassall corpuscles		 Pan keratin, keratin 5/6, p53, p40, CD10, SOX2
B lymphocytes CD20
Thymic macrophages CD68
Interdigitating reticulum cells CD23, CD35
Langerhans cells
Eosinophils		 CD1a, S-100
Plasma cells
Mast cells		 CD130
Neuroendocrine cells CD56
Myoid cells
Germ cells		 Desmin
Sebaceous glands Keratin

Regarding the normal immunohistochemical characteristics of the thymus, few studies show that the normal thymus will show positive staining for epithelial, lymphoid B- and T-cell markers. However, this staining pattern may vary in the different anatomic areas of the thymus (cortex vs. medulla). Lymphoid markers will include Tdt, CD20, CD45, CD8, CD4, and CD23, which may be expressed predominantly in the cortex or medulla while others may be expressed more homogenously in both components ( Fig. 11.3A–G ). Similarly, epithelial markers include the pan keratin, keratin 5/6, p63, p40, and CD10, which stains positive in both components (cortex and medulla) and may be predominant in one area more than the other ( Fig. 11.4A–F ). In addition to these common epithelial and lymphoid markers, the thymus may also positively stain for S-100 protein, CD99, CD1a, SOX2, NGF (nerve growth factor), EGFR, XIAP (X-linked inhibitor of apoptosis protein) ( Fig. 11.5 ). As more antibodies are produced, testing them in the normal thymus may provide more information of the positive or negative reactions in the components of the normal thymus.

Fig. 11.3, (A) Immunohistochemical stain for CD45 showing positive staining in lymphocytes of the cortex and medulla; (B) CD4 shows a strong positive staining of lymphocytes of the cortex and medulla; (C) CD8 shows a strong positive staining of lymphocytes predominantly in the thymic cortex; (D) Tdt shows a strong positive staining of lymphocytes predominantly in the thymic cortex; (E) CD20 shows a strong positive staining of lymphocytes predominantly in the thymic medulla; (F) CD23 shows a positive staining in some lymphocytes of the thymic medulla; (G) PAX5 shows a positive staining in scattered lymphocytes of the thymic medulla and cortex.

Fig. 11.4, (A) Immunohistochemical stain for pan keratin shows positive staining in epithelial cells of the cortex and medulla; (B) keratin 5/6 shows positive staining of epithelial cells of the cortex and medulla; (C) p40 shows positive staining of epithelial cells of the cortex and medulla.

Fig. 11.5, (A) Immunohistochemical stain for S-100 protein shows positive staining in cells predominantly in the thymic medulla; (B) CD1a shows strong positive staining in the thymic cortex and medulla; (C) immunohistochemical stain for CD99 shows a strong positive staining in the cortex of the normal thymus while weak in the medulla; (D) P63 shows scattered positive epithelial cells in the cortex and medulla of the normal thymus.

Thymic Tumors

As it has been stated, the wealth of tumoral conditions that may seed the mediastinal compartment is varied. However, for the purpose of this chapter, we will separate tumors according to their most likely place of origin: tumors originating from the thymus and tumors originating from adjacent tissues. Since we have already stated that the normal thymus shows a variety of cell types that potentially give rise to the gamut of tumors present in the mediastinum, it would be safe to divide tumors into broad categories:

Epithelial Neoplasms

  • Conventional thymic epithelial neoplasms: thymoma and thymic carcinoma

  • Salivary gland type tumors of the thymus.

  • Neuroendocrine neoplasms: low, intermediate, and high-grade neuroendocrine carcinoma (carcinoid, atypical carcinoid, small cell and large cell neuroendocrine carcinoma), paragangliomas, and parathyroid adenoma and carcinoma.

  • Germ cell tumors: all-inclusive.

Mesenchymal Neoplasms

  • All types of sarcomas

Neurogenic and Neuroectodermal Neoplasms

  • Small round cell tumors

Lymphoproliferative Neoplasms

  • Hodgkin lymphoma (HL)

  • Non-Hodgkin lymphoma

Thymic Epithelial Tumors

THYMOMA

Thymomas are among the most common tumors of the mediastinum. Most of these tumors affect the anterior mediastinum and may involve the posterior mediastinum. Interestingly, even though thymomas seem to be among the most common epithelial neoplasms of the thymus, their true incidence is difficult to estimate. Epidemiologic studies contain biases. One important drawback is that for some authors the diagnosis of thymoma denotes a benign condition, which will not be recorded among the malignant tumoral conditions. On the other hand, the other bias is that cases that have been coded under the designation of “malignant thymomas” may in fact represent thymic carcinoma, and since “malignant thymomas” are the ones capture in some epidemiologic data, it is very likely that the vast majority of thymomas–encapsulated thymomas–are not accounted in those studies. Nevertheless, it has been estimated that the occurrence of “thymoma” is approximately 0.15 per 100,000 person-years, more commonly in patients older than 25 with a possible predilection for men than women. Other studies have been more general and have accounted for an estimate of 1.7 per million per year. Interestingly in other studies with different focus, researcher have identified that thymomas appear to be more common in Asian and Pacific islander patients. However, it is clear the need for more comprehensive epidemiologic data when it comes to thymomas.

Clinical Features

The clinical symptoms of patients with thymoma may develop into different groups: (1) those in which the tumor is associated with a particular condition/syndrome and (2) those in which the tumor is unrelated to any particular condition/syndrome.

Patients in whom there is no particular syndrome associated may be completely asymptomatic and the tumor is discovered during a routine radiographic imaging or may present with nonspecific symptoms of cough, dyspnea, and/or chest pain. Some of those symptoms may be related to the size of the tumor and the compression of adjacent anatomic structures. This group of patients may be approximately 50%. On the contrary, the association of thymomas with a plethora of specific conditions is well known, and myasthenia gravis (MG) is one of the leading common associations. Recently, in a large series of cases of thymoma, the authors identified approximately 17% of thymomas in patients with MG while other autoimmune conditions were associated in approximately 3.8%. Also, important to note in this large series of cases is the presence of another associated malignancy, which accounted for 6.8%. However, it is important to highlight that the number of clinical conditions associated with thymomas is extensive. ,

The clinical outcome of patients with thymomas is closely linked to the staging at the time of diagnosis. Therefore, it is critical that proper staging takes place at the time of surgical resection.

Histologic Classification

This may be one of the most contentious areas in mediastinal pathology, as there is no general agreement on the best classification system. Some classifications have been criticized for being too simplistic, others for lacking scientific support, and others for lacking clinical support. Interestingly, the most commonly quoted classifications of thymomas essentially divide tumors in a similar manner by the presence of lymphocytes and epithelial cells. However, at this point it is highly important to acknowledge that the current World Health Organization (WHO) position regarding the classification of thymomas was never meant to represent a classification or even less “an official classification.” The WHO blue book of 1999 clearly states that the letters and numbers used in that publication do not represent a classification of thymomas but truly a “translator,” of previous classifications. The larger problem is that in subsequent series of books from the WHO, the letters and numbers were made official, which constitutes the most unscientific classification of any tumor.

From the practical point of view, the three most quoted classifications of thymoma are presented in Table 11.2 with the respective WHO translator.

TABLE 11.2
Commonly Used Nomenclatures in the Classification of Thymomas
Bernatz Muller-Hermelink Suster-Moran WHO Translator
Lymphocyte rich Cortical Thymoma B1
Mixed cellularity Mixed (cortical/medullary) Thymoma B2 (Bernatz Mixed)
Epithelial Rich Well-differentiated thymic carcinoma Atypical thymoma B3
Spindle cell Medullary Thymoma A

Staging

Just as with the classification of thymomas, the staging has also become contentious as more recent approaches like the TNM system has been put forward. Unfortunately, those who have endorsed the TNM system have done so with a leap of faith as there are no clinicopathologic correlations addressing the importance or lack of it with a meaningful series of thymomas. Nevertheless, there have been several attempts at providing meaningful information regarding the best approach to provide clinical outcomes to patients with thymoma. One of the most popular staging systems is the one by Masaoka in 1981 in a series of 96 patients. However, several issues questioning the statistically meaningful difference between the stages II and I have been raised. In addition, there are some other technical issues between macroscopic and microscopic issues that may create some confusion regarding how to stage some thymoma patients. More recently what may be considered a more user-friendly classification was introduced in which the thoracic surgeon and pathologist worked to provide a more accurate staging system and one that can be easily implemented by any pathologist. This surgical staging system allows for the better triaging of patients who may need only surgical resection and those who may benefit for additional medical treatment as the system is based on limited and invasive disease. This more recent approach has been initially proposed using a study of 250 thymoma resections and later confirmed using a study of more than 1400 thymoma resections. ,

For practical use, this staging approach is as follows:

  • Stage 0 —encapsulated tumor. No evidence of tumor invasion into adjacent structures ( Fig. 11.6A )

    Fig. 11.6, Pictographical view of thymoma staging schema: (A) stage 0—encapsulated thymoma; (B) Stage 1—Minimally invasive thymoma in which tumor has breached the capsule; (C) Stage IIA—the tumor has directly invaded the pleura or lung, or the innominate vein; (D) Stage IIB—tumor invades the pericardium; (E) Stage IIC—tumor invades the great vessels; (F) Stage IIIA—intrathoracic invasion so-called drop metastasis.

  • Stage I —Invasive tumor that has breached the capsule of the tumor. The tumor extends into the perithymic fat (see Fig. 11.6B ), but it is not compromising adjacent structures (pleura, pericardium, etc.).

  • Stage II— Direct invasion

  • Stage III —Metastatic disease

We are aware of a more recent staging system using a TNM system; however, if one follows that proposal, one can easily identify that the system has borrowed the T from either Masaoka or Moran’s approach while the N will essentially will be 0 and the M will inevitably be 0 in the overwhelming majority of cases as thymomas rarely, if at all, will present with metastatic disease. Interesting to highlight is that the TNM proposal interpretation of pleural invasion or pericardial invasion may be interpreted as metastatic disease in the TNM approach, which is faulty as mediastinal thymomas invade adjacent structures instead of producing metastatic nodules in the pleural, pericardium, or any other adjacent mediastinal structures. Similarly, the tumor often involves great vessels, which could not be interpreted as metastatic disease. In short, the TNM system may be a good system for conventional carcinomas in which tumor size and nodal disease can play a role in the clinical outcome of patients; however, in the former, such features do not correlate with invasiveness of the tumor while in the latter, nodal disease is essentially absent, thus, relegating the T and N.

Pathologic Features

Macroscopic Features

The macroscopic features of thymomas are as varied as its microscopic features. The tumors may vary in size from a few centimeters to more than 10 cm in greatest diameter. The tumors may show a lobulated appearance, cystic changes, hemorrhagic changes, necrotic areas, or a combination of those features. In some cases, the tumor may be well-circumscribed while in others the tumor may invade the adipose tissue or adjacent mediastinal structures such as the pericardium or pleura. It is important to highlight that the gold standard to provide definitive staging is the microscopic evaluation of the structures invaded or the encapsulation of the tumor.

Microscopic Features

At this point, it is important to highlight that we discourage any classification attempt based on biopsy specimens, and considered that any attempt at classifying a thymoma based on limited tissue may eventually prove incorrect after the surgical resection of the tumor, if that is performed. Therefore, the interpretation of thymomas and their spectrum of growth pattern are really based on surgical resections.

Conventionally, thymomas with lymphocytic component in different proportion may represent the majority of cases while tumors lacking a lymphocytic component are not common. It has been stated in a large series of cases that the spindle cell growth pattern of thymomas represents no more than 20% of these tumors while those showing lymphocytic component in different proportion may represent somewhere around 50% to 60%. Therefore, approximately 20% to 30% of the tumor may show different growth patterns.

Because of the different growth pattern that thymomas may show, the use of immunohistochemical studies may also vary. However, we cannot ignore the fact that thymomas are epithelial tumors and, as such, may show positive staining with different epithelial markers. Because of the presence of a lymphoid component, the use of lymphoid markers is common. Important to highlight at this point is the normal constituents of the normal thymus and the immunohistochemical stains that may be positive in the normal thymus, which essentially may recapitulate what is seen in thymomas. Due to such similarities, it is very important to recognize that in small biopsies, the interpretation of morphology and immunohistochemistry be carefully evaluated.

Box 11.1 depicts a list of different growth patterns that have been described in thymomas, and the knowledge of those growth patterns become the driver force to the use of immunohistochemical stains to arrive a proper interpretation.

BOX 11.1
Specific Growth Patterns Described in Thymomas

  • Cystic thymomas

  • Rhabdomyomatous thymoma

  • Plasma cell thymoma

  • Thymoma with pseudosarcomatous stroma

  • Micronodular thymoma with lymphoid B-cell hyperplasia

  • Thymoma with hemorrhage, necrosis, infarction, and cystic changes

  • Ancient (sclerosing) thymoma

  • Adenomatoid spindle cell thymoma

  • Thymoma with papillary and pseudopapillary features

  • Microcystic thymoma

  • Desmoplastic thymoma

  • Thymomas with glandular differentiation

  • Thymomas with clear cell component

  • Thymomas with neuroendocrine morphology

  • Thymoma with signet ring cell-like features

  • Alveolar thymoma

  • Thymomas with sebaceous differentiation

  • Mucinous thymoma

Immunohistochemical Features

Even though the diagnosis of thymoma can be established on morphologic grounds, immunohistochemical stains have become part of the repertoire as an aid for the diagnosis of thymomas. However, due to the lack of a large series on these tumors addressing their immunohistochemical features, most of what is known derives from small series of cases or the report of unusual growth pattern of thymomas in which immunohistochemistry was used to define the tumor more properly. Knowledge of the immunohistochemical properties of thymomas has been gained over the last few decades as immunohistochemistry has also become more advanced. Over the last decades different immunohistochemical studies have focused on different aspects of the tumor. However, emphasis has been on the proper identification of epithelial and lymphoid cells; therefore, most of what is known on thymomas derives from studies with epithelial and lymphoid markers ( Fig. 11.7A–F ). At this juncture, it is important to highlight that the practical use of immunohistochemistry in the diagnosis of thymomas can be summarized as follows: epithelial cells likely show positive staining for pan keratin, keratin 5/6, p40, and p63, while showing negative staining for epithelial membrane antigen (EMA). Regarding the lymphoid component, the use of Tdt, CD3, and CD45 may show strong positive staining in those thymomas with lymphoid component ( Fig. 11.8A–D ). CD20 is usually negative or only scattered lymphoid cells are positive. Also, the immunoreactivity in atypical thymomas may show stronger positive reaction while the lymphoid markers may show scattered positive cells ( Fig. 11.9A–D ). It is important to highlight that CD5 may also stain thymomas in at least 30% of cases. Even though reports on the role of PAX8 in the diagnosis of thymomas is seen in the literature, it is important to recognize that PAX8 polyclonal antibody may show positive staining in tumors cells. However, PAX8 monoclonal antibody is generally negative. More recently, thymomas have also been evaluated for PDL-1 and may show membranous staining in about 60% to 70% of the cases. However, the significance of PDL-1 regarding the treatment and clinical outcome is still unknown.

Fig. 11.7, (A) Low power view of a thymoma with prominent lymphocytic component; (B) higher magnification showing perivascular spaces and prominent lymphoid component; (C) immunohistochemical stain for pan keratin decorates epithelial cells; (D) Tdt decorates immature lymphocytes; (E) p40 show numerous epithelial cells with nuclear positive staining; (F) CAM 5.2 low molecular weight keratin also shows positive staining in epithelial cells.

Fig. 11.8, (A) Low power view of a mixed cellularity thymoma showing epithelial and lymphoid cells almost in equal proportions; (B) higher magnification of a mixed cellularity thymoma showing the biphasic nature of the neoplasm; (C) Tdt show positive staining in immature lymphocytes; (D) p40 immunostain shows nuclear staining of epithelial cells.

Fig. 11.9, (A) low power view of an atypical thymoma showing predominance of epithelial cells; (B) higher magnification showing sheets of epithelial cells and scattered lymphocytes; (C) keratin 5/6 show strong positive staining in epithelial cells; (D) Tdt shows numerous immature lymphocytes admixed with the epithelial cells.

Thymoma Variants

The spectrum of growth patterns that thymomas may show is extensive and beyond the scope of this chapter (see Box 11.1 ). However, it is important to highlight some variants that may pose a problem in interpretation.

  • Spindle cell thymoma (WHO type A) may be confused with another spindle cell neoplasm. In this regard, spindle cell thymomas may also show positive staining for pan keratin, keratin 5/6, p40, p63 ( Fig. 11.10A–E ) and negative staining for EMA. However, some spindle cell thymomas may show focal staining for TTF1, Bcl-2, keratin 7, calretinin, and synaptophysin. Therefore, the importance of a wider panel of immunohistochemical stains when in doubt about a particular type of spindle cell neoplasm.

    Fig. 11.10, (A) Spindle cell thymoma; (B) pan keratin showing positive staining in the spindle cells; (C) keratin 5/6 also show positive staining in the spindle cells; (D) vimentin showing positive staining in spindle cells; (E) Bcl-2 shows weak focal positive staining in spindle cell.

  • Micronodular thymoma with lymphoid B-cell component, described in 1999, is characterized by the presence of epithelial nodules composed of elongated or spindle cells embedded in a rich lymphoid stroma with numerous germinal centers. Contrary to the conventional thymomas with lymphoid component in which the tumor shows positive staining for T-cell markers, in this particular variant, the lymphoid stroma shows prominent B-cell component. CD45 and CD20 show strong positive reaction in the lymphoid component, while keratin stains separate the epithelial nodular component ( Fig. 11.11A–C ).

    Fig. 11.11, (A) Low power view of a micronodular thymoma showing lymphoid hyperplasia; (B) keratin decorates the epithelial component; (C) CD20 shows strong positive staining in the B-lymphocytes.

  • Rhabdomyomatous thymoma is another variant in which the tumor has the epithelial component and shows the presence of myoid cells in different proportions. Myoid cells can be seen in different growth patterns of thymoma, whether spindle cell, lymphoid component, or predominantly epithelial and can occasionally be seen in thymic carcinoma. These tumors show positive staining for epithelial markers in the epithelial component of the tumor while the myoid cells may show positive staining for myoglobin, desmin, and myo-D ( Fig. 11.12A and B ).

    Fig. 11.12, (A) Rhabdomyomatous thymoma showing two distinct populations—epithelial cells and myoid cells; (B) myoglobin staining showing strong positive staining in the myoid cells.

  • Thymoma with pseudosarcomatous stroma (WHO metaplastic thymoma) is another unusual variant of thymoma originally described in 1997 in six cases. The tumor characteristically shows prominent epithelial component admixed with extensive areas of a cellular spindle cell component. While the epithelial component may show atypical features such as larger cells with prominent oval nuclei and prominent nucleoli, mitotic activity is not present. Also, the spindle cell component does not show either mitotic activity or cellular atypia. Interestingly, the tumor does not show any metaplastic changes and the spindle cell component possibly represent an exuberant component of the commonly seen fibrous bands associated with thymomas. The tumor shows positive staining with the conventional epithelial markers such as pan keratin, keratin 5/6, p63, and p40 while the spindle cell component is negative for the epithelial markers and show strong positive reaction with vimentin ( Fig. 11.13A –E). These tumors have a similar clinical outcome as otherwise conventional thymomas.

    Fig. 11.13, Atypical thymoma with pseudosarcomatous stroma (a.k.a. metaplastic thymoma) showing islands of epithelial cells alternating with a spindle nonneoplastic component; (B) keratin showing positive staining in the epithelial cells; (C) p40 showing positive staining in the epithelial component; (D) clusters of CD3 lymphocytes; (E) scattered immature T cell showing positive staining with Tdt.

  • Plasma cell thymoma has a marked plasma cell component instead of the common lymphocytic component. In this setting, it is necessary to use immunohistochemical stains kappa and lambda to rule out the possibility of a plasma cell malignancy. The conventional epithelial markers would be positive in the epithelial component of the tumor ( Fig. 11.14A–C ).

    Fig. 11.14, (A) Thymoma rich in plasma cells. (B) Kappa chain stain decorating many plasma cells. (C) Lambda chain stain decorating many plasma cells.

Thymic Carcinoma

Thymic carcinomas are rare and require a true clinical-radiologic-pathologic correlation to make a final determination as to whether the tumor is of thymic origin or from a different source. Most of that problem derives from the fact that a great majority of thymic carcinomas are of the squamous type; therefore, on morphological grounds, the separation of a thymic squamous cell carcinoma or a squamous cell carcinoma from a different origin may not be possible. Thus, requiring a critical thoracic radiographic analysis to make such determination.

Shimosato et al. is credited for the original description of thymic carcinoma, with few series of cases subsequently reported. Contrary to thymomas, there is no association of thymic carcinoma with specific medical conditions such as MG or any other autoimmune disease. Thus, most clinical manifestations of thymic carcinoma are rather nonspecific and are commonly represented by cough, chest pain, and dyspnea. More recently, in a series of 65 cases of thymic carcinomas (excluding neuroendocrine carcinomas), the authors identified the stage of the tumor at the time of diagnosis as one of the most important factors in determining its clinical behavior.

Staging For Thymic Carcinoma

The TNM system appears to be more reliable than using the Masaoka staging system proposed for thymoma. ,

This staging system is as follows:

Thymic Carcinoma Staging ( Fig. 11.15A–C )

  • T1— tumor limited to the thymic gland.

  • T2 —tumor invading the visceral pleura, lung, pericardium, great vessels, chest wall, or diaphragm.

  • T3 —direct extrathoracic tumor extension, beyond the thoracic inlet (consisting of the manubrium, the first thoracic vertebra, and the first ribs and their cartilages) or diaphragm

  • N0 —no lymph node metastasis

  • N1 —lymph node to intrathoracic lymph nodes

  • M0 —no distant metastasis

  • M1 —distant metastasis (indirect tumor spread, including metastasis to extrathoracic lymph nodes).

Fig. 11.15, Thymic carcinoma staging system (A) T1—tumor limited to the mediastinal compartment; (B) T2—tumor involving different structures within the thoracic cavity or diaphragm; (C) T3—tumor beyond the thoracic inlet or below the diaphragm.

Thus, grouping the cases as follows using the TNM system:

  • Stage I —T1N0M0

  • Stage II —T2N0M0

  • Stage III —T3N0M0

    • Any T, N1, M0

    • Any T, any N, M1

This suggested staging system appears to more accurately predict the clinical outcome in patients with thymic carcinoma. However, it is also important to highlight that for this staging system to work, it is essential to obtain lymph nodes during the surgical procedure in order to properly stage these patients.

Pathologic Features

Grossly, thymic carcinomas have been described as ill-defined tumors with infiltrative borders, which may range in size from a couple of centimeters to more than 10 cm in greatest diameter. The presence of hemorrhage and necrosis has been associated with high-grade thymic carcinomas.

Histologically, thymic carcinomas may also show a wide spectrum of differentiation and numerous growth patterns. However, most thymic carcinomas correspond to either well or poorly differentiated squamous cell carcinomas. Rarely primary thymic adenocarcinomas occur, and the determination of the site of origin becomes the main diagnostic issue. Thymic adenocarcinomas have been separated into those that show prominent mucinous component and those with a prominent non-mucinous component. Similarly, papillary carcinoma has been grouped as thymic adenocarcinomas and may show features of both papillary and micropapillary adenocarcinoma. Box 11.2 depicts the different growth patterns associated with thymic carcinoma.

BOX 11.2
Growth Patterns Associated With Thymic Carcinoma
NUT, Nuclear protein in testis.

  • Squamous cell carcinoma, keratinizing

  • Sarcomatoid carcinoma

  • Lymphoepithelioma-like carcinoma

  • Papillary carcinoma

  • Clear cell carcinoma

  • Rhabdoid carcinoma

  • Hepatoid carcinoma

  • Anaplastic carcinoma

  • Micronodular carcinoma with lymphoid hyperplasia

  • Rhabdomyomatous thymic carcinoma

  • NUT carcinoma

  • Adenocarcinoma

  • Undifferentiated thymic carcinoma

By immunohistochemistry, it is expected that using similar markers used for thymoma could be helpful in evaluating thymic carcinomas. In addition, since most thymic carcinomas are squamous cell carcinomas of different type of differentiation and growth pattern, the use of markers such as keratin, p63, p40, and keratin 5/6 would be helpful markers to evaluate these tumors, including the positive staining for CD5 in thymic carcinomas. However, CD5 may also be positive in a subset of thymomas; therefore, the positivity of CD5 must be correlated with the histologic features of the tumor. Other markers that have been described as positive in thymic carcinomas include calretinin, mesothelin, WT1, HBME-1, Ber-Ep4, CD15, CEA, B72.3, MOC-31, Foxn1, CD205, and synaptophysin ( Fig. 11.16A–G ). Regarding thymic adenocarcinoma, we observed that these tumors might show positive staining for keratin 7, keratin 20, CD5, CDX2, and CD117. Therefore, there needs to be a close clinical and radiologic correlation established before rendering the diagnosis of thymic adenocarcinoma, as the histologic features are similar to adenocarcinomas in other more common locations such as lung or gastrointestinal tract.

Fig. 11.16, (A) Thymic carcinoma showing fibrous bands; (B) thymic carcinoma showing islands of tumor cells in a haphazard distribution; (C) thymic carcinoma showing cellular atypia and mitotic activity; (D) immunohistochemical stain for keratin 5/6 shows strong reactivity in tumor cells; (E) p63 show strong positivity in tumor cells; (F) CD5 shows strong positivity in tumor epithelial cells; (G) synaptophysin shows weak staining in tumor cells.

One important tumor condition that needs to be mentioned is the midline carcinoma, also known as NUT (nuclear protein in testis) carcinoma. This particular tumor appears to be more common in young patients who may present with a mediastinal mass. Histologically, these tumors are poorly differentiated carcinoma, likely squamous cell type that show positive staining by immunohistochemistry for the NUT antibody. It is also important to mention that these particular tumors may also show specific translocations t(15;19), (q15;p13), (q12;p13.1), t(11;15;19), which are essential in the final interpretation of this particular tumor.

At the molecular level, there are no comprehensive studies on thymic carcinomas. However, reports of HER gene amplification, increase EGFR and HER2 gene copy numbers, hypermethylation in the promoter region of CDKN2, deletions in exon 19 of EGFR, have been reported.

Salivary Gland Type Tumors

Although an unusual group of tumors in the thymic area, this family of tumors shares similar histopathologic features as their counterparts in the salivary glands. It is therefore important to properly exclude the possibility of metastatic disease. The gamut of tumors that have been described in the thymus is similar to those described in the salivary glands. Although the malignant tumors are more common, such as mucoepidermoid carcinoma (MEC), epithelial-myoepithelial carcinoma, and adenoid cystic carcinoma, there are some benign neoplasms such as sebaceous adenoma that have been reported as primary tumors in the thymus.

Mucoepidermoid Carcinoma

Of all the salivary gland type tumors of the thymus, MEC represents the most commonly reported. , The tumor appears to be more common in adults although there are rare case reports in children. Patients may present with nonspecific symptoms including cough, chest pain, and dyspnea. The histologic features and immunohistochemical profile is similar to those described in the salivary glands, and these tumors have been separated into low and high-grade carcinomas, which correlates with their clinical outcome.

Grossly, these tumors are cystic and solid, attaining sizes of more than 10 cm and usually confined to the mediastinal compartment.

Histologically, MEC is characterized by the presence of sheets of epidermoid cells without keratinization admixed with mucous producing cells (so-called mucocytes) in varying proportions. The presence of clear cells (intermediate cells) varies from case to case.

In general, low grade MEC do not show increase mitotic activity, nuclear atypia, hemorrhage, and/or necrosis. These features would be in keeping with a high grade MEC. It is common that these tumors also show cystic changes in which the cysts are lined by squamous epithelium without keratinization and in some areas; one can also identify the presence of mucous producing cells.

By immunohistochemistry, as one would expect, the epidermoid component may show positive staining for pan-keratin, keratin 5/6, p40, and p63. In addition, a mucicarmine histochemical stain will highlight the mucous contents in the so-called mucocytes ( Fig. 11.17 ). Regarding the association of thymic MEC and MALM rearrangement, there is limited information and some reports have shown rearrangement while others have not. , However, mastermind-like protein (MALM) is an important tool in the diagnosis of MEC, but a negative result should not preclude the diagnosis of MEC.

Fig. 11.17, (A) Low power view of a thymic mucoepidermoid carcinoma (MEC) showing sheets of tumor cell without keratinization; (B) epidermoid component admixed with mucous secreting cells; (C) mucicarmine stain shows positive reaction is the so-called mucocytes; (D) MEC showing positive staining for keratin 5/6; (E) MEC showing positive staining for p40.

Epithelial-Myoepithelial Carcinoma

This particular neoplasm is unusual in the mediastinum. The only case reported in literature is a 25-year-old man with an anterior mediastinal mass and no other history of this tumor in the neck area. Due to the unusual occurrence of this tumor in the thymic area, it is difficult to determine the natural course of this tumor in the mediastinum.

The histologic features of this tumor are essentially the same as those in the salivary gland and are characterized by a proliferation of duct-like, tubules, or sheets of cells. In addition, this duct proliferation is composed of an outer layer of cells with a clear cytoplasm (myoepithelial layer) and an inner layer representing the epithelial layer. Mitotic activity, necrosis, and hemorrhage are unusual. By immunohistochemistry, the tumor cells stain positively for vimentin, smooth muscle actin, S-100 protein, and keratin ( Fig. 11.18A–D ).

Fig. 11.18, (A) Low power view of thymic epithelial-myoepithelial carcinoma showing focal lobulation; (B) higher magnification showing the presence of clear cells; (C) keratin showing positive staining; (D) smooth muscle actin shows positive staining.

Adenoid Cystic Carcinoma

The occurrence of this tumor in the mediastinum is rare, and for a while now, they are reported as thymic carcinomas. All the cases described in the literature are found in adults. The clinical course of this tumor in the mediastinum is difficult to determine; however, cases of metastatic disease have been described.

The histologic features are also similar to tumors of the salivary glands. Characteristically, the tumors show a cylindromatous or tubular growth pattern in which the gland-like structures are composed of two rows of cells. Mitotic activity and nuclear atypia are minimal. By immunohistochemistry, the tumor may also show positive staining for vimentin, smooth muscle actin, S-100 protein, and keratin. Other stains that may show positive staining include MYB, CD5, CD10, keratin 5/6, p63, and p40.

Sebaceous Lymphadenoma

This is an unusual benign tumor of the thymus. Only two cases have been reported in adults with an anterior mediastinal mass. The clinical and radiologic findings in these patients do not allow for a specific diagnosis; therefore, the final interpretation is done after surgical resection of the mass, which is curative in these patients.

Histologically, these tumors share similar features as their counterparts in the salivary gland, which includes epithelial proliferation arranged in islands of cells some with cystic changes embedded in a lymphoid stroma. However, the most important and relevant finding is the presence of areas of sebaceous differentiation. By immunohistochemistry, the tumor may show positive staining for keratin, keratin 5/6, and p40 in the epithelial component while the lymphoid component may show positive staining for CD45, CD20, and scattered Tdt+ cells. The use of adipophilin may prove helpful in identifying the sebaceous component ( Fig. 11.19A–C ).

Fig. 11.19, (A) Thymic sebaceous adenoma showing islands of epithelial cells embedded in a lymphoid stroma; (B) higher magnification showing islands of epithelial cells with sebaceous differentiation; (C) immunostain for adipophilin show positive staining in the sebaceous component.

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