PERSPECTIVES AND PATTERNS OF SPREAD
There is a need to view generalized systems from their embryogenesis to their histogenesis in addition to their ubiquitous anatomy to provide insights into the malignancies that arise within them.
PERSPECTIVES AND PATTERNS OF SPREAD
The generalized sites can give rise to primary tumors (T)—sarcomas rather than carcinomas—in many different anatomic sites but in addition, the lymphoid system and the circulatory system are intimately related to N and M categories, respectively. In contrast to carcinomas, sarcomas can arise in a large variety of anatomic sites because the tissues are located in the many different regions that constitute the human body architecture. Their patterns of spread depend on the exact site of tumor origin. The anatomy that will be portrayed will largely be the extremities.
Each generalized anatomic site (GAS) will be concisely reviewed in this introduction.
The GASs are the ectoderm integument system and mesodermal systems, that is, connective tissues, musculoskeletal and lymphoid, with a wide spectrum of cell types.
Thus, the GAS's TNM staging is complex conceptually; in addition there are an infinite number of potential geographic loci in a GAS tissue. Each GAS normal tissue consists of a variety of cell types, which results in a wide array of histopathologic classifications. The complexity is in applying one TNM staging system when the tumor can be located in numerous and varied geographic anatomic regions. Each major generalized system will be presented more from the histogenic than the anatomic perspective.
The spread of lymphatic and hematogenous metastases varies with body anatomy site.
In embryogenesis, the vertebrate body plan is established by the HOX genes and forms a surface ectoderm, a mesoderm, and an endoderm. Each somite differentiates into a dermatome, a myotome, and a sclerotome with a section of the splanchnopleura, the primordium of the visceral organs (Fig. 49.1).
• The ectoderm forms the integument, composed of a keratinized epithelial layer with glands and invagination with a large variety of cells that can transform into tumors.
• The mesoderm is a dense cellular tissue surrounded by mesenchyme and gives rise to the musculoskeletal system, soft connective tissue of dermis, gastrointestinal (GI) tract connective tissue stroma, and the cardiac mesoderm. The embryonic cardinal system of the veins will develop an extensive network of arteries and veins postnatally. The formation of endothelium and primitive blood cells comes from condensation of mesenchyme. Capillaries of vessels and lymphatics form in the base mesenchyme of each organ. The mesenchyme forms the lymphatic system as part of other organs such as tonsils, vermiform appendix, gut-associated tissues, the respiratory system with its bronchus-associated lymphatic system (BALT), and various mucous membranes (MALTs). The ability to detect antigens that are self versus foreign is inherent to three major types of lymphocytes: B cells, T cells, and NK cells. These immunocompetent cells each has its specific identity and functions, giving rise to a highly varied list of lymphomas. T lymphocytes account for the majority of circulating lymphocytes and differentiate in the thymus. B lymphocytes differentiate in bursa of Fabricius–like organs from γ-interferon–inducible lysosomal thiol reductase and bone marrow.
• Endoderm or gut tube provides the epithelial lining of various viscera and systems, including the respiratory and digestive systems, and some of the parenchyma of organs such as liver, pancreas, urinary bladder, urethra, thyroid, and parathyroid glands. This germ layer gives rise to a large variety of cancers.
To recapitulate: The anatomic odyssey through 60 anatomic sites is based largely on carcinomas and on concepts of regional anatomy and TNM cancer staging. Three-dimensional oncoanatomy is conceived on patterns of cancer spread. That is, each cancer is assigned to a designated anatomic isocenter in which the major common cancers arise. The primary tumor (T) pattern of spread is then presented in six basic directions: superior–inferior, medial–lateral, and anterior–posterior (SIMLAP). Each cancer site has specific sentinel and regional lymphatic and nodal drainage (N) and venous drainage to a target organ (M).
• The segmented human body plan consists of somites arranged along three axes: caudiocranial or superior inferior and medial lateral and anterior posterior (Fig. 49.1).
• Each segment consists of annealed trigeminal layers.
• These trigeminal somites provide specific landmarks that can serve as references.
Figure 49.1 | Derivatives of the three germ layers.
The anatomic neoplastic odyssey, in addition to the 60 specific primary sites, includes six generalized anatomic systems: the integumentary system, the musculoskeletal systems, and the lymphoid and hematopoietic systems. The sixth system, the cardiovascular system, is low in incidence for primary tumors, but is the major distribution and transport means of circulating cancer cells to distant and remote sites. Unlike specific site cancers, these malignancies can arise in a large variety of locations, making them a true challenge to diagnose, stage, and manage.
INTEGUMENT SYSTEM
Perspective
The skin and its derivative cellular elements consist largely of keratinized squamous epithelial cells with numerous distinct cell types resting on connective tissue dermis, each of which can result in a tumor. The integument can be transformed into malignancy most often due to ultraviolet rays from the sun. This is especially true for fair skin-skinned people and individuals who enjoy sunbathing. The integumentary system (Fig. 49.2) is the anatomic site that results in more cancers than all of the other primary sites together.
• The incidence of skin cancers has continued to rise rapidly over the last 30 years (Table 49.1). Skin cancers are the most common of all cancers and among the most preventable. In the United States alone, 900,000 to 1,200,000 new cases are predicted each year. The high curability of basal and squamous cell skin cancers reduces the threat to life, but disfigurement can occur in individuals who are predisposed genetically (xeroderma pigmentosa), children irradiated for acne treatment, or sun worshippers, owing to the multiplicity of lesions. Basal cell cancers rarely spread.
• Melanomas are the antithesis to ordinary skin cancers, in that widespread metastases can occur with these malignancies, which are measured in millimeters. Essential to understanding the TNM staging system is the need to study the cellular complexity of epidermal and dermal layers. There are a myriad of different cells, up to 20 to 25 in the skin, each of which can become malignant. To understand the biologic behavior of these highly varied cellular components, an understanding of the cellular and physiologic activities of the integument is essential. The melanocyte at the epidermal–dermal interface is a cell with long dendritic processes that extend between cells into the basal stratum.
Figure 49.2 | Overview of integumentary system. Comparison between thin skin in the arm and thick skin in the palm, including contents of the connective tissue dermis.
SOFT TISSUE SYSTEMS
Perspective
Musculoskeletal systems consist of soft tissues as connective tissue (Fig. 49.3A) and muscle (Fig. 49.3B), each of which can give rise to malignancies that are referred to as sarcomas rather than carcinomas.
• Soft tissue sarcomas are a unique class of tumors, distinct from skin cancers. As a class, soft tissue tumors are highly varied despite their origin from the omnipresent mesenchymal cell. The mesenchymal cell, through a derepression process, can proliferate and dedifferentiate, yielding multiple histopathologic subtypes (Table 49.2). The degree of malignancy is based more on the tumor grade than on the tissue type and in fact dominates in TNM staging and classification over anatomic extent of the malignant infiltration. There are many nuances and clinical challenges for the same tumor types in different parts of the anatomy. Soft tissue tumors arising in the extremity are more manageable and favorable than those in truncal and axial locations. Of particular note is the predominance of soft tissue sarcomas in children and the relative rarity of epithelial cancers, which is the reverse of the situation with regard to adult malignancies. Muscle per se can give rise to a variety of sarcomas, reflecting the type of muscle cell. Most rhabdosarcomas are embryonal and occur in childhood. An element of gene deletions and overexpression is often associated, with both benign and malignant growth abnormalities being present in pediatric populations. Proto-oncogenes can be expressed in these circumstances, providing genetic and chromosomal biomarkers that may be useful in the future for staging.
The mesenchymal soft tissue and muscle compartments contain a highly variegated population of cell types. Each derivative normal cell can yield a malignancy. The pediatric population is prone to develop sarcomas rather than carcinomas in view of accelerated musculoskeletal growth early in childhood (1 to 6 years) and in adolescence (12 to 18 years).
Figure 49.3 | Overview of oncoanatomy. A. The mesenchymal cells give rise to a variety of loose connective tissue (LCT) elements and include fibrocytes, fibroblasts, adipocytes, macrophages, and mast cells, which include both collagen and reticular and elastic fibers. B. Muscle compartments are composed of muscle cells and, in addition, cardiac muscle. Muscle cells are multinucleated and tend to hypertrophy rather than undergo hyperplasia.
OSSEOUS SYSTEMS
Perspective
• Bone tumors: The classification and staging of bone tumors has been as varied as their malignant histopathologic typing, which often requires supplementary radiographic images to ascertain their location and origin (Table 49.3). Again, as in other sarcomas, the grade impacts staging, as does anatomic extent, but to a lesser degree than anatomic size. Rules for classification allow for the use of imaging technologies ranging from magnetic resonance imaging (MRI) to computed tomography (CT) and, to some extent, radioisotope 99mTc scanning. Biopsy is an essential aspect of staging and needs to be thoughtfully located to allow for subsequent en bloc bone tumor resection for more accurate histopathology typing and grading.
The anatomic aspects of skeletal growth are essential to understanding biologic behavior and patterns of spread of osseous malignancies (Fig. 49.4). The fundamental organization of bone formation as endochondral or intramembranous is the key to appreciating how the skeleton grows, models, and remodels into compact and cancellous bone. Each bone—long, short, cuboid, and flat—is organized and grows differently as a function of age. Malignant tumors tend to occur in sites of major growth activity, that is, the distal or proximal physis of long bone, that is, the distal femur or proximal humeral physis. Neoplasms are more likely to occur at puberty and in young, growing adults than in the elderly because of the loss of mitotic potential with age. The histopathology of bone tumors is highly varied and depends on the derivative normal cell.
Figure 49.4 | Overview of skeletal tissue. Endochondral ossification, illustrating the progressive stages of bone formation (from cartilage model to bone) and including the histology of a section of formed bone.
LYMPHOID SYSTEM
Perspective
The lymphoid system (Fig. 49.5) is ubiquitously distributed, and lymphomas affect all age groups. The lymphoid system consists of an elaborate fine network of channels that drain into a lymphatic chain of nodes, eventually emptying into the right lymphatic duct or thoracic duct. In addition to regional lymph nodes, there are numerous extranodal collections of lymphoid tissue. The lymphoid system, although generally associated with the nodal category of cancer spread, has a large variety of B cell and T cell lymphomas (Table 49.4).
• Hodgkin's disease: The staging of anatomic extent in both Hodgkin's disease and lymphoma led to the term “lymph node regions” (LNR) defined in 1965. Although they are not based on any physiologic or natural anatomic boundaries, LNRs have become accepted by clinical consensus. The diaphragm acts as the great divide, with the cisterna chyli located inferior to the right diaphragmatic leaf and giving rise to the thoracic duct, which courses through the thorax, where it crosses over to the left side at T4 and terminates in the left neck. The anatomy of lymphomas in terms of “lymph node–bearing regions” needs to be reconciled with “regional first-station nodes” of normal anatomic structures that constitute organ primary sites that give rise to cancer. Extranodal sites are “E,” although in some sense they are equivalent to the “T” of cancers. The concept of retrograde spread from a lymph node to a structure such as Waldeyer's ring or lung may be treated as a subgroup of stage, namely, IIE, whereas bone marrow, liver, pleura, or cerebrospinal fluid requires a stage IV disseminated designation.
• Lymphomas are a heterogeneous group of malignancies that often present as either limited or diffuse adenopathy.
• Anaplastic large-cell lymphoma, ALK-negative The classification of lymphoid malignancies has mutated to its present diversity because of the continual progress of immunobiology, which is superimposed on descriptive histopathology. Immunophenotyping and genetic features have resulted in 25 different categories of lymphoma, including Hodgkin's disease. The Revised European–American Classification is now the standard adopted by the World Health Organization, which has B cell and the T cell/natural killer cells as the great divide. The staging workup to determine anatomic extent is demanding because numerous ancillary procedures include sophisticated imaging, exploratory procedures, and biopsy proof of involvement.
Figure 49.5 | Overview of lymphoid and lymphatic system. Location and distribution of the lymphoid organs and lymphatic channels in the body. Internal contents of the lymph node and spleen are illustrated in greater detail.
• Mycosis fungoides is a primary cutaneous T cell lymphoma that involves soft tissues and regional lymph nodes and has a TNM classification that is clinically used and deserves to be maintained.
HEMATOPOIETIC SYSTEM
Perspective
The hematopoietic system (Fig. 49.6B) is constituted by the bone marrow and its cellular products in the blood. The bone marrow, although intimately related to the lymphoid system in a neoplastic sense, is integrated with bone anatomically. Fetal bone marrow at birth occupies the shaft of all long bones in their medullary cavity and then recedes at puberty and adolescence to proximal portions of the humerus and femur.
• Multiple myelomas: Multiple myeloma is a neoplastic disorder characterized by a single clone of plasma cells, believed to be derived from B cells. Diffuse, small, lytic bone lesions are more common than solitary plasmacytomas, which are highly curable. For the diagnosis of multiple myeloma, 10% of bone marrow cells on aspiration need to be plasma cells; the production of monoclonal (M) protein encountered in serum and urine is characteristic of this disease.
• The leukemias have not been included in TNM classification and are considered disseminated diseases; anatomic staging per se may not be relevant. However, these diseases of white blood cells are either myeloid or lymphoid neoplasms and provide a view of the future, in that molecular biology technology has enabled the identification of leukemia-specific cytogenetic and molecular signatures. The correlation of clinicopathologic courses and a specific cytogenetic marker can lead to the development and use of specific targeted therapy to molecular events. The ability to detect minimal residual disease provides a sharper endpoint to terminate aggressive cyclic chemotherapy and/or radiation regimens. Generally, leukemias are divided into acute or chronic, depending on whether the clonal hematopoietic stem cell disorder is characterized by arrested differentiation of stem cells leading to immature blast cells. This block in differentiation may occur in hematopoietic lineages, before lineage commitment, or during developmental stages within a lineage.
Figure 49.6A | Morphology of acute myeloid leukemia (AML) in the traditional French-American-British (FAB) classification, now within the framework of the World Health Organization (WHO) classification “AML—not otherwise categorized.”
Figure 49.6B | Overview of hematopoietic system. Differentiation of a pluripotent hemopoietic stem cell into the myeloid stem cell line and lymphoid stem cell line during hemopoiesis.
Malignant Myelodysplastic syndromes and Leukemias originate from proliferations of either leukocytes or lymphocytes. According to the WHO, a diagnosis of acute myelogenous leukemia must have 20% blasts in the bone marrow. The blasts require signatures of cytochemical or immunophenotypic traits of myeloid cells. The WHO classification of Acute Myeloid Leukemias is listed in Table 49.5A and are morphologically presented in Figure 49.6Abased on the French American British (FAB) classification.
The chronic Myeloproliferative syndromes usually involve proliferation of more mature myeloid lineages i.e. granulocytes, erythrocytes, or megakaryocytes. Their tabulation (Table 49.5B) emphasizes their acute leukemia conversion rate, bone marrow features, and genetic factors.
CARDIOVASCULAR SYSTEM
Perspective
The cardiovascular system (Fig. 49.7) is the major means of circulation of blood cells, nutrients, and electrolytes to all normal tissues and organs in the body. The main components are the heart and an elaborate vascular tree consisting of arteries carrying oxygenated blood, veins returning deoxygenated blood, and a vast mesh of microvascularization, which is the microcirculation of capillaries in all normal tissues and organs. Although neoplastic disease rarely affects the heart as a primary site, it is the major means of distributing neoplastic cancer and sarcoma cells to remote sites resulting in disseminated metastases. The venous system is of greater interest to explain the distribution of metastases than the arterial system.
The concept of oligometastases as the first stage of a more disseminated process is defined as a limited number or a few foci of cancer cells in one organ system. Although there are numerous circulating cells, oligometastases may be the initial phase of metastatic cancer residing in another organ system than the one in which the cancer cell originated. The argument as to a genetically programmed “seed versus soil” as the basis for metastases is not addressed. The anatomic basis for oligometastases is hypothesized on the basis of venous drainage of the primary site and the target metastatic organ being the first to receive the released cancer cells. The four most common sites for remote metastases are lung, liver, bone, and lymphoid.
• Lung: Pulmonary metastases are the most common because the entire venous hypoxic blood is returned to the heart via the superior and inferior vena cava. Primary cancer sites such as head and neck, lung, breast, male genitourinary, and female gynecologic cancers tend to appear initially as lung metastases. Bone and soft tissue sarcomas tend to appear in lung first as the target metastatic organ.
• Liver: The digestive system from the distal esophagus to the rectum drains into portal circulation; solitary or oligometastases to the liver are frequently present for gastrointestinal tract cancers.
• Bone's medullary cavity consists of sinusoidal sites that attract metastatic cells. Thus, the bone marrow is an optimal site to initiate metastases in bone, with the vertebrae as the most common osseous metastases, as well as the proximal portion of the femur and pelvis. The prostate is the most common primary cancer site, followed by breast and lung. The Batson circulation is a rich network of intervertebral veins that interconnects with the periprostatic plexus, the hemiazygos, and azygos veins so that a retrospread from primary sites can float malignant cells into vertebrae.
• Lymphoid: Because lymph node involvement is so common, one needs to note that all lymphatics drain into the cisterna chyli and then into the thoracic duct, which drains into the left neck at the junction of the internal jugular and subclavian veins. The first sign of a hidden primary is often a left supraclavicular node, so-called Virchow's node.
Figure 49.7 | Overview of cardiovascular system. Comparison (transverse sections) of a muscular artery, large vein, and the three types of capillaries.
TNM STAGING CRITERIA
TNM PATTERNS OF SPREAD AND STAGING CRITERIA
Each of the generalized systems has classification and staging criteria that are unique and idiosyncratic to that tissue/organ. As such, each system and its associated malignancies are presented separately.
Overview of the Oncoanatomy
The oncoanatomy of each generalized system is concisely described, with a more thorough presentation offered in the chapter dealing with the staging of its malignant tumors.
Orientation of Three-planar Oncoanatomy
Because major regional sectors—head and neck, thorax, abdomen, male and female pelvis—have been thoroughly covered in the presentation of the 50 primary cancer sites, the focus of the oncoanatomy is the appendicular anatomy, that is, lower and upper limbs.
Rules for Classification and Staging
The value and importance of cross-sectional imaging are well demonstrated and recognized when determining the anatomic extent of the malignancy involving a generalized site. CT, MRI, single-photon emission computed tomography, and positron emission tomography each have a role in both the initial staging and follow-up evaluation. Detailed oncoimaging recommendations are offered in relation to each site.
CANCER STATISTICS AND SURVIVAL
Skin cancers are the most preventable and most curable. Hodgkin's disease was the first lymphoma to become highly curable; the other lymphomas followed because of continued gains in survival with combination chemotherapy and biologic response modifiers. The leukemias are being controlled with aggressive supralethal chemoradiation therapy and bone marrow transplantation. Acute lymphoblastic leukemia in children has a very high survival rate. Soft tissue and bone sarcoma remain challenging to cure; equally important is limb preservation. Detailed statistics and survival are presented in each chapter devoted to a generalized site. Figure 49.8 illustrates the dramatic gains in survival over the last five decades and shows the trajectory of pediatric malignancies rising from incurability to curability as testimony to the multidisciplinary approach to a variety of sarcomas of these generalized anatomic systems.
Figure 49.8 | Trajectory of soft tissue sarcoma curability.