Ebook Histology for pathologists (4/E): Part 2

21
Serous Membranes
Da rryl Ca rte r

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La w r e n c e Tr u e

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Ch ris to p h e r N. Otis

ANATOMY 585

REACTIVE MESOTHELIUM 595
Reactive versus Neoplastic Mesothelium 596
Reactive Mesothelium versus Carcinoma 596
Endosalpingiosis and Endometriosis 597
Fibrous Pleurisy 598
Multilocular Peritoneal Inclusion Cyst 598

FUNCTIONAL ANATOMY 586
MESOTHELIAL CELLS 588
Morphology 588
Histochemistry 589
Immunohistochemistry 591
Ultrastructure 593
SUBMESOTHELIAL LAYER 593
Histochemistry 593
Immunohistochemistry 595
Interactions o Mesothelial and Submesothelial Cells

REFERENCES

599

595

ANATOMY
The mesothelium lines the pleural, pericardial, and peritoneal cavities. Mesothelial cells on the serous surfaces
appear as a simple or cuboidal epithelium, although they
are of mesodermal origin. They are supported by a brous
submesothelial layer, which becomes continuous with the
outer layer of invested viscera. The serous membranes show
functional differentiation according to their derivation from
visceral or parietal mesoderm.
Because of space limitations, description of the gross
anatomy of the mesothelium must be somewhat truncated, but some areas have functional differentiation that
is re ected by their histologic features. The pleura is a
continuous membrane that covers the chest wall and the
lungs. The visceral pleura coats the entire pulmonary surface, including the major and minor ssures that divide the
lungs into lobes, whereas the parietal pleura extends over
the ribs, sternum, and supporting structures and is re ected
over the mediastinal structures on both right and left. Posteriorly in the mediastinum, the two layers of parietal pleura
are separated by a thin band of brovascular connective tissue. Superiorly, the cervical pleura is re ected into the retroclavicular area over the apex of the lung and is coated by a

thickened layer of brous tissue and skeletal muscle; inferiorly, the diaphragmatic pleura represents its caudal extent.
Anteriorly, the pleura is re ected over part of the pericardium. The posterior visceral pleura becomes continuous
with the diaphragmatic pleura over the pulmonary ligament.
The heart and great vessels lie in the pericardium, which is
lined by a continuous layer of mesothelium. The visceral

(epicardial) side is connected to the myocardium, and the
parietal (pericardial) layer rests on a dense brous tissue
layer containing branches of the internal mammary and
musculophrenic vessels, descending aorta, and branches of
the vagus, phrenic, and sympathetic nerves. The thoracic
surface of the pericardium is coated with parietal pleura.
The peritoneum is a nearly continuous membrane lining the potential space between the intra-abdominal viscera
and the abdominal wall. In females, it is normally interrupted by the lumina of the fallopian tubes. Anatomically, it
is more complex than either the pleura or the pericardium.
The parietal layer covers the abdominal wall, diaphragm,
anterior surfaces of the retroperitoneal viscera, and the
pelvis. The visceral peritoneum invests the intestines and
other intra-abdominal viscera. The elongated structures in
which the parietal and visceral layers come together are the
mesentery, which contains blood vessels, lymphatics, lymph
nodes, and nerves.
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The greater omentum is a double sheet with four layers
of mesothelium between which there are numerous blood
vessels and adipose tissue, which may be abundant; lymphatics and lymph nodes are less prominent than in the
mesentery. The peritoneal cavity is grossly divided into the
greater sac over the intestines, the retrogastric lesser sac,
the right and left retrocolic areas, and the pelvis. Several
outpouchings of peritoneum are often seen in pathology

laboratories. Inguinal hernia sacs are pouches of parietal
peritoneum, often invested with brous tissue and occasionally with skeletal muscle, which have been pushed
through the abdominal musculature into the inguinal canal.
Umbilical or ventral hernias are also outpouchings of peritoneum, but the specimens received by pathologists after
surgery for their repair are usually preperitoneal broadipose tissue pushed ahead of the parietal peritoneum rather
than mesothelium itself.
The scrotum acquires a lining of parietal mesothelium, the
processus vaginalis, into which the testes descend during the
seventh month of gestation. A mesothelial layer forms the surface of the tunica vaginalis. Distention of this mesothelial sac
on the tunica vaginalis results in a hydrocele—communicating
with the peritoneal cavity when congenital but noncommunicating in acquired hydroceles. The sac of an inguinal hernia communicates with the peritoneal cavity and not with
the mesothelium-lined space of the scrotum. Both hernia
and hydrocele sacs are capable of a wide range of reactive
changes.

FUNCTIONALANATOMY
The functional anatomy of the pleura was described by
Sahn (1) and Pistolesi et al. (2). The pleura is a continuous membrane surrounding a space that normally contains
approximately 10 mL of clear colorless uid. The surface
is lined by a single layer of mesothelial cells anchored to
a basement membrane that lies on layers of collagen and
elastic tissues containing vascular and lymphatic vessels.
The lining mesothelial cells are 16 to 40 µ m in diameter,
have rounded nuclei, usually displaying a nucleolus, and a
relatively large amount of cytoplasm. Although the visceral
and parietal pleurae are opposing parts of the same continuous membrane, there are major functional differences
between them.
The human visceral pleura is thick relative to that seen
in some other mammals (3) and is similar to that of horses,
cattle, sheep, and pigs (4). It has an arterial blood supply

from the bronchial arteries, with a venous return that passes
rst into the pulmonary veins and then into the left atrium
except for certain hilar regions that are drained by bronchial veins into the right atrium. The lymphatics that pass
through the visceral pleura are the super cial layer of pulmonary lymphatics with extensive connections to the peribronchial, perivascular, and interlobular lymphatic spaces

FIGURE 21.1 Visceral pleura. The mesothelial cells on the sur ace are
f attened and, when viewed in pro le, so thin as to be barely evident. On
the posterior sur ace o the le t lower lobe, the dense submesothelial
layer is composed o collagen and elastin, and extends into adjacent
pulmonary interstitium and around pulmonary vessels.

and lymphoid tissue (5). Blood and lymphatic vessels are
invested by two layers of collagen and elastic bers; an
external elastic lamina supports the mesothelial cells and
an internal layer invests the vessels and becomes continuous with the pulmonary interstitium (Figures 21.1, 21.2).
Histologic identi cation of integrity of the visceral pleural elastin is considered clinically important in determining
pleural invasion by primary lung cancer, which is signi cant
for staging (6). However, the elastin layer of the visceral
pleura is also interrupted in non-neoplastic conditions of
the lung that extend to the pleura. In sheep, and probably
in humans, the thickness of the external layer increases
in both the craniocaudal and ventrodorsal directions, perhaps because of postural reasons (7). The visceral pleura is
innervated by branches of the vagus nerves and sympathetic
nerve trunks.
The parietal pleura is anatomically, histologically, and
functionally different. Although the single layer of mesothelial cells that lie on the surface of the parietal pleura
are cytologically similar to those that form the continuous
membrane over the visceral pleura, they are interrupted by
stomata which range in size from 2 to 12 µ m in diameter.
Li (8) described the stomata on the human diaphragmatic

pleura as usually penetrating deep through connective tissue with apparent communication between the pleural cavity and the underlying lymphatic lacunae. In some areas,
stomata were covered with great microvilli (longer and


CH AP TER 2 1 : Se ro u s Me m b ra n e s

FIGURE 21.2 Visceral pleura. Capillaries are prominent, the lymphatics are dilated, deeply placed and entirely invested by the submesothelial layer.

with a denser network of laments) on the surfaces of the
surrounding mesothelial cells. The underlying lymphatics
drain directly into intercostal lymphatics and then into the
mediastinum, where they are particularly dense along the retrocardiac surface (9–16).
Fluid and particulate matter extravasated from the
lung are collected in these lymphatics and passed into the
mediastinum, where the mesothelium covers collections
of macrophages called Kampmeier foci (17). Boutin et al.
(18) showed concentration of asbestos bers in these areas,
which are also termed “black spots” when there is concentration of carbon in individuals who have inhaled coal dust.
Miserocchi et al. (19) discussed asbestos ber accumulation in “black spots” corresponding to the stomata.
The arterial and venous blood supply to the parietal
pleura is from the intercostal vessels. The thickness of the
broelastic layer investing the parietal pleural lymphatics is
relatively constant and considerably less than that of most
of the visceral pleura, suggesting that it serves as a membrane across which uid may diffuse. The parietal pleura is
innervated by branches of the intercostal nerves, which are
responsible for the pain associated with pleurisy.
Wassilev et al. (20) described stomata on the peritoneum of the abdominal wall, omentum, mesentery, ovaries
and pelvis as well as on the underside of the diaphragm.
They found variation in the structure of the stomata according to location. The parietal stomata were clustered, oval in
shape and delimited by attened mesothelial cells, whereas

the hepatic stomata were deeper gaps in adjacent cuboidal

587

mesothelial cells and were covered or occluded by the
microvilli on the surface of mesothelial cells. Li and Yu (21)
found that the diaphragmatic stomata were approximately
10 µ m2 in size, among cuboidal but not attened mesothelial cells, and opened into submesothelial connective tissue
in which there was a rich plexus of lymphatics, which they
suggested carried away peritoneal uid and particles.
The serous membranes serve as a selective barrier for
uid and cells. A small volume of uid is required for capillary action to facilitate adherence of visceral and parietal
pleurae as the lungs and chest wall expand and contract.
Elements of the serous membranes regulate uid interchange to keep this uid at a minimal level to prevent compromise of the lung volumes. Control appears to be at the
capillary level because uid is freely diffusible through visceral mesothelium and is collected in parietal lymphatics via
stomata in the parietal mesothelium. The bushy, elongated
microvilli, which are the diagnostic hallmark of mesothelial
cells, are sometimes enlarged where associated with stomata. Another level of control results from the relatively low
protein content (1.0 to 1.5 g/dL) of pleural uid. The point
of protein regulation is unknown, although there is speculation that it occurs at the level of mesothelial microvilli (21).
In the thoracic cavity, the direction of ow appears to be
via diffusion from capillaries of both visceral and parietal
pleurae, with resorption primarily through parietal pleural
capillaries. Turnover is estimated at 0.7 mL/hr (21) (Figure
21.3). Small molecules (less than 4 nm in diameter) diffuse through the intercellular spaces and junctions between
mesothelial cells. Loss of control results in serous effusions
such as those seen in congestive heart failure.

FIGURE 21.3 Model o the dynamics o pleural f uid ormation. A transudate rom capillaries in visceral and parietal pleurae is partly reabsorbed by those capillaries and the rest di uses into the pleural space,
where it is resorbed via stomata into parietal pleural lymphatics.

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S E C TIO N VI: Th o ra x a n d Se ro u s Me m b ra n e s

Larger molecules, up to 50 nm in diameter, are transferred across the mesothelium by pinocytotic uptake and
transcellular transport. Larger structures, such as cells
in bloody effusions, are transported via the stomata and
“crevices.” Loss of control of these mechanisms results in
accumulation of exudative pleural uid. Mesothelial cells
express the secretory component of IgA, which is otherwise limited to surfaces with direct environmental contact (22,23). The glycoprotein-rich pleural uid acts as a
lubricant to minimize friction between visceral and parietal
pleurae. The site of synthesis and mechanisms of control
of the carbohydrate-rich fractions of the pleural uid are
unknown. The submesothelial connective tissue distributes
mechanical forces from the pleura uniformly throughout
the lungs. Such a redistribution of forces is not required of
the abdominal serosa. Both mesothelial cells and broblasts
contribute to collagen synthesis.

MESOTHELIALCELLS

FIGURE 21.5 At higher magni cation, a sheet o relatively normal mesothelial cells with abundant, clear cytoplasm and crisply de ned cell borders.
The centrally placed nuclei are small and have a homogenous chromatin.

Morphology
Normal mesothelial cells are rarely seen in histologic sections but may be evident in cytologic preparations of peritoneal washes taken during a laparotomy (Figure 21.4).
When thus visualized, they have abundant clear cytoplasm
with crisply de ned cell borders, small and centrally placed

nuclei with a homogeneous chromatin pattern, and usually
without a nucleolus (Figure 21.5).
In a variety of reactive processes, the mesothelial cells
undergo markedly proliferative and hyperplastic changes. A
relatively abundant cytoplasm is maintained, but the cell
borders are less sharply de ned. The nuclei are larger, both
absolutely and relatively, the chromatin pattern is more
hyperchromatic, and nucleoli are often present and prominent (Figures 21.6–21.9).

FIGURE 21.6 This detached ragment o reactive mesothelium shows
an intact mesothelial layer with cells in two phases o the reactive process shown in Figures 21.7, 21.8.

FIGURE 21.4 In this peritoneal wash specimen, a sheet o normal
mesothelial cells has been detached.

FIGURE 21.7 The reactive mesothelial cells rom the le t side o Figure
21.6 have abundant cytoplasm, and the nuclei are larger with a more
vesicular chromatin pattern. Nucleoli are present but not prominent.


CH AP TER 2 1 : Se ro u s Me m b ra n e s

FIGURE 21.8 The more reactive mesothelial cells rom the right side
o Figure 21.6 have less cytoplasm, larger nuclei with a more vesicular
chromatin pattern, and more prominent nucleoli.

As the hyperplastic changes in the reactive mesothelial cells progress, cell groups become smaller, and
individual cells predominate. When clustered, reactive
mesothelial cells present an irregular outside border. The
nucleus, and especially the nucleolus, may enlarge dramatically, but the nuclei are similar in size, shape, and

pattern from cell to cell. Normal mitotic gures may be
seen. The cytoplasm may become multivacuolated as the
cells degenerate and imbibe uid (Figures 21.10–21.18).

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FIGURE 21.10 This individual reactive mesothelial cell has a limited
amount o cytoplasm and a relatively large nucleus with a nucleolus. The cell border is highly irregular and uzzy, consistent with the
presence o the numerous elongated microvilli, which are evident on
electron microscopy (see Figure 21.24). The cytoplasm is divided into
an outer less dense layer and an inner denser layer, which, ultrastructurally, corresponds to the presence o intermediate laments with the
characteristics o keratin (see Figure 21.25).

Mesothelial positivity for histochemical stains that detect
negative groups, such as the positively charged dye Alcian
blue, is evidence of their content of acid mucoproteins.
That the intensity of staining reactions for acid mucosub-

stances is diminished by preincubating the tissue sections
in hyaluronidase is evidence that at least some of the terminal hexose groups of the mucosubstances are either
hyaluronic acid or chondroitin sulfate. Furthermore, the
fact that histochemical mucin is decreased, but not abolished, by incubating cells in neuraminidase before histochemical staining is evidence that some of the terminal
carbohydrate groups are sialated (24). MacDougall et al.
(25) have documented that neoplastic mesothelial cells
may stain with mucicarmine. Negativity for the periodic
acid-Schiff (PAS) reaction after sialase digestion is evidence that mesothelial cells lack signi cant quantities of
neutral mucoproteins.

FIGURE 21.9 In this sheet o reactive mesothelial cells, the cytoplasm
is smaller and the nuclei are relatively larger and have a more irregular

chromatin pattern.

FIGURE 21.11 Mesothelial reaction is requently associated with
inf ammatory cells. These reactive mesothelial cells, which are several
times the size o either neutrophils or lymphocytes, are joined as a pair.

Histochemistry


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S E C TIO N VI: Th o ra x a n d Se ro u s Me m b ra n e s

FIGURE 21.12 These reactive mesothelial cells are loosely joined
together. The uppermost cell has a vacuole in the cytoplasm, which
could be either a vesicle or an intracytoplasmic lumen.

FIGURE 21.15 Normal mitotic gures may be seen in the proli erating
cells o reactive mesothelium.

FIGURE 21.13 When reactive mesothelial cells are in groups, an irregular or “knobby” outside border is ormed, whereas acini orm a smooth
outer border. Note the “ uzzy” border on the mesothelial cell.

FIGURE 21.16 The nucleoli o reactive mesothelial cells may be
prominent.

FIGURE 21.14 Occasionally, very reactive mesothelial cells may show
cellular interactions similar to those o a keratin pearl.

FIGURE 21.17 Reactive mesothelial cells may degenerate and swell.

These three cells have abundant multivacuolated cytoplasm and large
nuclei with prominent nucleoli.


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591

FIGURE 21.18 When markedly reactive mesothelial cells orm irregular groups and combine with degenerating orms, they may mimic the
appearance o a mucin-producing adenocarcinoma.

The types of terminal carbohydrate groups of membrane proteins and lipids can also be characterized with
lectins, which have speci c and discrete ranges of sugar
group af nities. Concanavalin A mesothelial cell reactivity
indicates the presence of terminal groups that are either
mannose or glucose.

Immunohistochemistry
Immunohistochemical studies of serous membranes have
shown that mesothelium expresses a complex and varied
phenotype with overlap of other normal tissues and many
malignancies. The great majority of benign mesothelial proliferations express several keratins, especially AE1/AE3,
CK8/18 (Cam5.2), CK19, CK5/6 and CK7 that can be
detected with monoclonal antibodies immunoreactive with
the small, acidic, type I keratins (26) (Figure 21.19). (42).
Mesothelium does not express CK20 (27). Ovarian epithelial tumors express a spectrum of keratins similar to that of
mesothelium (28).

FIGURE 21.19 Keratin expression in mesothelium and detached mesothelial cells, stained with a cocktail o monoclonal antibodies (AE1/AE3).

FIGURE 21.20 Calretinin Immunohistochemical staining o both nucleus
and cytoplasm in benign mesothelial cells.

Mesothelial cells frequently and preferentially express
calretinin, podoplanin, HBME-1 and thrombomodulin, as
well as WT-1. Vimentin and desmin are also expressed by
reactive mesothelium, especially when in spindle form.
Calretinin, a calcium-binding protein of 29 kDa similar to S-100 protein, is found not only in both the nucleus
and the cytoplasm of reactive and neoplastic mesothelia
but also in some adenocarcinomas (29–32) (Figure 21.20).
Cytokeratin 5/6 is found in the cytoplasm of most mesothelial cells and squamous cell carcinomas, but few adenocarcinomas (33). WT-1, a product of Wilms’ tumor gene, is
found in the nucleus of reactive and neoplastic mesothelia
and in ovarian surface epithelium and tumors derived therefrom (34) (Figure 21.21). D2-40, an antigen characteristic
of lymphatic endothelium, is also expressed by mesothelial

FIGURE 21.21 WT-1 immunoreactivity in benign mesothelium is nuclear
(original magni cation 40×).


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FIGURE 21.22 D2-40 immunoreactivity in benign mesothelium is predominantly membranous.

cells with a high sensitivity (Figure 21.22), but it also marks
ovarian serous carcinoma (35).
Thrombomodulin, a transmembrane glycoprotein, gives
a membranous stain in not only about half the mesotheliomas but also in some adenocarcinomas. Mesothelium
less frequently and less reliably expresses other antigens,

including mesothelin, N-cadherin, E-cadherin, epithelial
membrane antigen (EMA), Her2/Neu and EGFR (36).
Mesothelial cells usually lack the glycoproteins detected
by antibodies to CEA, MOC-31 and BER-EP4 and the
determinant detected by Leu-M1 (CD15) (37–40). Latza
et al. (41) and Sheibani et al. (42) reported that BER-EP4 was
used to distinguish malignant epithelium (adenocarcinoma)
from malignant mesothelioma, but Gaffey et al. (43) and Otis
(44) reported BER-EP4 immunoreactivity in high proportions
of both benign and malignant mesothelial tumors, as well as
adenocarcinomas. The tissue speci c nuclear transcription
protein TTF-1 is important in the embryogenesis of thyroid
and lungs and is found in nuclei of pneumocytes and many
adenocarcinomas of the lung, but not in mesothelium (45).
Overlap between reactive and neoplastic mesothelia in
the expression of even a panel of antibodies leaves only the
demonstration of invasion of parietes or organs to con rm
the diagnosis of malignant mesothelioma in most cases. The
diagnosis of mesothelioma in situ requires demonstration of
invasive mesothelioma elsewhere in the same specimen or
in a subsequent specimen.
The plasticity of the immunophenotype of mesothelial cells is demonstrable in abnormal states. Although
mesothelium normally lacks sex steroid receptors, reactive
mesothelium adjacent to endometriosis expresses focal
immunoreactivity for estrogen and progesterone receptors
(46). Furthermore, reactive mesothelial cells can express

FIGURE 21.23 Keratin (AE1/AE3) immunoreactivity o proli erating submesothelial spindle cells.

the muscle cell cytoskeleton proteins, desmin and musclespeci c actin (47). There is experimental evidence that the

pattern of intermediate lament expression by mesothelial cells is dependent on shape and cell–cell interaction.
Induction of spindle morphology inhibits keratin synthesis.
In contrast, induction of an epithelioid morphology (eg,
with retinoids) stimulates keratin synthesis and inhibits
vimentin synthesis; the ability of cells to respond in this
manner also depends on the presence of cell–cell interactions (48) (Figures 21.23–21.26).

FIGURE 21.24 A patient with severe rheumatoid arthritis and pleural e usion with f orid reactive mesothelial hyperplasia o the pleura,
which may be di cult to distinguish rom neoplastic proli eration. The
proli erating mesothelial cells may become entrapped in the brous tissue o organization and may mimic invasion.


CH AP TER 2 1 : Se ro u s Me m b ra n e s

593

pleura and in the visceral pleura. The other organelles found
in mesothelial cells are not speci c for them. Junctions of
all types are found—tight junctions that serve as a barrier
to certain molecules, gap junctions for cell–cell transport,
and desmosomes for cell–cell adherence. Intermediate laments are somewhat prominent; although they do not aggregate into bundles, they are often arranged in a perinuclear,
circumferential distribution (Figures 21.29, 21.30).

SUBMESOTHELIALLAYER
Much of the submesothelial layer is composed of collagen, elastin, and other extracellular proteins. Normally, the
submesothelial layer contains few cells, and most of these
are broblasts, but during reactive processes, the submesothelial layer may become much more prominent as myo broblasts, in ammatory cells, and capillaries proliferate there.

Histochemistry
FIGURE 21.25 The reactive mesothelium in this photomicrograph is

rom a hernia sac o an 18-month-old boy. It is composed o proli erating epithelioid cells on the sur ace and subjacent spindle-shaped cells
that give the impression o proli erating broblasts.

Ultrastructure
Numerous long microvilli (Figures 21.27, 21.28), measuring up to 3 µ m in length and 0.1 µ m in diameter, are present
and are more numerous in caudal portions of the parietal

The main constituents of the submesothelial tissue are glycosylated proteins, including glycosaminoglycans. Since the
majority of carbohydrate groups are negatively charged (as a
result of an abundance of hyaluronic acid and other acidic
groups), this extracellular matrix stains in a manner characteristic of acidic mucoproteins; that is, it is Alcian blue positive. That staining intensity can be diminished by treating
the section with hyaluronidase before histochemical staining is evidence that hyaluronic acid groups are responsible,
in large part, for the intensity of staining (21).

FIGURE 21.26 The reactive peritoneum shown in Figure 21.25 is shown at higher magni cation in H&E on
the le t. On the right, immunohistochemical stain or keratin (AE1/AE3) illustrates that both the epithelioid and
spindle cells are keratin positive, indicative o their mesothelial di erentiation.


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FIGURE 21.27 Mesothelial cells with their elongated microvilli, cover
the sur ace o the serosa. The subjacent stroma is composed o collagen and broblasts.

FIGURE 21.29 Ultrastructure o a mesothelial cell. Intermediate laments are arranged in a perinuclear distribution.

FIGURE 21.28 EM o a cluster o detached mesothelial cells within a
pleural e usion. Cytoplasmic lipid droplets impart a vacuolated appearance to some cells. Note the numerous long microvilli, which impart the

“ uzzy” appearance to these cells at the light microscopic level.

FIGURE 21.30 High magni cation o the luminal aspect o two mesothelial cells. Note the small tight junction, subjacent desmosome, and
the cytoskeletal laments within the microvilli.


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Immunohistochemistry
The antigens of the submesothelial layer can be categorized
into matrix constituents and antigens of the mesenchymal cells. The extracellular matrix materials are those typical of most connective tissues. Types I and III collagen and
bronectin are abundant. Elastin bers are plentiful and
basement membrane proteins, including type IV collagen and
laminin, are found at the mesothelial cell–stromal interface.
Proteoglycans are plentiful. The pattern of intermediate
lament expression by the submesothelial stromal cells varies with their state of excitation; quiescent cells express only
vimentin, but stromal cells in regions of injury or in ammation also synthesize keratin detectable with antibodies to
type I keratins (48).

Interactions of Mesothelial and
Submesothelial Cells
The submesothelial mesenchymal cell population serves
as the anchoring substratum for the mesothelium. Both
mesothelial and submesothelial cells contribute to the
extracellular proteins that comprise the matrix. Up to 3%
of the total protein synthesized by mesothelial cells are collagens and laminin.
Whether submesothelial cells serve as a source of
mesothelial cell renewal, either in normal development, or

in conditions of rapid mesothelial cell turnover, is a controversial topic. Earlier ultrastructural and kinetics studies,
using thymidine incorporation, suggested that stromal cells
contribute to the repopulation of denuded mesothelium
(49,50). This scheme is consistent with the observation
that submesothelial cells, when stimulated to proliferate,
synthesize keratin and assume a more epithelioid morphology. However, later studies have demonstrated that healing
of injured serosa is usually accomplished by multiplication
and migration of surface mesothelial cells at the edges of
the wounded area (51).

FIGURE 21.31 Internal mammary lymph node with large epithelioid
cells in the sinuses ound during coronary artery bypass gra t surgery
in a 61-year-old man. No pleural lesion was present.

tive, non-neoplastic submesothelial cells co-expressed lowmolecular weight cytokeratin and vimentin.
Reactive mesothelial cells have also been reported in
mediastinal lymph nodes by Brooks et al. (55), Parkash
et al. (56), and Argani and Rosai (57), but the mechanisms
by which they enter lymphatics and survive in the sinuses
of nodes are not known. This rare event may produce a
dif cult differential diagnosis. Clear demonstration of the
mesothelial phenotype of these cells excludes metastatic
carcinoma, but Sussman and Rosai (58) showed that mesothelioma may present as a lymph node metastasis. Therefore, follow-up may be the only way to make the distinction
between reactive benign mesothelial cells and metastatic
malignant ones (Figures 21.31, 21.32).
An uncommon manifestation of mesothelial proliferation is the psammoma body—a laminated calci ed structure
that most likely arises through concentric calci cation following cell death. Psammoma bodies are usually nonspeci c
because they may be observed in in ammatory processes

REACTIVEMESOTHELIUM

The capacity for mesothelial and submesothelial cellular
elements of serous membranes to react and proliferate to
produce morphologic patterns mimicking neoplasia is well
known and is frequently a source of diagnostic confusion with
malignancy. The process may be diffuse or localized (Figure
21.28). Mesothelial hyperplasia in herniorrhaphy or hydrocoele specimens is well described (52) and may be nodular,
demonstrate nuclear atypia and frequent mitotic gures, and
be accompanied by spindle cell elements. Amin (53) recently
reviewed the differential diagnosis of paratesticular mesothelial hyperplasia, adenomatoid tumors and other histologically
similar lesions. Bolen, Hammar, and McNutt (54) showed
that normal surface mesothelium expressed high- and lowmolecular weight cytokeratins and scattered submesothelial
cells expressed vimentin, but not keratin. However, reac-

FIGURE 21.32 Immunohistochemical stain or keratin (AE1/AE3) demonstrates the epithelioid cells singly and in groups. They were negative
or CEA, Leu-M1, BER-EP4, and B72.3 and hence were considered reactive mesothelial cells.


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FIGURE 21.33 Psammoma bodies in the le t pelvic peritoneum o a
58-year-old emale.

accompanied by mesothelial hyperplasia, malignant mesothelial neoplasia, or epithelial neoplasia (Figure 21.33).

Reactive versus Neoplastic Mesothelium
Serous membranes are covered by mesothelial cells, which
may show a broad range of reactive changes overlapping
those of malignant mesotheliomas, which are usually relatively low grade, well-differentiated malignancies. In 2000,

Churg et al. (59) described the characteristics which distinguish reactive mesothelium from neoplastic mesothelium
as zonation with the most cellular and atypical proliferation
adjacent to the surface and the proliferation of capillaries
perpendicular to the pleural surface in a “sunburst” pattern
in reactions. Reactive mesothelium also lacked nodular
expansion of the stroma, tumor necrosis, sarcomatous foci
and, most signi cantly, invasion of stroma, see Table 21.1.
At that time, there was no reliable immunohistochemical
discriminant between reactive and neoplastic mesothelia,
and they concluded that invasion was the most reliable feature to diagnose mesothelioma.
Nevertheless, a need for distinguishing the two entities
persists, especially on cytologic or small biopsy samples,
where invasion is not evident. Numerous reports of immunostains, singly and in combination, have been used. Among

TABLE 21.1

Reactive versus Neoplastic Mesothelium
Reactive

Neoplastic

Proli eration

Zonal

Di use

Capillaries

“Sunburst”

Random

Stromal expansion

Flat

Nodular

Necrosis

No

O ten

Spread

Con ned to pleura

Invades normal
stroma

them, Wu et al. (60) described the use of antibodies to
XIAP, X-linked inhibitor of apoptosis protein, a member of
the caspase family of apoptosis inhibitors, on mesothelium.
They reported no staining on normal mesothelium, staining
on 8% of reactive mesothelium and on 80% of mesotheliomas, but staining was also observed on other malignancies,
especially ovarian carcinomas in which 100% staining was
observed. Sato et al. (61), used two antibodies to CD146,
a cell adhesion molecule, on effusions and found immunocytochemical staining on all 23 mesotheliomas with one

or the other antibody, but no staining on reactive cases.
Hasteh et al. (62) reported that immunocytochemical staining with a panel of antibodies staining positively for EMA,
p53, and GLUT-1 and negatively for desmin was associated
with mesothelioma and the reverse was true for reactive
mesothelium. Kato et al. (63) used immunohistochemistry
for the identi cation of GLUT-1, a protein from a family of
glucose transporters, which facilitates the entry of glucose
into cells; in all 40 malignant mesotheliomas, the plasma
membranes were immunostained in a linear pattern, and
none of the reactive mesothelial cases were immunostained. However, Monaco et al. (64) compared GLUT-1
immunostaining with uorescence in situ hybridization
(FISH) testing for the p16 deletion and found the latter to
be more sensitive and speci c.
The p16 gene, which encodes the cyclin-dependent
kinase 4 inhibitor, CDKN2A, is deleted in most mesotheliomas. The use of FISH to detect this deletion in mesotheliomas has been exploited in pleural uid and formalin- xed,
paraf n-embedded tissues to distinguish normal, benign
and/or reactive mesothelium, in which p16 deletion is not
observed. from mesotheliomas. Illei et al. (65) reported deletions in 12 of 13 mesothelioma-containing pleural uids, but
none of the benign uids. Chiosea et al. (66) reported deletions in paraf n-embedded cases in 67% of pleural mesotheliomas but only 25% of peritoneal mesotheliomas and
none in reactive mesothelium. They also immunostained
for p16 product expression and found a lack of correlation
between deletion and expression. Takeda et al. (67) reported
deletions in 35 of 40 mesotheliomas and none in adenomatoid tumors, benign cystic mesotheliomas or reactive mesotheliomas, and Chung et al. (68) detected p16 deletions in
60% of malignant pleural mesotheliomas but not in reactive
mesothelium. It should be noted that p16 deletions occur
in other types of malignancies and are not mesothelioma
speci c, see Table 21.2. This area of investigation shows
great promise, but currently, the demonstration of invasion
of stroma remains the gold standard for the distinction of
reactive mesothelium from malignant mesothelium.

Reactive Mesothelium versus Carcinoma
The distinction of metastatic carcinoma from reactive
mesothelium is more readily accomplished by immunohistochemistry because the antigenic makeup of mesothelial and epithelial cells is fundamentally different.
The antibodies chosen for the diagnostic pro le relate to


CH AP TER 2 1 : Se ro u s Me m b ra n e s

597

TABLE 21.2

Differentiation of Reactive Mesothelium
from Neoplastic Mesothelium
Reactive

Neoplastic

XIAP

8%

80%

CD146

0%
Desmin

100%
EMA and p53

GLUT-1

Absent

Present

p16 deletion

Absent

Present

the metastatic malignancy considered in the differential
diagnosis. Differentiation from adenocarcinoma of the
lungs is based on its characteristic expression of TTF-1,
CEA, Napsin-A, MOC-31, BER-EP4, or B72.3 and their
absence in reactive mesothelium. Combinations of two or
more mesothelial and two or more epithelial markers are
often used (69–71). PAX 8 has been found useful in distinguishing ovarian lesions from mesothelial lesions (72).

FIGURE 21.35 Endosalpingiosis involving the omentum contains cystic
glands lined by mucinous epithelium with basally oriented nuclei and
apical cytoplasm. Periglandular stroma contains mononuclear inf ammatory cells.

Epithelial elements may be observed in glandular arrangements throughout the peritoneum, omentum, and within
lymph nodes. Such glandular structures were recognized in
the early 1900s and misinterpreted by some as metastatic

carcinoma, a mistake that is unfortunately still committed
today. Endometriosis and endosalpingiosis were expounded
upon by Sampson (73–75) earlier in this century, with reference to mechanisms of pathogenesis that are still debatable.
Endosalpingiosis refers to glandular spaces lined by epithelium similar to uterine tube epithelium, with three cell
types (ciliated, secretory, and intercalated cells) (76) (Figure
21.34). On occasion, psammoma bodies are present. Periglandular stroma containing chronic in ammatory cells is
separated from epithelium by PAS-positive basement membrane. Endosalpingiosis may be differentiated from endometriosis by the lack of endometrial stroma or evidence of
stromal hemorrhage associated with endometriosis (77–79).
This condition is seen exclusively in women and has been
reported in 12.5% of omenta removed during surgery in

females. A large proportion of these women have coexisting
benign disease of the uterine tube. The origin of the glandular
inclusions is debated but is most likely either related to the
in uence of müllerian development on the peritoneal mesothelium (coelomic lining) or is a sequela of disease within the
uterine tube resulting in extratubal growth of displaced tubal
epithelium. Although de nitive evidence of neoplasia arising
in endosalpingiosis has not been documented, considerable
dif culty may be encountered when differentiating extraovarian tumor implants removed in the setting of common
epithelial ovarian tumors from endosalpingiosis with cellular
atypia. Evaluation of the severity of epithelial atypia, mitotic
activity, the presence of ciliated cells, and the presence of
invasive characteristics may aid in establishing malignancy
in this setting. Metaplasia in endosalpingiosis may also be a
source of diagnostic dif culty—particularly mucinous metaplasia, which may be mistaken for metastatic mucinous
adenocarcinoma (Figures 21.35, 21.36).
Endometriosis may be de ned by the presence of glands
lined by endometrial-type epithelium surrounded by endometrial stroma, outside the uterine endometrial mucosa and
myometrium (80). The condition occurs most frequently
in women of childbearing age. It may occur in a variety

of body sites, ranging from the pelvic peritoneum to distant organs such as lungs, kidney, and skin, but the most

FIGURE 21.34 Endosalpingiosis involving the serosa o the uterus o a
56-year-old woman. Serous, intercalated, and occasional ciliated cells
are present, but endometrial stroma is not.

FIGURE 21.36 Mucicarmine stain o mucinous change in endosalpingiosis demonstrates intracytoplasmic mucin in apical cytoplasm.

Endosalpingiosis and Endometriosis


598

S E C TIO N VI: Th o ra x a n d Se ro u s Me m b ra n e s

FIGURE 21.37 Endometriosis involving the peritoneum with extension into the so t tissue o the anterior abdominal wall o a 23-year-old
woman. Endometrial glands and stroma are present.

frequent site is the peritoneal lining of the pelvic organs
(Figure 21.37). Although the histogenesis of endometriosis remains unclear, two general theories have been proposed. The ectopic growth of endometrial elements may
result from displacement of endometrial tissue, through
local means (such as entry of endometrium into the pelvis
through the uterine tubes) or via vascular routes to distant
organs (73,74). Another possibility includes metaplastic
change of the pelvic peritoneum along müllerian lines of
differentiation (81,82). Each mechanism may play a role in
the histogenesis of endometriosis.
Endometriosis may appear as brown–maroon foci on
the peritoneal surfaces and may be accompanied by brosis or adhesions. Microscopically, endometrial stroma surrounding endometrial epithelium is present (59). Response
to hormonal in uences is often seen and may be synchronous with intrauterine endometrium. Metaplasia occurs in

both epithelial and stromal elements, similar to metaplasias
encountered in the endometrium of the uterus. The presence of hemosiderin-laden macrophages and brosis may
be the only evidence that endometriosis had once been
present. However, a de nitive diagnosis of endometriosis
may not be rendered unless both endometrial glands and
stroma are seen.
Another common type of metaplasia, more frequently
observed in pregnant than in non-pregnant women, is
decidual change. Although usually encountered in the
submesothelial layer of pelvic peritoneal surfaces, decidual
change may be seen in distant sites including the serosal
surfaces of the liver, spleen, diaphragm, and within lymph
nodes. In these locations, decidual change may be mistaken for metastatic carcinoma or malignant mesothelioma
(Figure 21.38) (82).

Fibrous Pleurisy
Fibrous pleurisy is a benign reactive process that usually
occurs in the setting of organizing pleural effusions. The

FIGURE 21.38 Decidual change in the pelvis during pregnancy is seen
in subserosal tissue. Loosely cohesive cells with abundant eosinophilic
cytoplasm are present.

differential diagnosis of brous pleurisy and desmoplastic
mesothelioma may be extremely dif cult. Both may have
regions of increased cellularity in a predominantly brous
background containing spindle cells that are immunoreactive to keratin antibodies. Fibrous pleurisy tends to have a
higher cellularity immediately beneath the brinous exudative surface of the pleura and demonstrates a “layering” of
spindle cells parallel to the brosis with intervening brinous exudate. This organization imparts a histologic sense of
order to the reactive process that may assist in its recognition. Invasion, bland necrosis, and sarcomatous foci are not

seen in brous pleurisy (83) (Figure 21.39).

Multilocular Peritoneal Inclusion Cyst
Multilocular peritoneal inclusion cyst (MPIC) is a mesotheliallined multilocular lesion that occurs almost exclusively in
women. The lesion usually involves the pelvis, although it

FIGURE 21.39 The histologic appearance o brous pleurisy ref ects
its inf ammatory nature, with granulation tissue, brin, and a zonal pattern ranging rom active inf ammation to quiescent dense brosis.


CH AP TER 2 1 : Se ro u s Me m b ra n e s

599

FIGURE 21.40 MPIC in the omentum o a 73-year-old patient discovered incidentally at surgery or urogynecologic repair procedure. The
cysts vary in size, some being translucent while others are brotic, particularly toward the center o the mass.

may occur in other abdominal locations, including the omentum and mesentery. Usually MPIC is mass forming and may
attain diameters up to 20 cm. Grossly, it is composed of
multiple cysts, some of which may be thin walled and translucent (Figure 21.40). Histologically, the septa range from
thin and delicate to thickened and in amed. The mesothelial lining ranges from single attened cells to hobnail-type
cells. Squamous metaplasia of the lining mesothelium may
be present. Some regions may resemble the cellular pattern
of an adenomatoid tumor (Figures 21.41, 21.42) (84).

FIGURE 21.42 Some regions in MPICs may contain mesothelial proli erations that closely resemble an adenomatoid tumor.

The true nature of MPIC remains somewhat controversial, with some authors maintaining that it is a neoplasm
while others assert it is a reactive lesion that develops in
response to injury or even endometriosis. The original designation of multicystic mesothelioma re ects the notion that

the lesion is neoplastic. Recurrences are frequent, although
MPIC-related deaths probably do not occur (85).

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FIGURE 21.41 Histologically, MPICs ref ect the gross eatures, with
septae that vary in thickness and cysts that vary in size.

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S E C T IO N

VII

Alimentary Tract



22
Esophagus
Ha la El-Zim a ity

Ro b e rt H. Rid d e ll

■

EMBRYOLOGY 605
Esophageal Atresia 606
Esophageal Duplication 606
Lower Esophageal Rings and Webs
TOPOGRAPHYAND RELATIONS

ARTERIAL SUPPLY 621
VENOUS DRAINAGE 621
607

607

MACROSCOPIC/ENDOSCOPIC FEATURES
Glycogenic Acanthosis 609
Heterotopias 609
Esophageal Musculature 610

Lower Esophageal Sphincter 612
Gastroesophageal J unction 612

HISTOLOGY 614
Mucosa 614
Submucosa 617
Muscularis Propria
Serosa 620

609

620

EMBRYOLOGY
In the early stages of development, the notochord induces
the formation of the foregut from endoderm (1). At about
21 days’ gestation, septa arise from the lateral walls of the
foregut, fuse, and divide the foregut into the esophagus and
trachea. This process of septation begins at the carina and
extends cephalad, being completed by 5 to 6 weeks’ gestation (Figure 22.1).
The esophagus is initially lined by a thin layer of strati ed
columnar epithelium, which proliferates to almost occlude
the lumen (2). New vacuoles appear in the luminal cells of the
foregut and coalesce to form a single esophageal lumen with
a super cial layer of ciliated epithelial cells (2) (Figure 22.2).
As early as 8 weeks’ gestation, and beginning in the middle
third of the esophagus, ciliated cells appear. These extend
cephalad and caudally to almost cover the entire strati ed
columnar epithelium (2–4). At approximately 10 weeks,
a single layer of columnar cells populates the proximal

LYMPHATIC DRAINAGE 621
INNERVATION (NERVES AND INTERSTITIAL CELLS OF
CAJ AL) 621
DIAGNOSTIC CONSIDERATIONS 622
Barrett’s Esophagus 622
Gastroesophageal Re lux Disease 624
Lymphocytic Esophagitis 626
Ex oliative (Sloughing) Esophagitis (Esophagitis Dissecans
Super icialis) 626
Acute Necrotizing Esophagitis 626
Adenocarcinomas o the Gastroesophageal Region 626
ACKNOWLEDGMENT 627
REFERENCES

627

and distal ends of the esophagus (2). At approximately
4 months’ gestation, the esophageal cardiac-type glands
form as a result of the downward growth of these columnar cells into the lamina propria with subsequent proliferation and differentiation (3,5). They go distally as far as
the oxyntic mucosa, so that similar glands can be found in
the cardia. Some have used this to argue that the cardia is
therefore intrinsically part of the esophagus (6), although it
could just as easily be interpreted that they are just present
in all mucosae proximal to oxyntic mucosa.
At approximately 5 months’ gestation, strati ed squamous epithelium initially appears in the middle one-third of
the esophagus and extends cephalad and caudally, replacing the ciliated epithelium (3,4). The upper esophagus is
the last area to be replaced by squamous epithelium; and,
if this process of squamous replacement is not completed
at birth, there may be persistence of ciliated cells in the

upper esophagus (2,4). This may progress to gastric differentiation resulting in the so-called “inlet patch” (discussed
subsequently) (Figure 22.3).
605


606

S E C TIO N VII: Alim e n ta ry Tra ct

FIGURE 22.1 Fetal esophagus (late f rst trimester). Transverse section
overview o the esophagus demonstrating inner mucosal layer, middle
submucosal layer, and thin outer muscle layer. Note the vagus nerves
lying over the esophagus.

These residual cells are usually short lived, being replaced
by squamous epithelium within 2 to 3 days postpartum (4,7).
However, in some patients they either persist into adult life
or there is metaplasia back to ciliated cells (8). The single
layer of columnar cells is also replaced by squamous epithelium, although some cells may persist at birth, usually
located over the esophageal cardiac glands. The submucosal glands develop after the appearance of the squamous
epithelium and are likely derived from this squamous epithelial layer (4,7).
Development of the gastrointestinal neuromuscular
system begins at 4 weeks with neural crest cells entering
the foregut and migrating rostrocaudally. The myenteric
plexus develops rst, followed by formation of the submucosal plexus 2 to 3 weeks later. At about 6 weeks’ gestation,
the circular muscle layer develops, followed by the development of the longitudinal layer at approximately 9 weeks’
gestation. Initially, the muscularis propria consists entirely
of smooth muscles, after which striated muscles gradually
develop in the upper esophagus so that by 5 months, the
normal ratio and arrangement of both muscle types are

established (4). Interstitial cells of Cajal appear at week 9
and become closely associated with the myenteric plexus
(9). By week 14, the fetal gut has a mature appearance (9).
Developmental defects of the esophagus can be
attributed to errors in this morphogenetic sequence. This
includes esophageal atresia with or without tracheoesophageal stula, congenital esophageal stenosis, congenital
esophageal duplication and duplication cyst, congenital
esophageal rings, and congenital esophageal webs.

Esophageal Atresia

FIGURE 22.2 Fetal esophagus (late f rst trimester). The epithelial layer
is composed o stratif ed columnar epithelium. Note the lack o muscularis mucosae.

Esophageal atresia with or without tracheoesophageal stula
is the most common signi cant esophageal malformation,
with an incidence of approximately 1 in 3500 live births.
This anomaly is caused by a failure of the primitive gut to
recanalize in week 8 (10). Likewise, congenital esophageal
stenosis results from incomplete esophageal recanalization
during the eighth week of human embryologic development
(10). Congenital esophageal stenosis can be located at any
level of the esophagus, but is more frequent in the distal
third. It appears either as a web (membranous diaphragm)
or a long segment of esophagus with a thread-like lumen
( bromuscular stenosis). As there are often inclusions of
cartilage or respiratory glands embedded in the wall of the
esophagus in the region of the stricture, this anomaly may
also represent an incomplete separation of the respiratory
bud in some cases (10). The incidence of esophageal stenosis is low, occurring once in every 25,000 live births (11).

Esophageal Duplication
FIGURE 22.3 Fetal esophagus (third trimester). The epithelial layer at
this stage consists o stratif ed squamous epithelium with occasional
ciliated cells on the sur ace. Note the individual smooth muscle cells o
developing muscularis mucosae.

The notochord can induce the formation of the neural tube,
gastrointestinal tract, and other organ systems. It has been
shown experimentally that a split notochord can result in
the duplication of any region of the gastrointestinal tract (1),
which may include duplications of the esophagus ranging


CH AP TE R 2 2 : Es o p h a g u s

from the more common cysts to esophagus segments of
variable length (1,12,13). As a consequence of this ability
to induce development of more than one organ system, any
patient presenting with duplications, segmental or cystic,
should undergo radiologic evaluation that speci cally explores
for axial skeletal defects. Occurrence of abnormalities during
the phase of foregut septation is one proposed mechanism for
the formation of tracheoesophageal stulas (with or without
atresia) or of mediastinal cysts of bronchogenic or esophageal
origin (14,15). It has been suggested that esophageal duplications also may occur as a result of segments of fused vacuoles
formed during the vacuolization phase persisting and differentiating toward esophageal structures (1).

Lower Esophageal Rings and Webs
Congenital esophageal rings and esophageal webs are

thought to result from incomplete vacuolization of the
esophageal columnar epithelium during early embryonic
life. The congenital esophageal ring is a concentric extension of the normal esophageal tissue, usually consisting of
different anatomic layers including mucosa, submucosa,
and sometimes muscles. The location is variable, but most
are found in the distal esophagus (16).
Esophageal rings may originate from incomplete vacuolization of the esophageal columnar epithelium during
early embryonic life. However, they are also associated
with in ammatory conditions such as scleroderma (17),
and gastroesophageal re ux (18). Schatzki’s ring is the
most common esophageal ring and is found in 6 to 14%
of subjects undergoing an upper gastrointestinal series.
Schatzki’s ring is a mucosal ring located at the squamocolumnar junction. Since it is dif cult to exactly localize
the squamocolumnar junction and the lower esophageal
sphincter (LES), the exact anatomic relationship between
Schatzki’s ring and the squamocolumnar junction remains
controversial. Typically, it is associated with the proximal
margin of a hiatal hernia. It consists of two layers, mucosa
and submucosa, having squamous epithelium on its upper
surface and columnar epithelium on its lower surface (19).

607

The core of the ring consists of connective tissue plus
bers of the muscularis mucosae without contribution
from the muscularis propria.
The lower muscular ring is the most proximal and is
situated slightly more proximal than Schatzki’s ring, often
by a centimeter or two. Some have equated the lower muscular ring with the LES (20,21). Microscopically, this ring is
composed of a thickened circular smooth muscle with overlying squamous mucosa. The congenital esophageal web is

a thin, usually eccentric, transverse membrane covered by
normal squamous epithelium (16). These rings are usually
asymptomatic but may be associated with intermittent dysphagia, sometimes becoming progressive or associated with
attacks of sudden dysphagia (22).

TOPOGRAPHYANDRELATIONS
The adult human esophagus has cervical, thoracic, and
abdominal parts. The esophagus begins in the neck at the
cricoid cartilage, passes through the thorax within the posterior mediastinum, and extends for several centimeters
past the diaphragm to its junction with the stomach. The
overall length varies with trunk length, but in adults, the
average length is approximately 23 to 25 cm. In practice,
endoscopic distances are measured from the incisor teeth;
and, in the average male, the junction of the esophagus and
stomach is generally considered to be approximately 40 cm
from the incisors. This length may vary from approximately
38 to 43 cm. Although convenient and commonly used in
practice, the use of this distance is a crude and unreliable
measurement for locating the gastroesophageal junction. It
has been found that the esophageal length correlates with
height in children (23).
The International Classi cation of Diseases (ICD)
recognized three anatomic compartments traversed by the
esophagus: cervical, thoracic and abdominal (Table 22.1).
ICD also arbitrarily divides the esophagus into equal thirds:

TABLE 22.1

Regions of the Esophagus, Their Boundaries and Approximate Distances From the Incisors
Typical Esophagectomy

Anatomic
Name

Esophageal
Name

Anatomic Boundaries

(Variation ++)

Cervical

Upper

Hypopharynx to sternal notch

15 to <20 cm

Thoracic

Upper
Middle
Lower

Sternal notch to azygos vein
Lower border o azygos vein to in erior pulmonary
vein
Lower border o in erior pulmonary vein to
esophagogastric junction

20 to <25 cm
<25 to <30 cm
<30 to <40 cm

Abdominal

Lower
Esophagogastric
junction/
cardia

Esophagogastric junction to 5 cm below
esophagogastric junction
Esophagogastric junction to 5 cm below
esophagogastric junction

<40 to 45 cm
<40 to 45 cm


608

S E C TIO N VII: Alim e n ta ry Tra ct

15 cm
Ce rvica l s e gme nt (3 cm)
18 cm
Uppe r Thora cic S e gme nt
(6 cm)

24 cm
Mid Thora cic S e gme nt (8 cm)

32 cm
Lowe r Thora cic S e gme nt (8 cm)

40 cm

FIGURE 22.4 Esophageal segments with approximate lengths and distances rom the incisors.

upper, middle and lower, and this has formed the basis of
the UICC/AJCC and CAP schemas (Figure 22.4) (24).
Using the anatomic boundaries is far more logical than
“typical esophagectomy” which depend on the length of the
esophagus, which depends largely on the patients’ height.

FIGURE 22.5 Relationship o the
esophagus with normal esophageal constrictions. Barium swallow
o the normal esophagus (right)
demonstrates narrowing o the
lumen at the sites o constriction.

Where we are in the esophagus at 35cms is likely very different in Danny DeVito and Shaquille O’Neil!
Along its course, the normal esophagus has several
points of constriction (Figure 22.5). These occur at the
cricoid origin of the esophagus, along the left side of the
esophagus at the aortic arch, at the crossing of the left main
bronchus and left atrium, and where the esophagus passes
through the diaphragm. These constrictions may become

clinically signi cant if food or pills become lodged at these
sites of luminal narrowing, with the possibility of contact
mucosal injury. The most common sites for lodgment are at
the level of the aortic arch and left atrium, where, especially
in patients with left atrial enlargement, compression may
become signi cant (25–27).
Knowledge of the relationships of the esophagus with
other anatomic structures is important because these relationships may be directly affected by esophageal diseases
such as carcinoma or diverticula. Disease of adjacent structures may cause local compression of the esophagus, resulting in dysphagia or lodgement of food or pills.
The cervical portion of the esophagus is in relation,
in front, with the trachea; and at the common carotid artery
(especially the left, as it inclines to that side), and parts
of the lobes of the thyroid gland; the recurrent laryngeal
nerves ascend between it and the trachea; to its left side is
the thoracic duct.
In the thoracic segment, the esophagus continues posterior to the trachea to the level of bifurcation, a site for the
formation of the rare midesophageal diverticula secondary to
traction from in amed mediastinal lymph nodes (28). The
esophagus courses posterior to the left atrium. The azygos
veins ascend on either side of the thoracic segment. Initially,
the right and left vagus nerves run lateral to the esophagus,
giving branches that form plexi on the posterior and anterior


CH AP TE R 2 2 : Es o p h a g u s

esophageal surfaces. At variable sites in the lower thoracic
segment, the left and right nerves course onto the anterior
and posterior surfaces of the esophagus, respectively, divide
to form the anterior and posterior plexuses, and then reunite

to form the anterior and posterior vagal trunks that course
down to the stomach. An awareness that variations of this
pattern exist is most important for the surgeon performing
the now rare operation of vagotomy.
The abdominal portion of the esophagus lies in the
esophageal groove on the posterior surface of the left lobe
of the liver. It is short and only measures about 1.25 cm in
length, and only its front and left aspects are covered by
peritoneum. The esophagus enters the abdomen by passing
through the esophageal hiatus, which is formed by muscles
of the diaphragm and contains the phrenoesophageal ligament. In most cases, the muscle sling encircling the esophagus is formed entirely from the right diaphragmatic crus
(20,22), although variations of this pattern do occur. The
phrenoesophageal ligament arises from the fascia of the
abdominal diaphragm and divides into an ascending and a
descending leaf. The former passes up through the hiatus
to insert approximately 2 to 3 cm above the hiatus, whereas
the descending leaf has a variable insertion at or below the
gastroesophageal junction or even into the gastric fundus
(29). The liver forms an impression on the anterior aspect
of the esophagus. On the right side the junction with the
stomach is smooth, whereas on the left the junction forms a
sharp angle known as the incisura or angle of His.
The proposed functions of the phrenoesophageal ligament
include (a) assisting in maintaining the pressure differential
between the thorax and the abdomen, (b) providing xation
mechanisms with maintenance of the gastroesophageal junction within the abdomen during episodes of increased intraabdominal pressure, and (c) contributing to the competence
of the LES, thus representing a possible mechanism for the
absence of re ux in some patients with hiatal hernias (29–31).

609

glycogenic acanthosis consists of hyperplasia of the cells of
the prickle layer containing abundant glycogen. Glycogenic
acanthosis may resemble, and thus may be confused macroscopically with, monilial plaques or leukoplakia. Glycogenic
acanthosis should be considered a variant of normal with
as yet no de ned relationship to infection or malignancy.
However, there is an association with Cowden’s syndrome.

Heterotopias
Heterotopias are de ned as normal tissue occurring in sites
not expected for that tissue. In the literature, structures
accepted as esophageal heterotopias are inconsistently
de ned. Esophageal cardiac-type glands and ciliated epithelium have been considered as heterotopias (7,8,35,36)
or as embryologic remnants (4) by some investigators. The
categorization of melanocytes, Merkel cells, and endocrine
cells presents a similar problem because these cells have
not been regularly found in the esophagus (37,38). Melanosis has also been described (39–41).
Gastric-type mucosa occurring in the upper one-third
of the esophagus within 3 cm of the upper esophageal
sphincter is designated the “inlet patch” (4,7,35) (Figure
22.6). Macroscopically, the inlet patch typically has a deep
pink, velvety appearance (35), and presents either as a single patch or, less commonly, as multiple patches of gastric
mucosa situated just below the upper esophageal sphincter.
Microscopically, the patch can be lined with either cardiactype glands or gastric oxyntic mucosa. Helicobacter with a
variable chronic in ammatory cell in ltrate is common in
infected patients and re ux may facilitate their colonization (42) (Figure 22.7). Inlet patches have been found in
approximately 2 to 4% of esophagi (some gures are even
higher), and can be found at all ages (43,44). Nonetheless,
they are often overlooked at endoscopy as they are typically
small, and looking for them is often not a high priority. Most

MACROSCOPIC/ENDOSCOPICFEATURES
In the empty state, the esophagus has an irregular outline
as a result of the mucosa and the submucosa being thrown
into longitudinal folds. During endoscopy, insuf ation
causes distension so that these folds may not be appreciated, and the mucosa is seen to be a uniform white-pink.

Glycogenic Acanthosis
Glycogenic acanthosis can be seen in up to 25% of the
population with the combined use of endoscopy and even
barium studies (32–34). Macroscopically, glycogenic acanthosis interrupts the uniformity of the mucosa and presents
as white nodules or small plaques on the mucosal folds,
primarily in the distal one-third of the esophagus. These
lesions vary in size, may be up to 1 cm in diameter, and, if
extensive, may coalesce to larger plaques. Microscopically,

FIGURE 22.6 Proximal esophagus. Gastric body heterotopia situated
slightly distal rom the esophageal origin.