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Malignant Diseases
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TakeshiTerashima, NobuakiYagi, ShinyaMaejima,
andHiroyukiHarada
11
1 Lung Cancer/Bone
Metastasis
TakeshiTerashima
1.1 Concept andPathophysiology
Lung cancer is a malignant tumor arising from the
epithelial tissue from the bronchi to the alveoli.
1.2 Epidemiology
Smoking and passive smoking are known to be
reliable risk factors that increase the risk of developing lung cancer. In Japan, 112,000 people were
diagnosed with lung cancer in 2014. The number
of lung cancer-related deaths is the leading cause
T. Terashima
Department of Respiratory Medicine,
Tokyo Dental College, Ichikawa General Hospital,
Ichikawa, Chiba, Japan
N. Yagi
Department of Gastroenterology,
Asahi University Hospital, Gifu, Japan
S. Maejima (*)
Department of Internal Medicine, Matsumoto Dental
University, Shiojiri, Nagano, Japan
e-mail: shinya.maejima@mdu.ac.jp
H. Harada
Graduate School of Medical and Dental Sciences,
Tokyo Medical and Dental University,
Bunkyo-ku, Tokyo, Japan
of death from malignancy, with approximately
74,000 death in 2017in Japan.
1.3 Classication
The major histologic types are adenocarcinoma,
squamous cell carcinoma, neuroendocrine tumor,
and large cell carcinoma. Neuroendocrine tumors
include small cell carcinoma, large cell neuroendocrine carcinoma, and carcinoid tumor. The
diagnosis is made based on not only morphological but also immunohistochemical characteristics
(immunostaining patterns).
1.4 Symptoms
1.4.1 Symptoms Caused by
thePrimary Tumor
Common symptoms include cough, sputum,
wheezing, dyspnea, blood sputum, chest pain,
anorexia, and general malaise. In some cases, the
disease may be discovered by chance during a
physical examination without any subjective
symptoms.
1.4.2 Symptoms Caused by
Compression andInvasion
ofAdjacent Neighboring Organ
1. Hoarse voice: Lung cancer invasion or medi-
astinal lymph node metastasis causes recurrent
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023
T. Chiba, H. Yamada (eds.), Internal Medicine for Dental Treatments,
https://doi.org/10.1007/978-981-99-3296-2_11
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T. Terashima et al.
laryngeal nerve palsy, resulting in decreased
vocal cord movement and hoarseness.
2. Superior vena cava syndrome: Edema of the
face, neck, and upper limbs due to compression
of the superior vena cava caused by tumor or
lymph node metastasis.
3. Pancoast tumor: When a tumor in the apex
of the lung invades the brachial plexus, it
causes pain and dysesthesia from the shoulder
to the upper limbs. If the tumor invades the
cervical sympathetic nerves, it causes
Horner’s syndrome, which is characterized by
unilateral pupil constriction, eyelid ptosis,
enophthalmos, and hypohidrosis.
4. Pleuritis carcinomatosa: Exudative pleural
effusion and sometimes bloody pleural effusion due to invasion or metastasis of cancer to
the pleura. It causes thoracic back pain, respiratory failure, and dyspnea.
1.4.3 Symptoms DuetoDistant
Metastasis
The most frequent organs metastasized from lung
cancer are the brain, bone, lung, liver, and adrenal gland, and symptoms of metastasis impair
quality of life (QOL) and acitivities of dailiy living (ADL).
1. Brain metastasis: Lung cancer is the most
common primary organ for metastatic brain
tumors, accounting for more than 50%. It
presents with symptoms of cranial nerve and
intracranial hypertension. They include motor
and sensory disturbances, headache, nausea,
vomiting, convulsions, and disturbance of
consciousness.
2. Bone metastasis: Bone metastasis occurs in
30–40% of patients with advanced lung cancer. The vertebrae are the most common site
(42%), followed by the ribs (20%), pelvis
(18%), and femur (6%). The prognosis for
patients with bone metastases is approximately 8months. Events that occur with the
progression of bone metastases are called
bone-related events. They include pathological fractures, spinal cord compression, worsening of bone lesions requiring radiation
therapy or surgical treatment, and hypercalcemia. Bone-related events impair the QOL and
ADL of cancer patients and affect their prognosis. The main symptom of bone metastasis
is pain, and spinal cord compression caused
by spinal metastasis can lead to hypoesthesia
and muscle weakness. Simple X-ray
(Fig. 11.1a), CT, and MRI (Fig. 11.1b) are
useful for local diagnosis, while bone scintigraphy (Fig. 11.1c) and positron emission
tomography (PET)/CT (Fig.11.1d) are useful
for systemic evaluation.
Radiotherapy is effective in relieving pain.
Zoledronic acid, a bisphosphonate, and denosumab, an anti-receptor activator of NF-κB
ligand (RANKL) antibody, are recommended to
reduce the incidence of bone-related events. The
most important adverse events associated with
bisphosphonates and denosumab are osteonecrosis of the jaw and renal dysfunction. Denosumab
may cause hypocalcemia, and it is recommended
that calcium and vitamin D be supplemented and
that serum calcium levels be measured regularly.
1.5 Clinical Examination
andDiagnosis
When a tumor is suspected by chest X-ray
(Fig.11.2a), a chest CT scan (Fig.11.2b) is useful to differentiate the tumor from other diseases
and to determine the location, character, and
range of the shadow.
For denitive diagnosis, pathological examination of specimens obtained by sputum, bronchoscopy, CT-guided lung biopsy, lymph node
biopsy, pleurodesis, and thoracoscopic lung
biopsy is performed.
The clinical stage is determined based on the
TNM classication, where T indicates tumor:
size and invasion of the primary tumor; N indicates lymph node: lymph node metastasis; and M
indicates distant metastasis. For staging, contrastenhanced CT of the chest and abdomen, contrastenhanced MRI of the head, bone scintigraphy,
and PET are performed. The treatment strategy is
determined by histology, stage, and performance
status. Tumor markers are useful as diagnostic
aids and indicators of therapeutic efcacy. CEA
is used for adenocarcinoma, SCC, and CYFRA
ab
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for squamous cell carcinoma, and pro-GRP and
NSE for small-cell lung cancer.
1.6 Treatment
1.6.1 Small-Cell Lung Cancer
Small-cell lung cancer is classied as limited disease (LD) and extensive disease (ED). LD is
when the lesion is conned to the unilateral thorax, ipsilateral hilar lymph nodes, bilateral supraclavicular lymph nodes, or mediastinal lymph
nodes, while ED is when malignant pleural effusion is present or when the lesion extends beyond
LD. In LD, chemotherapy and radical thoracic
radiotherapy are used simultaneously.
Chemotherapy is the standard of care in ED.
1.6.2 Non-small Cell Lung Cancer
It includes adenocarcinoma and squamous cell
carcinoma. Surgery is recommended as standard
treatment for stage I, II, and IIIA tumors, in
which the primary tumor has not invaded surrounding organs and lymph node metastasis is
limited to the ipsilateral hilum.
Postoperative chemotherapy may also be
used. Concurrent chemoradiotherapy is recommended for stage III patients with mediastinal
lymph node metastasis. In recent years, maintenance therapy with immune checkpoint inhibi-
Fig. 11.1 (a) Simple X-ray (frontal view) shows a wink-
ing owl sign (arrow) on the left side of the fourth lumbar
vertebra. (b) MRI T1-weighted image shows a hypointense mass in the fourth lumbar vertebra with involvement
of the vertebral arch (arrow). (c) Bone scintigraphy shows
an increased uptake (arrow) in the fourth lumbar vertebra.
(d) PET/CT showed an increased uptake (arrow) in the
fourth lumbar vertebra in red color, extending to the vertebral arch
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c d
T. Terashima et al.
Fig. 11.1 (continued)
Fig. 11.2 (a) Simple chest X-ray shows a mass lesion (arrow) in the peripheral right upper lung eld. (b) Chest CT
shows a mass lesion (arrow) with irregular margins in the right upper lobe
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tors has been shown to be effective in patients
who responded to concurrent chemoradiotherapy.
Drug therapy is recommended for stage IV
patients with malignant pleural effusion or distant metastasis. In the past, chemotherapy with
cytotoxic drugs was the mainstay of treatment,
but molecular-targeted therapy is now recommended for patients with positive driver gene
mutations such as EGFR mutation, ALK gene
translocation, ROS1 rearrangements, and BRAF
gene mutation. In addition, immune checkpoint
inhibitors are also used as immunotherapy.
1.7 Prognosis
The 5-year survival rates by clinical stage are
approximately 80% for stages I and II, 25% for
stage III, and 5% for stage IV.
1.8 Recent Findings
Personalized therapy using biomarkers is advancing. Biomarkers are laboratory ndings that are
useful for predicting the effect of treatment and
selecting a treatment method. Cancer tissues and
plasma are used as specimens.
One is a driver gene, which is dened as one
whose mutations play a pivotal role in the development and progression of cancer. In lung cancer,
EGFR gene mutation, K-ras, ALK gene translocation, MET amplication/overexpression, HER2
overexpression, ROS1 rearrangements, and BRAF
gene mutation are known. In the past, each of these
genes was tested individually, but multiplex
genetic testing, which allows simultaneous testing
of multiple genes, has become possible. In particular, cancer-related gene testing using next-generation sequencers is becoming possible.
The other is the emergence of immunotherapy.
Surgery, irradiation, and chemotherapy were the
mainstays of treatment in the past, but in recent
years, immunotherapy has been added to them.
Although cancer cells are originally recognized
as non-self by the immune system and eliminated, the mechanism by which cancer cells
escape from the surveillance of the immune system and proliferate and progress has been eluci-
dated. The major immunosuppressive factors are
PD-1, PD-L1, and CTLA-4, which are called
immune checkpoints. Immune checkpoint inhibitors, such as anti-PD-1, anti-PD-L1, and antiCTLA- 4 antibodies, have been introduced to
selectively inhibit these factors. The expression
rate of PD-L1 in cancer tissues and the tumor
mutation burden, which is an indicator of the
number of gene mutations in cancer tissues, are
expected to be biomarkers for predicting the
response of immune checkpoint inhibitors.
2 Gastric Cancer
NobuakiYagi
2.1 Concept
Gastric cancer is dened as a malignant tumor of
gastric mucosal epithelial origin. Gastric cancer
accounts for more than 90% of all gastric malignancies and 15% of all cancers, and is the second
most common carcinoma in men and the fourth
most common in women (2017). It is classied
into early gastric cancer and advanced gastric
cancer according to the depth of the cancer lesion.
In Japan, about 130,000 people (90,000 men and
40,000 women) are affected and about 45,000
people (30,000 men and 15,000 women) die
annually. The age-adjusted mortality rate by sex
is decreasing in both sexes, and the age-adjusted
morbidity rate remains unchanged in males and
is decreasing in females [1].
2.2 Pathophysiology
Early gastric cancer is characterized by a cancerous lesion localizing on the mucosa (m) or submucosa (sm), with or without lymph node
metastasis. Advanced gastric cancer is characterized by invasion of the muscularis propria (mp),
subserosa (ss), and serosa (se). The morphological type of gastric cancer is shown in Fig.11.3
[2]. Histologically, gastric cancer can be divided
into two types: differentiated gastric cancer with
gland duct formation and undifferentiated gastric
cancer with poor gland duct formation.
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Superficial, flat
infiltrative
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T. Terashima et al.
Type 1
Mass
Type 2
Ulcerative
Type 3
Infiltrative
ulcerative
Type 4
Diffuse
Fig. 11.3 Macroscopic classication of gastric cancer. (Modied from [2])
Differentiated gastric cancer tends to occur in
atrophic gastric mucosa with intestinal metaplasia, and is more common in elderly patients associated with Helicobacter pylori (H. pylori)
infection. On the other hand, undifferentiated
gastric cancer originates from the gastric mucosa
with less atrophic changes and is more common
in younger patients. H. pylori infection is considered to be a major cause of gastric cancer regard-
Type 0-I
Protruding
Type 0-IIa
Sup. elevated
Type 0-IIb
Sup. flat
Type 0-IIc
Sup. depressed
Type 0-III
Excavated
advanced gastric cancer occurs in the cardia or
pyloric region, patients often suffer from
obstruction. Metastasis of advanced gastric
cancer may cause enlargement of supercial
lymph nodes (especially in the left supraclavicular node, called Virchow’s node metastasis), Douglas’ pouch metastasis, ovarian
metastasis (Krukenberg tumor), and carcino-
matous peritonitis.
less of differentiated or undifferentiated type, and
eradication therapy for chronic gastritis was covered by insurance in 2013 as a rst step toward
2.4 Diagnosis
destruction of gastric cancer and is widely conducted. In a study of post-endoscopic resection of
early gastric cancer, successful eradication was
reported to reduce the risk of gastric cancer by
about one-third.
The presence of gastric cancer is diagnosed by
X-ray examination, endoscopy, and biopsy speci-
mens. Endoscopic images of early gastric cancer
(Figs.11.4 and 11.5) and advanced gastric cancer
(Fig.11.6) are shown. Next, endoscopic ultraso-
nography (EUS), computed tomography (CT),
2.3 Symptoms
magnetic resonance imaging (MRI), and positron
emission tomography (PET) are performed to
Early stage gastric cancer without ulceration is
often asymptomatic, while cases with ulceration and advanced cancer often present with
symptoms such as epigastric pain, gastric discomfort, heartburn, nausea, anorexia, and
weight loss. Anemia, hematemesis, and melena
caused by bleeding from these lesions may be
the trigger for detection. In addition, when
investigate the depth of the cancer, invasion to
organs adjacent to the stomach such as the pan-
creas, liver, and intestines, and metastasis to dis-
tant organs and lymph nodes in order to diagnose
the degree of cancer progression (stage), which is
important for determining the therapeutic strategy.
Tumor markers may also be useful in detecting
tumors and judgment of therapeutic effect.
Type 0-II
Superficial
Type 0
ab
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Fig. 11.4 Early gastric cancer 0-IIa (slightly elevated), size in 30mm, greater curvature of the antrum. ① White light
observation. ② Chromoendoscopy with indigo carmine
203
①
Fig. 11.5 Early gastric cancer 0-IIc (slightly depressed),
size in 45mm, greater curvature of posterior wall in the
lower body. (a) White light observation: A reddish depression was observed in the lower body. A biopsy specimen
revealed carcinoma of the posterior wall (white arrow).
2.5 Prevention andScreening
②
(b) Magnied BLI observation. The reddish depression on
the greater curvature of the posterior wall in the lower
body shows irregular micro surface pattern and irregular
micro vascular pattern with demarcation line
gastric cancer are H. pylori infection and smok-
ing. In addition, high-salt foods have also been
In a gastric cancer epidemiological study targeting Japanese people, smoking cessation, moderate alcohol consumption, well-balanced diet,
physical activity, proper body shape, and prevention of infection are effective in preventing cancer in general. The most common causes of
reported to raise the risk of developing gastric
cancer [3].
The purpose of cancer screening is to reduce
deaths from cancer by early detection and appropriate treatment. In Japan, screening methods are
dened in the “Guidelines for Priority Health
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T. Terashima et al.
a
b
c
Fig. 11.6 Advanced gastric cancer type 1, type 2, and
type 3, surgical cases. (a) White light observation. Type 1
of the posterior wall of the antrum (Protruded type). (b)
White light observation. Type 2 of the lesser curvature in
Education and Cancer Screening for Cancer
Prevention (partially revised in 2016)” of the
Ministry of Health, Labour and Welfare. The
most effective screening methods for gastric cancer are “gastric X-ray examination” or “gastric
endoscopy” in addition to “interview” for both
men and women aged 50 years or older. The
examinations should be carried out once every
2years, but if there are symptoms of concern in
between, it is important to visit a medical institution without waiting for the next screening [4].
the antrum (Ulcered carcinomas with sharp and raised
margins type). (c) White light observation. Type 3 of the
greater curvature in the antrum (Ulcered carcinomas without dene limits type)
2.6 Treatment
The treatment method is determined by discussing with the patients and their family based on
the clinical stage of the cancer and the patient’s
general condition. Table11.1 shows the clinical
stage classication [2]. Treatment methods for
gastric cancer include endoscopic therapy, surgery, and drug therapy.
Endoscopic resection is recommended for
early-stage gastric cancer that is presumed to be
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Table 11
Clinical classication (cTNM, cStage: comprehensive
diagnosis based on imaging, review laparoscopic or laparotomy ndings)
(Reproduced with permission from [2])
Clinical stage classication
MO M1
NO N (+) Any N
T1 (M, SM)/T2 (MP) I II A
T3 (SS)/T4a (SE) II B III
T4b (S1) IV A
IV B
free of lymph node metastasis. Endoscopic resection is performed by endoscopic mucosal resection (EMR) and endoscopic submucosal
dissection (ESD). Recently, absolute indications
for EMR/ESD have been dened as “UL0
intramucosal carcinoma (cT1a) ≤2cm in length
and differentiated carcinoma,” and absolute indications for ESD have been dened as “(1) UL0
cT1a >2 cm in length and differentiated carcinoma; (2) UL1 cT1a ≤3cm in length and differentiated carcinoma; and (3) UL0 cT1a ≤2cm in
length and undifferentiated carcinoma” [5].
Endoscopic resection is a minimally invasive and
low-risk treatment method for the elderly and
inoperable patients, and gastric cancer is a eld
in which early detection and early treatment have
led to dramatic advances in treatment outcomes.
In advanced gastric cancer or the part of early
gastric cancer that can be surgically resected,
total gastrectomy, pyloric gastrectomy,
pylorus- preserving gastrectomy, and ventrolateral gastrectomy are performed by laparotomy or
laparoscopy. In the surgery, part or all of the
lesion and the stomach are removed, and at the
same time, lymph node dissection around the
stomach and gastrointestinal reconstruction are
performed. The major complications of surgery
include dysraphia, pancreatic juice leakage, pulmonary embolization, etc.
When distant metastasis or local progression
of gastric cancer makes curative resection difcult, anti-cancer drug therapy may be used. There
are two main types of drug therapy: chemotherapy for advanced or recurrent gastric cancer that
is difcult to remove by surgery and adjuvant
chemotherapy for the prevention of recurrence.
Gastric cancer can be treated with cytotoxic anticancer agents, molecular targeted agents, and
immune checkpoint inhibitors. Because of the
wide variety of side effects, patients should be
treated by specialists with informed consent.
3 Colorectal Cancer [6–9]
ShinyaMaejima
3.1 Concept
The colon is a gastrointestinal tract that reabsorbs
water and electrolytes (minerals) and expels nondigestible food and wastes, and consists of the
cecum, colon (ascending, transverse, descending,
and sigmoid), and rectum. Malignant tumors
occurring in the colon are called colorectal carcinomas, which are pathologically often highly differentiated adenocarcinomas.
3.2 Pathophysiology
It is associated with genetic and environmental
factors. Many colorectal cancers develop from
benign adenomas that undergo malignant transformation. Colorectal cancers are formed from
the multistep accumulation of many genetic
abnormalities, including activation of oncogenes
and inactivation of tumor suppressor genes and
mismatch repair genes. Inherited tumors include
the APC gene in familial adenomatous polyposis
and the mismatch repair gene in Lynch syndrome,
which causes microsatellite instability due to the
accumulation of errors in repeated base sequences
during DNA replication. Environmental factors
such as diet, alcohol consumption, physical
inactivity, obesity, and smoking are also considered to be important.
1
Hereditary diseases that cause various malignant tumors
such as colorectal cancer, uterine cancer, ovarian cancer,
gastric cancer, renal pelvis and ureteral cancer, and brain
tumor at a young age.
1
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T. Terashima et al.
3.3 Epidemiology
The number of colorectal cancers in Japan continues to increase due to the aging of the population and changes in dietary habits. In terms of the
number of cancer cases by site (2014), colorectal
cancer is the third most common cancer in men
after stomach and lung cancer, the second most
common cancer in women after breast cancer,
and the most common cancer in men and women
combined. In terms of the number of cancer
deaths (2017), it ranks rst in women, third in
men, and second in the total number of men and
women after lung cancer.
3.4 Categories
In Japan, the colorectal cancer treatment rules are
used [6]. Gross morphological classication is
from type 0 to type 5 (Fig.11.7, type 5 is unclassiable). The supercial type (type 0), in which
the depth of cancer invasion into the colon wall
(depth) is limited to the mucosa and submucosa,
is further divided into elevated and supercial
types. Early-stage cancers are those whose depth
is limited to the mucosa or submucosa, regardless
of the presence or absence of lymph node metastasis. In advanced cancer, the ulcer-localized type
(type 2) is common. The spread of cancer (degree
of progression) is expressed by stage (staging)
classication. The stage is determined by the
depth of the colon wall and the presence or
absence of lymph node metastasis or distant
metastasis to other organs such as the liver or
peritoneum. Accurate prediction of the stage
before treatment is very important in determining
the treatment strategy. There are two types of
stage classication: the clinical stage, which is
predicted by various imaging diagnoses before
treatment, and the pathological stage, which is
predicted after therapeutic resection. The nal
stage is the pathological stage, which determines
whether additional adjuvant therapy is required.
3.5 Symptoms
There are no specic symptoms, and they vary
according to the degree of cancer progression and
the affected site. In particular, early stage cancers
are often asymptomatic, regardless of the site. In
right-sided colorectal carcinoma, symptoms do
not appear until the disease progresses and worsens, because the intestinal contents are uid and
do not form a fecal mass. On the left side, transit
disturbances such as bloody stool and constipation are more likely to occur. Chronic subclinical
bleeding from the tumor may be detected during
the examination for anemia.
Type 0 (superficial type)
Type I (protruded type)
Ip
(pedunculated type)
Isp
Is
(sessile type)
Fig. 11.7 Macroscopic classication of colorectal cancer [6]
Type II (superficial type)
II a (superficial
elevated type)
II b (superficial flat type)
II c
(superficial depressed type)
Type 1
(protruded type)
Type 2 (well-defined
ulcerative type)
Type 3
(ill-defined ulcerative type)
Type 4
(diffusely infiltrating type)
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