Download Stage III - microscopic peritoneal implants outside of the pelvis

Ministry of Public Health of Ukraine
National O.O.Bohomolets Medical University
Oncology Department
Study Guide
of the Lecture Course “Oncology”
Part III
For the students of medical faculties
Worked out by I.B.Shchepotin MD, PhD, DSci, Prof; G.A.Vakulenko MD, PhD,
DSci, Prof; V.E.Cheshuk MD, PhD, DSci; A.S.Zotov MD, PhD; O.I.Sidorchuk
MD, PhD; V.V.Zaychuk MD, PhD; L.V.Grivkova MD, PhD; O.E.Lobanova
MD; I.N.Motuzyuk MD; Y.V.Levchishin MD.
Kyiv - 2008
Ministry of Public Health of Ukraine
National O.O.Bohomolets Medical University
Oncology Department
“APPROVED”
Vice-Rector for Educational Affairs
Professor O. Yavorovskiy
______________
“___” __________ 2008
Study Guide
of the Lecture Course “Oncology”
Part III
For the students of medical faculties
Worked out by I.B.Shchepotin MD, PhD, DSci, Prof; G.A.Vakulenko MD, PhD,
DSci, Prof; V.E.Cheshuk MD, PhD, DSci; A.S.Zotov MD, PhD; O.I.Sidorchuk
MD, PhD; V.V.Zaychuk MD, PhD; L.V.Grivkova MD, PhD; O.E.Lobanova
MD; I.N.Motuzyuk MD; Y.V.Levchishin MD.
Kyiv - 2008
The texts of the lectures are approved by the methodical counsel
of Oncology Department.
Protocol № 19 « 17 » march 2008.
CONTENTS
Lecture 12
Tumors of the soft tissue
Lecture 13
Skin cancer
Lecture 14
Melanoma
Lecture 15
Cervical cancer
Lecture 16
Ovarian cancer
Lecture 17
Uterine cancer
Literature
Lecture 12
Tumors of the soft tissue
Sarcomas are malignant (cancerous) tumors that develop in tissues which
connect, support, or surround other structures and organs of the body. In general, soft
tissue sarcomas do not seem to result from malignant changes or the dedifferentiation
of benign soft tissue tumors, and despite the variety of histologic subtypes, soft tissue
sarcomas have many clinical and pathologic features in common. The dominant
pattern of metastasis is hematogenous. Lymph node metastasis is rare (less than 5%).
Soft tissue sarcomas are rare. These neoplasm's constitute only 0,2-2,6% of the
malignant tumors and affect almost equal often men and women, more common in
the age of 20-50 years. However, sarcomas occur more often in children and young
adults.
Soft tissue sarcomas can arise almost anywhere in the body: muscles, tendons,
fibrous tissues, fat, blood vessels, nerves, and synovial tissues are types of soft tissue.
About 55% to 60% percent occur in the extremities (e.g., arms, legs); the rest begin in
the trunk (15% to 20%), head and neck area (8% to 10%), internal organs, or the
retroperitoneum (15%).
Some conditions of soft tissues are caused by inflammation or injury and can
form a mass that looks like a soft tissue tumor. Unlike a true tumor, they do not come
from a single abnormal cell, they have limited capacity to grow or spread to nearby
tissues, and never spread through the bloodstream or lymph system. Examples
include nodular fasciitis and myositis ossificans, which involve tissues under the skin
and muscle tissues, respectively. Although most soft tissue sarcomas do not have a
clearly defined cause, researchers have identified several factors that increase the
likelihood of developing these tumors. External radiation therapy is a wellestablished risk factor for soft tissue sarcoma, as shown by the fact that the incidence
of sarcomas is increased eightfold to 50-fold in patients treated with radiation therapy
for cancer. The risk appears to be related to the dose of radiation.
Another risk factor for soft tissue sarcomas is exposure to certain chemicals in
the workplace, including vinyl chloride, arsenic, herbicides such as phenoxyacetic
acids, and wood preservatives that contain chlorophenols. Chronic lymphedema (a
condition in which excess fluid collects in the tissue and causes swelling) following
radiation to, or surgical removal of, lymph nodes is also a risk factor.
Specific inherited genetic alterations are associated with an increased risk of
both bone and soft tissue sarcomas. The oncogenes (ie, genes that can induce
malignant transformation and tend to drive cells toward proliferation) that have been
implicated in the development of soft tissue sarcomas include MDM2, N-myc, cerbB2, and members of the ras family. Amplification of these genes in several
subtypes of soft tissue sarcomas has been shown to correlate with an adverse
outcome. Cytogenetic analysis of soft tissue tumors has also identified distinct
chromosomal translocations that code for oncoproteins associated with certain
histologic subtypes. The best characterized gene rearrangements have been found in
Ewing’s sarcoma (EWS–FLI-1 fusion), clear-cell sarcoma (EWS–ATF1 fusion),
myxoid liposarcoma (TLS–CHOP fusion), alveolar rhabdomyosarcoma (PAX3–
FHKR fusion), desmoplastic small round-cell tumor (EWS–WT1 fusion), and synovial
sarcoma (SSX–SYT fusion). Tumor suppressor genes play a critical role in cell growth
inhibition and can suppress the growth of cancer cells. However, these genes can be
inactivated by hereditary or sporadic mechanisms. Two such genes that are
particularly relevant to soft tissue tumors are the retinoblastoma (Rb) gene and the
p53 tumor suppressor gene. Mutations or deletions in the Rb gene can lead to the
development of retinoblastomas and sarcomas of the soft tissue and bone. In addition,
although mutations in the p53 tumor suppressor gene are the most common mutations
in human solid tumors, they have also been observed in 30% to 60% of soft tissue
sarcomas. There is also a high incidence of soft tissue sarcomas in patients with
germline mutations in the tumor suppressor gene p53 (ie, the Li-Fraumeni syndrome).
Certain inherited diseases are associated with an increased risk of developing
soft tissue sarcomas. Studies have focused on genetic changes that may lead to the
development of soft tissue sarcomas. For example, people with von Recklinghausen’s
disease (also called neurofibromatosis type 1 and associated with alterations in the
NF1 gene), hereditary leiomyomatosis and renal cell cancer syndrome (with
alterations in the FH gene), and hereditary retinoblastoma (with alterations in the
RB1 gene) are at increased risk of developing soft tissue sarcomas.
Kaposi’s sarcoma is a soft tissue sarcoma that sometimes develops in people
with human immunodeficiency virus (HIV) infection. The primary cause of Kaposi’s
sarcoma is infection with Kaposi sarcoma-associated herpesvirus (KSHV), or human
herpesvirus 8. However, people infected with KSHV, but not HIV, rarely develop
Kaposi’s sarcoma.
Soft tissue sarcomas are grouped together because they share certain
microscopic characteristics, have similar symptoms, and are generally treated in
similar ways. They are usually named for the type of tissue in which they begin.
There are many types of soft tissue tumors, and not all of them are cancerous. There
are about 50 different types of soft tissue sarcomas.
Histological classification on the soft tissue tumors (WHO 1998)
Grading of bone tumors is roughly based on the cellularity of the lesion
compared to the amount of extra cellular matrix, nuclear features, the presence of
mitotic figures and necrosis. Staging via the TNM system is normally not used,
because metastases in lymph nodes are not frequent in these lesions. Therefore
staging is based on degree of differentiation of the tumor tissue and local and distant
spread of the tumor.
I. Tumors and tumor-like lesions of the fibrous tissue.
А. Benignant: Fibromas: 1. Solid fibroma; 2. Soft fibroma (fibromyoma); 3.
Dermatofibroma (Fibrous histiocytoma ); 4. Elastofibroma of the back.
B. Benignant: Fibromatosis : 1. Scar fibromatosis; 2. Keloid; 3. Fasciitis
nodular; 4. Radiation fibromatosis; 5. Juvenile hyaline fibromatosis ; 6. Abdominal
fibromatosis (abdominal desmoid); 7. Aggressive fibromatosis (nonabdominal
desmoid); 8. Congenital fibromatosis.
C. Malignant: 1. Fibrosarcoma.
II. Fat tissue tumors.
А. Benignant: 1. Lipoma (including fibrolipoma, angiolipoma etc.); 2.
Intermuscular lipoma; 3. Hibernoma; 4. Angiomyolipoma; 5. Lipoblastomatosis; 6.
Diffuse lipomatosis.
Б. Malignant: 1. Liposarcoma.
III. Muscular tissue tumors
А. Smooth muscle tumors.
1. Benignant: а) Leiomyoma; б) angiomyoma; в) leiomyoblastoma.
2. Malignant: а) Leiomyosarcoma .
B. Striated muscle tumors.
1. Benignant: а) Rhabdomyoma ;
2. Malignant: а) Rhabdomyosarcoma .
IV. Blood vessels tumors.
А. Benignant.
1. Hemangioma : а) hemangioendothelioma benignant; b) capillary
hemangioma; c) cavernous; d) venous.
2. Intermuscular hemangioma (capillary, cavernous, arterio-venous);
3. System hemangiomatosis;
4. Hemangiomatosis with/without congenital arterio-venous fistula;
5. Hemangiopericytoma benignant, b) glomus tumor.
7. Angiolipoma.
В. Malignant.
1. Hemangioendothelioma malignant (angiosarcoma);
2. Hemangiopericytoma malignant.
V. Lymphatic vessels tumors.
А. Benignant.
1. lymphangioma: а) capillary; b) cavernous: c) cystic;
2. Lymphangiomyoma;
3. System lymphangiomyomatosis .
B. Malignant.
1. Lymphangioendothelioma malignant (lymphangiosarcoma);
VI. Synovial tissue tumors.
А. Benignant.
1. Benignant synovioma.
B. Malignant.
1. Synovial sarcoma.
VII. Mesothelial tissue tumors .
А. Benignant mesothelioma .
B. Malignant mesothelioma .
VIII. The tumors of the peripheral nerves.
А. Benignant.
1. Traumatic neuroma;
2. Neurofibroma;
3. Neurilemmoma (schwannoma );
4. Neurofibromatosis.
B. Malignant.
1. Malignant schwannoma (neurofibrosarcoma);
2. Primitive neuroectodermal tumor (peripheral neuroepitelioma PNET).
IX. Tumors of the sympatic ganglia.
А. Benignant. 1. Ganglioneuroma.
B. Malignant. 1. Neuroblastoma, ganglioneuroblastoma.
Х. Tumors of the paraganglious stuctures.
А. Pheochromocytoma: 1. Benignant; 2. Malignant.
B. Chemodectoma: 1. Benignant; 2. Malignant.
C. Nonclassified paraganglioma.
XI. Plurypotential mesenchymal tumors
А. Benignant: mesenchymoma.
B. Malignant : Malignant mesenchymoma.
ХII. Tumors of the possible extragenital origin.
А. Benignant. 1. Teratoblastoma.
B. Malignant.
1. Teratocarcinoma;
2. Embrional carcinoma.
XIII. Tumor with nonelucidated hystogenesis.
А. Benignant.
1. Granular cell tumor;
3. Soft tissue osteoma;
4. Myxoma.
2. Soft tissue chondroma;
B. Malignant.
1. Alveolar soft part sarcoma ;
2. Malignant granular cell tumor ;
3. Chondrosarcoma extraskeletal;
4. Osteosarcoma extrasceletal;
5. Malignant giant cell tumor of soft tissue/soft parts;
6. Malignant fibroxanthoma;
7. Kaposi's sarcoma ;
8. Giant cell tumor of tendon sheath.
ХIV. Nontumorous or tumor-like lesions of the soft tissue.
А. Xanthomas.
B. Ganglia.
C. Myositis ossi´ficans.
D. Proliferative myositis.
ХV. Nonclassified tumors of the soft tissue.
Tumors of Fat Tissue:
Lipomas are benign tumors of fat tissue. They are the most common benign
soft tissue tumor. Most are found under the skin, but they can develop anywhere in
the body.
Lipoblastomas are benign fat tumors that occur in infants and young children.
Hibernomas, like lipomas, are also benign fat tissue tumors. They are much
less common than lipomas.
Liposarcomas are malignant tumors of fat tissue. They can develop anywhere
in the body, but they most often develop in the thigh, behind the knee, and inside the
back of the abdomen. They occur mostly in adults between 50 and 65 years old.
Some liposarcomas grow very slowly, whereas others can grow quickly. Your doctor
can tell you which kind you have.
Tumors of Muscle Tissue
The human body has 2 types of muscle: smooth and skeletal.

Smooth muscle is found in our internal organs such as stomach,
intestines, blood vessels, or uterus (womb) and causes them to contract. These
muscles are involuntary - that is, we don't control their movement.

Skeletal muscle is sometimes called striated (because stripes can be seen
inside the cells under the microscope). This is the muscle that allows us to move our
arms and legs and other body parts when we want them to move -- that is, voluntary
movement.
Smooth muscle sarcomas
Leiomyomas are benign tumors of smooth muscle (or involuntary muscle).
Leiomyomas can arise almost anywhere in the body in either men or women because
they can start in tissues as widespread, for example, as blood vessels or intestine. The
most common of these is the fibroid tumor that develops in many women. It is really
a leiomyoma of the uterus.
Leiomyosarcomas are malignant tumors of involuntary muscle tissue. They can
grow almost anywhere in the body but are most often found in the retroperitoneum
and the internal organs and blood vessels where leiomyomas also arise. Less often,
they develop in the deep soft tissues of the legs or arms. They tend to occur in adults,
particularly the elderly.
Skeletal muscle sarcomas
Rhabdomyomas are benign tumors of skeletal muscle (the muscle that is
attached to bone and helps us to move). They are rare.
Rhabdomyosarcomas are malignant tumors of skeletal muscle. These tumors
commonly grow in the arms or legs, but they can also begin in the head and neck area
and in reproductive and urinary organs such as the vagina or bladder. Children are
affected much more often than adults.
Tumors of Peripheral Nerve Tissue
Nerves run throughout the body. The brain and spinal cord are also considered
central nerve tissue. The tumors discussed here are tumors of the nerves that run
throughout the body, but not the brain or spinal cord.
Neurofibromas, schwannomas (neurilemoma), and neuromas are all benign
tumors of nerves. These tumors can occur almost anywhere in the body. An inherited
condition called neurofibromatosis or von Recklinghausen disease causes people to
develop many neurofibromas throughout their body. Some of these, if they formed
from very large nerves such as those in the upper arms or neck, can become
malignant.
Malignant schwannomas, neurofibrosarcomas, or neurogenic sarcomas are
malignant tumors of the cells that surround a nerve. A new name for these is
malignant peripheral nerve sheath tumors.
Tumors of Joint Tissue
All of our joints are surrounded by tough tissue called synovium, which
produces the fluid that lubricates the joint surfaces so that they move smoothly.
Tumors of joints start in the synovium.
Nodular tenosynovitis is a benign tumor of joint tissue. It is most common in
the hands and is more common in women than in men.
Synovial sarcoma is a malignant tumor of the tissue around joints. The most
common locations are the knee and ankle. Other sites are the shoulder and hip. It
tends to occur mostly in children and young adults, but can also occur in older
people.
Tumors of Blood Vessels and Lymph Vessels
Hemangiomas are benign tumors of blood vessels. They are rather common,
are often present at birth, and can affect the skin or internal organs. They sometimes
disappear without treatment.
Glomus tumors are benign perivascular (around blood vessels) tumors. They
usually are found under the skin of the fingers.
Hemangiopericytoma is a tumor of perivascular tissue. It most often develops
in the legs, pelvis, and retroperitoneum (the back of the abdominal cavity). It is most
common in adults. These can be either benign or malignant. They don’t often spread
to distant sites, but tend to come back where they started, even after surgery.
Hemangioendothelioma is a blood vessel tumor that is less aggressive than
hemangiosarcoma but still considered a low-grade cancer. It usually invades nearby
tissues and sometimes can spread to distant parts of the body (metastasize). It may
develop in soft tissues or in internal organs, such as the liver or lungs.
Angiosarcomas are malignant tumors that can develop either from blood
vessels (hemangiosarcomas) or from lymph vessels (lymphangiosarcomas). These
tumors can sometimes develop in a part of the body that has been exposed to
radiation. Angiosarcomas are sometimes seen in the breast after radiation therapy for
breast cancer or in the arm on the same side as a breast that has been irradiated or
removed by mastectomy.
Kaposi sarcoma is a tumor formed by cells similar to those lining blood or
lymph vessels. It is most common in people with human immunodeficiency virus
(HIV) infection and the acquired immunodeficiency syndrome (AIDS), but it can also
develop in organ transplant patients who are taking medication to suppress their
immune system. It is probably related to infection with a virus called human
herpesvirus-8 (HHV-8).
Lymphangiomas are benign lymph vessel tumors that are usually present at
birth. Lymph is a type of fluid that circulates in every tissue of the body, ending up in
the venous system. It contains waste products from tissues and immune system cells.
Lymphangiosarcomas are the malignant lymph vessel form of angiosarcomas.
Tumors of Fibrous Tissue
Fibrous tissue forms tendons and ligaments and covers bones as well as other
organs in the body.
Fibromas, elastofibromas, superficial fibromatosis, and fibrous histiocytomas
are all benign tumors.
Fibrosarcoma is cancer of fibrous tissue. It usually affects the legs, arms, or
trunk. It is most common between the ages of 20 and 60, but can occur at any age,
even in infancy.
Fibromatosis is the name given to fibrous tissue tumor with features in between
fibrosarcoma and benign tumors such as fibromas and superficial fibromatosis. They
tend to grow slowly but, often, steadily. At one time they were called desmoid
tumors, when they were closely attached to skeletal muscles. Now they are called
musculoaponeurotic fibromatosis. They do not metastasize, but they can invade
nearby tissues and are sometimes fatal. Some doctors consider these to be a type of
low-grade fibrosarcoma; others believe they are a unique type of fibrous tissue
tumors. Certain hormones, particularly estrogen, increase the growth of some
desmoid tumors. Antiestrogen drugs are sometimes useful in treating desmoids that
cannot be completely removed by surgery.
Dermatofibrosarcoma protuberans (DFSP) is a slow-growing cancer of the
fibrous tissue beneath the skin, usually in the trunk or limbs. It invades nearby tissues
but rarely metastasizes.
Malignant fibrous histiocytoma (MFH) is most often found in the arms or legs.
Less often, it can develop inside the back of the abdomen. This sarcoma is most
common in older adults. Although it mostly tends to grow locally, it can spread to
distant sites.
Tumors of Uncertain Tissue Type
Through microscopic examination and other laboratory tests, doctors can
usually find similarities between most sarcomas and certain types of normal soft
tissues. However, some sarcomas have not been linked to a specific type of normal
soft tissue.
Myxoma is a benign tumor that usually is located in muscles but does not
develop from muscle cells. The cells of a myxoma produce mucus-like material, a
feature that distinguishes this tumor. It almost always occurs in adults.
Granular cell tumors are usually benign tumors of adults that occur often in the
tongue but can be found almost anywhere in the body.
Malignant mesenchymoma is a rare type of sarcoma that contains some areas
showing features of fibrosarcoma and other areas with features of at least two other
types of sarcoma.
Alveolar soft-part sarcoma is a rare cancer that mostly affects young adults.
The legs are the most common location of these tumors.
Epithelioid sarcoma most often develops in tissues under the skin of the hands,
forearms, feet, or lower legs. Adolescents and young adults are often affected.
Clear cell sarcoma is a rare cancer that often develops in tendons of the arms or
legs. Under the microscope, it shares some features with malignant melanoma, a type
of cancer that develops from pigment-producing skin cells. How cancers with these
features develop in parts of the body other than the skin is not known.
Desmoplastic small cell tumor is a rare sarcoma of adolescents and young
adults, found most often in the abdomen. Its name means that it is formed by small,
round cancer cells surrounded by scar-like tissue.
Other Types of Sarcoma
There are other types of tumors called soft tissue sarcomas, however, these are
all quite rare.
Clinical Presentation
Soft tissue sarcomas usually appear as a lump or mass, but they rarely cause
pain, swelling, or other symptoms. A lump or mass might not be a sarcoma; it could
be benign, a different type of cancer, or another problem. The size at presentation
usually depends on the location of the tumor. Tumors in the distal extremities are
often small when discovered, whereas tumors in the proximal extremities and
retroperitoneum can become quite large before they are apparent. Soft tissue
sarcomas grow in a centrifugal fashion and compress surrounding normal structures,
but rarely does impingement on bone or neurovascular bundles produce pain, edema,
and swelling. Infrequently, patients may initially exhibit obstructive gastrointestinal
symptoms or neurologic symptoms related to compression of the lumbar or pelvic
nerves.
The differential diagnosis of a soft tissue mass includes benign lesions,
including lipomas, lymphangiomas, leiomyomas, and neuromas. Besides sarcomas,
other malignant lesions, such as primary or metastatic carcinoma, melanoma, or
lymphoma, must also be considered. Small lesions that have not changed for several
years may just be closely observed. However, biopsy should be considered in patients
with all other types of tumors to establish a definitive diagnosis.
Diagnostic Imaging
The doctor performs a physical exam and may use the following procedures
and tests to diagnose soft tissue sarcoma:

X-rays create images of areas inside the body on film. Pretreatment
radiologic imaging is critical for defining the local extent of a tumor, staging the
disease, guiding biopsies, and aiding in diagnosis. Imaging studies are also crucial in
monitoring tumor changes after treatment, especially after preoperative chemotherapy
or radiation therapy, and in detecting recurrences after surgical resection. Each
imaging modality, however, has a particular place in patients with soft tissue
sarcomas. Although radiography is useful for providing information on primary bone
tumors, it is not useful for evaluating soft tissue tumors of the extremities.
Nonetheless, chest radiography should be performed in patients with primary sarcoma
to look for lung metastases.

Computed tomography (CT) can determine whether a soft tissue tumor
has metastasized (spread) to the lung or abdomen. CT scans, also called CAT scans,
can also be helpful in determining the size of the tumor and whether the tumor can be
accessed through surgery. CT of the chest should be considered for patients with
high-grade lesions or tumors larger than 5 cm (T2). Contrast-enhanced CT can assess
the extent of the soft tissue tumor burden and the proximity of the tumor to vital
structures. CT is also the preferred imaging technique for evaluating retroperitoneal
sarcomas. Current techniques can provide detailed information on the abdomen and
pelvis and delineate adjacent organs and vascular structures. CT of the abdomen and
pelvis should also be done when a myxoid liposarcoma is identified in an extremity,
because this subtype of soft tissue sarcoma often metastasizes to the abdomen.

Magnetic resonance imaging (MRI) scans can aid in diagnosis,
particularly in helping to distinguish soft tissue sarcomas from benign tumors, as well
as showing the extent of the tumor. MRIs are also used to monitor the patient after
treatment to see if the tumor has recurred. MRI is the preferred imaging modality for
extremity sarcomas. It can accurately delineate muscle groups and distinguish among
bone, vascular structures, and tumor. Sagittal and coronal views can show the
anatomic compartments in three dimensions. Special techniques, including magnetic
resonance angiography, can be performed if adjacent vascular structures must also be
delineated. Before the start of chemotherapy, contrast-enhanced T1-weighted MRI
can be used to determine the existence and extent of intratumoral necrosis. MRI is
also valuable for identifying tumor recurrence after surgery; a baseline image is
usually obtained three months after surgery.

A biopsy is the removal of cells or tissue for examination by a
pathologist. The pathologist studies tissue samples under a microscope or performs
other tests on the cells or tissue. A biopsy is the only sure way to tell whether a
person has cancer.
Biopsy Techniques
Fine-needle Aspiration Biopsy
Fine-needle aspiration biopsy is an acceptable method for the diagnosis of most
soft tissue sarcomas, particularly when it is performed in conjunction with clinical
and imaging studies. Fine-needle aspiration biopsy is the procedure of choice to
confirm or rule out a metastatic focus or local recurrence. If tumor grading is essential
for treatment planning, fine-needle aspiration biopsy has limitations. However, an
interventional radiologist may need to perform the biopsy of deeper tumors under
sonographic or CT guidance. The diagnostic accuracy of fine-needle aspiration
biopsy-based findings in patients with primary tumors ranges from 60% to 96%. In
general, the amount of material obtained by fine-needle aspiration biopsy is small,
and the diagnostic accuracy clearly depends on the experience and skill of the
cytopathologist.
Core-needle Biopsy
Core-needle biopsy is a safe, accurate, and economical procedure for
diagnosing soft tissue sarcomas. In addition, enough tissue is usually obtained for use
in several diagnostic tests, such as electron microscopy, cytogenetic analysis, and
flow cytometry. Complications occur in less than 1% of patients who undergo core
needle biopsy. The use of CT or sonography to guide a core-needle biopsy can
increase the yield of tumor tissue by more accurately pinpointing the location of the
tumor. Obviously, it is particularly important to precisely locate the needle in the
tumor mass to avoid sampling necrotic or cystic areas of the tumor that are of no
diagnostic value. The diagnostic accuracy of core-needle biopsy-based findings is
reported to be 93%.
Incisional Biopsy
Open biopsy is a reliable diagnostic method that obtains adequate tissue.
However, incisional biopsies are usually performed only when fine-needle aspiration
biopsy or core-needle biopsy specimens yield nondiagnostic findings. An open biopsy
ideally should be performed in a designated treatment center by the same surgeon
who will perform the definitive surgery. The biopsy incision should be oriented
longitudinally along the extremity to allow a subsequent wide local excision that
encompasses the biopsy site, scar, and tumor en bloc. A poorly oriented biopsy
incision can result in an excessively large surgical defect from a wide local excision,
which in turn necessitates a larger postoperative radiation therapy field to encompass
all tissue at risk. Adequate hemostasis must also be achieved at the time of biopsy to
prevent the dissemination of tumor cells resulting from the formation of hematomas
in adjacent tissue planes.
Excisional Biopsy
An excisional biopsy of easily accessible (superficial) extremity or truncal
lesions smaller than 3 cm can often be performed. However, the benefits of excisional
biopsies rarely exceed those of other biopsy techniques, and these procedures may
also cause postoperative complications that could ultimately delay definitive therapy.

Specialized testing of the tumor cells for chromosomal alterations may
also be conducted to aid in diagnosis. With the advent of molecular diagnosis,
considerable progress has been made in both accuracy of diagnosis and in
understanding of the potential genetic aetiological factors. Many sarcomas carry a
characteristic molecular imprint which allows their precise definition. The description
of fusion transcripts seen with synovial sarcoma allows the diagnosis of such tumors,
characteristically thought of as adolescent and adult tumors, to be identified in all age
groups, and this genetic signature allows the identification of synovial cell sarcoma in
sites not previously considered commonplace, such as the heart, brain and diaphragm.
It is clear that these lesions have nothing to do with the synovium and would be better
redefined, but that would seem unlikely. Evaluation of tissue micro-arrays has
allowed the distinction to be made between tumors whose behavior is difficult to
characterize. Progressively, the unique characterization of genetic fusion products has
been described and multiple other potential tumor suppressive tumor oncogenes have
been examined, for example Rb. However, the ability of these individual surface
oncogenes, or tumor suppressor genes, to be independent factors in outcome has not
yet been proven. It is equally true that behaviour of individual histologic subtypes is
clearly determined by the subtypes, i.e. the widely differing behavior of liposarcoma
with well-differentiated liposarcoma only rarely, if ever, having metastatic disease,
whereas the more pleomorphic sarcomas have a high rate of metastatic dissemination.
Treatment for soft tissue sarcomas is determined mainly by the stage of the
disease. The stage depends on the size of the tumor, the grade, and whether the
cancer has spread to the lymph nodes or other parts of the body.
Treatment options for soft tissue sarcomas include surgery, radiation therapy,
and chemotherapy. Accurate preoperative histologic diagnosis is of critical
importance in choosing the appropriate primary treatment strategy for patients with
soft tissue sarcomas. An intact primary tumor following biopsy affords the best
opportunity for the treatment planning team to evaluate the tumor’s proximity to vital
structures and for the surgeon to achieve a surgical resection with negative histologic
margins. In addition, the tumor can serve as a biologic marker of response in patients
who are to be enrolled in preoperative treatment protocols.
The overall five-year survival rate in patients with soft tissue sarcomas of all
stages remains only 50% to 60%. Most patients die of metastatic disease, which
becomes evident within two to three years of the initial diagnosis in 80% of cases.
However, several subsets of patients have benefited from multimodality treatment
approaches. For example, a multidisciplinary approach is taken in patients with soft
tissue sarcomas of the extremities; it includes a margin-negative resection plus
radiation therapy to the tumor bed and has resulted in local control rates up to and
exceeding 90%. Nonetheless, despite improvements in local control rates, metastasis
and death remain significant problems in patients with high-risk soft tissue sarcomas.
Patients considered at high risk of recurrence and death include those presenting with
metastatic disease, localized sarcomas at sites other than the extremities, or sarcomas
larger than 5 cm of an intermediate or high histologic grade (T2). Patients with
abdominal sarcomas continue to show particularly high rates of recurrence and poor
overall survival.
Surgery is the usual treatment for soft tissue sarcomas. For surgery to be
effective, the surgeon must remove the entire tumor with negative margins. Some
patients need reconstructive surgery. The type of surgical resection is determined by
several factors, including tumor location, tumor size, the depth of invasion, the
involvement of nearby structures, the need for skin grafting or autogenous tissue
reconstruction, and the patient’s performance status. Local therapy consisting of
surgery, either alone or in combination with radiation therapy when wide pathologic
margins are limited by anatomic constraints, is the approach taken in patients with
small (less than 5 cm) primary tumors with no evidence of distant metastatic disease.
However, amputation remains the treatment of choice for the estimated 5% of
patients whose tumor cannot be grossly resected with a limb-sparing procedure that
preserves function. Wide local excision is the primary treatment strategy for
extremity sarcomas, with the goal to resect the tumor with a 2-cm margin of
surrounding normal soft tissue. The biopsy site or tract (if applicable) should also be
included en bloc with the resected specimen. Soft tissue sarcomas are generally
surrounded by a zone of compressed reactive tissue that forms a pseudocapsule,
which may mistakenly be used by inexperienced surgeons to guide resection
(enucleation). Microscopic extensions of tumor beyond the pseudocapsule must
always be considered when planning surgery and radiation therapy. Patients with
microscopically positive surgical margins are at increased risk of local recurrence.
Indeed, margin status after surgical resection is an independent prognostic factor for
local recurrence. However, negative margins cannot be attained in some anatomic
areas because of the tumor’s proximity to vital structures. In addition, because neither
a positive surgical margin nor local recurrence has been shown to clearly adversely
affect overall survival, this should be taken into consideration if achieving clear
surgical margins would require amputation or substantial functional compromise of
an extremity.

Radiation therapy, also called radiotherapy, involves the use of high-
energy rays to kill tumorous cells. This therapy may be used before surgery to shrink
the tumor, after surgery to kill any cancer cells that may remain in the body, or both
before and after surgery. Radiation may come from a machine outside the body
(external radiation therapy). It can also come from radioactive materials placed
directly into or near the area where the cancer cells are found (internal radiation
therapy or radiation implant).

Chemotherapy may be used before or after surgery, and with or without
radiation therapy. The effectiveness of current anticancer drugs depends on the type
of sarcoma. Some sarcomas are very responsive to chemotherapy, while others do not
respond to current anticancer drugs. Some sarcomas with specific chromosomal
alterations can be treated with therapies targeted to the alteration. For example,
imatinib mesylate (Gleevec) is a targeted therapy used to treat GIST that has
metastasized.
New types of treatment are being tested in clinical trials. These include the
following:
High-dose chemotherapy with stem cell transplant
High-dose chemotherapy with stem cell transplant is a method of giving high
doses of chemotherapy and replacing blood -forming cells destroyed by the cancer
treatment. Stem cells (immature blood cells) are removed from the blood or bone
marrow of the patient or a donor and are frozen and stored. After the chemotherapy is
completed, the stored stem cells are thawed and given back to the patient through an
infusion. These reinfused stem cells grow into (and restore) the body's blood cells.
Targeted drug therapy
Targeted therapy is a type of treatment that uses drugs or other substances to
find and attack specific cancer cells without harming normal cells. Imatinib (Gleevec)
is a new type of targeted therapy called a tyrosine kinase inhibitor. It finds and blocks
an abnormal protein on cancer cells that causes them to divide and grow. Targeted
therapy may be used for gastrointestinal stromal tumors that cannot be removed by
surgery or that have spread to other parts of the body.
In the I-II stages 5-year survival achieves 70-80%.
In the advanced cases (III-IV stages) 5-year survival is less than 30%.
The more common reasons of the death are the distant metastases (to the lungs,
bones, liver & brain).
Lecture 13
Skin cancer
Precancerous skin diseases
Non-cancerous skin growths – is a big and various in its origin group of
tumors. There are two groups of precancerous conditions:
1)
Optional precancerous growths, which are rarely developed into the
malignant growths granted timely treatment.
2)
Obligate precancerous growths. Which are always developed into the
malignant growth.
The facultative precancerous growths include: skin horn, keratosis, senile skin
atrophy, atheroma, deep skin mycosis, keratoachanthoma, papilloma, red flat herpes.
Skin horn is cone-shaped new growth, which stands out of the skin level, it
has thick brown corneous surface and soft tissue. Most often it is localized on the
face skin, eyelids, auricles, hairy part of the head. Women are more susceptible to it.
About 10-12 % of patients had skin horns developed into the malignant growth. The
treatment is surgical operation.
Keratosis is characterized by dystrophic skin changes, which are presented by
the spots of keratinized layers of different thickness, grayish-yellowish color. Mostly
localized on the face skin, hairless part of head, body skin. The treatment is surgical
operation – excision and electrocoagulation.
Senile skin atrophy – it is shown by the thinning of the skin. In this case the
skin is withered, wrinkled, it peels off, it is possible to see the enlarged small blood
vessels. (telangiectasis ). The treatment is surgical operation.
Keratoachanthoma – non-malignant growth of the epidermis, which is hardly
distinguished from the skin cancer not only clinically but also histologically.
Therefore it has many synonyms: plural self-cured skin carcinoma, sebaceous
mollusk etc. Mostly elderly people have it, it is single, mainly it is localized on the
face skin, on the hands. Clinically it is thick, quickly growing nodule having
hemispherical surface and a cavity in the center, covered by x-disease-shaped coat. It
has
a
tendency
to
self-evolution.
The
treatment
is
surgical
excision,
electrocoagulation, cryodestruction.
The obligate growths include the pigmentary parchment-skin, Bouen tumor,
Cair disease.
Pigmentary parchment-skin – was first described by Caposhy M. in 1870 and
is considered as rare hereditary diseases, originated from the DNA inability to restore
the damage caused by the ultra-violet rays. The disease is manifested by the
heightened sensibility to the sun rays from childhood. In the beginning especially on
the open body parts disseminated skin pigmentation as plural spots and freckles
appears. The skin swells, gets red. Erythema is changed to disseminated rounded
pigment spots. Further skin becomes withered, here and there it is atrophic, easily
damaged. Enlarged skin blood vessels are seen in these sections – telangiectasis.
Gradually ulcers and warty overgrowths appear on the skin. Under existing
conditions even teenagers may have basal- and planocellular cancer and also
melanoma. In case of pigmentary parchment-skin there is a great likelihood of
primary-plural synchronous and metachronous tumors development.
If cancer appears on the background of the pigmentary parchment-skin, it
develops slowly and is very sensitive to radiotherapy. As preventive measures against
malignancy of the pigmentary parchment-skin it is possible to use sunscreen
ointments, to cover the open parts of body with the sunscreen creams.
Bouen tumor – (Bouen diskeratosis) shows itself as various spots with
characteristic polycyclic contours. Their surface is covered with hardly removed
scabs. When the scabs are removed it is possible to see a smooth surface, sometimes
moist papillary surface ( eczematous type). Most often the body skin is affected. The
disease is always ended up by malignant transformation.
The treatment is excision in the limits of the healthy skin and in case of the
malignization the medical tactics of the skin cancer is used.
Skin cancer (Cancroid)
In the structure of oncological diseases the skin cancer covers 10-15% of all
oncological growths.
Epidemiology
The sickness rate in case of the skin cancer is characterized by great cycling.
The biggest number of the diseases is observed in the countries with high isolation
level. For example in Bulgaria the sickness rate is 36 for 100.000 of inhabitants,
whereas in England it is 1.9, and in Ukraine – 35-38 cases for 100.000 inhabitants. It
is observed that countrymen are more likely to have the skin cancer than the city
dwellers.
Etiology
The factors which cause the skin cancer development are: high isolation, longterm contact with chemical carcinogens – the products of oil refining, coal, shale oils,
arsenic combinations, ionizing radiation, constant skin injuries ( mechanical injuries,
burns).
Patamorphology of the skin cancer
The skin cancer is developed from the basal cells of the multi-layer flat skin
epithelium. According to the histological structure it is possible to identify two forms
of the skin cancer: basal-cells (basalioma) and planocellular ( keratinized and nonkeratinized). Basalioma is observed in 60% of skin cancer cases, planocellular
carcinoma is observed in 30%. Non- non-keratinized form of the planocellular cancer
is lowly differentiated tumor and is characterized by quick infiltrative growth.
International classification according to the TNM system:
T- primary tumor
TX-there is no enough evidence for the primary tumor
T0- the primary tumor is not identified
Tis- Carsinoma in situ
T1-the tumor is 2 cm in the maximum measurement
T2- the tumor is more than 2 cm, but less than 5 cm in the maximum
measurement
T3- the tumor is more than 5 cm in the maximum measurement
T4- the tumor grows into the lower organs ( cartilages, muscles, bones).
In the case of synchronic primary-plural cancer, when there are several primary
tumors it is necessary to indicate their number in parentheses T2 ( 5). The T value is
evaluated by the biggest tumor.
N- the regional lymph nodes
Nх- there is no enough evidence for the evaluation of the regional lymph nodes
N0- there is no evidence of the regional lymph nodes affection
N1- the regional lymph nodes are affected
M- distant metastasis
MX- there is not enough evidence to identify distant metastasis
M0- distant metastasis are not identified
M1- there are distant metastasis
Stage 0
Tis
N0
M0
Stage I
T1
N0
M0
Stage II
T2
N0
M0
T3
N0
M0
T4
N0
M0
Any T
N1
M0
Any T
Any N
M1
Stage III
Stage IV
Clinical description
The clinical picture of cancer depends on the histological structure, on the
differentiation stage and on the tumor localization.
The planocellular cancer is the most often observed with the elderly people,
mainly situated on the face skin, auricles, upper and lower extremities, external
genitals. Clinically it is possible to identify three forms of the skin cancer: surface,
infiltrative or deep-penetrative and papillary.
The surface cancer is characterized by the white dense nodules with yellow or
white-grey tint, which can be localized at the skin level or higher. As developed the
central part becomes wet, erosions are created, the surface becomes rough, pink
colored, sometimes it is bleeding, it is covered with crusts, in periphery a thick rollershaped growth can be formed. The lower part of skin gets red, the evidence of the
inflammatory process appears. The characteristic feature of the tumor development is
the absence of pain even in case of the large dimension.
The infiltrative form is initially characterized by the appearance of moving,
hard, uneven nodules, which are covered by the unchanged epidermis. As developed
the nodules are transformed into the sores, infiltrate the subjacent tissues, the borders
get firm, become roller-shaped and unmoving when palpated, they early create
metastases in the regional lymph nodes. These forms are less successful in prognosis.
The papillary forms of cancer are characterized by the partial growth into the
depth of tissue, partial growth upwards to the surface, forming exofitic component, as
uneven-like growths, with clear contours. Its surface is covered by shallow sores,
which often bleed. The big cancerous sores are characterized by the dense painless
metastases in regional lymph nodes. The basal-celled cancer also in many cases
appears at an elderly age and is localized mostly on the face skin. Clinically it is
characterized by the appearance of the grey-pink dense nodule, which merges with
the skin and stands out on its surface. The tumor surface shells off, it is characterized
by the ulceration, which deepens with the growth of the tumor. The sore has thick
bottom, undermined borders, and it is painless. The tumor develops gradually,
affecting more and more areas of the skin. In this case there are no reactive changes
and the state of the patients remains satisfactory.
Nodal or exofitic form of the basal-celled cancer grows as the raised on the
skin surface nodule on the wide basis. Gradually deep cracks appear between separate
parts, where secretions of blood and pus with objectionable odor may accumulate.
The basal-celled cancer is not characterized by metastases.
Diagnostics
To diagnose the skin cancer it is important to use examination, palpation,
dermatoscopy and it is obligatory to perform cytological analysis of the scrape,
smear, incisionary biopsy. To diagnose the metastases in the regional lymph nodes it
is common to use the sonography- of the distant metastases, the radiography of the
pectoral cavity organs and the ultrasonography of the abdominal cavity. These
methods are sufficient to diagnose.
Differential diagnostics:

Red Lupus

Tuberculosis

Syphilitic gumma

Actinomycosis

melanoma

Non-malignant skin growths
Treatment
In case of the flat-celled skin cancer it is possible to use surgery, radiotherapy
and medicines. All these methods should be based on the strictly individual factors,
considering the tumor localization, clinical form, the disease stage and the
histological structure. Beside that the treatment should foresee functional and
cosmetic after-effects. Most of the authors believe that in the I-II stages of the disease
the radiotherapy is the most effective method ( the most effective is closely-focused
radiotherapy, total dose is 30-60 gr.), in case of III-IV stages they use combined
method. The surgical method requires - wide ablation of the tumor with the healthy
skin area around it ( not less than 2 cm) together with the hypodermic cellular tissue
and fascia. In those cases when it is impossible to make a wide ablation ( on the face),
the surgical treatment is combined with the radiotherapy or just use the radiotherapy.
In the presence of the enlarged regional lymph nodes, on suspicion of having
metastasis, lymphadenectomia is performed at the same time with the excision. In
those cases when the big mass of the tumor does not allow to use the abovementioned methods of treatment, the chemotherapy is applied.
In case of the basal-celled skin cancer the following methods of treatment are
used:
1)electroexcision –is applied in case of the tumors less than 1 cm in diameter (
the recovery takes place in 95 % of cases).
2) closely-focused radiotherapy – is applied in case of the face tumors (to
prevent the cosmetic defects). The recovery takes place in 90 % of cases. The defect
of the method is – depigmentation and the skin atrophy in the area of the radiation
treatment.
3) Excision with the primary wound closing. The recovery takes place in 95%
of cases.
4) When the cryotherapy of the skin cancer is used, it is necessary to do threefold freezing of the tumor in the scope of the 0.5-1 cm of the healthy skin until its
complete destruction. The healing of the wound takes place under the scab during 3-4
weeks with the formation of the elastic cosmetically nice scar. The relapse is treated
by the wide excision.
The prognosis in skin cancer case compared with the other malignant tumors
is the most favorable. In case of the regional lymph nodes metastases absence 5-years
survival is guaranteed in 75-80 % of cases, and when it is early diagnosed almost 80100 % of patients completely recover and do not have relapses. 5-years survival
with the regional lymph nodes -metastases and growing through the close organs and
tissues is only 24%.
Non-malignant and malignant skin tumors of the conjunctive tissue-like
origin.
Non-malignant and malignant skin tumors of the conjunctive tissue-like origin
are comparatively rare, more often in the young age. They are localized mostly on the
body skin and upper or lower extremities. Women have them more often.
Among the non-malignant tumors the most frequent are fibroma ( soft and
hard), dermatofibroma, lipoma, angioma, gemangioendotelioma, neurofibroma etc.
These tumors have different size, form and consistence, they grow slowly. They may
be the source of the malignant tumors development ( sarcomas). The treatment used
here is surgical.
Skin sarcomas come to 0.3% of the malignant tumors and are found with the
elderly people.
The histological classification of the skin sarcomas made by F.Faitcheva and
V. Andreyeva ( 1965):
1.The tumors of formed dense conjunctive fibrous tissue ( fibrosarcoma and
dermatosarcoma Darie).
2. The tumors of the fat base ( liposarcoma)
3.The tumors of muscle tissue ( miosarcoma)
4. The tumors of the blood and lymphatic vessels ( angiosarcoma,
angioendotelioma, Caposhy sarcoma, lymphangiosarcoma).
5.The tumors of the undifferentiated cells (undifferentiated sarcoma,
mixosarcoma).
The clinical picture.
Fibrosarcoma represents the single dense nodule, which is raised above the
skin surface. The tumor size amounts to 10 cm and more. The color of the skin is rosy
which turns into azure-red. Fibrosarcoma grows slowly and is rarely ulcerates.
Dermatosarcoma Darie – the tumor has flat plaques-like surface with the
outstanding nodules. The skin which covers them is normal. It grows slowly and
rarely creates metastasis, but it can relapse. The growth of the nodules can be
accompanied by change of their color, in which case they get blue-brown tint.
Sometimes the nodules become big, uneven and bleed. The tumor is more often
localized on the abdominal wall and thorax wall.
Liposarcoma is rarely found. It is clinically characterized by the appearance of
the single nodule which is situated in the hypodermic base. Its growing speed
depends on the histological form. The differentiated sarcoma grows slowly and
undifferentiated sarcoma may grow quickly. It can amount to the great size, and may
be characterized by the ulceration.
Angiosarcoma is rarely found. It has rough surface of bluish-reddish color,
often creates metastasis, can be characterized by the ulceration and bleeding.
Idiopathic plural haemorrhagic sarcoma ( Kaposhy sarcoma) is called after
the author, who first described it in 1972. There are about 35 synonyms –names of
this tumor ( pigmentary and teleangiectatic sarcomatosis, plural angioplastic
pigmentary sarcoma etc).
Histogenesis of this tumor is not mostly identified, but it is at the center of
attention because it belongs to the acquired immunodeficiency syndrome (AIDS).
The disease starts with the appearance of several pink nodules, which are
localized mostly in the area of distal, often symmetrical parts of the extremities.
Further new dense plural nodules appear, which merge and begin to occupy
more of the extremities surface or body surface, forming compact red-purple flat
tumors of the irregular shape. At the same time the significant hypostasis of the lower
extremities may occur - elephantiasis. In the case of AIDS the face is more likely
affected. Patients complain about itching, pain, bleeding and lymph ( лимфотечение)
of the affected areas. The tumor creates metastases. The course of the disease is
enduring with the periods of remission. The process has overall character with the
spreading to the proximal parts of the extremities and formation of the tumor nodules
in the internal organs, but sometimes there are cases of the spontaneous remission.
The tumor nodules can bleed. The disease is accompanied with the growing cachexy.
The treatment of the skin sarcoma - is surgical, closely-focused radiotherapy
with corticosteroids. In cases of the generalized forms of Kaposhy sarcomas the
cytostatic therapy is used – the combination of doxorubicin, vinblastin and bleomicin,
and also monochemotherapy with the prospidin. As the biotherapy they use intron A.
The timely treatment gives a positive result.
Lecture 14
Melanoma
Melanoma – is the malignant pigmentary tumor. The term “melanoma” ( from
the Greek “melanos” – black, dark) was suggested by Carswell in 1838. The
synonyms of melanoma: melanoblastoma, novocarcinoma, melanomalignoma.
Epidemiology.
The melanoma constitutes 1-10% of the malignant skin tumors and 0,3-0,9% of
all malignant human tumors. According to the official returns of the International
anticancer union the sickness rate in case of melanoma is 0,1-6,9 persons for 100.000
population in different countries of the world, and the average annual sickness rate
rise of this tumor in the world is about 5% ( in the USA – 4%, in Russia -3,9%) and
may be considered one of the highest among all malignant tumors. Most often the
melanoma is localized on the skin ( 70-80%), rarely in the eye area ( 5-7%) and it is
very rare in the area of other organs (gullet, rectum). In the Minor Asia countries the
indigenous people have melanoma 3,5 times rarely than the representatives of other
nationalities, who live in those states.
Etiology.
There are exogenous and endogenous factors in the development of the
melanoma.
1.The exogenous risk factors. This group is represented by the physical,
chemical and biological agents of the environment, which can directly and
immediately effect the skin.
 Physical factors: ultra-violet radiation from the sun, ionizing radiation,
electromagnetic radiation, fluorescence illumination, nevus traumatism.
 Chemical factors: harmful chemical agents used in the petrochemical,
chemical ( in particularly producing nitric acid), producing rubber plants, in the
production of vinyl chloride, polyvinyl chloride, plastic, benzol, pesticides.
 Biological factors: the nutrition quality (high level of daily protein and
adipose consumption), medical products (exogenous estrogens).
2. Endogenous risk factors. There are two groups:
1)
Biological constitution features, which presence raises the risk of the
melanoma development: racial and ethnic predisposition, the level of the body
pigmentation, hereditary (family) factors, anthropometric indexes, immune failings,
endocrine factors, reproductive women’ factors.
2)
The second group is represented by the predecessors of the melanoma,
that is such pathological skin changes , which can have the probability of the
malignant mutation: pigmentary parchment-skin, Dubrei melanosis, nevuses.
Precancerous Dubrei melanosis ( synonyms: melanosis Hatchinson spot,
limited precancerous melanosis, senile lentigo) is the pigmentary spot of different
size, of irregular oval shape, brown color of various intensity and strongly marked
along the edges. It has the rough surface- atrophic here and there, hyperkeratic and
papillomatous. Most often it is localized on the face skin, rarely on the body skin, on
the neck, hairy part of head, external women’s genitals. Dubrei melanosis
significantly less than the following nevuses can be the origin of the melanoma
development.
The increased accumulation of the melanoblasts in the various skin layers is
called nevus ( from latin naevus – birthmark). The nevuses can be innate and
acquired.
Blue nevus, or Yaddason Tiche nevus , also Otta nevus – is sharply bounded
round or oval new growth with more or less marked pigmentation, they are rarely
found and rarely turn into the melanoma, that is why in practical sense they are not
dangerous.
Gigantic pigmentary nevus- innate development anomaly. Clinically it shows
itself as skin pigmentation of various size ( from the palm size or bigger on the body
skin or extremities). The surface of the gigantic nevus can be warty, covered with
deep sores or with intensive hairiness.
In this connection it is common to distinguish pigmentary papillomatous,
verrucous and hairy nevus. The color of the nevus can be different – brown, black,
grayish. Gigantic pigmentary nevus presents a serious cosmetic defect.
Fibroepithelial nevus – is a round new growth, which raises above the skin,
having soft elastic consistence, brown color of different intensity. It is mostly
localized on the face rarely –on the body. It is almost never becomes malignant, but
patient often address to doctor because of the cosmetic reason.
Verrucous or papilloma-like nevus – growths of various shape, which raise
above the skin surface. Their surface is uneven, sometimes hyperkeratical, from lightbrown to dark-brown color. Verrucous nevus is most often localized on the body and
extremities, papillomatous nevus is localized on the hairy part of the head.
The patient’s reasons to address the doctor are: nevus traumatism or growth,
weeping nevus, unpleasant smell, pain, itching, cosmetic defect. That is why any
unpleasant sensations in the area of nevus should be regarded by the doctor as the
threat of melanoma development regardless of its belonging to the category
melanoma -risk nevus.
Pathomorphology of the melanoma.
The tumor develops from the pigment cells melanocitis. It is characterized by
the presence of the melanin pigment accumulation, although there are sometimes
pigmentless forms. Histologically it is common to distinguish 4 types of the cellular
melanoma system: epithelial, spindle-celled, mixed and small-celled. It is hard to
consider the melanoma unambiguously among the malignant epithelial tumors or
tumors of the conjunctive tissue –like ( соединительный) origin.
Metastases.
The melanoma occupies a special place among the malignant tumors, as
capable of quick metastases spreading. Practically there is no organs, where the
melanoma could not create metastases. But primarily it creates metastases in the
regional lymph nodes. It is important to note that in clinically unchanged lymph
nodes of 18-40% of patients metastases are histologically found.
(Gematogenously) Through the blood the melanoma creates metastases
practically in all organs and tissues. With all this going on, the metastases in the inner
organs can appear earlier than in the
metastases in the skin can develop.
lymph nodes. Very often gematogenous
International classification according to the TNM system:
T- primary tumor
Tis- melanoma in situ
T1-the tumor is less than 1mm thick; a) without ulceration and the invasion
level is II/III b)with ulceration or invasion level is IV/V.
T2- the tumor is 1,01-2.0 mm thick, a) without ulceration b)with ulceration
T3- the tumor is 2,01-4,0 mm thick; a) without ulceration b)with ulceration
T4- the tumor is more than 4 mm thick a) without ulceration b)with ulceration
N- regional lymph nodes
N1- metastases in 1 gland a)micrometastases 1; b)macrometastases 2
N2-metastases in 2-3 lymph nodes a) micrometastases1; b)macrometastases2
c)transitional metastases/satellites without metastatic lymph nodes
N3-4 and more metastatic lymph nodes or the conglomeration of lymph nodes,
or transitional metastases/satellites with metastatic lymph nodes
M-distant metastases
1a- there are distant metastasis on the skin, hypodermic or in the lymph nodes.
M1b – metastases in the lungs.
M1c – other visceral or any distant metastases.
1-micrometastases
are
diagnosed
after
the
observation
or
selective
lymphodenectomia.
2.- macrometastases - are clinically found metastases in the lymph nodes,
confirmed by the therapeutical lymphodenectomia or extracapsular spreading of
metastases in the lymph nodes.
Classification according to stages:
Clinical stages
Morphological stages
TNM
pTNM
0
Tis
N0
M0
Tis
N0
M0
IA
T1a
N0
M0
T1a
N0
M0
IB
T1
N0
M0
T1
N0
M0
b
b
IIA
T2a
N0
M0
T2a
N0
M0
T2
N0
M0
T2
N0
M0
b
IIB
b
T3a
N0
M0
T3a
N0
M0
T3
N0
M0
T3
N0
M0
b
IIC
b
T4a
N0
M0
T4a
N0
M0
T4
N0
M0
T4
N0
M0
T1-4a
N1
M0
N2
M0
N1
M0
N2
M0
N1
M0
N2
M0
N2
M0
N1
M0
b
III
III
Any T
b
N1
M0
N2
M0
N3
M0
A
a
T1-4a
a
III
T1-4b
B
a
T1-4b
a
T1-4a
b
T1-4a
b
T1-4a/b
c
III
C
T1-4b
b
T1-4b
N2
M0
Any T
N3
M0
Any T
Any N
Any M1
b
IV
Any T
Any N
Any M 1
Clinical picture.
Women are more likely to have the melanoma. 35-45 % of men have this
disease. Melanoma is mostly observed at the age of 30-60, its clinical picture can be
various, which can often present difficulties in diagnosing correctly.
The main signs of the nevuses malignisation are:

Disappearing of the skin pattern on the nevus surface;

appearance of the shiny, glossy nevus surface;

appearance of the asymmetry or contours irregularity (scalloped)
contours of nevus, that is changes of its shape;

Horizontal nevus growth;

Appearance of the subjective heat sensation, itching or pain in the nevus

Appearance of the single nodules ( satellites) around nevus;

Appearance single nodules on the surface of the nevus without its visual
area;
growth

Peeling of the nevus surface with the formation of the withered “scabs”;

Absence of hair or shedding of the hair on the nevus surface

Partial (irregular) or complete color change of nevus –melanoma (
melanoma) – appearance of the areas of so called bound depigmentation;

Vertical growth of nevus- melanoma above the surrounding areas.

The consistence change of the nevus-melanoma, which is defined with
palpation, that is its softening;

Ulceration of the epidermis above the nevus-melanoma;

Inflammation in the area of the nevus-melanoma and surrounding
tissues;

Weeping of the nevus-melanoma surface

Bleeding of the nevus-melanoma.
There are several clinical-anatomical forms of the melanoma:
1.Superficial melanoma with horizontal growth is 70% of all melanomas.
Clinically it is contoured formation, which rises above the skin surface, of brown
color. Atypical cells are localized in the upper layers of derma, spreading in lateral
direction. The prognosis is favorable as a rule.
2. Nodule-like ( nodous, nodular) form is found in 15% of cases. The tumor is
shaped like the flat nodule, rising above the skin suface, sometimes it is shaped like
polypus on the stem, of blue color, without any particular localization, and mostly
observed at the elderly age. The tumor cells spread vertically with quick derma
invasion. The prognosis is unfavorable.
3.Acrolentigo-like and mucous melanoma ( 10% of all melanomas). The
tumor has irregular contours, black, can be pigmentless. It grows slowly in radial
direction, usually in the upper layers of derma ( on the palms, feet). The prognosis
depends on the degree of the infiltrative tumor growth.
4. Malignant lentigo (melanoma-like freckles) – the rarest form. It develops at
the age of 70. It looks like the spot-like nodules from yellow-brown to almost black
color, 1,5-3mm in diameter, and are formed in the smooth freckles. The tumor grows
slowly, in radial direction in the upper layers of derma. The prognosis is favorable.
The diagnostics of melanoma is difficult because of the many forms of its
clinical picture, but the main diagnostics method is clinical one: studying anamnesis,
previous skin changes, external tumor shape, the state of the lymph nodes system.
Besides that it is common to perform dermatoscopy, echography, tumor
thermography and cytological analysis of the smears – the tumor prints, a sentinel
node biopsy. Other kinds of biopsy are prohibited. To exclude the presence of
metastasis in the glands it is common to do the ultrasonic examination and a sentinel
node biopsy of the lymph nodes. The diagnostic puncture of the pigmentary tumor
should be as much as possible approximated to the following medical treatment
(radiation treatment, surgery).The patient should be completely prepared to the
adequate surgery with anesthesia.
Another valuable additional examination is radioisotope scanning with the help
of radio-active 32 P. The criteria of malignant mutation for melanoma is threefold
increasing ( 300%) of the phosphorus accumulation over the tumor during 72 hours.
This method allows to diagnose lymphogenous and gematogenous metastases of the
tumor. Also rontgenologic and sonographic examination is performed, to diagnose
regional and distant metastases. Also as a way to diagnose they use total cutting
excisionary biopsy of the primary tumor.
Differential diagnostics:

Youth melanoma ( Spits nevus)

Blue nevus

Galo-nevus

Displastic nevuses

Cavernous thrombotic gemangioma

Non-malignant skin tumors

Malignant skin tumors

underungual, and underepidermal haematoma

onihomikosis

extrasexual chancre

metastases of the other histogenesis tumors into the skin
The treatment of the skin melanoma is mostly surgical. The surgical treatment
can be a part of the combined or complex treatment. The main requirements to the
surgical treatment:
1.
The incision of the skin should be performed within the distance of 3-5
cm from the tumor, in this case it is necessary to step back in the direction of the
regional lympho-outflow.
2.
It is necessary to ablate in one block the skin, hypodermic cellular tissue
and fascia.
3.
The surgery should be necessarily performed with the general anesthesia.
4.
When there is a suspicion of regional lymph nodes ( jugular, groin,
axillary ) having metastases the regional lymphadenectomy should be performed at
the same time. The biopsy of the boundary lymph nodes can give enough information
about the state of the regional lymph nodes.
5.
In most cases when the wound is being sewed up the plastic surgery
methods should be applied on the skin.
6.
Melanoma in situ ( atypical melanocitar hyperplasia, noninvasive
melanoma – I level according to Clark) minimal excision is allowed in principle, on
conditions that the borders of resection were free from the tumor when the
preparation was examined histologically. In practice the standard excision is less than
1 cm from the visible border of the tumor.
Stage I
Stage IA pT1aN0M0.
The standard treatment in case of IA and IB stages - is wide excision of the
tumor at the distance of 2 cm from the tumor borders.
Stage II
Stage IIA pT2b – 3a N0M0, IIB pT3b- 4aN0M0, IIC pT4aN0M0.
The standard excision is at the distance of 3 cm from the tumor borders.
Besides the tumor excision it is possible to perform immunotherapy using
interferon a-2b 3 ml ME/m2 of hypodermic injection 3 times per week during 3 years
or until the relapse and melanoma metastases.
Stage III
Stages IIIA pT 1-4a N1-2a, Mo, IIIB pT1-4b N1a-2c M0, IIIC pT1-4b N1b,
2b, 3 M0
The medical standard is wide excision of the primary tumor within 3 cm and
more combined with the regional lymphodenectomia. In case of need there can be
plastic replacement of the skin defect. Chemotherapy ( chemoimmunotherapy),
immunotherapy ( interferon a-2b,БЦЖ), polychemotherapy should be performed in
usual
or
modified
(
hyperthermia,
hyperglycemia
etc)
conditions.
As
polychemotherapy dacarbasin is used combined with the medications of platinum (
cisplatin), alkaloids of periwinkle ( vinblastin), the medications of urea nitromesil
group (lomustin). The effectiveness of polychemotherapy in this combination is 3040%, whereas in case of monochemotherapy with dacarbasin it is 15-25%.
Stage IV Any pT, any N, M1.
In spite of the little sensitiveness of disseminated melanoma to the
chemotherapy, the standard of this tumor treatment is systemic chemotherapy. The
objective reaction to dacarbasin ( DTIC) and the derivatives of nitrosourea- carmustin
( BCNU), lomustin (CCNU) do not exceed 20-25%. Most patients are observed to
have remissions from 3 to 6 months, although in some cases there are more prolonged
remissions. Along with monotherapy it is possible to apply multi-component schemes
including chemotherapeutic medicines, such as vinkaalkaloids, the derivatives of
platinum and taxans. The surgical treatment of IV stage melanoma can be performed
in the presence of the single metastases in the lungs, gastrointestinal tract, bones or
brain. Palliative resections are done, which in some cases are very effective and
significantly prolong life. For the cytoreductive purpose palliative lymphadenectomy
can be performed. Although the melanoma is rather radioresistant tumor, palliative
radiotherapy can relieve the patients state. Retrospective researches testify that with
the patients with plural metastases in the brain, the skeleton bones and the spinal
cord compression it is possible to achieve the significant reduction of the symptoms
and the decrease of the tumor size by means of radiotherapy. It is not established
however what function procedure is the most effective in case of the radiotherapy
applied to the bones and spinal cord metastases. In addition to melanoma treatment
main schemes it is common to use antiestrogens. ( tamoksifen).
Local relapses.
Not long ago among the local relapses were all repeatedly appearing tumors,
localized in the postoperative scar or in the skin area, as well as in the skin or
hypodermic cellular tissue at the distance of 5 cm from the scar or skin area (
лоскут). At the present time the local relapse is the repeated tumor within 2 cm from
the postoperative scar. The standard treatment of the local relapses is an excision
within the limits of the healthy tissues ( 1-3cm, depending on the anatomic
localization). The alternative method of the local relapses treatment of the melanoma
on the extremities is regional hyperthermic perfusion.
The frequency of the complete remissions when using tumor-necrotic factors
and melfalan attains 90%. In case of the absence of the complete regress the residual
changes should be excised. Since the regional relapses in more than the half patients’
cases are accompanied transit metastases, the performance of the regional
chemotherapy becomes especially urgent. The influence of the regional perfusion on
the patients survival is not proved.
The prognosis.
The prognosis in case of the skin melanoma depends on many factors, but
mainly on the progress stage, localization, size, the growth form of the tumor, on the
patients age and sex, on the character and adequacy of the chosen treatment method.
In case of the localized process 5-years survival is possible in 75-86 %, 10-years –
47%, in case of the regional metastases - 33-52% and 13% accordingly, in case of the
distant metastasis 5-years survival does not exceeds 5-12%.
Lecture 15
Cervical cancer
Epidemiology
Cervical cancer is a malignancy of the cervix. Worldwide, it is the second-most
common cancer of women. It may present with vaginal bleeding but symptoms may
be absent until the cancer is in its advanced stages, which has made cervical cancer
the focus of intense screening efforts utilizing the Pap smear. Most scientific studies
have found that human papillomavirus (HPV) infection is responsible for more than
90% of the cases of cervical cancer. According to a survey of 3,076 women 18 to 75
years of age, awareness about human papillomavirus (HPV) infection and its link to
cervical cancer is relatively low among American women. In 2006 an estimated
10,000 women in the United States will be diagnosed with this type of cancer and
nearly 4,000 will die from it.
Worldwide, cervical cancer is the second most common cancer in women (after
breast cancer) and is the third leading killer (behind breast and lung cancer). It affects
about 16 per 100,000 women per year and causes death in about 9 per 100,000 per
year. In the Ukraine, howeever, cervical cancer is the 3th most common cancer of
women. About 12,800 women in the Ukraine are diagnosed with cervical cancer and
about 4,800 die each year. Among gynecological cancers it ranks behind endometrial
cancer and ovarian cancer.
Epidemiologists working in the early 20th century noted that:
1. Cervical cancer was common in female sex workers.
2. It was rare in nuns, except for those who had been sexually active before
entering the convent.
3. It was more common in the second wives of men whose first wives had died
from cervical cancer.
4. It was rare in Jewish women.
5. In 1935, Syverton and Berry discovered a relationship between HPV and skin
cancer in rabbits.
Ethiology
Cervical cancer caused by a sexually transmitted agent. Initial research in the
1950s and 1960s put the blame on smegma (e.g. Heins et al 1958), but it wasn't until
the 1970s that human papillomavirus (HPV) was identified. A description by electron
microcopy was given earlier in 1949 and HPV-DNA was identified in 1963. It has
since been demonstrated that HPV is implicated in all cervical cancers. Specific viral
subtypes implicated are HPV 16, 18, 31 and 45. There are 7 common types of HPV:
16, 18, 31, 33, 42, 52 and 58. Types 16 and 18 are the most common cause of the
cancer. There are “low-risk” viruses which do not commonly turn into cancer and
“high-risk” viruses that are most likely to develop into cervical cancer, although both
can. Having several sexual partners is a major risk factor for developing HPV.
Although most HPV infections clear up on their own, the infections could increase to
major abnormalities or cervical cancer.
Doctors can test samples of cervical cells to determine types of HPV that may be
present. In some cases, HPV clears up on its own, and in some, there were no signs
until it was too late, and cervical cancer developed.
Risk factors
The following list of risk factors for cervical cancer: human papillomavirus
infection, smoking, HIV infection, chlamydia infection, dietary factors, oral
contraceptives, multiple pregnancies, use of the hormonal drug diethylstilbestrol
(DES) and a family history of cervical cancer.
The presence of strains 16, 18 and 31 of human papillomavirus (HPV) is the
prime risk factor for cervical cancer. The presence of HPV is a necessary condition
for the development of cervical cancer. A virus cancer link with HPV has been found
to trigger alterations in the cells of the cervix, leading to the development of cervical
intraepithelial neoplasia and cancer. HPV subtypes 16 and 18 introduce two genes
called E6 and E7 which code for proteins that inhibit p53 and Rb, which are two
important tumor suppressor genes in humans. The p53 gene product is involved in
regulation of apoptosis (cell suicide), and Rb is responsible for halting the cell cycle
at the G1-phase. When Rb function is impaired, the cell is allowed to progress to S-
phase and complete mitosis, resulting in proliferation and hence neoplastic
transformation.
Genital warts are caused by different HPV types, and are not related to cervical
cancer. The medically accepted paradigm, that a patient must have been infected with
HPV to develop cervical cancer, and is hence viewed as a sexually transmitted
disease. Not all women infected with HPV also develop cervical cancer. Use of
condoms will not always prevent transmission. Likewise, HPV can be transmitted by
skin-to-skin-contact with infected areas. HPV is thought to grow preferentially in the
epithelium of the glans penis, and scrupulous washing and cleaning of this area may
be preventative. The position on circumcision is controversial: some researchers
argue that routine neonatal circumcision is an acceptable way of preventing various
diseases (which include cervical carcinoma); others maintain that the benefits do not
outweigh the risks. However, there has not been any definitive evidence to support
this claim.
Symptoms
The early stages of cervical cancer may be completely asymptomatic. Vaginal
bleeding, contact bleeding or (rarely) a vaginal mass may indicate the presence of
malignancy. Also, moderate pain during sexual intercourse and vaginal discharge are
symptoms of cervical cancer. In advanced disease, metastases may be present in the
abdomen, lungs or elsewhere. Symptoms of advanced cervical cancer may include:
Loss of appetite, Weight loss, Fatigue, Pelvic pain, Back pain, Leg pain, Single
swollen leg, Heavy bleeding from the vagina, Leaking of urine or feces from the
vagina, and Bone fractures
The possibility to identify premalignant changes on a cervical smear has made
screening the major cause for referral of women with possible cervical neoplasia. In
many countries, women are advised to have a regular Pap smear to check for
premalignant changes.
Recommendations for how often a Pap smear should be done vary from once a
year to once every five years. If cervical cancer is detected early, it can be treated
without impairing fertility. Consistently abnormal smears may be a reason for further
diagnosis despite complete absence of symptoms.
Diagnosis
Diagnosis is made by doing a biopsy of the cervix, which often involves
colposcopy, or a magnified visual inspection of the cervix aided by using an acetic
acid (e.g. vinegar) solution to highlight abnormal cells on the surface of the cervix
(the portio). A Pap smear is insufficient for the diagnosis. Many researchers
recommend that since more than 99% of invasive cervical cancers worldwide contain
human papillomavirus, HPV testing should be carried out together with routine
cervical screening (Walboomers et al, 1999). However, given the prevalence of HPV
(around 80% infection history among the sexually active population) others suggest
that routine HPV testing would cause undue alarm to carriers.
Further diagnostic procedures are loop electrical excision procedure (LEEP) and
conisation, in which the inner lining of the cervix is removed to be examined
pathologically. These are carried out if the biopsy confirms severe dysplasia.
Types of malignant cervical tumors include the following:

M8070/3: squamous cell carcinoma (about 80-85%)

M8140/3: adenocarcinoma

M8560/3: adenosquamous carcinomas

M8041/3: small cell carcinoma

M8246/3: neuroendocrine carcinoma

M8720/3: melanoma

(varied): lymphoma
Staging
Cervical cancer is staged by the FIGO staging system, which is based on clinical
examination, rather than surgical findings. It allows only the following diagnostic
tests to be used in determining the stage: palpation, inspection, colposcopy,
endocervical
curettage,
hysteroscopy,
cystoscopy,
proctoscopy,
intravenous
urography, and X-ray examination of the lungs and skeleton, and cervical conization.
The TNM staging system .
Stage 0 - full-thickness involvement of the epithelium without invasion into the
stroma (carcinoma in situ)



Stage I - limited to the uterus
IA - diagnosed only by microscopy; no visible lesions
IA1 - stromal invasion less than 3 mm in depth and 7 mm or less
in horizontal spread

IA2 - stromal invasion between 3 and 5 mm with horizontal
spread of 7 mm or less
Treatment consists of surgery (including local excision) in early stages

IB - visible lesion or a microscopic lesion with more than 5 mm of depth
or horizontal spread of more than 7 mm

IB1 - visible lesion 4 cm or less in greatest dimension

IB2 - visible lesion more than 4 cm

Stage II - invades beyond uterus

IIA - without parametrial invasion

IB - visible lesion or a microscopic lesion with more than 5 mm of depth
or horizontal spread of more than 7 mm

IB1 - visible lesion 4 cm or less in greatest dimension

IB2 - visible lesion more than 4 cm


Stage II - invades beyond uterus
IIA - without parametrial invasion
Treatment consists of surgery and radiotherapy in advanced stages of the disease


IIB - with parametrial invasion
Stage III - extends to pelvic wall or lower ⅓ of the vagina

IIIA - involves lower ⅓ of vagina

IIIB - extends to pelvic wall and/or causes hydronephrosis or nonfunctioning kidney

IVA - invades mucosa of bladder or rectum and/or extends beyond true pelvis

IVB - distant metastasis
Treatment consists of chemotherapy and radiotherapy
Note that the FIGO stage does not incorporate lymph node involvement in
contrast to the TNM staging for most other cancers.
For cases treated surgically, information obtained from the pathologist can be
used in assigning a separate pathologic stage but is not to replace the original clinical
stage.
For premalignant dysplastic changes, the CIN (cervical intraepithelial neoplasia)
grading is used.
Treatment
Treatment consists of surgery (including local excision) in early stages and
chemotherapy and radiotherapy in advanced stages of the disease. An effective
vaccine, the HPV vaccine, for the two most common strains of HPV has recently
been licenced.
Microinvasive cancer (stage IA) is usually treated by hysterectomy (removal of
the whole uterus including part of the vagina). For stage IA2, the Lymph nodes are
removed as well. An alternative for patients who desire to maintain fertility is a local
surgical procedure such as a LEEP or cone biopsy.
If a cone biopsy was not able to produce clear margins, there is one possible
option left for those with early stage cervical cancer who would like to preserve their
fertility while treating their cervical cancer: a trachelectomy. For those in stage I
cervical cancer, which has not spread, this is a viable treatment option. It allows for
the preservation of the ovaries and uterus while surgically removing the cervical
cancer. This treatment option is not yet well known amongst doctors and is not yet
considered a standard of care. Furthermore, few doctors are trained in this fertility
sparing surgical option. Even the most experienced surgeon won't be able to promise
that this can be performed beforehand, as the extent of the spread of cervical cancer is
unknown until surgical microscopic examination is completed. As a result, there is
always the possibility for the need to convert to a hysterectomy if the surgeon is not
able to microscopically confirm clear margins of cervical tissue once the patient is
under general anesthesia in the operating room. This can only be done during the
same operation if the patient has given consent for a possible hysterectomy prior to
the operation.
Due to the fact of the possible risk of cancer spread to the lymph nodes in stage
1b cancers and some stage 1a cancers, the surgeon may also need to remove some
lymph nodes from around the womb. Once all the checks have been done and if all is
well, the cervix will be stitched closed with a cerclage. This will allow for
menstruation and fertilization but not dilation for a vaginal delivery, therefore
requiring any future births are delivered by cesarean section. A radical trachelectomy
is a smaller operation than hysterectomy, but more importantly allows for the
preservation of fertility. This operation can also be performed vaginally instead of
abdominally, however there are conflicting opinions as to which approach is better. A
radical abdominal trachelectomy with lymphadenecectomy usually only requires a 2to 3-day hospital stay with most women recovering very quickly (approximately 6
weeks).
Complications are generally uncommon, although women who are able to
conceive after surgery are prone to preterm labor or possible late miscarriage. It is
generally recommended to wait at least one year before attempting to become
pregnant after surgery. Recurrence in the residual cervix is a very rare event as long
as the cancer has been cleared with the trachelectomy. Even though recurrence is
rare, it is generally recommended for patients to practice vigilant prevention and
follow up care including pap screenings/colposcopy, with biopies of the remaining
lower uterine segment as needed (every 3-4 months for at least 5 years) to monitor for
any recurrance in addition to minimizing any new exposures to HPV through safe sex
practices until one is actively trying to conceive.
Early stages (IB1 and IIA less than 4 cm) can be treated with radical
hysterectomy with removal of the lymph nodes or radiation therapy. Radiation
therapy is given as external beam radiotherapy to the pelvis and brachytherapy
(internal radiation). For patients treated with surgery who have high risk features
found on pathologic examination, radiation therapy with or without chemotherapy is
given in order to reduce the risk of relapse.
Larger early stage tumors (IB2 and IIA more than 4 cm) may be treated with
radiation therapy and cisplatin-based chemotherapy, hysterectomy (which then
usually requires adjuvant radiation therapy), or cisplatin chemotherapy followed by
hysterectomy.
Advanced stage tumors (IIB-IVA) are treated with radiation therapy and
cisplatin-based chemotherapy.
Vaccine
Merck & Co. has developed a vaccine against four strains of HPV (6,11,16,18),
called Gardasil™. It is now on the market after receiving Food and Drug
Administration approval on June 8, 2006. Gardasil is targeted at girls and women of
age 9 to 26 because the vaccine only works if given before infection occurs;
therefore, public health workers are targeting girls before they begin having sex. The
use of the vaccine in men to prevent genital warts and interrupt transmission to
women is initially considered only a secondary market. The high cost of this vaccine
has been a cause for concern. Gardasil has received EU approval.
Glaxosmithkline has developed a vaccine called Cervarix™ which has been
shown to be 100% effective in preventing HPV strains 16 and 18 and is 100%
effective for more than four years. The two HPV strains (16 and 18) together cause
about 70% of cervical cancer cases. Cervarix should be approved by year's end.
Lecture 16
Ovarian cancer
Epidemiology
Ovarian cancer is the fifth leading cause of cancer death in women, the leading
cause of death from gynecological malignancy, and the second most commonly
diagnosed gynecologic malignancy. It is idiopathic, meaning that the exact cause is
usually unknown. The disease is more common in industrialized nations, with the
exception of Japan. In the United States, females have a 1.4% to 2.5% (1 out of 40-60
women between 55 and 74 years of age and approximately one quarter of ovarian
cancer deaths occur in women between 35 and 54 years of age) lifetime chance of
developing ovarian cancer. In the Ukraine – 15,5 causes of 100 000 women.
Older women are at highest risk. More than half of the deaths from ovarian
cancer occur in women
The risk for developing ovarian cancer appears to be affected by several factors.
The more children a woman has, the lower her risk of ovarian cancer. Early age at
first pregnancy, older ages of final pregnancy and the use of low dose hormonal
contraception have also been shown to have a protective effect. Ovarian cancer is
reduced in women after tubal ligation.
The link to the use of fertility medication, such as Clomiphene citrate, has been
controversial. An analysis in 1991 raised the possibility that use of drugs may
increase the risk for ovarian cancer. Several cohort studies and case-control studies
have been conducted since then without providing conclusive evidence for such a
link. It will remain a complex topic to study as the infertile population differs in
parity from the "normal" population.
There is good evidence that in some women genetic factors are important.
Carriers of certain mutations of the BRCA1 or the BRCA2 gene, more frequent in
some populations (e.g. Ashkenazi Jewish women) are at a higher risk of both breast
cancer and ovarian cancer, often at an earlier age than the general population.
Patients with a personal history of breast cancer or a family history of breast
and/or ovarian cancer, especially if at a young age, may have an elevated risk. A
strong family history of uterine cancer, colon cancer, or other gastrointestinal cancers
may indicate the presence of a syndrome known as hereditary nonpolyposis
colorectal cancer (HNPCC, also known as Lynch II syndrome), which confers a
higher risk for developing ovarian cancer. Patients with strong genetic risk for
ovarian cancer may consider the use of prophylactic oophorectomy after completion
of child-bearing.
A Swedish study, which followed more than 61,000 women for 13 years, has
found a significant link between milk consumption and ovarian cancer. According to
the BBC, "[Researchers] found that milk had the strongest link with ovarian cancer those women who drank two or more glasses a day were at double the risk of those
who did not consume it at all, or only in small amounts." Recent studies have shown
that women in sunnier countries have a lower rate of ovarian cancer, which may have
some kind of connection with exposure to Vitamin D.
Other factors that have been investigated, such as talc use, asbestos exposure,
high dietary fat content, and childhood mumps infection, are controversial and have
not been definitively proven.
"Associations were also found between alcohol consumption and cancers of the
ovary and prostate, but only for 50 g and 100 g a day."
Although 20% to 25% of all benign and malignant ovarian neoplasms are of
germ cell origin, only about 3% of these tumors are malignant. Germ cell
malignancies account for less than 5% of all ovarian cancers in Western countries but
they represent up to 15% of ovarian cancers in Asian and black societies, where
epithelial ovarian cancers are much less common.
Classification
I. Histology
Ovarian cancer is classified according to the histology of the tumor. Lesions differ
significantly in clinical features, management, and prognosis (ICD-O codes provided
where available):

Surface epithelial-stromal tumours are the most common and prototypic
ovarian cancers. They are thought to originate from the ovarian surface lining,
and
include
serous
cystadenocarcinoma
(8441/3),
and
mucinous
cystadenocarcinoma (8470/3). The abdominal cavity is lined with the same cells
that make up the ovarian surface lining, and it is possible to have cancer begin
there, in which case, it is called primary peritoneal cancer. Treatment, however,
is basically the same as treatment for ovarian cancer.

Sex cord-stromal tumors include lesions that are hormonally active such as the
estrogen-producing granulosa cell tumor (8620/3) and the virilizing SertoliLeydig cell tumor or arrhenoblastoma.

Germ cell tumors originate from dysplastic germ material and tend to occur in
young women and girls. Lesions include the dysgerminoma (9060/3), a form of
the choriocarcinoma (9100/3), and malignant forms of the teratoma (9083/3).
Malignant teratoma often contains endodermal sinus tumor (9071/3).
II.History
Ovarian cancer often is primary, but can also be secondary, the result of
metastasis from primary cancers elsewhere in the body. For example, from breast
cancer, or from gastrointestinal cancer (in which case the ovarian cancer is a
Krukenberg cancer).
III. Staging
Ovarian cancer staging is by the FIGO staging system and uses information obtained
after surgery, which can include a total abdominal hysterectomy, removal of (usually)
both ovaries and fallopian tubes, (usually) the omentum, and pelvic (peritoneal)
washings for cytology. The AJCC stage is the same as the FIGO stage.
Stage I - limited to one or both ovaries
IA - involves one ovary; capsule intact; no tumor on ovarian surface; no malignant
cells in ascites or peritoneal washings
IB - involves both ovaries; capsule intact; no tumor on ovarian surface; negative
washings
IC - tumor limited to ovaries with any of the following: capsule ruptured, tumor on
ovarian surface, positive washings
Stage II - pelvic extension or implants
IIA - extension or implants onto uterus or fallopian tube; negative washings
IIB - extension or implants onto other pelvic structures; negative washings
IIC - pelvic extension or implants with positive peritoneal washings
Stage III - microscopic peritoneal implants outside of the pelvis; or limited to the
pelvis with extension to the small bowel or omentum.
IIIA - microscopic peritoneal metastases beyond pelvis
IIIB - macroscopic peritoneal metastases beyond pelvis less than 2 cm in size
IIIC - peritoneal metastases beyond pelvis > 2 cm or lymph node metastases
Stage IV - distant metastases--in the liver, or outside the peritoneal cavity
* Para-aortic lymph node metastases are considered regional lymph nodes
(Stage IIIC).
Symptoms
1. sense of pelvic heaviness
2. vaginal bleeding
3. weight gain or weight loss
4. abnormal menstrual cycles
5. unexplained back pain that worsens over time
6. increased abdominal girth
7. non specific gastrointestinal symptoms:
–
vague lower abdominal discomfort
–
increased gas
–
indigestion
–
lack of appetite
–
nausea and vomiting
–
Bloody stool
–
inability to ingest usual volumes of food
–
bloating
8. Additional symptoms that may be associated with this disease:
–
increased urinary frequency/urgency
–
excessive hair growth
–
Fluid buildup in the lining around the lungs (Pleural effusions)
–
Positive pregnancy readings (in the absence of pregnancy. This is for
germ cell tumors only)
Note: There may be no symptoms until late in the disease.
Diagnosis
Ovarian cancer at its early stages(I/II) is difficult to diagnose until it spreads and
advances to later stages(III/IV). This is due to the fact that most of the common
symptoms are non-specific.
The blood test called CA-125 is useful in differential diagnosis and in follow up
of the disease, but it has not been shown to be an effective method to screen for earlystage ovarian cancer and is currently not recommended for this use.
A study funded by the American Cancer Society conducted at the H. Lee Moffitt
Cancer Center & Research Institute has found a correlation between high levels of
lysophospholipids (a type of fatty acid) with ovarian cancer patients and low levels of
lysophospholipids with healthy women. This potential biomarker can be detected by
a simple blood test. The blood test was 93% accurate as predictor of ovarian cancer
with less than 4% false positives of the 117 women studied.
Current research is looking at ways to combine tumor markers along with other
indicators of disease (i.e. radiology and/or symptoms) to improve accuracy. The
challenge in such an approach is that the very low population prevelance of ovarian
cancer means that even testing with very high sensitivity and specificity will still lead
to unacceptable numbers of false positive results. This is exemplified by the recent
discovery of proteomic predictors that showed 100% sensitivity and 95% specificity
A pelvic examination, including CT scan, trans-vaginal ultrasound, is also of
utility. Physical examination may reveal increased abdominal girth and /or ascites
(fluid within the abdominal cavity). Pelvic examination may reveal an ovarian or
abdominal mass. The pelvic exam can include a rectovaginal component for better
palpation of the ovaries.
Expectations (prognosis)
1. Ovarian cancer has a poor prognosis. It is disproportionately deadly because
symptoms are vague and non-specific. More than 60% of patients presenting
with this disease already have stage III or stage IV disease, when it has already
spread beyond the ovaries.
2. Ovarian cancers shed malignant cells into the naturally occurring fluid within the
abdominal cavity. These cells then have the potential to float in this fluid and
frequently implant on other abdominal (peritoneal) structures included the
uterus, urinary bladder, bowel, and lining of the bowel wall (omentum). These
cells can begin forming new tumor growths before cancer is even suspected.
3. More than 50% of women with ovarian cancer are diagnosed in the advanced
stages of the disease because no cost-effective screening test for ovarian cancer
exists. The five-year survival rate for all stages is only 35% to 38%. If, however,
diagnosis is made early in the disease, five-year survival rates can reach 90% to
98%.
Complications
-
spread of the cancer to other organs
-
progressive function loss of various organs
-
ascites (fluid in the abdomen)
-
blockage of the intestines
Germ cell ovarian cancer
Germ Cell Ovarian Cancer has a much better prognosis, but is rarer.
Germ cell ovarian cancer is a rare form of ovarian cancer: approximately 5% of
ovarian cancers are classified as germ cell. Treatment is often by chemotherapy drugs
that are similar to those used in the treatment of testicular cancer.
Germ cell neoplasms arise from the germ cell elements of the ovary and include
dysgerminoma,
endodermal
sinus
tumor,
embryonal
cell
carcinoma,
choriocarcinoma, teratoma, polyembryona, and mixed germ cell tumors. Unlike the
epithelial neoplasms, which tend to occur during the sixth decade of life, this group
of tumors tends to occur during the second and third decades and as a group is
associated with a better prognosis. Many of these neoplasms produce biologic
markers, which can be monitored to assess response to therapy.
Germ cell tumors are derived from the primordial germ cells of the ovary.
Whereas malignant germ cell tumors can arise in extragonadal sites, such as the
mediastinum and the retroperitoneum, the majority of germ cell tumors arise in
the gonad from the undifferentiated germ cells.
Ovarian Germ Cell Tumors can be divided into three major groups:
(1) benign tumors (usually dermoid cysts);
(2) malignant tumors that arise from dermoid cysts;
(3) primitive malignant germ cell tumors including dysgerminoma, immature
teratomas, embryonal carcinomas, and choriocarcinoma.
Dysgerminoma of the ovary is the female counterpart of the seminoma in the
male. It occurs primarily in young females and accounts for about 30-40% of germ
cell tumors. Grossly, the tumor is rather rubbery in consistency, smooth, rounded, and
thinly encapsulated, with a brown or grayish-brown color. This neoplasm is unilateral
in 85-90% of cases. It is a solid neoplasm, which may contain areas of softening due
to degeneration. Histologically, dysgerminoma mimics the pattern seen in the
primitive gonad, i.e., it has nests of germ cells that appear as large, rounded cells with
central nuclei that contain one or two prominent nucleoli surrounded by
undifferentiated stroma. Lymphocytes may invade the stroma and occasionally giant
cells are identified. A lymphocytic infiltrate is considered a favorable prognostic
indicator.
Endodermal sinus tumor of the ovary, previously called a yolk sac tumor, is
the second most common germ cell neoplasm, occurring in approximately 20% of
cases.
Symptoms, Signs and Diagnosis
Functional effects of germ cell or stromal tumors include hyperthyroidism,
feminization, and virilization. However, benign functional cysts are common in
young women; vaginal sonography or reexamination after 6 wk helps differentiate
cysts from tumors.
Mature cystic teratoma (dermoid cyst) are the most common germ cell tumors
and in this case all tissue is developmentally mature and there is little or no risk of
malignancy. Patients may be asymptomatic or present abdomino-pelvic pain or
increasing abdominal girth or a palpable abdominal mass.
Dysgerminomas are the most frequent malignant germ cell tumors in young
women (80% of cases). They are rarely pure dysgerminomas but are often mixed
with other cell types and synciotrophoblastic types secreting hCG.
Endodermal sinus tumor (yolk sac tumor). These are an association of extraembryonic mesodermal cells and endodermal cells. The mean age at diagnosis is 19
years and the incidence appears to increase with age.
Gonadoblastoma of the ovary is a rare neoplasm composed of nests of germ
cells and sex cord derivatives that are surrounded by connective tissue stroma.
Other tumors include embryonic carcinomas consisting of extra-embryonic and
embryonic teratoma-type pluripotential cells.
Laboratory Evaluation
When an ovarian malignancy is included in the list of diagnostic possibilities, a
limited number of laboratory tests are indicated. A complete blood count (CBC) and
serum electrolyte test should be obtained in all patients. Coagulation tests are not
indicated in the absence of a suggestive history of bleeding after minor trauma or
increased bruisability. Similarly, routine liver function tests are rarely helpful.
The serum hCG level should be measured in any female in whom pregnancy is a
possibility. In addition, a serum AFP and lactate dehydrogenase (LDH) should be
measured in young girls and adolescents who present with adnexal masses because
the younger the patient, the greater the likelihood of a malignant germ cell tumor.
Treatment
In contrast to epithelial ovarian neoplasms, most germ cell neoplasms are early
stage at the time of diagnosis. This observation, in conjunction with the low incidence
of bilaterality and the young age of most patients, for whom future fertility is an
issue, influences the surgical management of this group of neoplasms. For young
women with a germ cell neoplasm of the ovary, removal of the involved adnexa with
preservation of the normal-appearing contralateral adnexa and uterus is generally
advocated. In view of the low incidence of bilaterality, biopsy or bivalving the
contralateral ovary is not recommended because of the risk of peritubal and
periovarian adhesions. Complete surgical staging of germ cell neoplasms is the same
as for epithelial ovarian neoplasms and should be performed in all cases.
Most patients with advanced-stage germ cell malignancies or high-risk earlystage disease can be cured with combination chemotherapy. Bleomycin, etoposide,
and cisplatin are most commonly used.
Radiation Therapy
With respect to germ cell neoplasms, radiation therapy has been used
successfully in the treatment of patients with dysgerminoma.
Lecture 17
Uterine cancer
Uterine cancer is the most common cancer of the female reproductive system.
The uterus is the female reproductive organ in which a baby grows if a woman
becomes pregnant. The uterus consists of three main parts, the cervix is the lower
portion of the uterus, the broad middle part is the corpus or body, and the domeshaped top of the uterus is the fundus. When a woman develops uterine cancer, a
tumor is formed on her uterus of abnormal or old cells and can either be benign or
malignant.
Types
There are two different types of uterine cancer; the most common form begins in
the lining of the uterus, also known as the endometrium. This form of uterine cancer
can also be called endometrial cancer, or cancer of the uterus. The other, less
common form of uterine cancer, is uterine sarcoma, and this is when the cancer
develops in the outer layer of muscle tissue, myometrium, of the uterus.
Risk factors
- The ovaries in a woman’s reproductive system produce estrogen and progesterone.
The balances of these two hormones changes monthly making the endometrium
thicken in case of pregnancy or shed if no pregnancy occurs. When these
hormones shift towards more estrogen, stimulating the growth of the
endometrium, the risk for uterine cancer increases. Uterine cancer has several
internal causes usually due to the presence of extra estrogen.
- Women who experience more years of menstruation are at a higher risk of uterine
cancer. If menstruation begins before the age of 12 years old and continues into
a woman’s 50’s the risk is higher, because the more years of menstruation a
woman experiences the more years the endometrium is exposed to estrogen.
- Women who have never experienced pregnancy are at a higher risk, because the
body produces more progesterone during pregnancy protecting the endometrium
by lowering estrogen levels. Women who have never been pregnant do not
receive the benefit of this protection.
- Women who do not experience regular cycles are at an increased risk of uterine
cancer. Ovulation is regulated by estrogen. Irregular ovulation or failure to
ovulate increases a woman’s lifetime exposure to estrogen.
- Women with Type 2 diabetes or women who are obese are at more risk. These
two factors generally go hand in hand, because many people with Type 2
diabetes are obese. Although alone they are each risk factors, obese women with
Type 2 diabetes are at an increased risk, because fat tissues sometimes change
hormones into estrogen resulting in an increased level of estrogen. Fatty foods
can also directly affect estrogen metabolism increasing risk.
- Women who participate in Estrogen-only Replacement Therapy (ERT) (a form of
Hormone Replacement Therapy) are at a higher risk because ERT stimulates the
growth of the endometrium, placing estrogen alone after menopause.
- Uterine cancer is more prevalent in older women, because it takes several years to
develop. 95% of women with uterine cancer are over the age of 40. White
women are more likely to develop uterine cancer, but African American women
are more like to die from it.
Screening
There are no useful screening tests and/or pelvic exams that detect uterine
cancer. The disease is most often diagnosed because a woman shows symptoms of
the disease. Signs and symptoms of endometrial cancer include abnormal bleeding,
spotting, or other discharges from the vagina. Women who have gone through
menopause are especially encouraged to consult a physician if abnormal bleeding,
spotting, or discharges occur.
Symptoms
Approximately 90% of women diagnosed with uterine cancer have unusual
vaginal bleeding or bleeding after menopause. Most cases of uterine cancer
develop in women who have gone through menopause and whose periods have
stopped. However, there is a small percentage of cases of women under the age of
forty with uterine cancer. Although irregular bleeding may show up in other illnesses
such as hyperplasia or other non-cancerous conditions, contact a physician if any
irregular bleeding may occur. At first, the bleeding may appear watery, but over time
the discharge may contain more and more blood.
Vaginal discharge which doesn’t contain blood may also be a sign of uterine
cancer. Just because a woman can’t see the blood in the discharge itself, does not
mean that the cancer is not present. In approximately 10% of diagnosed cases, the
non-bloody discharge experienced by the patients proved to be cancerous. In any
case, any abnormal vaginal discharge should result in the consulting of a physician.
Sometimes, uterine cancers may progress into advanced stages before any signs or
symptoms are shown.
Additional signs of uterine cancer include pelvic pain and/or weight loss.
Although these symptoms do occur, they are usually develop in the later stages of the
disease. Medical help should be sought after immediately so that the disease is not
allowed to progress any further. The delaying of medical help only decreases the
chance of treating the disease successfully.
If a woman has any of the aforementioned symptoms then she is encouraged to
see a physician who can then come to a decision as to whether or not cancer is
present. The physician will ask for a list of symptoms and her medical family history.
If the cancer is there, a woman should then be instructed to visit a gynecologist. Early
diagnosis is very important when it comes to cancer of the uterus.
Treatment
There are many different treatments for cancer. Uterine cancer, however, is
treated most commonly with a smaller sampling of the possible treatments available
for cancer patients. After a diagnosis is received, patients usually begin one or two
different forms of therapy. The variety, aggressiveness, and overall length of time in
treatment depends entirely on the stage and severity of the cancer and the patient
(age, health, plans for the future, etc.). The most common treatments for uterine
cancer are surgery, radiation therapy, chemotherapy, and hormone therapy.
Surgery involves having a hysterectomy. Having a simple hysterectomy
(removal of the entire uterus) or radical hysterectomy (removal of the uterus,
surrounding tissues, and cervix) depends on the case.
The option of radiation therapy involves using high-energy radiation to destroy
the cancer cells. The procedure is done outside of the body and is not unlike having
an X-ray for a broken limb.
Chemotherapy involves taking a series of drugs (either by mouth or through a
vein) to kill the cancer cells. Chemotherapy is most often used when the cancer has
spread to other areas of the body.
Hormone therapy is mainly used to treat patients with endometrial stromal
sarcomas (A rare sarcoma in which the lesions form multiple foci in the myometrium
and in vascular spaces in other sites and the tissue and cells resemble endometrial
stroma cells). A progesterone-like hormone drug or a drug which stops the production
of estrogen can be used. Hormone therapy, however, is not often used and is still
being tested.
Prognosis
The Cancer Society estimates that 41,200 women will be diagnosed with uterine
cancer in 2006, and of those 7,350 will die. About 70% of all women diagnosed are
between the ages of 45-74. A woman’s chance of developing this cancer through out
her life time is about 1 in 38. 500,000 women have been diagnosed and survived this
cancer. This cancer is 40% more prominently found in white women, however an
African American women who is diagnosed with uterine cancer is twice as likely to
die. Doctors say that on average the five-year survival rate is at 84%, and this
percentage increases if the cancer is detected in early stages.
Prevention
Generally, uterine cancer is a result of internal factors that cannot be prevented,
however, a couple factors may help lower the risk of developing uterine cancer such
as: taking hormone therapy with progestin, a history of using birth control pills to
regulate cycles, and maintaining a healthy weight.
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