Bohomolets Oncology Lecture Methodical #3


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By Dr.Olga Lobanova from Oncology department

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Bohomolets Oncology Lecture Methodical #3

  1. 1. 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 facultiesWorked 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
  2. 2. 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 facultiesWorked 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
  3. 3. The texts of the lectures are approved by the methodical counselof Oncology Department.Protocol № 19 « 17 » march 2008.
  4. 4. CONTENTSLecture 12Tumors of the soft tissueLecture 13Skin cancerLecture 14MelanomaLecture 15Cervical cancerLecture 16Ovarian cancerLecture 17Uterine cancerLiterature
  5. 5. Lecture 12Tumors of the soft tissue Sarcomas are malignant (cancerous) tumors that develop in tissues whichconnect, support, or surround other structures and organs of the body. In general, softtissue sarcomas do not seem to result from malignant changes or the dedifferentiationof benign soft tissue tumors, and despite the variety of histologic subtypes, soft tissuesarcomas have many clinical and pathologic features in common. The dominantpattern of metastasis is hematogenous. Lymph node metastasis is rare (less than 5%). Soft tissue sarcomas are rare. These neoplasms constitute only 0,2-2,6% of themalignant tumors and affect almost equal often men and women, more common inthe age of 20-50 years. However, sarcomas occur more often in children and youngadults. 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 inthe trunk (15% to 20%), head and neck area (8% to 10%), internal organs, or theretroperitoneum (15%). Some conditions of soft tissues are caused by inflammation or injury and canform a mass that looks like a soft tissue tumor. Unlike a true tumor, they do not comefrom a single abnormal cell, they have limited capacity to grow or spread to nearbytissues, and never spread through the bloodstream or lymph system. Examplesinclude nodular fasciitis and myositis ossificans, which involve tissues under the skinand muscle tissues, respectively. Although most soft tissue sarcomas do not have aclearly defined cause, researchers have identified several factors that increase thelikelihood of developing these tumors. External radiation therapy is a well-established risk factor for soft tissue sarcoma, as shown by the fact that the incidenceof sarcomas is increased eightfold to 50-fold in patients treated with radiation therapyfor cancer. The risk appears to be related to the dose of radiation. Another risk factor for soft tissue sarcomas is exposure to certain chemicals inthe workplace, including vinyl chloride, arsenic, herbicides such as phenoxyacetic
  6. 6. acids, and wood preservatives that contain chlorophenols. Chronic lymphedema (acondition in which excess fluid collects in the tissue and causes swelling) followingradiation to, or surgical removal of, lymph nodes is also a risk factor. Specific inherited genetic alterations are associated with an increased risk ofboth bone and soft tissue sarcomas. The oncogenes (ie, genes that can inducemalignant transformation and tend to drive cells toward proliferation) that have beenimplicated in the development of soft tissue sarcomas include MDM2, N-myc, c-erbB2, and members of the ras family. Amplification of these genes in severalsubtypes of soft tissue sarcomas has been shown to correlate with an adverseoutcome. Cytogenetic analysis of soft tissue tumors has also identified distinctchromosomal translocations that code for oncoproteins associated with certainhistologic subtypes. The best characterized gene rearrangements have been found inEwing’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 synovialsarcoma (SSX–SYT fusion). Tumor suppressor genes play a critical role in cell growthinhibition and can suppress the growth of cancer cells. However, these genes can beinactivated by hereditary or sporadic mechanisms. Two such genes that areparticularly relevant to soft tissue tumors are the retinoblastoma (Rb) gene and thep53 tumor suppressor gene. Mutations or deletions in the Rb gene can lead to thedevelopment of retinoblastomas and sarcomas of the soft tissue and bone. In addition,although mutations in the p53 tumor suppressor gene are the most common mutationsin human solid tumors, they have also been observed in 30% to 60% of soft tissuesarcomas. There is also a high incidence of soft tissue sarcomas in patients withgermline mutations in the tumor suppressor gene p53 (ie, the Li-Fraumeni syndrome). Certain inherited diseases are associated with an increased risk of developingsoft tissue sarcomas. Studies have focused on genetic changes that may lead to thedevelopment of soft tissue sarcomas. For example, people with von Recklinghausen’sdisease (also called neurofibromatosis type 1 and associated with alterations in theNF1 gene), hereditary leiomyomatosis and renal cell cancer syndrome (with
  7. 7. alterations in the FH gene), and hereditary retinoblastoma (with alterations in theRB1 gene) are at increased risk of developing soft tissue sarcomas. Kaposi’s sarcoma is a soft tissue sarcoma that sometimes develops in peoplewith human immunodeficiency virus (HIV) infection. The primary cause of Kaposi’ssarcoma is infection with Kaposi sarcoma-associated herpesvirus (KSHV), or humanherpesvirus 8. However, people infected with KSHV, but not HIV, rarely developKaposi’s sarcoma. Soft tissue sarcomas are grouped together because they share certainmicroscopic characteristics, have similar symptoms, and are generally treated insimilar 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. Thereare 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 lesioncompared to the amount of extra cellular matrix, nuclear features, the presence ofmitotic figures and necrosis. Staging via the TNM system is normally not used,because metastases in lymph nodes are not frequent in these lesions. Thereforestaging is based on degree of differentiation of the tumor tissue and local and distantspread 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. Fasciitisnodular; 4. Radiation fibromatosis; 5. Juvenile hyaline fibromatosis ; 6. Abdominalfibromatosis (abdominal desmoid); 7. Aggressive fibromatosis (nonabdominaldesmoid); 8. Congenital fibromatosis. C. Malignant: 1. Fibrosarcoma. II. Fat tissue tumors.
  8. 8. 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) capillaryhemangioma; 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);
  9. 9. 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 tumorsА. Benignant: mesenchymoma.B. Malignant : Malignant mesenchymoma.ХII. Tumors of the possible extragenital origin.А. Benignant. 1. Teratoblastoma.B. Malignant.
  10. 10. 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. Kaposis 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 benignsoft tissue tumor. Most are found under the skin, but they can develop anywhere inthe body. Lipoblastomas are benign fat tumors that occur in infants and young children. Hibernomas, like lipomas, are also benign fat tissue tumors. They are muchless common than lipomas.
  11. 11. Liposarcomas are malignant tumors of fat tissue. They can develop anywherein the body, but they most often develop in the thigh, behind the knee, and inside theback 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 doctorcan 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 dont 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 becausethey can start in tissues as widespread, for example, as blood vessels or intestine. Themost common of these is the fibroid tumor that develops in many women. It is reallya leiomyoma of the uterus. Leiomyosarcomas are malignant tumors of involuntary muscle tissue. They cangrow almost anywhere in the body but are most often found in the retroperitoneumand 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 isattached to bone and helps us to move). They are rare. Rhabdomyosarcomas are malignant tumors of skeletal muscle. These tumorscommonly grow in the arms or legs, but they can also begin in the head and neck area
  12. 12. and in reproductive and urinary organs such as the vagina or bladder. Children areaffected much more often than adults. Tumors of Peripheral Nerve Tissue Nerves run throughout the body. The brain and spinal cord are also consideredcentral nerve tissue. The tumors discussed here are tumors of the nerves that runthroughout the body, but not the brain or spinal cord. Neurofibromas, schwannomas (neurilemoma), and neuromas are all benigntumors of nerves. These tumors can occur almost anywhere in the body. An inheritedcondition called neurofibromatosis or von Recklinghausen disease causes people todevelop many neurofibromas throughout their body. Some of these, if they formedfrom very large nerves such as those in the upper arms or neck, can becomemalignant. Malignant schwannomas, neurofibrosarcomas, or neurogenic sarcomas aremalignant tumors of the cells that surround a nerve. A new name for these ismalignant peripheral nerve sheath tumors. Tumors of Joint Tissue All of our joints are surrounded by tough tissue called synovium, whichproduces 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 inthe hands and is more common in women than in men. Synovial sarcoma is a malignant tumor of the tissue around joints. The mostcommon locations are the knee and ankle. Other sites are the shoulder and hip. Ittends to occur mostly in children and young adults, but can also occur in olderpeople. 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 sometimesdisappear without treatment.
  13. 13. Glomus tumors are benign perivascular (around blood vessels) tumors. Theyusually are found under the skin of the fingers. Hemangiopericytoma is a tumor of perivascular tissue. It most often developsin the legs, pelvis, and retroperitoneum (the back of the abdominal cavity). It is mostcommon in adults. These can be either benign or malignant. They don’t often spreadto distant sites, but tend to come back where they started, even after surgery. Hemangioendothelioma is a blood vessel tumor that is less aggressive thanhemangiosarcoma but still considered a low-grade cancer. It usually invades nearbytissues and sometimes can spread to distant parts of the body (metastasize). It maydevelop in soft tissues or in internal organs, such as the liver or lungs. Angiosarcomas are malignant tumors that can develop either from bloodvessels (hemangiosarcomas) or from lymph vessels (lymphangiosarcomas). Thesetumors can sometimes develop in a part of the body that has been exposed toradiation. Angiosarcomas are sometimes seen in the breast after radiation therapy forbreast cancer or in the arm on the same side as a breast that has been irradiated orremoved by mastectomy. Kaposi sarcoma is a tumor formed by cells similar to those lining blood orlymph vessels. It is most common in people with human immunodeficiency virus(HIV) infection and the acquired immunodeficiency syndrome (AIDS), but it can alsodevelop in organ transplant patients who are taking medication to suppress theirimmune system. It is probably related to infection with a virus called humanherpesvirus-8 (HHV-8). Lymphangiomas are benign lymph vessel tumors that are usually present atbirth. Lymph is a type of fluid that circulates in every tissue of the body, ending up inthe 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 otherorgans in the body.
  14. 14. Fibromas, elastofibromas, superficial fibromatosis, and fibrous histiocytomasare all benign tumors. Fibrosarcoma is cancer of fibrous tissue. It usually affects the legs, arms, ortrunk. 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 betweenfibrosarcoma and benign tumors such as fibromas and superficial fibromatosis. Theytend to grow slowly but, often, steadily. At one time they were called desmoidtumors, when they were closely attached to skeletal muscles. Now they are calledmusculoaponeurotic fibromatosis. They do not metastasize, but they can invadenearby tissues and are sometimes fatal. Some doctors consider these to be a type oflow-grade fibrosarcoma; others believe they are a unique type of fibrous tissuetumors. Certain hormones, particularly estrogen, increase the growth of somedesmoid tumors. Antiestrogen drugs are sometimes useful in treating desmoids thatcannot be completely removed by surgery. Dermatofibrosarcoma protuberans (DFSP) is a slow-growing cancer of thefibrous tissue beneath the skin, usually in the trunk or limbs. It invades nearby tissuesbut 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 mostcommon in older adults. Although it mostly tends to grow locally, it can spread todistant sites. Tumors of Uncertain Tissue Type Through microscopic examination and other laboratory tests, doctors canusually find similarities between most sarcomas and certain types of normal softtissues. However, some sarcomas have not been linked to a specific type of normalsoft tissue. Myxoma is a benign tumor that usually is located in muscles but does notdevelop from muscle cells. The cells of a myxoma produce mucus-like material, afeature that distinguishes this tumor. It almost always occurs in adults.
  15. 15. Granular cell tumors are usually benign tumors of adults that occur often in thetongue but can be found almost anywhere in the body. Malignant mesenchymoma is a rare type of sarcoma that contains some areasshowing features of fibrosarcoma and other areas with features of at least two othertypes 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 orlegs. Under the microscope, it shares some features with malignant melanoma, a typeof cancer that develops from pigment-producing skin cells. How cancers with thesefeatures develop in parts of the body other than the skin is not known. Desmoplastic small cell tumor is a rare sarcoma of adolescents and youngadults, 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 areall quite rare. Clinical Presentation Soft tissue sarcomas usually appear as a lump or mass, but they rarely causepain, swelling, or other symptoms. A lump or mass might not be a sarcoma; it couldbe benign, a different type of cancer, or another problem. The size at presentationusually depends on the location of the tumor. Tumors in the distal extremities areoften small when discovered, whereas tumors in the proximal extremities andretroperitoneum can become quite large before they are apparent. Soft tissuesarcomas 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
  16. 16. symptoms or neurologic symptoms related to compression of the lumbar or pelvicnerves. 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, orlymphoma, must also be considered. Small lesions that have not changed for severalyears may just be closely observed. However, biopsy should be considered in patientswith all other types of tumors to establish a definitive diagnosis. Diagnostic Imaging The doctor performs a physical exam and may use the following proceduresand 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.
  17. 17. 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 mostsoft tissue sarcomas, particularly when it is performed in conjunction with clinicaland imaging studies. Fine-needle aspiration biopsy is the procedure of choice toconfirm or rule out a metastatic focus or local recurrence. If tumor grading is essentialfor treatment planning, fine-needle aspiration biopsy has limitations. However, an
  18. 18. interventional radiologist may need to perform the biopsy of deeper tumors undersonographic or CT guidance. The diagnostic accuracy of fine-needle aspirationbiopsy-based findings in patients with primary tumors ranges from 60% to 96%. Ingeneral, the amount of material obtained by fine-needle aspiration biopsy is small, andthe diagnostic accuracy clearly depends on the experience and skill of thecytopathologist. Core-needle Biopsy Core-needle biopsy is a safe, accurate, and economical procedure fordiagnosing soft tissue sarcomas. In addition, enough tissue is usually obtained for usein several diagnostic tests, such as electron microscopy, cytogenetic analysis, andflow cytometry. Complications occur in less than 1% of patients who undergo coreneedle biopsy. The use of CT or sonography to guide a core-needle biopsy canincrease the yield of tumor tissue by more accurately pinpointing the location of thetumor. Obviously, it is particularly important to precisely locate the needle in thetumor mass to avoid sampling necrotic or cystic areas of the tumor that are of nodiagnostic value. The diagnostic accuracy of core-needle biopsy-based findings isreported 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 aspirationbiopsy or core-needle biopsy specimens yield nondiagnostic findings. An open biopsyideally should be performed in a designated treatment center by the same surgeonwho will perform the definitive surgery. The biopsy incision should be orientedlongitudinally along the extremity to allow a subsequent wide local excision thatencompasses the biopsy site, scar, and tumor en bloc. A poorly oriented biopsyincision can result in an excessively large surgical defect from a wide local excision,which in turn necessitates a larger postoperative radiation therapy field to encompassall tissue at risk. Adequate hemostasis must also be achieved at the time of biopsy toprevent the dissemination of tumor cells resulting from the formation of hematomas inadjacent tissue planes.
  19. 19. Excisional Biopsy An excisional biopsy of easily accessible (superficial) extremity or truncallesions smaller than 3 cm can often be performed. However, the benefits of excisionalbiopsies rarely exceed those of other biopsy techniques, and these procedures mayalso 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.
  20. 20. Treatment for soft tissue sarcomas is determined mainly by the stage of thedisease. The stage depends on the size of the tumor, the grade, and whether thecancer 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 criticalimportance in choosing the appropriate primary treatment strategy for patients withsoft tissue sarcomas. An intact primary tumor following biopsy affords the bestopportunity for the treatment planning team to evaluate the tumor’s proximity to vitalstructures and for the surgeon to achieve a surgical resection with negative histologicmargins. In addition, the tumor can serve as a biologic marker of response in patientswho are to be enrolled in preoperative treatment protocols. The overall five-year survival rate in patients with soft tissue sarcomas of allstages remains only 50% to 60%. Most patients die of metastatic disease, whichbecomes evident within two to three years of the initial diagnosis in 80% of cases.However, several subsets of patients have benefited from multimodality treatmentapproaches. For example, a multidisciplinary approach is taken in patients with softtissue sarcomas of the extremities; it includes a margin-negative resection plusradiation therapy to the tumor bed and has resulted in local control rates up to andexceeding 90%. Nonetheless, despite improvements in local control rates, metastasisand death remain significant problems in patients with high-risk soft tissue sarcomas.Patients considered at high risk of recurrence and death include those presenting withmetastatic disease, localized sarcomas at sites other than the extremities, or sarcomaslarger than 5 cm of an intermediate or high histologic grade (T2). Patients withabdominal sarcomas continue to show particularly high rates of recurrence and pooroverall survival. Surgery is the usual treatment for soft tissue sarcomas. For surgery to beeffective, the surgeon must remove the entire tumor with negative margins. Somepatients need reconstructive surgery. The type of surgical resection is determined byseveral factors, including tumor location, tumor size, the depth of invasion, theinvolvement of nearby structures, the need for skin grafting or autogenous tissue
  21. 21. reconstruction, and the patient’s performance status. Local therapy consisting ofsurgery, either alone or in combination with radiation therapy when wide pathologicmargins are limited by anatomic constraints, is the approach taken in patients withsmall (less than 5 cm) primary tumors with no evidence of distant metastatic disease.However, amputation remains the treatment of choice for the estimated 5% ofpatients whose tumor cannot be grossly resected with a limb-sparing procedure thatpreserves function. Wide local excision is the primary treatment strategy forextremity sarcomas, with the goal to resect the tumor with a 2-cm margin ofsurrounding normal soft tissue. The biopsy site or tract (if applicable) should also beincluded en bloc with the resected specimen. Soft tissue sarcomas are generallysurrounded 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 mustalways be considered when planning surgery and radiation therapy. Patients withmicroscopically positive surgical margins are at increased risk of local recurrence.Indeed, margin status after surgical resection is an independent prognostic factor forlocal recurrence. However, negative margins cannot be attained in some anatomicareas because of the tumor’s proximity to vital structures. In addition, because neithera positive surgical margin nor local recurrence has been shown to clearly adverselyaffect overall survival, this should be taken into consideration if achieving clearsurgical margins would require amputation or substantial functional compromise of anextremity. • 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).
  22. 22. • 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 thefollowing:High-dose chemotherapy with stem cell transplant High-dose chemotherapy with stem cell transplant is a method of giving highdoses of chemotherapy and replacing blood -forming cells destroyed by the cancertreatment. Stem cells (immature blood cells) are removed from the blood or bonemarrow of the patient or a donor and are frozen and stored. After the chemotherapy iscompleted, the stored stem cells are thawed and given back to the patient through aninfusion. These reinfused stem cells grow into (and restore) the bodys blood cells. Targeted drug therapy Targeted therapy is a type of treatment that uses drugs or other substances tofind 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 blocksan abnormal protein on cancer cells that causes them to divide and grow. Targetedtherapy may be used for gastrointestinal stromal tumors that cannot be removed bysurgery 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).
  23. 23. Lecture 13Skin cancer Precancerous skin diseases Non-cancerous skin growths – is a big and various in its origin group oftumors. 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 skinatrophy, atheroma, deep skin mycosis, keratoachanthoma, papilloma, red flat herpes. Skin horn is cone-shaped new growth, which stands out of the skin level, ithas thick brown corneous surface and soft tissue. Most often it is localized on theface 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. Thetreatment is surgical operation. Keratosis is characterized by dystrophic skin changes, which are presented bythe spots of keratinized layers of different thickness, grayish-yellowish color. Mostlylocalized on the face skin, hairless part of head, body skin. The treatment is surgicaloperation – excision and electrocoagulation. Senile skin atrophy – it is shown by the thinning of the skin. In this case theskin is withered, wrinkled, it peels off, it is possible to see the enlarged small bloodvessels. (telangiectasis ). The treatment is surgical operation. Keratoachanthoma – non-malignant growth of the epidermis, which is hardlydistinguished from the skin cancer not only clinically but also histologically.Therefore it has many synonyms: plural self-cured skin carcinoma, sebaceousmollusk etc. Mostly elderly people have it, it is single, mainly it is localized on theface skin, on the hands. Clinically it is thick, quickly growing nodule havinghemispherical surface and a cavity in the center, covered by x-disease-shaped coat. It
  24. 24. 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 andis considered as rare hereditary diseases, originated from the DNA inability to restorethe damage caused by the ultra-violet rays. The disease is manifested by theheightened sensibility to the sun rays from childhood. In the beginning especially onthe open body parts disseminated skin pigmentation as plural spots and frecklesappears. The skin swells, gets red. Erythema is changed to disseminated roundedpigment spots. Further skin becomes withered, here and there it is atrophic, easilydamaged. Enlarged skin blood vessels are seen in these sections – telangiectasis.Gradually ulcers and warty overgrowths appear on the skin. Under existingconditions even teenagers may have basal- and planocellular cancer and alsomelanoma. In case of pigmentary parchment-skin there is a great likelihood ofprimary-plural synchronous and metachronous tumors development. If cancer appears on the background of the pigmentary parchment-skin, itdevelops slowly and is very sensitive to radiotherapy. As preventive measures againstmalignancy of the pigmentary parchment-skin it is possible to use sunscreenointments, to cover the open parts of body with the sunscreen creams. Bouen tumor – (Bouen diskeratosis) shows itself as various spots withcharacteristic polycyclic contours. Their surface is covered with hardly removedscabs. When the scabs are removed it is possible to see a smooth surface, sometimesmoist papillary surface ( eczematous type). Most often the body skin is affected. Thedisease is always ended up by malignant transformation. The treatment is excision in the limits of the healthy skin and in case of themalignization 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 alloncological growths.
  25. 25. 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 isolationlevel. 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. Itis observed that countrymen are more likely to have the skin cancer than the citydwellers. Etiology The factors which cause the skin cancer development are: high isolation, long-term 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 skinepithelium. According to the histological structure it is possible to identify two formsof the skin cancer: basal-cells (basalioma) and planocellular ( keratinized and non-keratinized). Basalioma is observed in 60% of skin cancer cases, planocellularcarcinoma is observed in 30%. Non- non-keratinized form of the planocellular canceris 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 maximummeasurement T3- the tumor is more than 5 cm in the maximum measurement T4- the tumor grows into the lower organs ( cartilages, muscles, bones).
  26. 26. In the case of synchronic primary-plural cancer, when there are several primarytumors it is necessary to indicate their number in parentheses T2 ( 5). The T value isevaluated 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 Stage III T4 N0 M0 Any T N1 M0 Stage IV Any T Any N M1 Clinical description The clinical picture of cancer depends on the histological structure, on thedifferentiation 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, externalgenitals. 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 orwhite-grey tint, which can be localized at the skin level or higher. As developed thecentral part becomes wet, erosions are created, the surface becomes rough, pinkcolored, sometimes it is bleeding, it is covered with crusts, in periphery a thick roller-shaped growth can be formed. The lower part of skin gets red, the evidence of the
  27. 27. inflammatory process appears. The characteristic feature of the tumor development isthe 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 developedthe nodules are transformed into the sores, infiltrate the subjacent tissues, the bordersget firm, become roller-shaped and unmoving when palpated, they early createmetastases in the regional lymph nodes. These forms are less successful in prognosis. The papillary forms of cancer are characterized by the partial growth into thedepth of tissue, partial growth upwards to the surface, forming exofitic component, asuneven-like growths, with clear contours. Its surface is covered by shallow sores,which often bleed. The big cancerous sores are characterized by the dense painlessmetastases in regional lymph nodes. The basal-celled cancer also in many casesappears at an elderly age and is localized mostly on the face skin. Clinically it ischaracterized by the appearance of the grey-pink dense nodule, which merges withthe skin and stands out on its surface. The tumor surface shells off, it is characterizedby the ulceration, which deepens with the growth of the tumor. The sore has thickbottom, 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 changesand the state of the patients remains satisfactory. Nodal or exofitic form of the basal-celled cancer grows as the raised on theskin surface nodule on the wide basis. Gradually deep cracks appear between separateparts, 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 itis common to use the sonography- of the distant metastases, the radiography of thepectoral cavity organs and the ultrasonography of the abdominal cavity. Thesemethods are sufficient to diagnose.
  28. 28. 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, radiotherapyand medicines. All these methods should be based on the strictly individual factors,considering the tumor localization, clinical form, the disease stage and thehistological structure. Beside that the treatment should foresee functional andcosmetic after-effects. Most of the authors believe that in the I-II stages of the diseasethe radiotherapy is the most effective method ( the most effective is closely-focusedradiotherapy, total dose is 30-60 gr.), in case of III-IV stages they use combinedmethod. The surgical method requires - wide ablation of the tumor with the healthyskin area around it ( not less than 2 cm) together with the hypodermic cellular tissueand 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 havingmetastasis, lymphadenectomia is performed at the same time with the excision. Inthose cases when the big mass of the tumor does not allow to use the above-mentioned methods of treatment, the chemotherapy is applied. In case of the basal-celled skin cancer the following methods of treatment areused: 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 (toprevent the cosmetic defects). The recovery takes place in 90 % of cases. The defect
  29. 29. of the method is – depigmentation and the skin atrophy in the area of the radiationtreatment. 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 three-fold freezing of the tumor in the scope of the 0.5-1 cm of the healthy skin until itscomplete destruction. The healing of the wound takes place under the scab during 3-4weeks with the formation of the elastic cosmetically nice scar. The relapse is treatedby the wide excision. The prognosis in skin cancer case compared with the other malignant tumorsis the most favorable. In case of the regional lymph nodes metastases absence 5-yearssurvival is guaranteed in 75-80 % of cases, and when it is early diagnosed almost80-100 % of patients completely recover and do not have relapses. 5-years survivalwith the regional lymph nodes -metastases and growing through the close organs andtissues is only 24%. Non-malignant and malignant skin tumors of the conjunctive tissue-likeorigin. Non-malignant and malignant skin tumors of the conjunctive tissue-like originare comparatively rare, more often in the young age. They are localized mostly on thebody skin and upper or lower extremities. Women have them more often. Among the non-malignant tumors the most frequent are fibroma ( soft andhard), dermatofibroma, lipoma, angioma, gemangioendotelioma, neurofibroma etc.These tumors have different size, form and consistence, they grow slowly. They maybe the source of the malignant tumors development ( sarcomas). The treatment usedhere is surgical. Skin sarcomas come to 0.3% of the malignant tumors and are found with theelderly people. The histological classification of the skin sarcomas made by F.Faitcheva andV. Andreyeva ( 1965):
  30. 30. 1.The tumors of formed dense conjunctive fibrous tissue ( fibrosarcoma anddermatosarcoma 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 theskin surface. The tumor size amounts to 10 cm and more. The color of the skin is rosywhich turns into azure-red. Fibrosarcoma grows slowly and is rarely ulcerates. Dermatosarcoma Darie – the tumor has flat plaques-like surface with theoutstanding nodules. The skin which covers them is normal. It grows slowly andrarely creates metastasis, but it can relapse. The growth of the nodules can beaccompanied 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 oftenlocalized on the abdominal wall and thorax wall. Liposarcoma is rarely found. It is clinically characterized by the appearance ofthe single nodule which is situated in the hypodermic base. Its growing speeddepends on the histological form. The differentiated sarcoma grows slowly andundifferentiated sarcoma may grow quickly. It can amount to the great size, and maybe 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 afterthe author, who first described it in 1972. There are about 35 synonyms –names ofthis tumor ( pigmentary and teleangiectatic sarcomatosis, plural angioplasticpigmentary sarcoma etc).
  31. 31. Histogenesis of this tumor is not mostly identified, but it is at the center ofattention because it belongs to the acquired immunodeficiency syndrome (AIDS). The disease starts with the appearance of several pink nodules, which arelocalized mostly in the area of distal, often symmetrical parts of the extremities. Further new dense plural nodules appear, which merge and begin to occupymore of the extremities surface or body surface, forming compact red-purple flattumors of the irregular shape. At the same time the significant hypostasis of the lowerextremities may occur - elephantiasis. In the case of AIDS the face is more likelyaffected. Patients complain about itching, pain, bleeding and lymph ( лимфотечение)of the affected areas. The tumor creates metastases. The course of the disease isenduring with the periods of remission. The process has overall character with thespreading to the proximal parts of the extremities and formation of the tumor nodulesin 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 radiotherapywith corticosteroids. In cases of the generalized forms of Kaposhy sarcomas thecytostatic 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.
  32. 32. Lecture 14Melanoma Melanoma – is the malignant pigmentary tumor. The term “melanoma” ( fromthe Greek “melanos” – black, dark) was suggested by Carswell in 1838. Thesynonyms of melanoma: melanoblastoma, novocarcinoma, melanomalignoma. Epidemiology. The melanoma constitutes 1-10% of the malignant skin tumors and 0,3-0,9% ofall malignant human tumors. According to the official returns of the Internationalanticancer union the sickness rate in case of melanoma is 0,1-6,9 persons for 100.000population in different countries of the world, and the average annual sickness raterise of this tumor in the world is about 5% ( in the USA – 4%, in Russia -3,9%) andmay be considered one of the highest among all malignant tumors. Most often themelanoma is localized on the skin ( 70-80%), rarely in the eye area ( 5-7%) and it isvery rare in the area of other organs (gullet, rectum). In the Minor Asia countries theindigenous people have melanoma 3,5 times rarely than the representatives of othernationalities, who live in those states. Etiology. There are exogenous and endogenous factors in the development of themelanoma. 1.The exogenous risk factors. This group is represented by the physical,chemical and biological agents of the environment, which can directly andimmediately 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).
  33. 33. 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 differentsize, of irregular oval shape, brown color of various intensity and strongly markedalong the edges. It has the rough surface- atrophic here and there, hyperkeratic andpapillomatous. Most often it is localized on the face skin, rarely on the body skin, onthe neck, hairy part of head, external women’s genitals. Dubrei melanosissignificantly less than the following nevuses can be the origin of the melanomadevelopment. The increased accumulation of the melanoblasts in the various skin layers iscalled nevus ( from latin naevus – birthmark). The nevuses can be innate andacquired. Blue nevus, or Yaddason Tiche nevus , also Otta nevus – is sharply boundedround or oval new growth with more or less marked pigmentation, they are rarelyfound and rarely turn into the melanoma, that is why in practical sense they are notdangerous. Gigantic pigmentary nevus- innate development anomaly. Clinically it showsitself as skin pigmentation of various size ( from the palm size or bigger on the bodyskin or extremities). The surface of the gigantic nevus can be warty, covered withdeep sores or with intensive hairiness.
  34. 34. 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 mostlylocalized on the face rarely –on the body. It is almost never becomes malignant, butpatient often address to doctor because of the cosmetic reason. Verrucous or papilloma-like nevus – growths of various shape, which raiseabove the skin surface. Their surface is uneven, sometimes hyperkeratical, from light-brown to dark-brown color. Verrucous nevus is most often localized on the body andextremities, 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 anyunpleasant sensations in the area of nevus should be regarded by the doctor as thethreat of melanoma development regardless of its belonging to the categorymelanoma -risk nevus. Pathomorphology of the melanoma. The tumor develops from the pigment cells melanocitis. It is characterized bythe presence of the melanin pigment accumulation, although there are sometimespigmentless forms. Histologically it is common to distinguish 4 types of the cellularmelanoma system: epithelial, spindle-celled, mixed and small-celled. It is hard toconsider the melanoma unambiguously among the malignant epithelial tumors ortumors of the conjunctive tissue –like ( соединительный) origin. Metastases. The melanoma occupies a special place among the malignant tumors, ascapable of quick metastases spreading. Practically there is no organs, where themelanoma could not create metastases. But primarily it creates metastases in theregional lymph nodes. It is important to note that in clinically unchanged lymphnodes of 18-40% of patients metastases are histologically found.
  35. 35. (Gematogenously) Through the blood the melanoma creates metastasespractically in all organs and tissues. With all this going on, the metastases in the innerorgans can appear earlier than in the lymph nodes. Very often gematogenousmetastases in the skin can develop. 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 invasionlevel 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)macrometastases2c)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 selectivelymphodenectomia. 2.- macrometastases - are clinically found metastases in the lymph nodes,confirmed by the therapeutical lymphodenectomia or extracapsular spreading ofmetastases in the lymph nodes. Classification according to stages: Clinical stages Morphological stages TNM pTNM
  36. 36. 0 Tis N0 M0 Tis N0 M0 IA T1a N0 M0 T1a N0 M0 IB T1b N0 M0 T1b N0 M0 T2a N0 M0 T2a N0 M0 IIA T2b N0 M0 T2b N0 M0 T3a N0 M0 T3a N0 M0 IIB T3b N0 M0 T3b N0 M0 T4a N0 M0 T4a N0 M0 IIC T4b N0 M0 T4b N0 M0 III Any T N1 M0 N2 M0 N3 M0 IIIA T1-4a N1a M0 T1-4a N2a M0 IIIB T1-4b N1a M0 T1-4b N2a M0 T1-4a N1b M0 T1-4a N2b M0 T1-4a/b N2c M0 IIIC T1-4b N1b M0 T1-4b N2b M0 Any T N3 M0 IV Any T Any N Any M 1 Any T Any N Any M1 Clinical picture. Women are more likely to have the melanoma. 35-45 % of men have thisdisease. Melanoma is mostly observed at the age of 30-60, its clinical picture can bevarious, 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 area; • Appearance of the single nodules ( satellites) around nevus;
  37. 37. • Appearance single nodules on the surface of the nevus without its visual 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 browncolor. Atypical cells are localized in the upper layers of derma, spreading in lateraldirection. The prognosis is favorable as a rule. 2. Nodule-like ( nodous, nodular) form is found in 15% of cases. The tumor isshaped like the flat nodule, rising above the skin suface, sometimes it is shaped likepolypus on the stem, of blue color, without any particular localization, and mostlyobserved at the elderly age. The tumor cells spread vertically with quick dermainvasion. The prognosis is unfavorable. 3.Acrolentigo-like and mucous melanoma ( 10% of all melanomas). Thetumor has irregular contours, black, can be pigmentless. It grows slowly in radialdirection, usually in the upper layers of derma ( on the palms, feet). The prognosisdepends on the degree of the infiltrative tumor growth. 4. Malignant lentigo (melanoma-like freckles) – the rarest form. It develops atthe age of 70. It looks like the spot-like nodules from yellow-brown to almost black
  38. 38. color, 1,5-3mm in diameter, and are formed in the smooth freckles. The tumor growsslowly, 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 itsclinical 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, tumorthermography and cytological analysis of the smears – the tumor prints, a sentinelnode biopsy. Other kinds of biopsy are prohibited. To exclude the presence ofmetastasis in the glands it is common to do the ultrasonic examination and a sentinelnode biopsy of the lymph nodes. The diagnostic puncture of the pigmentary tumorshould be as much as possible approximated to the following medical treatment(radiation treatment, surgery).The patient should be completely prepared to theadequate surgery with anesthesia. Another valuable additional examination is radioisotope scanning with the helpof radio-active 32 P. The criteria of malignant mutation for melanoma is threefoldincreasing ( 300%) of the phosphorus accumulation over the tumor during 72 hours.This method allows to diagnose lymphogenous and gematogenous metastases of thetumor. Also rontgenologic and sonographic examination is performed, to diagnoseregional and distant metastases. Also as a way to diagnose they use total cuttingexcisionary 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
  39. 39. • onihomikosis • extrasexual chancre • metastases of the other histogenesis tumors into the skin The treatment of the skin melanoma is mostly surgical. The surgical treatmentcan be a part of the combined or complex treatment. The main requirements to thesurgical 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 thetumor 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.
  40. 40. Besides the tumor excision it is possible to perform immunotherapy usinginterferon a-2b 3 ml ME/m2 of hypodermic injection 3 times per week during 3 yearsor 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 andmore combined with the regional lymphodenectomia. In case of need there can beplastic replacement of the skin defect. Chemotherapy ( chemoimmunotherapy),immunotherapy ( interferon a-2b,БЦЖ), polychemotherapy should be performed inusual or modified ( hyperthermia, hyperglycemia etc) conditions. Aspolychemotherapy dacarbasin is used combined with the medications of platinum( cisplatin), alkaloids of periwinkle ( vinblastin), the medications of urea nitromesilgroup (lomustin). The effectiveness of polychemotherapy in this combination is30-40%, 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 thechemotherapy, the standard of this tumor treatment is systemic chemotherapy. Theobjective reaction to dacarbasin ( DTIC) and the derivatives of nitrosourea- carmustin( BCNU), lomustin (CCNU) do not exceed 20-25%. Most patients are observed tohave remissions from 3 to 6 months, although in some cases there are more prolongedremissions. Along with monotherapy it is possible to apply multi-component schemesincluding chemotherapeutic medicines, such as vinkaalkaloids, the derivatives ofplatinum and taxans. The surgical treatment of IV stage melanoma can be performedin the presence of the single metastases in the lungs, gastrointestinal tract, bones orbrain. Palliative resections are done, which in some cases are very effective andsignificantly prolong life. For the cytoreductive purpose palliative lymphadenectomycan be performed. Although the melanoma is rather radioresistant tumor, palliativeradiotherapy can relieve the patients state. Retrospective researches testify that withthe patients with plural metastases in the brain, the skeleton bones and the spinal
  41. 41. cord compression it is possible to achieve the significant reduction of the symptomsand the decrease of the tumor size by means of radiotherapy. It is not establishedhowever what function procedure is the most effective in case of the radiotherapyapplied to the bones and spinal cord metastases. In addition to melanoma treatmentmain 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 orhypodermic 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 fromthe postoperative scar. The standard treatment of the local relapses is an excisionwithin the limits of the healthy tissues ( 1-3cm, depending on the anatomiclocalization). The alternative method of the local relapses treatment of the melanomaon the extremities is regional hyperthermic perfusion. The frequency of the complete remissions when using tumor-necrotic factorsand melfalan attains 90%. In case of the absence of the complete regress the residualchanges should be excised. Since the regional relapses in more than the half patients’cases are accompanied transit metastases, the performance of the regionalchemotherapy becomes especially urgent. The influence of the regional perfusion onthe patients survival is not proved. The prognosis. The prognosis in case of the skin melanoma depends on many factors, butmainly on the progress stage, localization, size, the growth form of the tumor, on thepatients 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 thedistant metastasis 5-years survival does not exceeds 5-12%.
  42. 42. Lecture 15Cervical cancerEpidemiology Cervical cancer is a malignancy of the cervix. Worldwide, it is the second-mostcommon cancer of women. It may present with vaginal bleeding but symptoms maybe absent until the cancer is in its advanced stages, which has made cervical cancerthe focus of intense screening efforts utilizing the Pap smear. Most scientific studieshave found that human papillomavirus (HPV) infection is responsible for more than90% of the cases of cervical cancer. According to a survey of 3,076 women 18 to 75years of age, awareness about human papillomavirus (HPV) infection and its link tocervical cancer is relatively low among American women. In 2006 an estimated10,000 women in the United States will be diagnosed with this type of cancer andnearly 4,000 will die from it. Worldwide, cervical cancer is the second most common cancer in women (afterbreast cancer) and is the third leading killer (behind breast and lung cancer). It affectsabout 16 per 100,000 women per year and causes death in about 9 per 100,000 peryear. In the Ukraine, howeever, cervical cancer is the 3th most common cancer ofwomen. About 12,800 women in the Ukraine are diagnosed with cervical cancer andabout 4,800 die each year. Among gynecological cancers it ranks behind endometrialcancer 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
  43. 43. Cervical cancer caused by a sexually transmitted agent. Initial research in the1950s and 1960s put the blame on smegma (e.g. Heins et al 1958), but it wasnt untilthe 1970s that human papillomavirus (HPV) was identified. A description by electronmicrocopy was given earlier in 1949 and HPV-DNA was identified in 1963. It hassince been demonstrated that HPV is implicated in all cervical cancers. Specific viralsubtypes 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 thecancer. 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 bothcan. 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 tomajor abnormalities or cervical cancer. Doctors can test samples of cervical cells to determine types of HPV that may bepresent. In some cases, HPV clears up on its own, and in some, there were no signsuntil it was too late, and cervical cancer developed.Risk factors The following list of risk factors for cervical cancer: human papillomavirusinfection, smoking, HIV infection, chlamydia infection, dietary factors, oralcontraceptives, 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 theprime risk factor for cervical cancer. The presence of HPV is a necessary conditionfor the development of cervical cancer. A virus cancer link with HPV has been foundto trigger alterations in the cells of the cervix, leading to the development of cervicalintraepithelial neoplasia and cancer. HPV subtypes 16 and 18 introduce two genescalled E6 and E7 which code for proteins that inhibit p53 and Rb, which are twoimportant tumor suppressor genes in humans. The p53 gene product is involved inregulation of apoptosis (cell suicide), and Rb is responsible for halting the cell cycleat the G1-phase. When Rb function is impaired, the cell is allowed to progress to S-
  44. 44. phase and complete mitosis, resulting in proliferation and hence neoplastictransformation. Genital warts are caused by different HPV types, and are not related to cervicalcancer. The medically accepted paradigm, that a patient must have been infected withHPV to develop cervical cancer, and is hence viewed as a sexually transmitteddisease. Not all women infected with HPV also develop cervical cancer. Use ofcondoms will not always prevent transmission. Likewise, HPV can be transmitted byskin-to-skin-contact with infected areas. HPV is thought to grow preferentially in theepithelium of the glans penis, and scrupulous washing and cleaning of this area maybe preventative. The position on circumcision is controversial: some researchersargue that routine neonatal circumcision is an acceptable way of preventing variousdiseases (which include cervical carcinoma); others maintain that the benefits do notoutweigh the risks. However, there has not been any definitive evidence to supportthis claim.Symptoms The early stages of cervical cancer may be completely asymptomatic. Vaginalbleeding, contact bleeding or (rarely) a vaginal mass may indicate the presence ofmalignancy. Also, moderate pain during sexual intercourse and vaginal discharge aresymptoms of cervical cancer. In advanced disease, metastases may be present in theabdomen, lungs or elsewhere. Symptoms of advanced cervical cancer may include:Loss of appetite, Weight loss, Fatigue, Pelvic pain, Back pain, Leg pain, Singleswollen leg, Heavy bleeding from the vagina, Leaking of urine or feces from thevagina, and Bone fractures The possibility to identify premalignant changes on a cervical smear has madescreening the major cause for referral of women with possible cervical neoplasia. Inmany countries, women are advised to have a regular Pap smear to check forpremalignant changes. Recommendations for how often a Pap smear should be done vary from once ayear to once every five years. If cervical cancer is detected early, it can be treated
  45. 45. without impairing fertility. Consistently abnormal smears may be a reason for furtherdiagnosis despite complete absence of symptoms.Diagnosis Diagnosis is made by doing a biopsy of the cervix, which often involvescolposcopy, or a magnified visual inspection of the cervix aided by using an aceticacid (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 researchersrecommend that since more than 99% of invasive cervical cancers worldwide containhuman papillomavirus, HPV testing should be carried out together with routinecervical screening (Walboomers et al, 1999). However, given the prevalence of HPV(around 80% infection history among the sexually active population) others suggestthat routine HPV testing would cause undue alarm to carriers. Further diagnostic procedures are loop electrical excision procedure (LEEP) andconisation, in which the inner lining of the cervix is removed to be examinedpathologically. 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 clinicalexamination, rather than surgical findings. It allows only the following diagnostictests to be used in determining the stage: palpation, inspection, colposcopy,endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, intravenousurography, and X-ray examination of the lungs and skeleton, and cervical conization. The TNM staging system .
  46. 46. 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 non-functioning kidney IVA - invades mucosa of bladder or rectum and/or extends beyond true pelvis IVB - distant metastasis Treatment consists of chemotherapy and radiotherapy
  47. 47. Note that the FIGO stage does not incorporate lymph node involvement incontrast to the TNM staging for most other cancers. For cases treated surgically, information obtained from the pathologist can beused in assigning a separate pathologic stage but is not to replace the original clinicalstage. For premalignant dysplastic changes, the CIN (cervical intraepithelial neoplasia)grading is used. Treatment Treatment consists of surgery (including local excision) in early stages andchemotherapy and radiotherapy in advanced stages of the disease. An effectivevaccine, the HPV vaccine, for the two most common strains of HPV has recentlybeen licenced. Microinvasive cancer (stage IA) is usually treated by hysterectomy (removal ofthe whole uterus including part of the vagina). For stage IA2, the Lymph nodes areremoved as well. An alternative for patients who desire to maintain fertility is a localsurgical procedure such as a LEEP or cone biopsy. If a cone biopsy was not able to produce clear margins, there is one possibleoption left for those with early stage cervical cancer who would like to preserve theirfertility while treating their cervical cancer: a trachelectomy. For those in stage Icervical cancer, which has not spread, this is a viable treatment option. It allows forthe preservation of the ovaries and uterus while surgically removing the cervicalcancer. This treatment option is not yet well known amongst doctors and is not yetconsidered a standard of care. Furthermore, few doctors are trained in this fertilitysparing surgical option. Even the most experienced surgeon wont be able to promisethat this can be performed beforehand, as the extent of the spread of cervical cancer isunknown until surgical microscopic examination is completed. As a result, there isalways the possibility for the need to convert to a hysterectomy if the surgeon is notable to microscopically confirm clear margins of cervical tissue once the patient isunder general anesthesia in the operating room. This can only be done during the
  48. 48. same operation if the patient has given consent for a possible hysterectomy prior tothe operation. Due to the fact of the possible risk of cancer spread to the lymph nodes in stage1b cancers and some stage 1a cancers, the surgeon may also need to remove somelymph nodes from around the womb. Once all the checks have been done and if all iswell, the cervix will be stitched closed with a cerclage. This will allow formenstruation and fertilization but not dilation for a vaginal delivery, thereforerequiring any future births are delivered by cesarean section. A radical trachelectomyis a smaller operation than hysterectomy, but more importantly allows for thepreservation of fertility. This operation can also be performed vaginally instead ofabdominally, however there are conflicting opinions as to which approach is better. Aradical abdominal trachelectomy with lymphadenecectomy usually only requires a 2-to 3-day hospital stay with most women recovering very quickly (approximately 6weeks). Complications are generally uncommon, although women who are able toconceive after surgery are prone to preterm labor or possible late miscarriage. It isgenerally recommended to wait at least one year before attempting to becomepregnant after surgery. Recurrence in the residual cervix is a very rare event as longas the cancer has been cleared with the trachelectomy. Even though recurrence israre, it is generally recommended for patients to practice vigilant prevention andfollow up care including pap screenings/colposcopy, with biopies of the remaininglower uterine segment as needed (every 3-4 months for at least 5 years) to monitor forany recurrance in addition to minimizing any new exposures to HPV through safe sexpractices until one is actively trying to conceive. Early stages (IB1 and IIA less than 4 cm) can be treated with radicalhysterectomy with removal of the lymph nodes or radiation therapy. Radiationtherapy is given as external beam radiotherapy to the pelvis and brachytherapy(internal radiation). For patients treated with surgery who have high risk featuresfound on pathologic examination, radiation therapy with or without chemotherapy isgiven in order to reduce the risk of relapse.
  49. 49. Larger early stage tumors (IB2 and IIA more than 4 cm) may be treated withradiation therapy and cisplatin-based chemotherapy, hysterectomy (which thenusually requires adjuvant radiation therapy), or cisplatin chemotherapy followed byhysterectomy. Advanced stage tumors (IIB-IVA) are treated with radiation therapy andcisplatin-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 DrugAdministration approval on June 8, 2006. Gardasil is targeted at girls and women ofage 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. Theuse of the vaccine in men to prevent genital warts and interrupt transmission towomen is initially considered only a secondary market. The high cost of this vaccinehas been a cause for concern. Gardasil has received EU approval. Glaxosmithkline has developed a vaccine called Cervarix™ which has beenshown 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 causeabout 70% of cervical cancer cases. Cervarix should be approved by years end.
  50. 50. Lecture 16Ovarian cancer Epidemiology Ovarian cancer is the fifth leading cause of cancer death in women, the leadingcause of death from gynecological malignancy, and the second most commonlydiagnosed gynecologic malignancy. It is idiopathic, meaning that the exact cause isusually unknown. The disease is more common in industrialized nations, with theexception of Japan. In the United States, females have a 1.4% to 2.5% (1 out of 40-60women between 55 and 74 years of age and approximately one quarter of ovariancancer deaths occur in women between 35 and 54 years of age) lifetime chance ofdeveloping 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 ovariancancer 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 atfirst pregnancy, older ages of final pregnancy and the use of low dose hormonalcontraception have also been shown to have a protective effect. Ovarian cancer isreduced in women after tubal ligation. The link to the use of fertility medication, such as Clomiphene citrate, has beencontroversial. An analysis in 1991 raised the possibility that use of drugs mayincrease the risk for ovarian cancer. Several cohort studies and case-control studieshave been conducted since then without providing conclusive evidence for such alink. It will remain a complex topic to study as the infertile population differs inparity 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 insome populations (e.g. Ashkenazi Jewish women) are at a higher risk of both breastcancer 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 breastand/or ovarian cancer, especially if at a young age, may have an elevated risk. A
  51. 51. strong family history of uterine cancer, colon cancer, or other gastrointestinal cancersmay indicate the presence of a syndrome known as hereditary nonpolyposiscolorectal cancer (HNPCC, also known as Lynch II syndrome), which confers ahigher risk for developing ovarian cancer. Patients with strong genetic risk forovarian cancer may consider the use of prophylactic oophorectomy after completionof child-bearing. A Swedish study, which followed more than 61,000 women for 13 years, hasfound a significant link between milk consumption and ovarian cancer. According tothe 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 thosewho did not consume it at all, or only in small amounts." Recent studies have shownthat women in sunnier countries have a lower rate of ovarian cancer, which may havesome 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 havenot been definitively proven. "Associations were also found between alcohol consumption and cancers of theovary and prostate, but only for 50 g and 100 g a day." Although 20% to 25% of all benign and malignant ovarian neoplasms are ofgerm cell origin, only about 3% of these tumors are malignant. Germ cellmalignancies account for less than 5% of all ovarian cancers in Western countries butthey represent up to 15% of ovarian cancers in Asian and black societies, whereepithelial ovarian cancers are much less common. Classification I. Histology Ovarian cancer is classified according to the histology of the tumor. Lesions differsignificantly in clinical features, management, and prognosis (ICD-O codes providedwhere available):  Surface epithelial-stromal tumours are the most common and prototypic ovarian cancers. They are thought to originate from the ovarian surface lining, and
  52. 52. 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 Sertoli- Leydig 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 ofmetastasis from primary cancers elsewhere in the body. For example, from breastcancer, or from gastrointestinal cancer (in which case the ovarian cancer is aKrukenberg cancer). III. Staging Ovarian cancer staging is by the FIGO staging system and uses informationobtained 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.
  53. 53. Stage I - limited to one or both ovariesIA - involves one ovary; capsule intact; no tumor on ovarian surface; no malignant cells in ascites or peritoneal washingsIB - involves both ovaries; capsule intact; no tumor on ovarian surface; negative washingsIC - tumor limited to ovaries with any of the following: capsule ruptured, tumor on ovarian surface, positive washings Stage II - pelvic extension or implantsIIA - extension or implants onto uterus or fallopian tube; negative washingsIIB - extension or implants onto other pelvic structures; negative washingsIIC - 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 pelvisIIIB - macroscopic peritoneal metastases beyond pelvis less than 2 cm in sizeIIIC - 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