METASTATIC TUMORS OF THE JAW
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METASTASIS...ROUTES ...METASTATIC CASCADE......THEORIES.....JAW METASTASIS
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METASTATIC TUMORS OF THE JAW
- 1. METASTATIC TUMOURS OF THE JAW DR UPAMA SISHAN
- 2. 2 Metastasis History Metastatic cascade Routes of metastasis Molecular mechanism of metastasis Metastatsis to Orofacial region Metastatic tumours of the jaw Classification
- 4. 4 What is cancer metastasis? The process of metastasis involves invasion of lymphatics, blood vessels or body cavities by tumour followed by transport and growth of secondary tumor masses that are discontinuous with the primary tumor. ROBBINS Approx 30% of newly diagnosed patients with solid tumours present with metastases. They are the major cause of cancer-related morbidity and mortality.
- 5. LeDran 1757: Noted that malignant tumors begin as localized disease, then spread to regional lymph nodes & then enter the circulation to subsequently appear in the lung Bichat 1801: Tumors contain both parenchyma and stroma Recamier 1829 : Used the term “Metastases” Metastasis Pre-1900
- 6. Breach the underlying basement membrane Transverse the interstitial connective tissue Penetrate the vascular basement membrane
- 7. METASTATIC CASCADE: 2 PHASES: (1)INVASION OF EXTRACELLULAR MATRIX Detachment of the tumor cells from each other Attachment to the matrix components Degradation of ECM Migration of tumour cells (2) VASCULAR DISSEMINATION AND HOMING OF TUMOR CELLS
- 9. DETACHMENT OF THE TUMOR CELLS FROM EACH OTHER 1. Normal cells are adhered to one another via transmembrane glycoproteins (E-cadherins) 2. Downregulation of E-cadherin expression 3. Decreased ability for adherence and facilitation of detachment from the primary tumour
- 10. ATTACHMENT TO THE MATRIX COMPONENTS 1. Expression of integrins by tumour cells serve as receptors for ECM components 2. Receptor-mediated attachment of tumour cells to laminin & fibronectin 3. Increased density of receptors = increased invasiveness
- 12. DEGRADATION OF ECM 1. Secretion of proteolytic enzymes by tumour cells 2. Induction of host cell protease synthesis (eg. type IV collagenase) 3. Cleavage of type IV collagen of the epithelial & vascular basement membranes
- 13. Matrix degrading proteases can be classified into four major classes, depending on the nature of the active sites, which are 1. Matrix metalloproteinases 2. Serine proteinases 3. Cysteine proteinases 4. Aspartyl proteinases Metalloproteinases MMP2 and MMP9 - collagen IV MMP1 - collagen I
- 14. MIGRATION OF TUMOUR CELLS 1. Cleavage products of matrix components have growth-promoting, angiogeneic and chemotactic activities 2. Promotion of migration of tumour cells through loosened ECM, and through the degraded basement membrane
- 15. During cancer progression, a variety of tumor cells show changes in their plasticity by morphological & phenotypical conversions Epithelial to mesenchymal transition (EMT) Collective to amoeboid transition (CAT) Mesenchymal to amoeboid transition (MAT)
- 19. ROUTES OF METASTASIS Metastasis occurs by following four routes: 1. Transcoelomic 2. Lymphatic spread 3. Haematogenous spread 4. Transplantation or implantation
- 21. MOLECULAR GENETICS OF METASTASIS DEVELOPMENT metastasis is genetically controlled with the involvement of both enhancing and suppressing modifiers
- 22. Metastasis Promoting Genes Gene Tissue Site Function ARM-1 Lymphoma Promotes adhesion of tumor cells to the endothelium ATX Breast, Liver, Lung, Melanoma, Teratocarcinoma cytoskeletal reorganization and motility; G- protein coupled receptor activation CD44 Multiple sites cell-cell interactions; activates HGF/c-Met pathway Cox2 Breast, Colorectal, Gastric Prostaglandin synthase; induces VEGF Cyr61 Breast Mediates adhesion; Erb-B2/3/4 pathway Ezrin Liver, Ovary, Pancreas, Prostate, Uterus Membrane-cytoskeletal linker; RHO and RAC interactions HMG-I(Y) Breast, Cervical, Colorectal, Prostate, Skin, Thyroid, Uterus Regulated by EGF and MMP-9 Laminin-5 Multiple sites EGF and TGF-a induce expression of laminin subunits; cell adhesion, motility c-Met Multiple sites Activated by HGF; Modulates Ras and PI3 kinase
- 23. Metastasis Suppressor Genes - I Gene Tissue Site Function Annexin7 Prostate calcium-dependent GTPase; substrate for PKC and other kinases associated with proliferation BRMS1 Breast, Melanoma gap-junctional communication CC3 Colon, Lung serine/threonine kinase CEACAM1-4S Breast, Colon Bax pathway CRSP3 Melanoma transcriptional co-activator DAP-kinase Multiple sites calcium/calmodulin-dependent serine/threonine kinase; pro-apoptotic pathway E-cadherin Multiple sites Wnt signaling; cytoskeleton; cell-cell adhesion HEPSIN Ovarian, Prostate, Renal transmembrane serine protease HPIHSa Breast non-histone heterochromatin-associated protein KAI-1 Breast, Prostate Transmembrane tetraspondin; role in adhesion, motility, growth regulation, and differentiation; integrin interaction KiSS1 Breast, Melanoma Modulates Rho, Rac, and MAPK signaling Maspin Breast, Colon, Oral Squamous Cell, Prostate Serine protease inhibitor; binds collagen and can modulate integrins Melastatin Melanoma Calcium channel protein
- 24. 27 Reason for organ selectivity “Seed and soil” theory ( paget): 1899 the provision of a fertile environment in which compatible tumor cells could grow Mechanistic theory (James Ewing) : 1929 determined by the pattern of blood flow.
- 25. CHEMOKINES IN METASTASIS AND ANGIOGENESIS
- 26. Oro-facial region - rare 1-1.5% of all malignant oral tumors. Soft tissues Jaw bones Or both The jawbones were more frequently affected than the oral soft tissues. McMillan and Edwards summarized – approx 80% - mandible 15% - maxilla 5% in both the jaws the attached gingiva was the most commonly affected in the oral soft tissues. Metastasis to the oro-facial region:
- 27. 40-70 years Almost equal gender distribution in jawbone metastases Male to female ratio of 2:1 in oral soft tissues Most common sources - the lung, breast, kidney & bone. Breast - common - metastasize to the jawbones.(female patients) Lung - common source - metastasize to the oral soft tissues.(male patients)
- 28. METASTATIC TUMOURS OF THE JAW
- 29. METASTATIC TUMOURS TO THE JAW IN MEN METASTATIC TUMOURS TO THE JAW IN WOMEN
- 30. A review of literature 390 well-documented cases of metastatic lesions to the jawbones Hirshberg et al Condylar 3.5% Premolar- 38%Molar – 55% Angle and ramus – 29% Coronoid – 1.6% Mandible: 316 cases- 81% Maxilla. - 53 cases (13.6%) Both jaws - 21 cases (5.4%) -
- 31. Metastasis to the jaw bones hematogenous route requires hematopoietically active bone marrow well connected with sinusoidal vascular spaces. focal osteoporotic bone marrow defects in the edentulous mandible .
- 32. WHY BONE? (i) High blood flow especially to the red marrow coupled with abundant sinusoids (ii) Sluggish blood flow in the metaphysis facilitating intimate interaction between endothelium & tumor cells (iii) A large source of immobilized growth factors (TGF, insulin- like growth factors, FGF, PDGF, BMP’s & calcium) (iv) Continuous & dynamic turnover of bone matrix that can unlock vast resources (cytokines and growth factors) that are needed for tumor survival.
- 33. Osteolytic metastasis: Breast cancer metastases - osteolytic overexpression of osteoclast inducing factors : Parathyroid Hormone Related Protein (PTHrP), interleukin (IL)-8 and IL-11
- 34. Osteoblastic metastasis: bone morphogenetic proteins (BMPs), Wnt family ligands, endothelin-1 platelet-derived growth factor (PDGF). IGF & TGF-β
- 35. Clinical presentation grow rapidly causing pain difficulty in chewing Dysphagia disfigurement intermittent bleeding leading to poor quality of life. bony swelling with tenderness pathological fracture. tooth mobility & trismus Paresthesia in the area innervated by the mandibular alveolar dental nerve.
- 36. Hirshberg revealed 56 cases - tooth extraction preceded the discovery of the metastases. may mimic odontogenic infections & other disease conditions late diagnosis Tooth extraction can serve as a promoting factor in the metastatic process. numb chin or mental nerve neuropathy - possibility of a metastatic disease in the mandible. These features when seen in a patient with a known malignancy, it is termed as ‘mental nerve neuropathy’ or the “numb chin syndrome”
- 37. RADIOLOGICAL FINDINGS do not possess a pathognomonic radiographic appearance. the balance between osteoblastic & osteoclastic activity - the phenotype of metastatic bone lesions. from prostate cancer - form osteoblastic lesions in bone. from kidney, lung, or breast cancers are more often osteolytic. they may also occur as a solitary radiolucency of the jawbone which may simulate an infected cyst or osteomyelitis. The entire mandible - moth-eaten appearance. The cortical bone of adjacent structures such as the mandibular canal, maxillary sinus & nasal floor is resorbed.
- 38. The criteria of Clausen and Poulsen in identifying metastatic diseases of the jaw. That is: 1. The lesion must be a true metastasis localized to the bone tissue, as distinguished from direct invasion by a primary tumor of a contiguous structure. 2. The lesion has to be microscopically verified as malignant 3. The primary site of the lesion has to be known.
- 39. OSTEOLYTIC LESIONS Pulmonary carcinoma Breast carcinoma Colorectal carcinoma Oesophageal carcinoma Hepatocellular carcinoma Neuroblastoma Pancreatic carcinoma Renal carcinoma Thyroid carcinoma Prostate carcinoma Alveolar soft part sarcoma osteosarcoma OSTEOBLASTIC LESIONS Working classification
- 40. BREAST CARCINOMA Female Genetic mutation: BRCA 1, BRCA2,p53, PTEN 4th – 6th decade Buccal & lingual cortical expansion. Mandible common site Clusters & duct like arrangement of malignant epithelial cells between segments of bone and into bone marrow spaces. with large nuclei containing prominent nucleoli nested at the osseos periphery
- 42. HER2 (CD340) is an oncogene which is overexpressed in many cases of breast carcinomas most commonly used marker other markers - PR, ER etc Immunohistochemistry showing HER2 positivity in breast carcinoma metastatic to mandible.
- 43. PULMONARY CARCINOMA Most common - jaw of males. Lymphatic & hematogenous spread Insidious onset- difficult to detect- early to metastasize- poor prognosis Average survival time: 7 months 5th – 7th decade Posterior mandible - common History - smoking Solid islands of atypical epithelial cells in desmoplastic stroma. Marked nuclear pleomorphism in the tumoral islands Cytoplasmic vacuoles are seen scattered atypical mitoses focal formation of glandular structures
- 44. PTH-rp IL – 1 IL – 7 RANKL TNF- a
- 45. COLORECTAL CARCINOMA Starts in colon or rectum Gene mutation of APC, STK11 & p53 Above 50 years Male Mandible ( foll by maxilla) Multiple glandular structures Stroma desmoplastic in many areas Glandular cells show varying degrees of dysplastic features Histopathological features:
- 46. IMMUNOHISTOCHEMISTRY • shows strong positivity for CK17 & CK9 • moderate positivity for CK20, CK5/6, P53, P63 CDX2 & CEA Immunohistochemistry showing moderate staining for CDX2
- 47. RENAL CELL CARCINOMA (RCC) Begins in the proximal convoluted tubule Deletion in one or both copies of chromosome 3p Hematogenous route 5th – 6th decade Male Mandible ,maxilla & paranasal sinuses parotid & submandibular glands Expansion of cortical bone Pathological fracturesH&E stain of a clear cell RCC showing clear cells with prominent cell borders and prominent vasculature.
- 48. IMMUNOHISTOCHEMISTRY RCC will be positive with Vimentin CD10 Renal cell carcinoma marker (RCC-Ma) Epithelial Membrane Antigen (EMA Vimentin +ve tumor cells
- 49. THYROID CARCINOMA Papillary & follicular thyroid carcinoma – metastasize to jaws. More – follicular Overall mortality – 50% Clinical features: Female Mandible - molar area Painful swelling Cortical bone expansion Pathological fracture
- 50. Typical appearance of papillary carcinoma with complex and branching papillae - Enlarged & elongated nuclei with crowding & overlap - Irregular nuclear contour - Chromatin clearing with peripheral margination of chromatin, giving rise t Orphan Annie Eye nuclei;
- 51. HISTOPATHOLOGY – FOLLICULAR CARCINOMA small/medium-sized follicles containing colloid to trabecular or solid growth pattern. Microfollicular/solid pattern of growth of the neoplasia surrounded by a thick capsule displaying, focally, capsular invasion
- 52. IMMUNOHISTOCHEMICAL MARKERS HBME-1 follicular thyroid carcinoma Papillary carcinomas - express CK19 with strong diffuse cytoplasmic reactivity. This marker is expressed focally in reactive thyroid follicular epithelium.
- 53. PANCREATIC CARCINOMA Inherited gene mutations: BRCA2, P16/CDKN2A, PRSS1 Acquired gene mutations: P53,p16,KRAS, BRAF, DPC4 5TH- 6TH DECADE Male 2 cases - posterior mandible HISTOPATHOLOGIC FEATURES proliferation of tumor cells which sometimes aggregate together. These cells secrete mucin which can be seen as cystic spaces.. Tumor cells forming glands and containing intracellular mucin.
- 54. IMMUNOHISTOCHEMISTRY The tumor cells are stained positive with cytokeratin 7 and cytokeratin 9. Tumor cells positive for cytokeratin 7.
- 55. PROSTATE CARCINOMA Genetic mutation: RNASEL, BRCA1, BRCA2, MSH2, MLH1 Above 50 years HISTOPATHOLOGICAL FEATURES composed of small glands, the individual glands having a irregular round configuration & cribriform pattern.
- 56. IMMUNOHISTOCHEMISTRY Immunohistochemically, prostate carcinoma stains positive for prostate acid fosfatase
- 57. metastasis to the jaw is rare with 50 reported cases in the literature. Posterior mandibular body, ramus, condyle Hematogenous pathway 25 – 88 years Strong male predisposition HEPATOCELLULAR CARCINOMA
- 58. Cells that resemble hepatocytes growing in a trabecular Pattern. There is rich vascularity and little fibrous stroma HEPATOCELLULAR CARCINOMA IMMUNOHISTOCHEMICAL ANALYSIS Glypican-3 HepPar1 CD34
- 59. ESOPHAGEAL CARCINOMA Body and ramus of mandible - Male
- 60. Moderate to poorly differentiated primary esophageal adenocarcinoma with similar morphology to the mandibular metastasis A case of a 69 year-old male patient – Lawes et al Mandibular metastasis
- 61. IMMUNOHISTOCHEMISTRY The tumor shows positivity for CDX-2 CK7 CK15 CK20 EMA
- 62. NEUROBLASTOMA Extracranial Solid tumours in infancy and childhood. Arising from neural crest elements of SNS. Primary site – adrenal gland Mutation: ALK gene, KIF 1 B gene Mandible - common Median age – 3 years Metastasis to mandibular area is fast. composed of sheets of small cells with hyperchromatic nuclei & scanty cytoplasm. have a lobular appearance as a result of the presence of thin fibrovascular septa between groups of tumour cells. Homer wright rossette pattern seen
- 63. 26 cases of ASPS of the oral cavity reported in the literature 22 cases (84.5%) - tongue 12 cases (46%) - dorsum region 6 cases (23%) the base region 1 case - mandible. Soft tissue tumours. Weiss S.W, Goldblum ALVEOLAR SOFT PART SARCOMA PRIMARY SITES: In adults - in the lower extremities Infants and children - head and neck( orbit and tongue).
- 64. are uniformly malignant; there is no benign counterpart of the tumor microscopic picture varies little from tumor to tumor uniformity of the microscopic picture is a constant and typical feature of the lesion HISTOPATHOLOGICAL FEATURES;
- 65. Osteosarcoma is a highly malignant neoplasm of bone that rarely metastasizes to the mandible Growing parts of the skeleton metaphyseal growth plates in the femur, tibia & humerus. Related to loss of the P53 tumor suppressor gene, retinoblastoma tumor suppressor genes Equal – maxilla & mandible Mandible – posterior body & horizontal ramus Maxilla – inferior portions( alveolar ridge, sinus floor, palate) OSTEOSARCOMA
- 66. A case of osteosarcoma that metastasized to the mandibular ramus from the femur in a 36-year-old man is presented Nakamura et al Histologically the tumor consisted of consisted of islands of small round cells separated by dense fibrous tissue. The histopathologic and immunohistochemical appearances were identical to those of the femoral tumor except for osteoid formation, which was found in the femoral lesion but not in the mandibular one . Thus the lesion was histologically diagnosed as small cell osteosarcoma, metastatic from the femur.
- 67. HISTOLOGICAL FINDINGS An intraoral incisional biopsy Histopathologic examination pathologist may not provide an exact diagnosis) If any history of a previous tumor exists - compare (microscopic findings of the metastatic lesion should be with that of the primary tumor). special staining, IHC procedure & electron microscopy Once a metastatic tumor is suspected - Advanced imaging, scintigraphy & regional investigations based on the suspected source should be done to find out or confirm the origin & identify any other areas of secondary spread.
- 68. LAB TESTS BLOOD TEST URINE TESTS FNAC BIOPSY URINE TESTS IMMUNOHISTOCHEMISTRY
- 69. DIAGNOSTIC AIDS RADIOGRAPHS BONE SCAN COMPUTED TOMOGRAPHY (CT) MAGNETIC RESONANCE IMAGING (MRI POSITRON EMMISION TOMOGRAPHY (PET)
- 70. TREATMENT CHEMOTHERAPY HORMONE THERAPY BISPHOSPHONATES IMMUNOTHERAPY RADIATION THERAPY SURGERY ABLATION
- 71. CONCLUSION The diagnosis of a metastatic lesion in the oral region is challenging, both to the clinician and to the pathologist.. Hence, careful clinical and histopathological assessement lead to definitive diagnosis of the metastatic lesion and its origin.
- 72. Kumar G.S, Manjunatha B.S. Metastatic tumors to the jaws and oral cavity. Journal of Oral and Maxillofacial Pathology 2013;17(1):71-5. Robbins and Cotran Pathologic basis of disease, 7th ed. Meyer I, Shklar G. Malignant tumors metastatic to the mouth and jaws. Oral Surg Oral Med Oral Pathol. 1965;20:350–62. Nishimura Y, Yakata H, Kawasaki TT, Nakajima T. Metastatic tumors of the mouth and jaws. A review of the Japanese literature. J Oral Maxillofac Surg. 1982;10:253 Zachariades N. Neoplasms metastatic to the mouth, jaws and surrounding tissues. J Cranio Maxillofac Surg. 1989;17:283 Hirshberg A, Leibovich P, Buchner A. Metastatic tumors to the jawbones: Analysis of 390 cases. J Oral Pathol Med. 1994;23:337–41 Clausen F, Poulsen H. Metastatic carcinoma to the jaws. Acta Pathol Microbiol Scand. 1963;57:361–74 Hirshberg A, Leibovich P, Horowitz I, Buchner A. Metastatic tumors to post- extraction site. J Oral Maxillofac Surg. 1993;51:1334–7.
- 73. Cell Adhesion and Its Endocytic Regulation in Cell Migration during Neural Development and Cancer Metastasis Takeshi Kawauchi Delayed Metastasis to the Mandible of Esophageal Adenocarcinoma Kathryn P. Lawes, Martin Danford, and Silvana Di Palma Metastasis of lung adenocarcinoma to the mandible: Report of a case Ahmet Ferhat Misir
Editor's Notes
- Models of metastasis. (a) Chambers and co-workers, only a very small population of injected cells (2%) form micrometastases, 87% are arrested in the liver. not all of the micrometastases persist, and the progressively growing metastases that kill the mice arise only from a small subset (0.02%) of the injected cells. (b) Muschel and co-workers a new model for pulmonary metastasis in which endothelium-attached tumor cells that survived the initial apoptotic stimuli proliferate intravascularly. the extravasation of tumor cells is not a required for metastatic colony formation and that the initial proliferation takes place within the blood vessels. (c) The unique ability of aggressive tumor cells to generate patterned networks, similar to the patterned networks during embryonic vasculogenesis, and concomitantly to express vascular markers associated with endothelial cells, their precursors and other vascular cells has been termed 'vasculogenic mimicry' by Hendrix and co-workers
- Reciprocal interactions of tumor cells with the extracellular matrix (ECM), tumor-associated macrophages (TAM), carcinoma-associated fibroblasts (CAF), mesenchymal stem cells (MSC), and endothelial cells (EC). These interactions are mediated by direct cell-to-cell contact and/or the release of cytokines, chemokines, growth factors, matrix metalloproteases (MMPs), and ECM proteins. Eventually this results in epithelial-mesenchymal transition (EMT) of tumor cells, their migration, invasion, and dissemination to distant organs and the formation of metastases. For reasons of clarity, other stromal cell populations, e.g. lymphocytes and known interactions among different stroma cell populations are not shown. TAMs promote the angiogenic switch and neovascularization as well as malignant transition of the tumor cells by secretion of specific pro-angiogenic factors (VEGF, IL-1β, TNF-α, angiogenin, semaphorin 4D), or indirectly through the release of MMP-9 Tumor cell-derived TGF-β stimulates reactive oxygen species (ROS)-dependent expression of α-smooth muscle actin in the fibroblasts leading to their differentiation into myofibroblasts
- 1. Transcoelomic The spread of a malignancy into body cavities via penetrating the surface of the peritoneal, pleural, pericardial, or subarachnoid spaces. For example, ovarian tumors can spread transperitoneally to the surface of the liver. 2. Lymphatic spread Lymphatic spread allows the transport of tumor cells to lymph nodes and ultimately, to other parts of the body. most common route of metastasis for carcinomas. In contrast, it is uncommon for a sarcoma to metastasize via this route. h the lymphatic system does eventually drain into the systemic venous system via the azygous vein, and therefore these metastatic cells can eventually spread through the haematogenous route. 3. Haematogenous spread This is typical route of metastasis for sarcomas, but it is also the favored route for certain types of carcinoma, such as those originating in the kidney (renal cell carcinoma). Because of their thinner walls, veins are more frequently invaded than are arteries, and metastasis tends to follow the pattern of venous flow. 4. Transplantation or implantation Cancer cells may spread to lymph nodes (regional lymph nodes) near the primary tumor. This is called nodal involvement, positive nodes Localized spread to regional lymph nodes near the primary tumor is not normally counted as metastasis, although this is a sign of worse prognosis.
- He proposed that the processes of metastasis did not occur by chance but, rather, that certain favoured tumour cells with metastasis activity (the ‘seed’) had a special affinity for the growth-enhancing milieu within specific organs (the ‘soil’, i.e., organs providing a growth advantage to the seeds). He concluded that metastases developed only when the seed and soil were compatible In 1929, James Ewing challenged Paget’s Theory occurs by purely mechanical factors that are a result of the anatomical structure of the vascular System But later concluded that common regional metastatic involvement could be attributed to anatomical or mechanical considerations (efferent venous circulation or lymphatic drainage to regional lymph nodes, but that metastasis to distant organs from numerous types of cancers were indeed site specific. The ‘seed-soil’ theory proposed by Paget is accepted as the basic mechanism for cancer metastasis. Many studies have proved the ‘seed-soil theory’ that the potential of a tumor cell to metastasize depends on its interactions with the homeostatic factors that promote tumor cell growth, survival, angiogenesis, invasion and metastasis
- The significance of chemokine-receptor expression on cancer cells. a | Cancer cells in a primary tumour have metastatic potential, but do not always express chemokine receptors. b | Some cancer cells acquire chemokine-receptor expression by gene mutation, gene fusion or local conditions, such as hypoxia. c | If local levels of the specific chemokine ligand are low, chemokine-receptor-expressing cancer cells can now respond to high levels of ligand at sites of metastasis and migrate towards the chemokine gradient. Alternatively, the acquisition of chemokine receptor might make tumour cells more likely to invade and spread. d | Chemokine ligand at the metastatic site can deliver anti-apoptotic and proliferative signals, and induce tumour-necrosis factor-alpha. This cytokine can initiate a pro-tumour inflammatory network in the surrounding stroma. Hence, the chemokine ligand encourages the tumour cells to survive and grow. Up-regulation of CXCR4 expression has been observed in cancer cells and neoplastic tissues in HNSCC [132, 166-168]. Furthermore, it was reported that hypoxia enhances CXCR4 expression by activating HIF-1α in oral squamous cell carcinoma. There has been considerable interest regarding the fact that chemokines regulate leukocyte trafficking and recruitment, leading to the hypothesis that tumor cells might use analogous, chemokine-dependent mechanisms for targeting to specific secondary sites. There is increasing evidence that epithelial tumor cells exploit mechanisms that normally regulate leukocyte trafficking and homing. The distinct pattern of chemokine receptor expression by cancer cells has a critical role in determining the site(s) of metastatic spread. Fibroblasts and endothelial cells in TME play a crucial role in the response to tumor-derived cytokines. Not only do stromal cells respond to signals from tumor cells, but also the stromal cells themselves can induce tumor growth.
- Antigens that are present in early neoplastic tissues are transported to lymphoid organs by dendritic cells (DCs) that activate adaptive immune responses resulting in both tumour-promoting and antitumour effects. . Activation of B cells and humoral immune responses results in chronic activation of innate immune cells in neoplastic tissues. Activated innate immune cells, such as mast cells, granulocytes and macrophages, promote tumour development by the release of potent pro-survival soluble molecules that modulate gene-expression programmes in initiated neoplastic cells, culminating in altered cell-cycle progression and increased survival. Inflammatory cells positively influence tissue remodelling and development of the angiogenic vasculature by production of pro-angiogenic mediators and extracellular proteases. Tissues in which these pathways are chronically engaged exhibit an increased risk of tumour development. By contrast, activation of adaptive immunity also elicits antitumour responses through T-cell-mediated toxicity (by induction of FAS, perforin and/or cytokine pathways) in addition to antibody-dependent cell-mediated cytotoxicity and antibody-induced complement-mediated lysis but this is the mechanism which is suppressed in lichen planus. Emerging information indicating that immune cells may not only be involved in tumor prevention but also tumor development has resulted in an additional term called immunoediting, indicate that the function of immune cells is altered by tumor cells to support rather than prevent tumorigenesis.
- Oro-facial region - rare 1-1.5% of all malignant oral tumors 40-70 years. In younger patients - common in jaw bones compared to soft tissues. equal gender distribution The most common sources - primary cancers from the lung, breast, kidney & bone. Breast is the most common primary site for tumors that metastasize to the jawbones Lung is the most common source for cancers that metastasize to the oral soft tissues.
- ATTAC HED GINGIVA : rich capillary network of chronically inflamed gingiva- mechanism that entraps the malignant cells proliferating capilaaries have a fragmented basement membrane thro wch the tumour cells can easily penetrate
- DIAGNOSIS OF THESE TUMORS IS CHALLENGING BOTH TO THE CLINICIAN AND PATHOLOGIST IT HAS GREAT CLINICAL SGNIFICNACE BECOS IN 30% CASES ORAL PRESENTATION IS THE FIRST SIGN OF THE MALIGNANT DISEASE.
- most common mandible( 316) cases (81%) 53 cases (13.6%) - the maxilla. In 21 cases (5.4%) - both jaws. In the mandible, the Molar area was involved in 55%) of the casesfollowed by the premolar area (38%). The metastatic lesion was situated in the angle and ramus in 29%); the condyle was involved in 11 cases (3.5%)) and the coronoid process only in 5 cases (1.6%). In the maxilla, the tumor was located most frequently in the premolar and molar area (58.7%).
- From this viewpoint, osteolytic metastases are believed to be caused by osteoclast-activating factors — the most important of which might be parathyroid-hormonerelated peptide (PTHrP) — and which are released by tumour cells in the bone microenvironment. breast cancer cells, when present in the bone microenvironment, overproduce PTHrP, and this leads to osteoclastic bone resorption24. Consequently, active growth factors are released from bone that cause proliferation of breast cancer cells. This stimulates further production of PTHrP, which, in turn, causes more bone loss5
- The steps involved in tumour-cell metastasis from a primary site to the skeleton The primary malignant neoplasm promotes new blood-vessel formation, and these blood vessels carry the cancer cells to capillary beds in bone. Aggregates of tumour cells and other blood cells eventually form embolisms that arrest in distant capillaries in bone. These cancer cells can then adhere to the vascular endothelial cells to escape the blood vessels. As they enter the bone, they are exposed to factors of the microenvironment that support growth of metastases.
- Recent studies on the mechanism by which cancers metastasize to bone have shown that cancer cells alter the physiologic balance between bone resorption and bone formation. Breast cancer metastases are frequently osteolytic and this has been attributed to overexpression of osteoclast inducing factors such as Parathyroid Hormone Related Protein (PTHrP), interleukin (IL)-8 and IL-11. [9],[10],[11] Predominantly, osteoblastic metastasis is mediated by osteoblast promoting factors like bone morphogenetic proteins (BMPs), Wnt family ligands, endothelin-1 and platelet-derived growth factor (PDGF). Furthermore, the release of matrix embedded growth factors like insulin-like growth factor (IGF) and transforming growth factor-β (TGF-β) upon osteolysis promotes the induction of osteoclast promoting factors
- Analysis of the literature by Hirshberg revealed 56 cases in which tooth extraction preceded the discovery of the metastases.(tumor was assumed to be present in the area before extraction). A soft tissue mass extruding from a recent extraction wound with pain In many of these cases the metastatic tumor is present in the area before the extraction causing pain, swelling and loosening of teeth. These symptoms lead the clinician to extract the affected tooth. metastasis probably develops after extraction. Tooth extraction can serve as a promoting factor in the metastatic process. Metastatic lesions may mimic odontogenic infections and other disease conditions - late diagnosis by the unwary clinician. Patient complaining of numb chin or mental nerve neuropathy should always raise the possibility of a metastatic disease in the mandible, signifies deep invasion of the tumor into the bone and involvement of the inferior dental or mental nerves. These features when seen in a patient with a known malignancy, it is termed as ‘mental nerve neuropathy’ or the “numb chin syndrome
- Histopathologicaly, clusters and duct-like arrangement of malignant epithelial cells with large nuclei, containing prominent nucleoli nested at the osseous tissue periphery is a feature of breast carcinoma. Pleomorphism and hyperchromatism can also be seen in some cases
- Premetastatic niche and bone homing. Modulation of the bone microenvironment by circulating breast cancer cells results in priming of the bone marrow as a premetastatic niche through tumor cell secretion of OPN, HPSE, and PTHrP. Colonization of the bone and recruitment of HSC occur by tumor cell expression of integrins (αvβ3), RANK, CXCR4, MMP-1, IL-11, and CTGF. CXCL12 (SDF-1) expression on osteoblasts facilitates homing of tumor cells to bone.
- Histopathologicaly, it shows malignant tumoral tissue consisting of solid islands composed of atypical epithelial cells in desmoplastic stroma. There is markednuclear pleomorphism in the tumoral islands and cytoplasmic small vacuoles are seen
- lung cancer cells are characterized by distinct cytokine profile and growth factors- include parathyroid hormone-related peptide (PTHrP), IL-1, IL-7, receptor activator of nuclear factor-B ligand (RANKL), & tumor necrosis factor (TNF-α) which are involved in the stimulation of osteoclast differentiation & activation.
- HISTOPATHOLOGY It consists of multiple glandular structures, the stroma is desmoplastic in many areas. The glandular cells show varying degrees of dysplastic features according to the degree of differentiation
- The most common histological type of RCC is the clear cell type which shows proliferation of neoplastic clear cells. Clear cell RCC may exhibit a variety of histoarchitectural patterns including solid, alveolar, and acinar forms. Individual cells are characterized by a large clear cytoplasm and centrally located nuclei. Cellular and nuclear pleomorphism, atypia, and conspicuous nucleoli are also seen. Small areas of necrosis are seen in a few cases, and typical and atypical mitosis were rarely found. The alveolar pattern is separated by a thin layer of fibrous connective tissue. A profuse network of small, thin-walled sinusoid-like blood vessels on the periphery of alveolar units is a characteristic diagnostic feature
- The diagnosis of papillary carcinoma is based on nuclear morphology of a thyroid neoplasm - Enlarged and elongated nuclei with crowding and overlap; - Irregular nuclear contour - Chromatin clearing with peripheral margination of chromatin, giving rise to what has been described as Orphan Annie Eye nuclei; Multiple micronucleoli located immediately underneath the nuclear membrane; - Nuclear grooves resulting from irregularity of nuclear contour seen in 2 dimensions; - Intranuclear cytoplasmic pseudoinclusions from the accumulation of cytoplasm in prominent nuclear grooves
- Multiple micronucleoli located immediately underneath the nuclear membrane; - Nuclear grooves resulting from irregularity of nuclear contour seen in 2 dimensions; - Intranuclear cytoplasmic pseudoinclusions from the accumulation of cytoplasm in prominent nuclear grooves
- It is composed of small glands, the individual glands having a irregular round configuration and cribriform pattern. Both of these architectural patterns are accompanied by cytological abnormalities in the form of nuclear enlargement, hypercromasia, and prominent nucleoli
- a case of a 69 year-old male patient where 7 years elapsed between the diagnosis and successful treatment of a poorly differentiated, stage pT2N0 primary esophageal adenocarcinoma and re-presentation with jaw pain due to a metastatic mandibular deposit squamous mucosa with underlying corium and a deep-seated tumor composed of ducts with some cystic dilatation, and cytologically atypical, mitotically active cells These gave strong immunohistochemical positivity for CK20, CK7 and CDX2 and were negative for PSA, TTF1 and CK5/6 (Fig. 3). This pattern favoured metastatic adenocarcinoma consistent with gastrointestinal tract origin, including the pancreatic and hepatobiliary tract, although a primary intraosseous adenocarcinoma of the mandible could not be completely excluded. Additional clinical information was obtained that 7 years previously, the patient had a 35 × 25 mm pT2N0 moderately to poorly differentiated adenocarcinoma confined to the esophagus at 30 cm (Fig. 4). A review of the slides showed that the esophageal tumor was morphologically similar on microscopy (Fig. 5) to the mandibular metastasis
- The adenocarcinoma has a typical morphology; it is composed of cohesive clusters of cells arranged in glands and has the cytologic features of a malignancy (variable nuclear size, nuclear staining, and nuclear shape). Mitoses, in the neoplastic cells, are abundant.82
- Histological examina-tion revealed multiple pieces of a cellular neoplasm showing anorganoid pattern of growth with small nests invading in betweenlamellar and reactive woven bone fragments (Fig. 1). The cells hadgranular pale eosinophilic cytoplasm and round nuclei. The cellsnests were surrounded by delicate fibrovascular septae highlightedby smooth muscle actin stain. The neoplastic cells showed uniformmorphology without significant atypia or increased mitotic activity.There was no evidence of remnants of odontogenic epithelium ordystrophic calcifications (Fig. 1). PAS-diastase stain demonstratedintracytoplasmic granules. Immunohistochemical stains showedthe lesional cells to be uniformly reactive with TFE3 (nuclear pat-tern), CD44, and CD68 (Fig. 2). Desmin showed focal rare positivecells. AE1/AE3, PAX2, RCC, chromogranin, synaptophysin, thy-roglobulin, s100, and CD1a were all negative within the lesional cell population. Ultrastructural studies using transmission electronmicroscopy showed large membrane bound secretory granuleswith rectangular foci of crystallization (Fig. 2). These findings sup-port a diagnosis of alveolar soft part sarcoma. Given the extremerarity of ASPS as primary neoplasm of bone, a metastatic focus was favored.
- An intraoral incisional biopsy & histopathologic examination is the means to confirm and identify a malignant tumor & it's metastatic origin. The pathologist may not provide an exact diagnosis (metastatic lesion does not represent a single disease & histological appearance is variable). If any history of a previous tumor exists; the microscopic findings of the metastatic lesion should be compared with that of the primary tumor. special staining, immunohistochemical procedure, and electron microscopy may be performed to identify the nature of primary tumor. Once a metastatic tumor is suspected - Advanced imaging, scintigraphy ®ional investigations based on the suspected source should be done to find out or confirm the origin & identify any other areas of secondary spread.