Oral Pathology module **Connective Tissue disorders** DENT4217  **THE UNIVERSITY OF** **WESTERN** **AUSTRALIA** **Acknowledgement** of country The University of Western Australia acknowledges that its campus is situated on Noongar land, and that Noongar people remain the spiritual and cultural custodians of their land, and continue to practise their values, languages, beliefs and knowledge. **Artist: Dr Richard Barry Walley OAM**  **Learning outcomes** * To develop a basic knowledge of reactive, benign and malignant connective tissue lesions that may occur in the oral cavity. * To recognise the common causes of various types of localised gingival lesions - Epithelium - Lamina propria - Papillary layer - Reticular layer - Submucosa - Minor salivary gland - Nerve & vein - Bone  Classification of Connective Tissue Disorders Group Reactive/congenital Neoplasms Fibrous •Fibroma /fibroepithelialpolyp •Peripheral giant cell granuloma •Peripheral ossifying fibroma •Epulis fissuratum (inflammatory fibrous hyperplasia) •Inflammatory papillary hyperplasia •Generalized gingival hyperplasia •Giant cell fibroma •Myofibroma •Aggressive Fibromatosis •Solitary fibrous tumor •Fibrosarcoma •Fibrous histiocytoma, benign and malignant •Nodular fasciitis Vascular •Pyogenic granuloma •Varix; other acquired malformations •Benign vascular malformation •Lymphangioma •Hemangioma •Angiosarcoma •Kaposi's sarcoma •Hemangiopericytoma Neural •Traumatic neuroma •Neurofibroma •Granular cell tumor •Schwannoma (neurilemoma) •Mucosal neuromas of MEN III •Palisaded encapsulated neuroma •Malignant peripheral nerve sheath tumor Adipose tissue •Herniated fat pad •Lipoma and Liposarcoma Muscle •Smooth muscle •Striated muscle •Leiomyoma and Leiomyosarcoma •Rhabdomyoma and Rhabdomyosarcoma **FIBROMA ("BITE" OR "IRRITATION" FIBROMA, FIBROEPITHELIAL OR FIBROVASCULAR POLYP), AND GIANTCELL FIBROMA** • This occurs at any age group without sex predilection and consists of a dome-shaped nodule or papule that may be white/keratotic, mucosa-colored, or ulcerated. It is located in areas readily traumatized by biting (i.e., buccal mucosa, lateral tongue, and lower lip mucosa) or on the gingiva where plaque accumulates. 6 **FIBROMA (“BITE” OR “IRRITATION” FIBROMA, FIBROEPITHELIAL OR FIBROVASCULAR POLYP), AND GIANTCELL FIBROMA** 7    **FIBROMA ("BITE" OR "IRRITATION" FIBROMA, FIBROEPITHELIAL OR FIBROVASCULAR POLYP), AND GIANTCELL FIBROMA** THE UNIVERSITY OF WESTERN AUSTRALIA • A nodular mass of dense fibrous connective tissue • Normal, hyperkeratotic, or ulcerated surface epithelium 8   **Ossifying fibrous epulis** **(peripheral ossifying fibroma)** • A common, swelling of the gingiva characterized by a core of fibrous connective tissue exhibiting the formation of variable amounts of amorphous deposits of calcifications • Mostly seen in children and young adults • A reactive lesion to local irritation • **Clinically:** • Red to pink, firm gingival nodule • • typically arise from the interdental papilla • • smooth surfaced, can be ulcerated • • 1 cm in diameter; can be larger Often shows calcification on radiograph 9  **Ossifying fibrous epulis** **(peripheral ossifying fibroma)** * A nodular mass of cellular fibrous connective tissue * contains bone, or cementum-like material * covered by normal or ulcerated surface epithelium 10   **Angiogranuloma (pyogenic granuloma)** * A common reactive vascular lesion **Aetiology** * A reactive lesion to local irritation or trauma * Some are attributed to the effect of female hormones * Tumour-like overgrowth of granulation tissue **Clinical features** * F>M; the prevalence is higher in women during pregnancy * Most common on the gingiva (75% of all oral cases) * tongue, lips, and buccal mucosa 11  **Angiogranuloma (pyogenic granuloma)** * Bright-red to dark-red, soft nodule * smooth or lobulated surface; often ulcerated * often bleeds easily * <1 cm in diameter; can be larger * Pregnancy tumour (**granuloma gravidarum**): a pyogenic granuloma that develops on the gingiva during pregnancy * Epulis Granulomatosa: a pyogenic granuloma that develop in a healing extraction socket  **Angiogranuloma (pyogenic granuloma)** ▪Nodular mass of granulation tissue ▪dilated blood vessels in a loose fibrous stroma, with acute and chronic inflammatory infiltrate ▪normal or ulcerated overlying surface epithelium 13   # **Peripheral Giant Cell Granuloma (Giant Cell Epulis)** * • A relatively common growth on the gingiva or the alveolar ridge characterized by a proliferation of multinucleated giant cells that resemble osteoclasts. **Aetiology** * • A reactive lesion to local irritation or trauma **Clinical features** * • Exclusively on the gingiva or edentulous alveolar ridge * **❑Red to blue-purple, firm gingival nodule** * **❑typically arise from the interdental papilla** * **❑smooth surface; may or may not be ulcerated** * **❑typically < 1 cm in diameter; can be larger** * **❑may cause cupping resorption of the underlying alveolar bone**   **Peripheral Giant Cell Granuloma (Giant** **Cell Epulis)** **THE UNIVERSITY OF** **WESTERN** **AUSTRALIA** • **Microscopy** • A nodular proliferation composed of osteoclast-like multinucleated giant cells in a cellular and haemorrhagic background • osteoclast-like multinucleated giant cells • cellular fibrous stroma • extravasated RBCs, and haemosiderin pigmentation • normal or ulcerated overlying surface epithelium   **Epulis Fissuratum (Inflammatory fibrous hyperplasia;** **denture epulis)** A reactive overgrowth of fibrous connective tissue in response to an ill- fitting denture **Aetiology** • Trauma from an overextended or ill-fitting denture **Clinical features** • In the alveolar vestibule adjacent to a denture flange • more frequently along the anterior vestibule 16   **Epulis Fissuratum (Inflammatory fibrous hyperplasia;** **denture epulis)** Histopathology • A hyperplasic mass of fibrous connective tissue • often with folds and grooves • Hyperplastic, hyperkeratotic, or ulcerated surface epithelium 17  **Reactive Gingival Nodules** THE UNIVERSITY OF WESTERN AUSTRALIA Diagnosis Pyogenic granuloma (lobular capillary hemangioma) (see also Chapter 6) Peripheral ossifying fibroma (fibroma with osseous metaplasia) Peripheral giant cell granuloma **Histopathology** * Nodule of densely collagenous fibrous tissue with scattered vessels and variable edema and inflammation; crevicular epithelium with underlying plasma cells are often seen; when uninflamed, it is indistinguishable from a traumatic fibroma (**see Fig. 5.12A-C**) * Lobular or more frequently, nonlobular proliferation of endothelial cells and small, dilated capillaries; often ulcerated and inflamed (**see Figs. 5.13A**) * Endothelial cells show reactive atypia sometimes with focal "hobnail" pattern and hyperchromatic nuclei (**see Fig. 5.13B-C**); mitotic figures are often present * May see fibrosis depending on stage of organization (**Fig. 5.13D-E**) * Cellular proliferation of spindled fibroblast-like cells with deposition of osteoid, woven bone with variable osteoblastic rimming, cementum droplets or cementicles (psammoma body-like) (**see Figs. 5.14** and **5.15**); sometimes lamellar bone is present * Spindle cells have ovoid nuclei, dispersed chromatin, and inconspicuous nucleoli and the spindle cell pro- liferation may have a storiform pattern (**Fig. 5.16**); the amount of calcified material is variable (**Fig. 5.17**) * There may be clusters of multinucleate giant cells similar to peripheral giant cell granuloma (**see Fig. 5.18**) * Bone morphogenetic protein has been identified in the spindled fibroblast-like cells * Proliferation of monocytic and multinucleate giant cells (osteoclast-like or foreign body type) usually in sheets; giant cells contain 20–30 evenly distributed nuclei; mitoses may be seen in monocytic cells; fresh hemorrhage and hemosiderin deposits are usually present especially beneath the grenz zone (**see Figs. 5.19** and **5.20**) * May see concomitant osseous metaplasia similar to peripheral ossifying fibroma * Giant cells are positive for TRAP, RANK, and osteoprotegrin 18  <img src=" https://files.nc.orels.sh/pdfs/ea03a3d5-e990-4886-8968-0fb531d0411a/images/f814b73b-eaf9-445a-8b01-574ea9094e43.jpeg "> <img src=" https://files.nc.orels.sh/pdfs/ea03a3d5-e990-4886-8968-0fb531d0411a/images/2290f679-b1d6-44ec-b98a-f2a890479f64.jpeg "> **Inflammatory Papillary Hyperplasia** (Denture Papillomatosis) * A pebbly overgrowth of the oral mucosa, usually occurs beneath a denture **Aetiology** * Ill-fitting denture, a denture that is worn 24 hours a day, or denture stomatitis **Clinical features** * Multiple, pink to red, edematous or fibrous papules * On the hard palate beneath a denture base * mainly the palatal vault  **Microscopy** * Multiple papules of edematous fibrous connective tissue * Normal or hyperplastic surface epithelium 20  **THE UNIVERSITY OF** **WESTERN** **AUSTRALIA** * Epulis = a growth arising from the gingiva * it means "on the gum" * Often used to describe localized hyperplastic gingival lesions * Fibrous epulis (firm mass on the gingiva) * Vascular epulis (angiogranuloma on the gingiva) * Fibrous epulis with calcification (peripheral ossifying fibroma) * Giant-cell epulis (peripheral giant cell granuloma) * Denture epulis (epulis fissuratum) **Generalized gingival enlargements** | **Lesion or condition** | **Special characteristics** | | :---------------------- | :-------------------------- | | Hyperplastic gingivitis | Examples: associated with puberty, pregnancy, diabetes | | Drug-related gingival hyperplasia | Examples: phenytoin, calcium channel blockers cyclosporine; may be fibrotic | | Gingival fibromatosis | May be hereditary; onset in childhood | | Leukemic infiltrate | Gingival swelling and bleeding | | Wegener's granulomatosis (granulomatosis with polyangitis) | 'Strawberry gingivitis'; may have palatal ulceration and destruction; kidney, lung or nasal septum involvement; often with a skin rash, conjunctivitis or hearing loss | | Scurvy | Vitamin C deficiency | 21  **Giant Cell Fibroma** THE UNIVERSITY OF WESTERN AUSTRALIA * A variant of fibroma with distinctive features * Compared to the common "irritation" fibroma: * does not appear to be caused by trauma * occurs most frequently on the gingiva * many demonstrate rough, papillary surface * can be mistaken for a papilloma * large stellate, multinucleated fibroblasts microscopically Retrocuspid Papilla * Small, pink papules on the lingual gingiva of the lower cuspids * frequently bilateral lesions * microscopic features similar to giant cell fibroma * do not require excision  **Vascular Anomalies [Hemangiomas and** **Vascular Malformations]** Major types: ▪vascular tumours and vascular malformations Classification of Vascular Anomalies Vascular Tumours * Infantile Hemangioma * Superficial * Deep * Congenital Hemangioma▪ * Noninvoluting congenital hemangioma (NICH) * Rapidly involuting congenital hemangioma (RICH) Vascular Malformations ▪Capillary malformation ▪Venous malformation ▪Arteriovenous malformation ▪Lymphatic malformation 23 **THE UNIVERSITY OF** **WESTERN** **AUSTRALIA** **General Features** Hemangiomas * Benign tumors * the most common tumors of infancy * Most lesions are not present at birth (arise during the first 8 weeks of life) * few present at birth * Display a rapid growth phase (endothelial cell proliferation) * typically followed by gradual involution * some show rapid involution or do not undergo involution Vascular Malformations * Hamartomatous growths composed of blood or lymphatic vessels with normal endothelial cell turnover * Present at birth and persist throughout life * Categorized according to the type of vessel involved into: * capillary, venous, or arteriovenous, or lymphatic * Categorized according to the hemodynamic features into: * low-flow vs. high-flow 24  THE UNIVERSITY OF WESTERN AUSTRALIA ### Congenital Hemangioma * Present at birth * Subtypes: * Rapidly involuting congenital hemangioma (RICH) * shows rapid regression, with full involution by 9 to 14 months of age * Noninvoluting congenital hemangioma (NICH) * does not undergo involution ### Microscopy * Early phase – a proliferation of plump endothelial cells forming indistinct vascular lumina * Mature phase – capillary-sized vascular spaces lined by flattened endothelial cells * Involution phase – get replaced by fibrous connective tissue  **THE UNIVERSITY OF** **WESTERN** **AUSTRALIA** **Venous Malformation** - Low-flow anomaly **Clinical features** - Blue-purple mass - present at birth - thrombi and phleboliths can form within (because of slow blood flow) **Microscopy** - Dilated thin-walled veins **Treatment** - Observation, sclerotherapy, or surgical excision - Sclerotherapy: injection of sclerosing agents into the lesion to induce fibrosis 26  THE UNIVERSITY OF WESTERN AUSTRALIA **Kaposi Sarcoma** * A vascular malignancy caused by human herpes virus 8 **Etiology** * Human herpesvirus 8 (HHV-8)/Kaposi sarcoma-associated herpesvirus (KSHV) **Subtypes** I. Classic II. Endemic III. Iatrogenic (transplant-associated) IV. Epidemic (AIDS-related) **AIDS-Related Kaposi Sarcoma** **Clinical** * Mainly manifests as multiple lesions on the skin or oral mucosa * oral lesions are seen in more than 50% of patients * Predilection for adult homosexual males * Considered as an AIDS-defining cancer  THE UNIVERSITY OF WESTERN AUSTRALIA * Oral lesions * strong predilection for the palate and gingiva * early lesions appear as purple macules => plaques and nodules **Microscopy** * A cellular proliferation of spindle cells surrounding slit-like vascular spaces **Treatment** * Often regresses with combined antiretroviral therapy (cART) * Other options include surgery, irradiation, intralesional chemotherapeutic agents (e.g. vinblastine), intralesional sclerosing agents (sodium tetradecyl sulfate), and systemic chemotherapy  **References** 29 • Odell E. 2018. Cawson's Essentials of Oral Pathology and Oral Medicine • Woo SB. 2023. Oral Pathology. A Comprehensive Atlas and Text • Sapp JP, Eversole LR, Wysocki GP. 2004. Contemporary oral and maxillofacial pathology.