6.2 Changes in the oral cavity associated with systemic diseases

A dentist must bear in mind that some changes in the oral cavity including oral mucosal defects may represent early symptoms of systemic diseases. It is not uncommon that a dentist is the first to suspect a systemic disease. For this reason, it is necessary to know what diseases can represent such first signs and what are the systemic diseases those symptoms can point to, including some diseases of the GIT, endocrine glands, haemorrhagic diseases and metabolic disorders.

The living organism and metabolism consist of a multitude of complex biochemical reactions necessary for energetic supply of the cells and for creating new matter. Undesirable changes can affect any constituents of the metabolism such as the basic substances including sugars, lipids and proteins, as well as other substances such as vitamins, minerals, enzymes and hormones. Metabolic changes are closely related with nutrition disorders – they are associated with the food intake, composition, its processing in the GIT and use in the tissues. The metabolism is also influenced by the endocrine glands, the functional changes of which can lead to mucosal manifestations. Sex hormones also directly influence the morphology of the mucosa and can lead to changes in the oral mucosa both under physiological (puberty, gravidity) and pathological conditions, often in interaction with nervous and immune system.

6.2.1 Changes in the oral cavity associated with diseases of haematopoiesis and vessels

The first symptoms of some blood diseases may manifest in the oral cavity. This is especially true about myeloproliferative diseases, causing excessive growth of immature blood cells. Such cells are functionally impaired and the complications that arise are actually due to the lack of normal blood elements. In addition, these patients are usually treated with a number of drugs that can also have a toxic effect on the oral mucosa.

Diseases associated with the red blood cells



Of many anaemias, the etiology of which can be completely different, only some will be mentioned here, specifically those that are practically always accompanied by manifestations in the oral cavity.

Pernicious anaemia (Addison-Biermer anaemia)

Etiologically, it is caused by a lack of Castle intrinsic factor in irreversible atrophic gastritis. The disease usually manifests around the fiftieth year of age.

Clinical picture: General symptoms result from the anaemic syndrome associated with paleness, exhaustion, weakness and exertion dyspnoea, which is accompanied by tachycardia and systolic murmur. Cardiac hypoxia leads to myocardial steatosis with yellow stripes (so-called tiger heart). Clinically, tongue afflictions (Hunter glossitis, Möller-Hunter glossitis) manifest by paraesthesia and burning of the tongue, taste perception can be altered. The disease has three stages. In the first, acute, stage, fissures, erosions and macular efflorescences develop on the lingual mucosa. In the second, subchronic, atrophic changes of the filiform papillae appear and in the third, chronic, stage, atrophy of the mucosa occurs.

Similar changes can be observed in megaloblastic anaemia, the etiology of which is different. Such etiologies may include partial or total gastrectomy, malabsorption syndrome, Crohn’s disease, extensive lesions of the intestines by diverticulosis or resection of the bowel where vitamin B12 absorption normally occurs; it can also develop in full vegetarians and in pregnancy in cases of insufficient intake of the folic acid. Atrophic glossitis may be also induced by some drugs such as cytostatics.

People suffering with a relatively common neuroanemic syndrome may develop, in addition to the anaemic symptoms, also neurologic ones. Such symptoms include tendon hyporeflexia, reduced muscular strength and unsteady walking. Mental performance of such patients is often also affected, sometimes to the degree of loss of consciousness. Histologically, signs of demyelination can be found in the lateral and posterior grey columns of the spinal cord, more rarely in spinal ganglions and peripheral nerves.

Th.: Vitamin B12, the treatment is managed by departments of (internal) medicine.

Sideropenic anaemia

It results from Fe deficiency; it is a typical hypochromic anaemia. Mostly, it develops as a “loss-induced” anaemia after chronic bleeding (after menorrhagia in women, after GIT or other organ bleeding in both sexes). Other etiological factors include reduced content of Fe in the diet, Fe absorption disorders or combination of both.

Clinical picture: Anaemic symptomatology (dyspnoea, exhaustion, weakness, faintness, sensitiveness to cold, impaired capability of concentration, irritability, reduced performance, GIT symptoms, loss of appetite). In the oral cavity, atrophic glossitis with absence of papillae is observed. Subjectively, the patients complain about tongue burning or pain (in particular after intake of irritating foods). Fissures and atrophy of the oral mucosa or painful corners of the mouth can also develop. Sometimes, changes on the esophageal mucosa can appear, which can result in dysphagia.

The complex of symptoms occurring on the mucosa of the upper GIT, is summarily termed sideropenic dysphagia (Patterson–Kelly syndrome, Plummer-Vinson syndrome). This disease is characterized by a combination of hypochromic anaemia, dysphagia (if stenosing esophagitis of the upper esophagus is present), koilonychia (spoon nails), changes in the oral cavity and achlorhydria. Lesions in the oral cavity are the same as those found in sideropenic anaemia with the characteristic atrophic oral mucosa with furrows, possibly also of the oral cavity and esophagus with fissures or erosions of the corners of the mouth. Xerostomia is often present. Based on these defects, leukoplakia and squamous cell carcinoma often develop, which is the reason that this syndrome is considered precancerous. Middle-aged women are the most commonly affected population group.

Th.: Increasing dietary intake of Fe is the key to treatment of this disease. Fe can be administered orally or parenterally.

Aplastic anaemia

The cause of this disease is impaired haematopoiesis in the bone marrow. Both the general and local symptoms are similar to those observed in agranulocytosis.

Polyglobulia (polycythaemia vera, Vaquez-Osler disease)

This disease is the opposite of anaemia. In particular, the deep red to cyanotic colour of the lips, face and oral mucosa is conspicuous. The affected patients suffer with epistaxis and gum bleeding. The tongue is usually smooth, the filiform papillae atrophic. The patient can suffer major bleeding after surgical interventions (e.g. after tooth extraction).

Diseases associated with white blood cells

Leukemia and lymphomas


It is not uncommon for a patient with acute haemoblastosis to visit his dentist due to the problems in the oral cavity first. The most common manifestations include a major induration of the gingiva, which is oedematous, enlarged and hyperplastic (due to inflammatory changes and infiltration of the connective tissue with non-mature blood elements). It can be of livid colour, have a tendency to bleed and it often partially or even completely overgrows the dental crowns. Other manifestations include ulcers with undermined margins, accompanied with bad breath. Necroses can affect the gingiva as well as the tongue and tonsils that may be enlarged so much as to cause respiratory difficulties. Such conditions contraindicate any surgical procedures in the oral cavity. The picture can be modified by the development of opportunistic infections (typically candidosis).

Dg.: Complete blood count must be taken, examination of the medulla and biopsy are necessary for confirming the diagnosis.


Extramedullar forms of plasmocytoma can (albeit very rarely) manifest in the oral cavity (although the manifestations are much more common in the upper respiratory tract – nasal or maxillary sinuses and epipharynx). Knots of greyish discoloration can form on the mucosa and there is a tendency to ulcerate.


Primary amyloidosis is a systemic or organ-specific disease belonging into the group of monoclonal gammopathies. Rarely, amyloid may be formed in the tongue, either in the muscles or in the vascular walls. Sometimes, protruding tumour-like deposits can be formed (besides the oral cavity, such deposits can be formed also i the skin, eye end bladder). The mucosa of the dorsum of the tongue is smooth, practically without papillae, with a marked yellowish-grey discoloration. When amyloidosis develops, it is always necessary to anticipate the affliction of the oral mucosa.



This haematologic disease is characterized by a significantly reduced count or complete absence of granulocytes. It can be of idiopathic etiology (primary agranulocytosis) or the causes can be known (secondary agranulocytosis); it is associated with altered immunoallergic reactions to some drugs (some analgesics, antidiabetics, antiepileptics, antirheumatics, antibiotics, etc.). In predisposed patients, such reaction leads after a certain time (a week to several years) to haematopoiesis disorders. Other causes may include some infections of bacterial (TBC, typhus, septicaemia), viral (hepatitis, rubeola, flu), or protozoan (malaria) origin, ionizing radiation, benzene and its derivatives, etc. It is typically associated with marked systemic symptoms such as fever, exhaustion, pain in the throat and/or dyspnoea.

Petechiae and necroses of various extents form in the oral cavity – on the mucosa of the gingiva, soft and hard palate, esophagus, tonsils, sometimes even on the tongue, lips and buccal mucosa. Oral lesions are often associated with increased salivation, mastication can be painful. The necroses can afflict the bone, lead to its sequestration and to loose teeth. When making the diagnosis, it is always beneficial to keep in mind that any time a therapy-resistant ulcerative necrotic gingivostomatitis is detected, haematopoiesis disorders must be suspected. Similar changes are also common in AIDS and other diseases of the immune system. In agranulocytosis, local manifestations in the oral mucosa are almost a rule.

Th.: Treatment of lesions in the oral cavity is local and symptomatic, the systemic therapy is managed by a haematologist.

Dif. dg.: The finding of ulcerative disintegration on the pale background (without erythematous margins and surroundings) is crucial.

Haemorrhagic disorders (bleeding diathesis)

Haemorrhagic diseases manifest by excessive bleeding that can be spontaneous, posttraumatic or following surgical procedures. Such disorders can be congenital (haemophilia, von Willebrand disease, Osler-Weber-Rendu disease) or acquired. Bleeding disorders can be provoked by some drugs (analgesics, antipyretics), infections (increase in the susceptibility of the vascular wall), autoantibodies, etc. In the orofacial region, the symptoms of bleeding disorders are often especially obvious and often represent the first symptom that can bring attention to the possible disorder. Bleeding disorders can be divided into the following groups: disorders of the platelets and vascular wall disorders (both count among primary haemostasis disorders) and coagulopathies (secondary haemostasis disorders).

Thrombocytopenia and thrombocytopathy


The term thrombocytopenia means quantitative changes in the number of thrombocytes while the term thrombocytopathy denotes qualitative defect of the platelets. These defects can be (rarely) congenital but usually, they are acquired. The degree of bleeding depends on the number of functional platelets. Bleeding into the skin and mucosa associated with the development of small petechiae usually occurs (which is never the case in haemophilia!) as well as bleeding into internal organs. The most widely known thrombocytopenia is the idiopathic autoimmune thrombocytopenic purpura (morbus maculosus Werlhof); the clinical picture is characterized by bleeding with formation of petechiae, suffusions and haematomas at various sites including the oral mucosa. Laboratory tests show reduced thrombocyte count and pathological result of the Quick’s test, the PTT is normal.

Th.: Therapy is managed by haematologists; local therapy is similar to that in haemophilia.


Coagulopathies are caused by a lack of one of the plasmatic factors. Haemophilias are the most common coagulopathies. Haemophilia A is a congenital defect of the pro-coagulation activity of the low-molecular component of the factor VIII while in haemophilia B, the lack of factor IX (Christmas factor) is observed. Both diseases affect males while females are the carriers. A fraction of the diseases can be caused by a new mutation so this disease must be considered even if the patient has no family history of the disease. Haemophilia C is characterized by a defect of the Factor XI (both males and females are equally affected).

Clinical picture: The severity of clinical manifestations is directly proportional to the activity of the coagulation factors in the plasma. Bleeding into the GIT is one of the first symptoms, together with bleeding into the joints and muscles. In the oral cavity, bleeding into the mucosa and muscles occurs, especially into the tongue and the oral floor (especially haematoma formation), and bleeding from the gums. Petechiae do not occur (neither on the skin nor on the mucosa). Bleeding after tooth extraction can be very dangerous (in these patients, the dentist must not perform any surgical procedure without a previous haematologic examination and patient conditioning).

Dg.: Activity of coagulation factors VIII, IX (XI) is to be tested; PTT is prolonged, Quick test is normal.

Th.: The systemic therapy is managed by haematologists. Dental procedures that can be expected to bleed should be always consulted with a haematologist in these patients. Tooth extraction and other surgical procedures requiring haematological conditioning are usually performed with hospitalization. Such conditioning of the patient may include administration of the missing coagulation factor (or antifibrinolytics). After the procedure, the wound is to be locally treated to reduce bleeding (suture, tissue adhesives).

Intramuscular injections as well as coagulation-affecting drugs (aspirin, NSAIDs) should be avoided.

Acquired coagulopathies are associated with the anticoagulation treatment with coumarins (vitamin K inhibitors), they can occur in disorders of the vitamin K absorption and in serious damage to the liver (disruption of synthesis of coagulation factors).



Disorders of the vascular wall can arise as a result of bacterial or viral infection (sepsis), after the use of certain drugs and in the lack of vitamin C (scurvy). These diseases affect in particular capillaries. A typical symptom of vasculopathies is the formation of haematomas of various extent, from dot-like petechiae to extensive ecchymoses. Besides, bleeding from various tissues and organs occurs. Of the congenital vasculopathies, the hereditary haemorrhagic telangiectasia (teleangiectasia hereditaria hemorrhaegica, Osler-Weber-Rendu disease) with dysplasia of the supportive tissue of the tiny vessels is the most common. Clinically, teleangiectasias of various sizes can be found on the skin and mucosa. In the oral mucosa, they develop in particular on the lips, tongue and soft palate. It bleeds easily after small injuries or even spontaneously.

Th.: Symptomatic – coagulation of the teleangiectasias.

Systemic vasculitis affecting small vessels occur relatively commonly in the children age – an “allergic-toxic” Henoch-Schönlein purpura. It usually develops after a catarrh of the upper respiratory tract, first as a rash, turning later into a haemorrhagic maculopapular exanthema (enanthema). In the oral cavity, it predominantly affects the tongue and oral floor, developing petechiae or haemorrhages. The exclusion of the allergen is crucial, corticoids are used in severe cases

Vascular anomalies


A group of vascular anomalies includes, according to the currently used classification, vascular malformations and benign vasoformative tissue tumours, which are formed by growths of blood vessel (hemangioma) or lymph vessel (lymphangioma) cell types.

Predilection sites of those growths are in the head and neck region. They can be congenital (can regress spontaneously or, on the contrary, grow) or represent trauma-induced reactive lesions. Hemangiomas can occur both on the surface and deep in the body (in the muscles or even bones). If the tongue is affected, they can lead to macroglossia. Cavernous haemangiomas usually appear as a painless, soft bluish growth with negligible palpation resistance. A multiple occurrence in a single patient is called haemangiomatosis. Capillary haemangioma is red and can be a part of congenital syndromes such as Sturge-Weber syndrome – an encephalotrigeminal angiomatosis that develops due to the persistence of embryonic vessels and affects the skin of the face, oral mucosa, meninges and brain. The manifestations are unilateral in the region of the trigeminal nerve (especially the 1st and 2nd branches). Accompanying symptoms may include congenital glaucoma, ocular angiomas, epileptiform cramps, hemiparesis and oligophrenia.

Lymphangiomas usually appear in the infant age. The lesions often affect the tongue, with the appearance of small blisters (lymphangioma simplex) or multiple whitish and red small cysts (lymphangioma cavernosum). Cystic lymphangioma is usually located in the submaxillary region and on the neck and has a hemispheric or ovoid shape.

Th: Many haemangiomas and lymphangiomas require only observation. If they grow, are subject to repeated injuries or bleeding, they can be removed by sclerotization (aethoxysclerol application), laser, cryodestruction or surgically (extensive angiomas must be first examined using angiography).

6.2.2 Changes in the oral cavity associated with diseases of heart and circulatory system

There are two reasons why the attending dentist must consider cardiac and circulatory diseases. One is that people with such problems (e.g. hypertension, congenital or acquired cardiac defects, chronic cardiac failure, etc.) require special attention and must be prepared before dental treatment (e.g. to prevent bacterial endocarditis in patients with cardiac defects). The other reason is associated with changes manifesting in the oral cavity that can be caused by cardiovascular diseases. Such changes mostly include disorders of the terminal vascular bed, manifesting in the mouth in particular by changes of the lingual mucosal relief. Such changes result from the development of varices and rarely, they can be associated with complications (thrombotization, bleeding). The underside of the tongue is most commonly affected. In the right heart cardiac failure, the tongue can be enlarged and the mucosa can be of purplish-blue colour. In left-sided insufficiency, carmine red discoloration can be observed, usually without any changes in the size of the tongue. Advanced arteriosclerotic changes in the oral mucosa can manifest by mucosal atrophy.

6.2.3 Changes in the oral cavity associated with respiratory diseases

In diseases of the upper respiratory tract (rhinitis, pharyngitis, tonsillitis, tracheitis), bad breath can occur if fever is present. Such diseases are also often associated with the development of acute exacerbation of chronic gingivitis (or with acute gingivitis as such) as a result of the pain and discomfort in the mouth that lead to limited hygiene and plaque development. The mucosa can be dry, lips dry and cracked. In pneumonia, besides aforementioned gingivitis, thickened coating of the tongue can be observed, as well as eruptions of herpes labialis (also called herpes febrilis). In bronchiectasis and pulmonary abscess, foetus ex ore is usually present. Secondary ulceration on the oral mucosa is a rare complication of pulmonary TBC.

6.2.4 Changes in the oral cavity associated with diseases of the GIT

Lesions similar to aphthae (aphthoid ulcers) often appear in patients with GIT problems. In deficiency of vitamins and some elements (Fe), the typical deficiency manifestations include smooth tongue and painful corners of the mouth. If esophagus is affected together with the oral cavity, dysphagia can occur. Acute inflammations of the gastric mucosa can be associated with thick whitish moist coating of the tongue. On the other hand, disappearance of the coating and atrophic mucosa can be found in chronic inflammations of the gastric mucosa. In sudden GIT colics (especially if the peritoneum is irritated), the coating of the tongue can be thick with brownish discoloration and the tongue is dry.

In diseases of the liver, atrophic changes of the lingual mucosa can occur, especially atrophy of the filiform papillae. At first, this is particularly apparent on the tip of the tongue; later on, the whole surface can be affected. The tongue is dark red, moist, almost without coating but with slight hyperkeratosis.

Pigmentation of lips and oral mucosa can represent a diagnostically valuable symptom in intestinal polyposis (Peutz-Jeghers syndrome).

Changes on the oral mucosa are also often observed in inflammatory bowel diseases; besides mucosal lesions, in more advanced stages of the disease, manifestations of malabsorption (i.e, of deficiency of some nutrients) are also likely to appear.

Crohn’s disease (morbus Crohn)


Crohn’s disease is a chronic inflammatory granulomatous disease that can manifest in any part of the GIT but most commonly affects the junction of the small and large intestine (with the inflammation penetrating the entire intestinal wall). Mostly, young individuals are affected. The etiology is not yet fully understood, it is most likely an autoimmune inflammation.

Clinical picture: Changes in the oral mucosa appear in approx. 20 % of patients and may precede the intestinal manifestations; they are however more common in later stages of progression of the disease. The lesions (aphthoid ulcers) are similar to aphthae and appear on the lining mucosa. Mucosal induration (in particular of labial and buccal mucosa) can be observed, as well as granulomatous gingivitis, angular cheilitis, in some cases even atrophic glossitis.

Th: The diagnosis is to be established and treatment managed by a gastroenterologist. Locally, the use of antiseptics can be recommended to prevent or suppress secondary bacterial infections.

Ulcerative colitis (colitis ulcerosa)


This chronic inflammatory disease mostly affects the colonic mucosa.

Clinical picture: In some patients, aphthoid ulcers can be found in the oral cavity along with small superficial necroses, pustules and vegetations on an erythematous mucosa with belt-like arrangement (pyostomatitis vegetans).

Th: The diagnosis is to be established and treatment managed by a gastroenterologist. Locally, the use of antiseptics can be recommended to prevent or suppress secondary bacterial infections.

Celiac disease (gluten enteropathy)

This immune system-associated systemic disease characterized by reaction to the presence of gluten in the diet and damage to the intestinal mucosa is diagnosed by proving the presence of anti gluten antibodies. The oral mucosa is affected approximately in 10 % of patients in whom aphthous lesions occur.

6.2.5 Changes in the oral cavity associated with diseases of the kidney

Uremic stomatitis


In the oral cavity, it only manifests at the late stage of the disease by a painful erythema or ulcerations with pseudomembranous coatings. The tongue can be dry, brownish coated, lips are chapped. Xerostomia is present. Gingival bleeding and bleeding into the submucosal tissues is common as it is caused by dysfunction of thrombocytes (either due to the renal disease as such or as a secondary result of repeated dialysis). Candidosis and other opportunistic infections can appear. In the terminal stage of the chronic renal failure, in uremia, bad breath is a typical finding.

6.2.6 Changes in the oral cavity associated with metabolic and endocrine disorders

Glycogenoses and mucopolysaccharidoses


These disorders of glycogen synthesis or degradation are caused by a hereditary lack of enzymes, which leads to an increased deposition of glycogen into the tissues. Depending on the type and location of the enzymatic defect, several subtypes of this disease can be distinguished, in one of which, Pompe disease (glycogen storage disease type II, autosomal recessive hereditary disease with a deficiency of lysosomal acid 1,4-glucosidase) glycogen storage into the muscles of the tongue can be observed.

Mucopolysaccharidoses are diseases with congenital disorders of the metabolism of mucopolysaccharides; the lack of some of the lysosomal enzymes involved in glycosaminoglycans cleavage causes their deposition in various tissues, including those of the oral cavity.

Diabetes mellitus


Changes on the oral mucosa in diabetes are variable and usually secondary. They depend on the type of diabetes, its duration, compensation, and the presence of systemic complications. Bright red smooth tongue (atrophic glossitis) is a typical finding in the oral cavity. Diabetes patients are also significantly more susceptible to infectious diseases. Therefore, they suffer more often with inflammatory changes and complications caused by bacteria; similarly, fungal infections are more common (denture stomatitis, stomatitis angularis), many diabetic patients also complain about insufficient saliva production and resulting xerostomia. Burning of the mucosa and taste perception disorders (stomatodynia, glossodynia) are also common. A non-inflammatory hypertrophy of the glandular parenchyma of the parotid glands – sialoadenitis in the form of a bilateral induration of parotid glands, Charvat’s sign – is also more commonly found in diabetics. A combination of diabetes and hypertension with the affliction of the oral cavity in the form of the oral lichen is called Grinspan syndrome. In diabetics (in particular in the non-compensated ones), gingivitis and periodontitis are more common than in the general population; they also progress more rapidly than in healthy individuals. Multiple periodontal abscesses can also be present.

Insufficient function of the thyroid gland (hypothyroidism)


In adults, the general symptoms of hypothyroidism include exhaustion, sleepiness, sensitivity to cold, constipation, anaemia, dry pale skin, etc. In the region of the mouth and face, mucoprotein and mucopolysaccharide infiltrations (myxoedema) occur, in particular in the tongue (macroglossia) and eyes (lid oedema). Xerostomia is also often present.

Congenital hypothyroidism (endemic cretinism) is a developmental disorder caused usually by lack of iodine in the mother’s diet during pregnancy. Children are born with a severe mental handicap, suffer with delayed growth and other impairments. In the oral cavity, the disease manifests through delayed growth of teeth, enamel dysplasia and macroglossia.

Increased function of the thyroid gland (hyperthyroidism)

Principal symptoms include enlargement of the thyroid gland (goitre), palpitations, increased blood pressure, sometimes arrhythmia, and intolerance of heat, trembling at rest, exophthalmos (in Graves-Basedow disease) and moist warm skin. It is usually not associated with any symptoms in the oral cavity (although trembling of the tongue can be present in some cases). When treating a patient with hyperthyroidism, however, the dentist must be careful with administering anaesthetics with adrenalin (risk of thyrotoxic crisis).

Increased function of the parathyroid glands (hyperparathyroidism)

Increased production of parathormone (mostly due to adenoma of the parathyroid glands) leads to hypercalcemia and hypophosphatemia, which determines the systemic symptoms. In the oral cavity, so-called brown tumour (giant cell reparative granuloma) can develop, which is a benign tumour of resorptive character. If this tumour is found, the calcium-phosphate metabolism must always be examined.

Primary hypofunction of the adrenal cortex (Addison’s disease)


If the adrenal cortex is damaged (infection, autoimmune processes, tumours), the lack of adrenal hormones stimulates the pituitary gland and production of ACTH and MSH increases, leading to the development of melanin hyperpigmentations on the skin (bronze skin) and on the oral mucosa (graphite-like spots). See Chapter 6.3.1 for more information.


Acromegaly occurs if the growth hormone (somatotropin) is produced in large amounts even after the normal growth is terminated. This is mostly caused by an eosinophilic adenoma of the pituitary, more common in women (2nd to 3rd decade of life, can follow gravidity but can also later follow the menopause). Changes in configuration of the acral parts are typical – dysmorphic changes of the face, enlargement of the distal parts. Enlargement of the tongue (macroglossia) is often associated with development of the plicated tongue.

6.2.7 Paraneoplastic processes

Paraneoplastic processes (paraneoplasia) are symptoms or diseases accompanying tumorous growth in another location. The reasons for paraneoplastic changes are not always clear, reasons may include substances released by the tumour or other mechanisms. In the oral cavity, paraneoplastic processes include e.g. acanthosis nigricans (can indicate a malignant disease of the stomach and colon) or pemphigoid that can also signal the development of a malignant tumour in the organism.