Cutaneous paraneoplastic syndromes (overview) L83.x

Paraneoplastic syndromes are defined as a heterogeneous group of nonmetastatic, reactive, therapy-resistant, morbid skin and mucosal diseases based on humoral distant effects of visceral malignancies that are not due to a local tumor effect but are causally or formally genetically linked to the presence of the tumor. Accordingly, they may regress after removal of the primarius. Paraneoplastic syndromes may manifest before or during tumor disease. They may precede the tumor by a long time. Recurrences of the triggering primarius can also lead to the recurrence of cutaneous symptoms.

Earlier, and now outdated, definitions suggested specificity of cutaneous symptoms to a particular tumor. This hypothesis has been disproved for most paraneoplasias, although some specificity is given for erythema necrolyticum migrans, due to the underlying pathogenesis (pancreatic carcinoma).

Considered nonparaneoplastic are:

• Skin infiltrates of the primary tumor or cutaneous metastases of solid tumors of other organs, as well as leukemic skin infiltrates.
• Humoral distant effects of a primary tumor, e.g., in Cushing's disease, by a cortisol-producing NNR tumor (in contrast, ectopic ACTH secretion in small cell lung carcinoma/thymoma/pancreatic carcinoma is considered a paraneoplastic syndrome/paraneoplastic form of Cushing's disease)

• Tumorous and non-tumorous skin manifestations of genodermatoses

The classification proposed here avoids the division into "obligate" and "facultative". On the one hand, it is made according to the important clinical valence, namely the degree of probability with which a clinical symptom can be classified as paraneoplastic.

• Paraneoplastic probability = high association(h)
• Paraneoplastic probability = medium association (m)
• Paraneoplastic probability = rare (association known, only single casuistry)(s).

On the other hand, the absolute frequency of the clinical entity in question should be considered (e.g., bullous pemphigoid, relatively common clinical entity, rarely paraneoplastic).

Paraneoplasticgeneral symptoms: Paraneoplastic general symptoms suggestive of advanced tumor disease are common. It is the so-called B-symptom triad which, when the symptoms occur together, gfls. combined with pruritus, have a high degree of probability (h) for an underlying tumor complex:

• Night sweats (h)
• fever (m)
• anorexia (h)
• (+pruritus)

Acquired (proliferative) keratinization disorders (paraneoplastic production of growth factors)

• Paraneoplastic acanthosis nigricans (maligna)(h): Association mainly with gastric carcinoma 56%, liver carcinoma (cholangiocarcinoma) 7%, less frequently with uterine carcinoma, ovarian carcinoma and others.
• Leser-Trélat syndrome (h) (variant of acanthosis nigricans): eruptive onset of multiple seborrheic kewratoses (trunk and extremities)
• Paraneoplastic acrokeratosis (bazex)(h): Associated with squamous cell carcinoma of the tongue, pharynx, larynx, esophagus. DD: Acral psoriasis.
• Tripe palms(h): Very rare (about 100 published cases) skin disorder (minus variant of acanthosis nigricans) affecting the hands and feet. It is characterized by thickened skin that resembles the gastric mucosa of some animals. Tripe palms occur concurrently with acanthosis nigricans in about 7 out of 10 cases (see Fig.). Association with gastrointestinal carcinoma.
• Pityriasis rotunda (?): Association with acute myeloid leukemia; chronic lymphocytic leukemia, hepatocellular carcinoma.
• Acquired filiform keratosis palmoplantaris (?): Association with bronchial carcinoma, renal cell carcinoma, rectal carcinoma, malignant melanoma, and chronic terminal renal failure described.

• Spiny hyperkeratosis in multiple myeloma (h): Very rare clinical picture with characteristic spiculated skin manifestations. Individual case reports. Occurring already in the early stage of multiple myeloma (or other gammopathies) (the clinical picture was described in parallel under the name "trichodysplasia spinulosa").

• Ichthyosis acquisita (pseudoichthyoses)(s): Non-hereditary ichthyosiform skin changes in the context of other diseases or due to incorrect, drying, usually exaggerated skin care. In rare cases also occurring as a paraneoplastic syndrome.

Inflammatory paraneoplastic skin changes

• Pyoderma gangraenosum(s) Polycyclic, destructive, sterile neutrophilic autoinflammatory ulcerative dermatitis. In about 4.0% of cases association with hematologic neoplasms such as: multiple myeloma, lymphoma, plasmocytic, IgA deficiency, congenital, myeloproliferative disorders (myeloid leukemia, hairy cell leukemia, myelofibrosis, Hodgkin, M., polycythemia vera , monoclonal gammopathies).
• Paraneoplastic pemphigus(h): Rare, clinically severe variant of pephigus with painful mucosal erosions of the conjunctiva, oral mucosa, esophagus, bronchi, lungs (fibrosing alveolitis), bowel. Association with: non-Hodgkin's lymphoma (42%). Association also with T-cell lymphomas, chronic lymphocytic leukemia (29%), Castleman lymphomas (!), malignant thymomas (10%), and sarcomas of various etiologies.
• Erythema necroticans migrans (h): Originally defined as obligate cutaneous paraneoplasia in glucagon-secreting pancreatic tumor (glucagonoma: about 80% metastatic at diagnosis) (also called glucagonoma syndrome). The thesis of "tumor specificity" has been questioned by recent reports after the clinical picture was described in connection with hepatitis B and C, adenocarcinomas, bronchial carcinomas and squamous cell carcinomas.
• Erythema gyratum repens (Gammel)(h): Rare clinical picture originally described as "obligate cutaneous paraneoplasia" in carcinomas of the breast (6%), female genitalia, pharynx, bronchi (in 50% of cases), esophagus, or stomach. Erythema gyratum repens has also been described in non-tumor diseases (e.g., rheumatoid arthritis).
• Papuloerythroderma Ofuji(m): Very rare in European populations (preferred in Asian ethnic groups), extensive, maculo-papular, considerably pruritic, exanthematous skin manifestation with tendency to confluence and possibly erythroderma (see Fig.), with blood eosinophilia, leukopenia, and IgE elevation. Associations with underlying malignancies such as cutaneous T-cell lymphoma and leukemias.

Autoimmunologically induced paraneoplastic skin lesions.

• Systemic lupus erythematosus(m): in patients with lung and gynecologic tumors.
• Dermatomyositis (paraneoplastic)(h): Associated with ovarian, breast, and colorectal carcinoma. Less commonly with bladder carcinoma, pancreatic carcinoma, renal carcinoma. Note: The malignancy risk of dermatomyositis patients with anti-TIF1γ is increased 27-fold. TIF-1γ ubiquitinates the tumor suppressor gene p53, thereby downregulating it, resulting in decreased apoptosis of tumor cells.
• Palmar fasciitis with polyarthritis (PFPAS) (h) Symmetric, painful swelling of the hands with accentuated palmar tissue induration "woody hands" often leads to progressive flexion contractures similar to Dupuytren's disease. Ovarian carcinoma or other urogenital carcinoma is present in more than half of known cases.
• Polymyositis (s): low risk for precipitating tumor disease.
• Bullous pemphigoid(s): low paraneoplastic risk (paraneoplastic bullous pemphigoid). Association with prostate carcinoma, rectal carcinoma, bronchial carcinoma.
• Lichen planus pemphigoides(s): low paraneoplastic risk, single casuistics.
• Immune thrombocytopenia (Evans syndrome: immune thrombocytopenia): Autoimmune disorder associated with two or more cytopenias. Association with lymphoid tumor disease/ Hodgkin's lymphoma).

Skin lesions in rheumatologic-paraneoplastic syndromes

Rheumatologic-paraneoplastic syndromes are rare, but represented an important differential diagnosis to classical rheumatologic syndromes.

• Pancreatitis-panniculitis-polyarthritis syndrome (h) Polyarthritis together with panniculitis, often occurs in patients with pancreatitis when lipase levels are severely elevated. In acinar cell carcinoma of the pancreas, PPP often occurs with high lipase levels and poor.
• Pachydermoperiostosis secondary (paraneoplastic(m). Association with primary lung cancer, malignant pleural mesothelioma. Furthermore, also with chronic lung disease.
• Remitting seronegative symmetrical synovitis with pitting edema(m): Acute symmetrical soft tissue swelling of the dorsum of the hand and foot. Poor therapeutic response to cortisone is suggestive of the presence of malignancy, which is present in about one-third of patients.
• Hypertrophic osteoarthropathy (Marie-Bamberger)(h) Association with thoracic malignancies and especially lung carcinomas (increased production of "Vascular Endothelial Growth Factor /VEGF, leads to differentiation of the periosteum to osteoblasts. The result is drumstick finger -toe, arthritis, arthralgias, bone pain especially in tibia and femur due to osteoproliferation) .

Paraenoplastic skin changes due to paraproteinemia (see below Paraproteins and skin changes)

Skin lesions caused by paraproteinemias are paraneoplastic syndromes, where the monoclonal immunoglobulin is mostly produced by very slowly proliferating, primarily non-malignant plasma cells in the bone marrow.

• Close associations exist with: AL-type amyloidosis, cryoglobulinemia, POEMS syndrome, scleromyxoedema, lichen myxoedematosus, scleroedema adultorum (Buschke), prickly hyperkeratoses, TEMPI syndrome, xanthogranuloma, necrobiotic, xanthomas, plane, Schnitzler syndrome.
• Intermediate associations exist with: pyoderma gangraenosum, Sweet syndrome, vasculitis, leukocytoclastic, pemphigus, IgA pemphigus.

Endocrinological paraneoplasias

• Hyperprolactinemia (ectopic prolactin release)(h) association with breast carcinoma.
• Hyperthyroidism (paraneoplastic) (ectopic TRH and TSRH production). Association with bladder mole and chorionic carcinoma.
• Endogenous Cushing's syndrome (ectopic/paraneoplastic ACTH secretion)(h) . Association with lung carcinomas, C-cell carcinomas, protatacarcinoma, and carcinoids. Note: A central Cushing's syndrome = Cushing's disease, due to a microadenoma of the anterior pituitary is not a paraneoplastic syndrome).
• Acromegaly (paraneoplastic) (ectopic, GHRH and GH secretion)(h) association with carcinoid, bronchial, ovarian, mammary, thyroid, colon carcinomas and others.
• Carcinoid paraneoplasia (ectopically produced serotonin)(h). Association with lung and pancreatic carcinoma.

Paraneoplastic syndromes due to disturbances in electrolyte balance.

• Hypercalcemia (ectopically produced parathyroid hormone-related protein - PTHrP). Associated with squamous cell carcinoma of the lung, head and neck tumors, bladder tumors).
• Hypocalcemia (ectopically produced calcitonin). Association with breast carcinoma, small cell lung carcinoma, medullary thyroid carcinoma.
• Disturbances of water and electrolyte balance, including hyponatremia (ectopic production of vasopressin). Associated with small cell and non-small cell lung carcinoma.

Paraneoplasia in hematologic disorders.

• Erythrocytosis (polyglobulia): ectopic production of erythropoietin/erythropoietin-like substances (mainly in renal cell carcinomas,- and liver tumors, cerebellar hemangioblastomas, lung tumors).
• Leukocytosis: ectopic production of hematopoietic cytokines (G-CSF, GM-CSF, interleukin-3, interleukin-6) (association with lung carcinomas, gatrointestinal tumors, ovarian carcinomas, tumors of the genitourinary tract). Clinically, leukocytoses are associated with various disease patterns e.g. Sweet syndrome,

  pustulosis acute generalized exanthematous (AGEP) and others

  .

• Hematoeosinophilia(m) As a paraneoplastic syndrome (e.g. in various solid tumors). Carcinomas of colon, stomach, ovary, pancreas, cervix uteri, and thyroid; bronchial carcinomas. Hematoeosinophilias may be associated with numerous skin disorders (e.g., hypereosinophilic dermatitis , see below for eosinophilia, skin disorders)

• Thrombocytosis (>500/nl)(s): Ectopic production of interleukin-6, possibly thrombopoietin. (In 10-15% of patients with thrombocytosis association with bronchial, pancreatic, gastrointestinal, breast, genitourinary, ovarian, prostate carcinomas and lymphomas). Clinical:Hypercoagulopathy with thromboembolic events in patients (pancreatic carcinoma, lung carcinoma); secondary erythromelalgia.

Paraneoplastic inflammatory/occlusive vascular disease.

• Phlebitis saltans (Trousseau syndrome)(h): Very rare disorder; stranded "jumping" superficial thrombophlebitis that is considered a monitor early symptom of an occult visceral tumor (e.g., pancreatic cancer - C25.8). Unlike varicophlebitis, it also affects primary non-varicose veins.
• Paraneoplastic vasculitides(s): Cutaneous leukocytoclastic vasculitis is the most common form of vasculitis associated with malignancy and palpable purpura of the lower extremities. Rather rare is association with lymphoma, breast carcinoma, hair cell eukemia, and solid tumors.
• Raynaud's phenomenon paraneoplastic(s): Associated with neoplasms of the lung, ovary, and uterus.

• Gangrene acral symmetric(s): Formation of procoagulant substances by the neoplasm. Associated are neoplasms of the lung, ovary, and uterus (Kopterides P et al 2004; Mittal A et al (2017).

Other

• Acquired angioedema(s) due to C1. inhibitor deficiency: Originally, the adjective "acquired" was used to refer to "acquired C1 esterase inhibitor deficiency" and thus was used opposite to hereditary angioedema (see below Complement system). In rare cases association with lymphoma.
• Hypertrichosis lanuginosa acquisita(h): Pathogenetically, a hypothetical "pilotropic factor" is held responsible in paraneoplasias, which is thought to occur mainly in metastatic carcinomas. The significance of dysproteinemia, protein deficiency, and/or hormonal influences (adrenal) cannot be conclusively assessed.
• Subacute sensory neuropathy (h): rare peripheral neuropathy. Formation of autoantibodies (anti-Hu) (association with lung tumors).

The cause of many paraneoplasias is unclear. Presumably, mutations in the course of tumorigenesis alter not only the proliferation metabolism but also the performance metabolism of the cancer cells. The consequence is the synthesis of biologically active substances. These include:

• Ectopically formed hormones and hormone-like acting polypeptides.
• Tumor-induced humoral or cell-mediated pathological immune responses
• Tumor-induced production of growth factors
• Tumor-induced production of cytokines (cehmokines)

The effects on the integument are correspondingly diverse.

Skin diseases and monitorial indices of the skin in malignant tumors. Paraneoplastic dermatoses

1. Blum A, Grossmann S, Rohm S, Rocken M (2003) Facultative paraneoplasia of the skin. Dtsch Med Wochenschr 128: 2257-2260
2. Blum A, Rohm S, Grossmann S, Rocken M (2003) Obligate paraneoplasias of the skin. Dtsch Med Wochenschr 128: 2195-2199
3. Bonnecaze AK et al (2016) Keratosis punctata of the palmar creases in a 68-year-old African-American man. BMJ Case Rep bcr2016216050.
4. Cohen PR (2006) Granuloma annulare, relapsing polychondritis, sarcoidosis, and systemic lupus erythematosus: conditions whose dermatologic manifestations may occur as hematologic malignancy-associated mucocutaneous paraneoplastic syndromes. Int J Dermatol 45: 70-80
5. Kopterides P et al (2004) Digital gangrene and Raynaud's phenomenon as complications of lung adenocarcinoma. Lancet Oncol 5:549.
6. Lai TS et al (2020) Paraneoplastic Raynaud's phenomenon associated with metastatic ovarian cancer: A case report and review of the literature. Gynecol Oncol Rep 33:100575.
7. Lokineni S et al (2021) Paraneoplastic Raynaud's phenomenon as an initial manifestation of lung cancer? Eur J Case Rep Intern Med 8:002690
8. Niebauer G (1984) Malignancy and cutaneous paraneoplastic syndromes. Dermatologist 35: 602-608
9. Pinos-Leóna L et al (2016) Pityriasis rotunda and hyperprolactinemia. Actas sifiligraphicas 107: 535-537.
10. Sardiña González C et al (2022) Paraneoplastic syndromes review: the great forgotten ones. Crit Rev Oncol Hematol 174:103676.
11. Zappasodi P, Forno C, Corso A, Lazzarino M (2006) Mucocutaneous paraneoplastic syndromes in hematologic malignancies. Int J Dermatol 45: 14-22