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Earlier, and now outdated, definitions suggested specificity of cutaneous symptoms to a particular tumor.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 based on the important clinical significance, 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 individual cases)(s)

On the other hand, the absolute frequency of the clinical entity in question must be taken into account (e.g. bullous pemphigoid, relatively frequent clinical picture, rarely paraneoplastic).

Paraneoplastic general symptoms: Paraneoplastic general symptoms that indicate advanced tumor disease are common. It is the so-called B-symptom triad that has a high degree of probability (h) for an underlying tumor complex if the symptoms occur together, possibly combined with pruritus:

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

Acquired (proliferative) cornification 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, etc.
• Leser-Trélat syndrome (h) (variant of acanthosis nigricans): eruptive occurrence of multiple seborrheic keratoses (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 disease (minus variant of acanthosis nigricans) affecting the hands and feet. It is characterized by thickened skin that resembles the stomach lining of some animals. Tripe palms occur simultaneously with acanthosis nigricans in about 7 out of 10 cases (see figure). Association with gastrointestinal carcinomas.
• 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 insufficiency described.

• Spiky hyperkeratosis in multiple myeloma (h): Very rare clinical picture with characteristic spiky skin symptoms. Individual case descriptions. Already occurring in the early stages of multiple myeloma (or other gammopathies) (the clinical picture was described in parallel under the name "trichodysplasia spinulosa").

• Ichthyosis acquisita (pseudoichthyosis)(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 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 diseases (myeloid leukemia, hairy cell leukemia, myelofibrosis, Hodgkin, M., polycythemia vera, monoclonal gammopathies).
• Paraneoplastic pemphigus(h): Rare, clinically severe variant of pemphigus with painful mucosal erosions of the conjunctiva, oral mucosa, esophagus, bronchi, lungs (fibrosing alveolitis), intestines. Association with: Non-Hodgkin's lymphomas (42%). Association also with T-cell lymphomas, chronic lymphocytic leukemia (29%), Castleman lymphomas (!), malignant thymomas (10%) and sarcomas of various origins.
• Erythema necroticans migrans (h): Originally defined as obligate cutaneous paraneoplasia in glucagon-secreting pancreatic tumors (glucagonoma: approx. 80% metastasized at diagnosis) (also known as glucagonoma syndrome). The theory of "tumor specificity" has been called into question by more 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-tumorous diseases (e.g. rheumatoid arthritis).
• Papuloerythroderma Ofuji(m): Very rare in European populations (preferably in Asian ethnic groups), extensive, maculo-papular, considerably itchy, exanthematic skin manifestation with a tendency to confluence and possibly erythroderma (see figure), with blood eosinophilia, leukopenia and IgE elevation. Associations with underlying malignant diseases such as cutaneous T-cell lymphoma and leukemia.

Autoimmunologically induced paraneoplastic skin changes

• Systemic lupus erythematosus(m): in patients with lung and gynecological tumors.
• Dermatomyositis (paraneoplastic)(h): Associated with ovarian, breast and colorectal carcinoma. Less frequently with bladder carcinoma, pancreatic carcinoma, renal carcinoma. Note: The risk of malignancy in dermatomyositis patients with anti-TIF1γ is increased 27-fold. TIF-1γ ubiquitinates the tumor suppressor gene p53, thereby downregulating it, which leads to reduced apoptosis of tumor cells.
• Palmar fasciitis with polyarthritis (PFPAS) (h) Symmetrical, painful swelling of the hands with accentuated palmar tissue hardening "woody hands" often leads to progressive flexion contractures similar to Dupuytren's disease. In more than half of the known cases, ovarian carcinoma or another urogenital carcinoma is present.
• Polymyositis (s): low risk of triggering 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, individual cases.
• Immune thrombocytopenia (Evans syndrome: immune thrombocytopenia): Autoimmune disease associated with two or more cytopenias. Association with lymphatic tumor diseases/ Hodgkin's lymphoma)

Skin changes in rheumatologic-paraneoplastic syndromes

Rheumatologic-paraneoplastic syndromes are rare, but represent an important differential diagnosis to classic rheumatologic clinical pictures.

• Pancreatitis-panniculitis-polyarthritis syndrome (h) Polyarthritis together with panniculitis often occurs in patients with pancreatitis with highly elevated lipase levels. In acinar cell carcinoma of the pancreas, PPP often occurs with high lipase levels and worse.
• Pachydermoperiostosis secondary (paraneoplastic(m). Association with primary lung cancer, malignant pleural mesothelioma. Also associated with chronic lung diseases.
• Remitting seronegative symmetrical synovitis with pitting edema(m): Acute symmetrical soft tissue swelling of the back of the hand and foot. Poor response to cortisone therapy is indicative 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 into osteoblasts. The consequences are drumstick fingers and toes, arthritis, arthralgia, bone pain, especially in the tibia and femur due to osteoproliferation).

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

Skin changes that occur with paraproteinemias are to be regarded as paraneoplastic syndromes, whereby the monoclonal immunoglobulin is usually produced by very slowly proliferating, primarily non-malignant plasma cells in the bone marrow.

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

Endocrinological paraneoplasia

• 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 carcinoma, C-cell carcinoma, protatic carcinoma and carcinoids. Note: Central Cushing's syndrome = Cushing's disease caused by a microadenoma of the anterior pituitary gland is not a paraneoplastic syndrome).
• Acromegaly (paraneoplastic) (ectopic, GHRH and GH secretion)(h) Association with carcinoid, bronchial, ovarian, breast, thyroid, colon carcinomas, etc.
• Carcinoid paraneoplasia (ectopically produced serotonin)(h). Association with lung and pancreatic carcinoma.

Paraneoplastic syndromes due to disorders of the 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). Associated with breast carcinoma, small cell lung carcinoma, medullary thyroid carcinoma.
• Disorders of water and electrolyte balance, including hyponatremia (ectopic production of vasopressin). Association with small cell and non-small cell lung carcinoma.

Paraneoplasia in hematologic diseases

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

  acute generalized exanthematous pustulosis (AGEP), etc.

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

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

Paraneoplastic inflammatory/occlusive vascular diseases

• Phlebitis saltans (Trousseau syndrome)(h): Very rare disease; strand-like "jumping" superficial thrombophlebitis, which is considered an early monitoring symptom of an occult visceral tumor (e.g. pancreatic carcinoma - C25.8). Unlike varicophlebitis, it also affects veins that are not primarily varicose.
• Paraneoplastic vasculitis(s): Cutaneous leukocytoclastic vasculitis is the most common form of vasculitis associated with malignancies and palpable purpura of the lower extremities. Rather rare is an association with lymphomas, breast carcinomas, hair cell eukemias and solid tumors.
• Raynaud's phenomenon paraneoplastic(s): Associated with neoplasms of the lung, ovaries and uterus

• Gangrene acral symmetrical(s): Formation of procoagulant substances by the neoplasm. Associated with neoplasms of the lung, ovaries 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" referred to an "acquired C1 esterase inhibitor deficiency" and was thus used in contrast to hereditary angioedema (see below complement system). In rare cases, association with lymphomas.
• Hypertrichosis lanuginosa acquisita(h): Pathogenetically, a hypothetical "pilotropic factor" in paraneoplasia is held responsible, which is said to occur primarily in metastatic carcinomas. The significance of dysproteinemia, protein deficiency and/or hormonal influences (adrenal gland) cannot be conclusively evaluated.
• 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