Skin: A mirror of internal malignancy

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Department of Dermatology, Shree Krishna Hospital, Pramukh Swami Medical College, Karamsad, Gujarat, India
Address for correspondence: Dr. Rita V. Vora, Skin OPD, Room Number 111, Shree Krishna Hospital, Pramukh Swami Medical College, Karamsad – 388 325, Anand, Gujarat, India. E-mail: gro.htlaehraturahc@vvatirCopyright : © Indian Journal of Medical and Paediatric OncologyThis is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.


Skin manifestations are a reflection of many of the internal diseases. Sometimes, skin disease may be the only manifestation of the internal disease. Internal malignancies may give rise to a number of cutaneous manifestations through their immunological, metabolic, and metastatic consequences. Curth proposed criteria to establish a causal relationship between a dermatosis and a malignant internal disease. Malignancy can present with a plethora of cutaneous manifestations. Here, we describe in brief about various skin manifestations of internal malignancies.Key words: Cutaneous manifestationsinternal malignancyparaneoplastic syndrome


Skin manifestations are a reflection of many of the internal diseases; sometimes skin disease may be the only presenting complaint of many of the internal disorders. Internal malignancy, whether organ-specific or hematological can present with a plethora of cutaneous manifestations. The skin lesions can occur as secondaries or as paraneoplastic syndromes or as a part of certain genetic syndromes.[1] Internal malignancy is also one such entity which indicates its existence by various skin manifestations, so a close observation and a suspicious mind are required for detection of internal malignancy through cutaneous findings. Internal malignancies may give rise to a number of cutaneous manifestations through their immunological, metabolic, and metastatic consequences. Skin disease may sometimes provide the first clue for the diagnosis of internal malignancy. Curth proposed criteria by which a causal relationship between a dermatosis and a malignant internal disease might be evaluated.[2] These requirements include the following: (a) Both conditions start at the same time, (b) both conditions follow a parallel course, (c) the condition is not recognized as a part of a genetic syndrome, (d) a specific tumor occurs with a certain dermatosis, (e) the dermatosis is not common, and (f) a high percentage of the association is noted. In a recent Indian study, skin changes were found in 27% of patients with internal malignancies. Cutaneous metastasis was seen in 6% and other skin lesions in 25%. Secondaries in the skin usually present as papules, plaques, and nodules, common site being the anterior abdominal wall. The skin is an infrequent site for metastasis and is only the eighteenth most common site. Cutaneous metastases can arise at any age. However, in keeping with the increased incidence of malignant disease in later life, most cutaneous metastases occurred during or after the fifth decade.[3] The anterior chest wall is reported as the most common site for cutaneous metastatic lesions, and it held good for this study as well wherein 32% of the lesions were in the chest wall.[4,5] The morphological patterns of cutaneous metastases corresponded with the primary tumors and their evaluation helped localize unknown primary malignancies. In cases with known primaries, cutaneous metastases upstaged the malignancy and affected the prognosis.[6]


Direct tumor spread can occasionally arise after diagnostic or therapeutic interventions such as needle aspiration of a tumor, pleural biopsy, drainage of malignant ascites, or placement of other drains in the vicinity of a tumor. “Tumor spillage,” direct contamination of wounds with tumor cells during a laparoscopy or surgical procedure, was once a problem in nearly 20% of cases but is now uncommon; laparoscopic port site metastasis rates and laparotomy wound metastasis rates due to direct tumor inoculation are both in the order of 0.8%.[7] Carcinoma erysipeloides resembles erysipelas but without the pyrexia or toxemia; tumor cells lie within dilated lymphatic vessels in the skin. This pattern is again most commonly seen in breast carcinoma but occurs due to melanoma and pelvic cancers (when it affects the lower abdomen or thigh); it can also occur due to carcinomas of the oral cavity or associated glands, as well as with upper abdominal cancers (stomach, pancreas) or lung cancer.

Cutaneous metastasis occurs in 1%–5% of all patients with internal cancers.[8] Autopsy studies suggest a higher frequency of skin metastasis than may be apparent from clinical studies; in some studies up to 9% of patients with internal cancer have had skin metastases, a large analysis suggesting that 5% is usual,[9] and in about 0.5%–1% a metastasis is the presenting feature of internal cancer.[10,11] Of patients with metastatic cancer, 10% have cutaneous metastases.[12] The most common sources of cutaneous metastases are breast, melanoma, lung, colon, stomach, upper aerodigestive tract, uterus, and kidney; the most common skin metastases from a previously unknown primary tumor originate from the kidney, lung, thyroid, or ovary.[11,13,14] Seventy-five percent of metastases are found in the 25% of body surface area that comprises the head, neck, and upper trunk.[11]

They may be the first sign of extranodal disease in up to 8% of those with metastatic cancer, especially carcinoma lung, kidney, and ovaries. Internal malignancies may metastasize to the skin by direct invasion from underlying structures, by extension through lymphatics, or by embolization into lymphatics or blood vessels. The preferential route by which tumor metastasize often determines the location of its metastasis. Carcinoma breast presents as gross lymphedema of ipsilateral limb skin ulcerations, scaly plaques of Paget’s disease, or rarely Peaud’orange-like carcinoma of cuirasse. Carcinoma of oral cavity usually presents with squamous cell carcinoma (SCC) which ulcerates on the face. Lymphoma, leukemia, and myeloproliferative disorders can present with cutaneous infiltration. Renal cell carcinoma mostly metastasizes to scalp and face, but urinary tract malignancies commonly metastasize to abdominal skin. Sister Mary Joseph’s nodule (an umbilicated subcutaneous nodule) arises due to metastasis from intra-abdominal malignancy chiefly gastric carcinoma. Thyroid and renal cell carcinoma present with a pulsatile tumor mass and a bruit through overlying skin. Fistula may be seen in carcinoma of urinary bladder or larynx.[15] Carcinoma en cuirasse is seen in carcinoma breast, stomach, kidney, and lungs due to carcinomatous lymphatic permeation. Carcinoma telangiectodes involve carcinoma breast. Extramammary Paget’s disease is seen in in situ epithelial carcinoma, genitourinary, or gastrointestinal malignancy.


A number of mechanisms underlie the association of genodermatoses with internal malignancy; these include chromosomal instability, faulty DNA repair mechanisms, abnormal lymphocyte function, and immunosurveillance, and in some cases, a combination of these. More precise genetic diagnosis, understanding of mechanisms, awareness of the benefits, and ability to focus screening of family members for genetic abnormalities or for cancers, is a constantly evolving area within dermatology and pediatric medicine in particular. Internal malignancies are linked to many of genomic instabilities. Gardner’s syndrome characterized by multiple epidermoid cysts, fibromas, and pilomatrixomas. Peutz–Jeghers syndrome manifests as mucocutaneous pigmentation in peri- and intra-oral regions with risk of gastrointestinal malignancy.[16] Howel–Evans syndrome (palmoplantar keratoderma) involves the risk of esophageal carcinoma. Basal cell nevus syndrome (Gorlin’s syndrome) manifests as multiple basal cell carcinomas, mandibular keratocysts, dyskeratotic pits of palms, and soles with the risk of medulloblastoma and ovarian tumors.[17] Familial melanoma syndrome (dysplastic nevus syndrome) has multiple atypical melanocytic nevi with the risk of pancreatic, gastrointestinal, lung, breast, and laryngeal carcinoma.[18] Xeroderma pigmentosum presents with severe photosensitivity, marked reduction in the threshold for sunburn, myriads of lentigines with the risk of ocular, and cutaneous malignancy [Figures ​[Figures11 and ​and22].[19] Von Hippel-Landau syndrome presents with hemangiomas and cafe-au-lait spots with risks of hemangioblastoma of the central nervous system (CNS), pheochromocytoma, renal and pancreatic adenoma, carcinoma, and cysts.[20] Neurofibromatosis type 1 and 2 presents with multiple peripheral neurofibromas, cafe-au-lait macules, axillary freckles with the risk of CNS tumors. LAMB syndrome (Carney’s syndrome) is characterized by lentigines, atrial myxomas, mucocutaneous myxomas, blue nevi with the risk of gonadal hormone secreting tumors, malignant thyroid tumors [Table 1].[21] Cowden’s disease (multiple hamartoma and neoplasia syndrome) shows warty “cobblestone” hyperplasia of the mucosal surfaces, particularly tongue and buccal mucosa, periorificial facial papules, acral warty keratosis, and punctuate keratosis with gastrointestinal polyposis and cysts or polyps of female genitourinary system along with breast adenocarcinoma.[22] Muir–Torre syndrome presents with sebaceous lesions and keratoacanthoma with the risk of hereditary nonpolyposis colon cancer. Ataxia telangiectasia (Louis-Bar syndrome) shows oculocutaneous telangiectasia with the risk of leukemic and breast carcinoma.[23] Bloom syndrome characterized by sun sensitive telangiectasia, cafe-au-lait macules with the risk of lymphoproliferative neoplasia. Rothmund–Thomson syndrome presents with photosensitivity, poikiloderma along with the risk of osteosarcoma and myelodysplasia.


Several carcinogens such as arsenic, vinyl chloride, and radiation can produce various cutaneous manifestations. Chronic arsenic toxicity causes diffuse or spotty rain drop pigmentation, hypopigmented macules, punctuate palmoplantar keratosis, Bowen’s disease, etc., vinyl chloride causes scleroderma-like skin changes with Raynaud’s phenomenon and osteolysis of distal phalanges. Radiation causes radiation dermatitis of the neck which may indicate developing papillary carcinoma of the thyroid. Radiation dermatitis or multiple basal cell carcinomas over spine may indicate leukemia.


Paraneoplastic dermatoses are skin conditions that have an association with internal malignancy but are not themselves malignant. They may be classified in a variety of ways; some authors include genodermatoses within the spectrum of paraneoplastic disorders[24] whereas others view these as a separate group[25,26] or distinguish between paraneoplastic dermatoses,[27] hereditary paraneoplastic syndromes,[28] and hormonally mediated paraneoplastic syndromes. They may be classified according to strength of association with malignancy [Table 221] association with certain types of malignancy,[29,30] by the type of eruption that occurs (papulosquamous, vascular, etc.) or by the apparent mechanism (hormone paraneoplastic syndromes have a wide clinical spectrum, and it is due to certain cytokines like transforming growth factor alpha or peptides released by the malignant cells).[31,32] Curth’s criteria are used to identify the association between various dermatoses and underlying neoplasia. Disorders that fit Curth’s criteria include acanthosis nigricans and possibly a sign of Leser–Trelat, Bazex’s syndrome, Carcinoid syndrome, erythema gyratum repens, hypertrichosis lanuginose, ectopic adrenocorticotropic hormone (ACTH) syndrome, Glucagonoma syndrome, neutrophilic dermatosis, Paget’s disease, and paraneoplastic pemphigus.[33] Disorders-associated statistically with cancer include dermatomyositis, extrmammary Paget’s disease, exfoliative dermatitis, mycosis fungoides, palmer keratoses, generalized pruritus without primary cutaneous eruption, porphyria cutanea tarda, and pityriasis rotunda.[34] Dermatoses possibly associated with cancer includes arsenical keratoses, erythema annulare centrifugum, acquired ichthyosis, multicentric reticulohistiocytosis, necrobiotic xanthogranuloma, classic pyoderma gangrenosum, polymyositis, tripe palms, vasculitis, and vitiligo.


Icterus is due to extrahepatic destruction due to malignancy of gallbladder, pancreas, bile duct, or adjacent bowel. Melanosis is due to melanin which is seen in ACTH-producing tumors, primary pituitary tumor, metastasis to pituitary gland, and malignant melanoma. Hemochromatosis is diffuse gray pigmentation of skin due to hemosiderin deposition seen in hepatocellular carcinoma [Table 3].[21] Xanthomas are seen in multiple myeloma, myelocytic leukemia, myelomonocytic leukemia, diffuse histiocytic lymphoma, and cutaneous T-cell lymphoma. Systemic amyloidosis is seen in multiple myeloma.


Flushing is seen in carcinoid syndrome; unilateral flushing is seen in contralateral lung cancer with Pancoast syndrome. Palmer erythema occurs in primary or metastatic liver tumor. Telangiectasias is seen in ataxia telangiectasia, Bloom’s syndrome, xeroderma pigmentosum. Localized telangiectasia occurs on anterior chest wall in breast carcinoma. Generalized telangiectasia occurs in malignant angioendotheliomatosis. Progressive telangiectasia is seen in carcinoid tumors. Lymphoma is the most common cause of purpura. Acute leukemia leads to disseminated intravascular coagulation which causes purpura. Leukocytoclastic vasculitis is seen in SCC of bronchus, renal cell carcinoma, leukemia, and lymphoma.[35] Digital ischemia is seen in carcinoma pancreas, stomach, small bowel, ovary, and kidney. Migratory superficial thrombophlebitis is seen in tumors of stomach, pancreas, prostate, lung, liver, bowel, gallbladder, and ovary. Type 1 cryoglobulinemia is associated with multiple myeloma, Waldenstrom’s macroglobulinemia, and B-cell malignancies. Deep vein thrombosis is associated with mucinous adenocarcinoma, myeloproliferative disorders, and metastatic cancers.[36] Erythromelalgia is seen in polycythemia vera and essential thrombocytopenia.[37]


Paraneoplastic pemphigus seems to have an association with non-Hodgkins lymphoma, chronic lymphocytic leukemia (CLL), Castleman tumor, thymoma, etc. Pemphigus is associated with thymoma, Hodgkin’s disease. Herpes gestationis is associated with hydatidiform mole and germ cell tumor. Epidermolysis bullosa acquisita is associated with carcinoma of bronchus along with amyloidosis and multiple myeloma. Linear IgA dermatosis is associated with lymphoma, CLL, carcinoma bladder and esophagus, and hydatidiform mole. Cicatricial pemphigoid is seen in carcinoma lung, stomach, colon, and endometrium.[38]


Acanthosis nigricans is seen in gastric and intra-abdominal adenocarcinoma.[33] May be seen in carcinoma lung, uterus, esophagus, pancreas, colon, breast, ovary, or prostate, as well as lymphoma. Acquired ichthyosis is seen in Hodgkin’s lymphoma, carcinoma lung, breast, and cervix. Palmer hyperkeratosis is seen in esophageal carcinoma; palmoplantar keratoderma is seen in breast or ovarian carcinoma. Tripe palms occur in gastric and lung carcinoma. Erythroderma is seen in leukemia, lymphoma. Paraneoplastic acrokeratosis of Bazex characterized by symmetric erythematous and violaceous scaly papules on hands, feet, knees, ears, and nose is seen in SCC of oropharynx, larynx, lung, esophagus, and thymus.[39] Florid cutaneous papillomatosis is characterized by multiple acuminate keratotic papules is seen in carcinoma stomach, breast, lungs, and ovary.[40] Sign of Leser–Trelat (rapid increase in size of multiple seborrheic keratosis) is seen in adenocarcinoma of stomach or colon. Multiple cherry angiomas are associated with solid tumors.[41] Multiple skin tags are associated with colonic polyps. Pityriasis rotunda characterized by fixed, annular, scaly, noninflamed, and hyperpigmented lesions on trunk occurs in hepatocellular carcinoma.


Dermatomyositis is seen in carcinoma ovary, lung, pancreas, stomach, colorectal, and lymphoma. Lupus erythematosus occurs in lymphoma, thymoma. Scleroderma is seen in carcinoma lung, esophagus. Systemic lupus erythematosus is associated with lymphoreticular malignancies, myeloma, and paraproteinemias.


Skin involvement occurring in these disorders ranges from very nonspecific like purpura, through to highly specific features such as cutaneous deposits of the malignancy as in lesions of leukemia cutis. There may be features that suggest a particular diagnosis like oral leukemic deposits, most typically seen in myelomonocytic leukemia, or other cutaneous disease associations as seen with neurofibromatosis type 1 associated with juvenile xanthogranuloma and juvenile myelomonocytic leukemia.[42,43,44] Involvement of the skin as a part of a multisystem tumor differs from metastases from solid tumors in both mechanism, as well as the fact that lesions are often widespread. Specific cutaneous infiltrations of the skin may occur with myeloproliferative disorders, more commonly with lymphoma, but can also occur with leukemia.[45]


Internal carcinoma is an important cause of pruritus though it is rare and nonspecific. Mechanisms that may be involved include secondary metabolic effects like uremia, cholestasis, or due to iron-deficiency anemia, acquired ichthyosis or xerosis. Paul et al. in his 6-year study, in patients with generalized pruritus, found no significant increase in malignancy.[46] Itch may be a severe problem in patients with Hodgkin’s disease and may indicate a poorer prognosis.[47] Other hematological disorders such as Sézary syndrome, mycosis fungoides, myelomatosis and leukemia, may also cause generalized pruritus.[48,49] In polycythemia rubra vera (PRV), the initiating factor appears to be rapid cooling of the skin as encountered after bathing. This is thought to be due to the release of pruritogens by degranulated mast cells.[50] However, patients with PRV can also develop intractable itching unrelated to bathing. Many other visceral carcinomas that can cause pruritus include breast and gastrointestinal cancers and carcinoid syndrome.[51]

Nerve damage by a tumor at any site can cause neuropathic pain or pruritus. The patterns that are most likely to present to a dermatologist are brachioradial pruritus and localized facial or nasal pruritus. Brachioradial pruritus[52] most commonly affects the lateral upper arm or dorsum of the forearm. Most of these cases are mechanical due to bony abnormalities, but a case due to a spinal tumor has been reported, with rapid resolution of symptoms after treatment.[53] Brain tumors are an uncommon cause of pruritus localized to the face.[52,54] Pruritus limited to the nostrils is particularly linked with tumors invading the floor of the fourth ventricle, but tumors elsewhere in the brain and other cerebral lesions (e.g., abscesses), as well as trigeminal neuralgia, can also produce this distribution of pruritus.


Erythema gyratum repens characterized by erythematous bands moving in waves over the body occurs in carcinoma breast, lung, bladder, prostate, cervix, stomach, esophagus, and multiple myeloma.[55] Erythema annulare centrifugum is associated with CLL, malignant histiocytosis, Hodgkin’s disease and carcinoma bronchus, nasopharynx, prostate, ovary, or rectum. Subcutaneous fat necrosis is seen in acinar cell carcinoma of the pancreas. Sweet syndrome characterized by generalized, crimson, agminate papules to large red plaques is seen in acute myelocytic leukemia, myelodysplastic syndrome, multiple myeloma, and lymphoma. Less commonly, it is seen with embryonal carcinoma of testis, ovarian carcinoma, gastric carcinoma and adenocarcinoma of breast, prostate, and rectum. Hypertrichosis lanuginosa acquisita which is the growth of villous hairs over face and ears is caused mainly by drugs but associated with tumors of colon, rectum, bladder, lung, pancreas, gallbladder, uterus, and breast.[56] Necrolytic migratory erythema characterized by erythema, vesicles, pustules, bullae and erosions involving face, intertriginous area, and perigenital region is seen in glucagonoma syndrome. Porphyria cutanea tarda is associated with liver carcinoma.[56] Pyoderma gangrenosum is associated with acute myelogenous leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma, and polycythemia rubra vera. Paraneoplastic sweating is seen in Hodgkin’s lymphoma, liver metastasis due to release of pyrogens from tumor. Herpes Zoster and Herpes Simplex are associated with lymphomas and leukemias. Insect bite hypersensitivity is seen in hematological malignancies like CLL and also in Ebstein–Barr virus-associated lymphoproliferative disease. Clubbing is seen in bronchogenic carcinoma and mesotheliomas.[57] Scleromyxedema is seen in multiple myeloma, Waldenstrom’s macroglobulinemia, Hodgkin’s or non-Hodgkins lymphoma, or leukemias.

Lichen planus may rarely be induced by neoplasia.[58]

Urticaria especially cold urticaria and peripheral gangrene as a result of circulating cryoglobulins, though uncommon, is linked with myeloma and lymphoma.[59]

Erythroderma and exfoliative dermatitis have both been linked with malignancy.[33,49] In around 10% cases, the causative neoplasm is mycosis fungoides or its leukemic variant, Sézary syndrome. There are additionally reported cases of erythroderma with cancers of liver, lung, colon, stomach, pancreas, thyroid, prostate, and cervix.[33,49,60] Ofuji papuloerythroderma has also been associated with peripheral T-cell nonepidermotrophic cutaneous lymphoma.[61] Granuloma annulare has been reported in association with lymphomas, other hematological malignancies, and uncommonly with solid tumors.[62]

“Insect bite-like” reactions are reported in hematological malignancy, usually chronic lymphocytic leukemia.[63] Cutis verticis gyrata may occasionally occur as a paraneoplastic phenomenon.[64] Mental neuropathy (“numb chin syndrome”) may occur as a feature of metastatic disease and is considered an indicator of poor prognosis.[65] Tumors causing it include breast, thyroid, renal, lung, prostate, lymphomas, and melanoma.


Skin acts like a mirror for various underlying diseases, especially malignancies. Skin manifestation may be sometimes the only symptom of underlying disease. Many underlying malignancies present with cutaneous manifestations, few of them being specific. A keen eye is, therefore, required by a dermatologist to treat all the skin conditions keeping associated malignancies in mind.

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Conflicts of interest

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Skin manifestations associated with tumours of the brain. Br J Dermatol. 1975;92:675–8. [PubMed: 1182081]55. Tyring SK. Reactive erythemas: Erythema annulare centrifugum and erythema gyratum repens. Clin Dermatol. 1993;11:135–9. [PubMed: 8339188]56. Mclean DI, Haynes HA. Cutaneous manifestations of internal malignant disease: Cutaneous paraneoplastic syndromes. In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, editors. Fitzpatrik’s Dermatology in General Medicine. 6th ed. New York: McGraw-Hill; 2003. pp. 1783–96.57. Benedek TG. Paraneoplastic digital clubbing and hypertrophic osteoarthropathy. Clin Dermatol. 1993;11:53–9. [PubMed: 8339201]58. Helm TN, Camisa C, Liu AY, Valenzuela R, Bergfeld WF. Lichen planus associated with neoplasia: A cell-mediated immune response to tumor antigens? J Am Acad Dermatol. 1994;30(2 Pt 1):219–24. [PubMed: 8288781]59. Neittaanmäki H. Cold urticaria. Clinical findings in 220 patients. J Am Acad Dermatol. 1985;13:636–44. [PubMed: 4078052]60. Nicolis GD, Helwig EB. Exfoliative dermatitis. A clinicopathologic study of 135 cases. Arch Dermatol. 1973;108:788–97. [PubMed: 4271796]61. Grob JJ, Collet-Villette AM, Horchowski N, Dufaud M, Prin L, Bonerandi JJ. Ofuji papuloerythroderma. Report of a case with T cell skin lymphoma and discussion of the nature of this disease. J Am Acad Dermatol. 1989;20(5 Pt 2):927–31. [PubMed: 2523913]62. Cohen PR. 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. 2006;45:70–80. [PubMed: 16426383]63. Davis MD, Perniciaro C, Dahl PR, Randle HW, McEvoy MT, Leiferman KM. Exaggerated arthropod-bite lesions in patients with chronic lymphocytic leukemia: A clinical, histopathologic, and immunopathologic study of eight patients. J Am Acad Dermatol. 1998;39:27–35. [PubMed: 9674394]64. Ross JB, Tompkins MG. Cutis verticis gyrata as a marker of internal malignancy. Arch Dermatol. 1989;125:434–5. [PubMed: 2923457]65. Burt RK, Sharfman WH, Karp BI, Wilson WH. Mental neuropathy (numb chin syndrome). A harbinger of tumor progression or relapse. Cancer. 1992;70:877–81. [PubMed: 1643620]

Cytomegalovirus, Epstein-barr, Diet and Leukemia.

‘For 30 years I’ve been obsessed by why children get leukaemia. Now we have an answer’

Newly knighted cancer scientist Mel Greaves explains why a cocktail of microbes could give protection against disease.

Mel Greaves has a simple goal in life. He is trying to create a yoghurt-like drink that would stop children from developing leukaemia.

The idea might seem eccentric; cancers are not usually defeated so simply. However, Professor Greaves is confident and, given his experience in the field, his ideas are being taken seriously by other cancer researchers.

Based at the Institute of Cancer Research in London, Greaves has been studying childhood leukaemia for three decades. On Friday, it was announced that he had received a knighthood in the New Year honours list for the research he has carried out in the field.

“For 30 years I have been obsessed about the reasons why children get leukaemia,” he says. “Now, for the first time, we have an answer to that question – and that means that we can now start thinking about ways to halt it in its tracks. Hence my idea of the drink.”

In the 1950s, common acute lymphoblastic leukaemia – which affects one in 2,000 children in the UK – was lethal. Today 90% of cases are cured, although treatment is toxic, and there can be long-term side effects. In addition, for the past few decades, scientists have noticed that numbers of cases have actually been increasing in the UK and Europe at a steady rate of around 1% a year.

“It is a feature of developed societies but not of developing ones,” Greaves adds. “The disease tracks with affluence.”

Acute lymphoblastic leukaemia is caused by a sequence of biological events. The initial trigger is a genetic mutation that occurs in about one in 20 children.

“That mutation is caused by some kind of accident in the womb. It is not inherited, but leaves a child at risk of getting leukaemia in later life,” adds Greaves.

For full leukaemia to occur, another biological event must take place and this involves the immune system. “For an immune system to work properly, it needs to be confronted by an infection in the first year of life,” says Greaves. Without that confrontation with an infection, the system is left unprimed and will not work properly.”

And this issue is becoming an increasingly worrying problem. Parents, for laudable reasons, are raising children in homes where antiseptic wipes, antibacterial soaps and disinfected floorwashes are the norm. Dirt is banished for the good of the household.

In addition, there is less breast feeding of infants and a tendency for them to have fewer social contacts with other children. Both trends reduce babies’ contact with germs. This has benefits – but also comes with side effects. Because young children are not being exposed to bugs and infections as they once were, their immune systems are not being properly primed.

“When such a baby is eventually exposed to common infections, his or her unprimed immune system reacts in a grossly abnormal way,” says Greaves. “It over-reacts and triggers chronic inflammation.”

As this inflammation progresses, chemicals called cytokines are released into the blood and these can trigger a second mutation that results in leukaemia in children carrying the first mutation.

“The disease needs two hits to get going,” Greaves explains. “The second comes from the chronic inflammation set off by an unprimed immune system.”

In other words, a susceptible child suffers chronic inflammation that is linked to modern super-clean homes and this inflammation changes his or her susceptibility to leukaemia so that it is transformed into the full-blown condition.

From this perspective, the disease has nothing to with power lines or nuclear fuel reprocessing stations, as has been suggested in the past, but is caused by a double whammy of interacting prenatal and environmental events, as Greaves outlined in the journal Nature Reviews Cancer earlier this year.

Crucially, this new insight offers scientists a chance to intervene and to stop leukaemia from developing in the first place, he adds. “We do not yet know how to prevent the occurrence of the initial prenatal mutation in the womb, but we can now think of ways to block the chronic inflammation that happens later on.”

To do this, Greaves and his team have started working on the bacteria, viruses and other microbes that live in the human gut. These help us digest our food but they also give an indication of the bugs we have been exposed to in life. For example, people in developed countries tend to have far fewer bacterial species in their guts, it has been found – and that is because they have been exposed to fewer species of microbes in the early stages of their lives, a reflection of those “cleaner” lives they are now living.

“We need to find ways of reconstituting their microbiomes – as we term this community of microbes. We also need to find which are the most important species of bacteria for priming a child’s immune system.”

To do this, Greaves is now experimenting on mice to find out which bugs are best at stimulating rodent immune systems. The aim would then be to follow up with trials on humans in two or three years.

“The aim is to find six or maybe 10 species of microbes that are best able to restore a child’s microbiome to a healthy level. This cocktail of microbes would be given, not as a pill, but perhaps as yoghurt-like drink to very young children.

“And it would not just help prevent them getting childhood leukaemia. Cases of conditions such as type 1 diabetes and allergies are also rising in the west and have also been linked to our failure to expose babies to bacteria to prime children’s immune systems. So such a drink would help cut numbers of cases of these conditions as well.

“I think the prospect is incredibly exciting. I think we could use this to reduce the risk not just of leukaemia but a number of other very debilitating conditions.”

Leukaemia: the facts

Blood cells are manufactured in bone marrow. Red blood cells, which carry oxygen round our bodies, white blood cells, which fight infection, and platelets, which stop bleeding, are created when your body needs them. But when a person develops leukaemia, too many white blood cells are released, which stop the normal cells in your bone marrow from growing. As a result, the amount of normal red cells, white cells and platelets in your blood is reduced – and your health suffers.

Of the many types of leukaemia, the most common in young people are acute lymphoblastic leukaemia and acute myeloid leukaemia.

Source: Teenage Cancer Trust

My Thoughts: Leukemia, Blood, T-Cells, Soft Tissue Injuries and Stem Cells

One of the factors in my disorder is that the locations of tumors on my body were located at the sites of prior soft tissue injury.

If Leukemia is a cancer of the blood, would an injury also facilitate the growth of another tumor at some point following the injury at that site?

And at this point which kind of stem cells would be the ones at work to form a cancerous tumor?

Stem Cell Information – Are Stem Cells Involved in Cancer?

Cancer: Impact and Challenges

Data from 2007 suggest that approximately 1.4 million men and women in the U.S. population are likely to be diagnosed with cancer, and approximately 566,000 American adults are likely to die from cancer in 2008.1 Data collected between 1996 and 2004 indicate that the overall 5-year survival rate for cancers from all sites, relative to the expected survival from a comparable set of people without cancer, is 65.3%.1 However, survival and recurrence rates following diagnosis vary greatly as a function of cancer type and the stage of development at diagnosis. For example, in 2000, the relative survival rate five years following diagnosis of melanoma (skin cancer) was greater than 90%; that of cancers of the brain and nervous system was 35%. Once a cancer has metastasized (or spread to secondary sites via the blood or lymph system), however, the survival rate usually declines dramatically. For example, when melanoma is diagnosed at the localized stage, 99% of people will survive more than five years, compared to 65% of those diagnosed with melanoma that has metastasized regionally and 15% of those whose melanoma has spread to distant sites.2

The term “cancer” describes a group of diseases that are characterized by uncontrolled cellular growth, cellular invasion into adjacent tissues, and the potential to metastasize if not treated at a sufficiently early stage. These cellular aberrations arise from accumulated genetic modifications, either via changes in the underlying genetic sequence or from epigenetic alterations (e.g., modifications to geneactivation- or DNA-related proteins that do not affect the genetic sequence itself).3,4Cancers may form tumors in solid organs, such as the lung, brain, or liver, or be present as malignancies in tissues such as the blood or lymph. Tumors and other structures that result from aberrant cell growth, contain heterogeneous cell populations with diverse biological characteristics and potentials. As such, a researcher sequencing all of the genes from tumor specimens of two individuals diagnosed with the same type of lung cancer will identify some consistencies along with many differences. In fact, cancerous tissues are sufficiently heterogeneous that the researcher will likely identify differences in the genetic profiles between several tissue samples from the same specimen. While some groupings of genes allow scientists to classify organ-or tissue-specific cancers into subcategories that may ultimately inform treatment and provide predictive information, the remarkable complexity of cancer biology continues to confound treatment efforts.

Once a cancer has been diagnosed, treatments vary according to cancer type and severity. Surgery, radiation therapy, and systemic treatments such as chemotherapy or hormonal therapy represent traditional approaches designed to remove or kill rapidly-dividing cancer cells. These methods have limitations in clinical use. For example, cancer surgeons may be unable to remove all of the tumor tissue due to its location or extent of spreading. Radiation and chemotherapy, on the other hand, are non-specific strategies—while targeting rapidly-dividing cells, these treatments often destroy healthy tissue as well. Recently, several agents that target specific proteins implicated in cancer-associated molecular pathways have been developed for clinical use. These include trastuzumab, a monoclonal antibody that targets the protein HER2 in breast cancer,5 gefitinib and erlotnib, which target epidermal growth factor receptor (EGFR) in lung cancer,6 imatinib, which targets the BCR-ABL tyrosine kinase in chronic myelogenous leukemia,7 the monoclonal antibodies bevacizumab, which targets vascular endothelial growth factor in colorectal and lung cancer,8 and cetuximab and panitumumab, which target EGFR in colorectal cancer.8 These agents have shown that a targeted approach can be successful, although they are effective only in patients who feature select subclasses of these respective cancers.

All of these treatments are most successful when a cancer is localized; most fail in the metastatic setting.9–11 This article will discuss the CSC hypothesis and its supporting evidence and provide some perspectives on how CSCs could impact the development of future cancer therapy.

Defining The “Cancer Stem Cell”

A consensus panel convened by the American Association of Cancer Research has defined a CSC as “a cell within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor.”12 It should be noted that this definition does not indicate the source of these cells—these tumor-forming cells could hypothetically originate from stem, progenitor, or differentiated cells.13 As such, the terms “tumor-initiating cell” or “cancer-initiating cell” are sometimes used instead of “cancer stem cell” to avoid confusion. Tumors originate from the transformation of normal cells through the accumulation of genetic modifications, but it has not been established unequivocally that stem cells are the origin of all CSCs. The CSC hypothesis therefore does not imply that cancer is always caused by stem cells or that the potential application of stem cells to treat conditions such as heart disease or diabetes, as discussed in other chapters of this report, will result in tumor formation. Rather, tumor-initiating cells possess stem-like characteristics to a degree sufficient to warrant the comparison with stem cells; the observed experimental and clinical behaviors of metastatic cancer cells are highly reminiscent of the classical properties of stem cells.9

The CSC Hypothesis And The Search For CSCs

The CSC hypothesis suggests that the malignancies associated with cancer originate from a small population of stem-like, tumor-initiating cells. Although cancer researchers first isolated CSCs in 1994,14 the concept dates to the mid-19th century. In 1855, German pathologist Rudolf Virchow proposed that cancers arise from the activation of dormant, embryonic-like cells present in mature tissue.15 Virchow argued that cancer does not simply appear spontaneously; rather, cancerous cells, like their non-cancerous counterparts, must originate from other living cells. One hundred and fifty years after Virchow’s observation, Lapidot and colleagues provided the first solid evidence to support the CSC hypothesis when they used cell-surface protein markers to identify a relatively rare population of stemlike cells in acute myeloid leukemia (AML).14 Present in the peripheral blood of persons with leukemia at approximately 1:250,000 cells, these cells could initiate human AML when transplanted into mice with compromised immune systems. Subsequent analysis of populations of leukemia-initiating cells from various AML subtypes indicated that the cells were relatively immature in terms of differentiation.16 In other words, the cells were “stem-like”—more closely related to primitive blood-forming (hematopoietic) stem cells than to more mature, committed blood cells.

The identification of leukemia-inducing cells has fostered an intense effort to isolate and characterize CSCs in solid tumors. Stem cell-like populations have since been characterized using cell-surface protein markers in tumors of the breast,17 colon,18 brain,19 pancreas,20,21 and prostate.22,23 However, identifying markers that unequivocally characterize a population of CSCs remains challenging, even when there is evidence that putative CSCs exist in a given solid tumor type. For example, in hepatocellular carcinoma, cellular analysis suggests the presence of stem-like cells.24Definitive markers have yet to be identified to characterize these putative CSCs, although several potential candidates have been proposed recently.25,26 In other cancers in which CSCs have yet to be identified, researchers are beginning to link established stem-cell markers with malignant cancer cells. For instance, the proteins Nanog, nucleostemin, and musashi1, which are highly expressed in embryonic stem cells and are critical to maintaining those cells’ pluripotency, are also highly expressed in malignant cervical epithelial cells.27 While this finding does not indicate the existence of cervical cancer CSCs, it suggests that these proteins may play roles in cervical carcinogenesis and progression.

Do CSCs Arise From Stem Cells?

Given the similarities between tumor-initiating cells and stem cells, researchers have sought to determine whether CSCs arise from stem cells, progenitor cells, or differentiated cells present in adult tissue. Of course, different malignancies may present different answers to this question. The issue is currently under debate,9,12 and this section will review several theories about the cellular precursors of cancer cells (see Fig. 9.1).


Figure 9.1. How Do Cancer Stem Cells Arise? The molecular pathways that maintain “stem-ness” in stem cells are also active in numerous cancers. This similarity has led scientists to propose that cancers may arise when some event produces a mutation in a stem cell, robbing it of the ability to regulate cell division. This figure illustrates 3 hypotheses of how a cancer stem cell may arise: (1) A stem cell undergoes a mutation, (2) A progenitor cell undergoes two or more mutations, or (3) A fully differentiated cell undergoes several mutations that drive it back to a stem-like state. In all 3 scenarios, the resultant cancer stem cell has lost the ability to regulate its own cell division.

© 2009 Terese Winslow

Hypothesis #1:

Cancer Cells Arise from Stem Cells. Stem cells are distinguished from other cells by two characteristics: (1) they can divide to produce copies of themselves, or self-renew, under appropriate conditions and (2) they are pluripotent, or able to differentiate into most, if not all, mature cell types. If CSCs arise from normal stem cells present in the adult tissue, de-differentiation would not be necessary for tumor formation. In this scenario, cancer cells could simply utilize the existing stem-cell regulatory pathways to promote their self-renewal. The ability to self-renew gives stem cells long lifespans relative to those of mature, differentiated cells.30 It has therefore been hypothesized that the limited lifespan of a mature cell makes it less likely to live long enough to undergo the multiple mutations necessary for tumor formation and metastasis.

Several characteristics of the leukemia-initiating cells support the stem-cell origin hypothesis. Recently, the CSCs associated with AML have been shown to comprise distinct, hierarchically-arranged classes (similar to those observed with hematopoietic stem cells) that dictate distinct fates.31 To investigate whether these CSCs derive from hematopoietic stem cells, researchers have used a technique known as serial dilution to determine the CSCs’ ability to self-renew. Serial dilution involves transplanting cells (usually hematopoietic stem cells, but in this case, CSCs) into a mouse during a bone-marrow transplant. Prior to the transplant, this “primary recipient” mouse’s natural supply of hematopoietic stem cells is ablated. If the transplant is successful and if the cells undergo substantial self-renewal, the primary recipient can then become a successful donor for a subsequent, or serial, transplant. Following cell division within primary recipients, a subset of the AML-associated CSCs divided only rarely and underwent self-renewal instead of committing to a lineage. This heterogeneity in self-renewal potential supports the hypothesis that these CSCs derive from normal hematopoietic stem cells.31 It should be noted, however, that the leukemia-inducing cells are the longest-studied of the known CSCs; the identification and characterization of other CSCs will allow researchers to understand more about the origin of these unique cells.

Hypothesis #2: Cancer Cells Arise from Progenitor Cells.

The differentiation pathway from a stem cell to a differentiated cell usually involves one or more intermediate cell types. These intermediate cells, which are more abundant in adult tissue than are stem cells, are called progenitor or precursor cells. They are partly differentiated cells present in fetal and adult tissues that usually divide to produce mature cells. However, they retain a partial capacity for self-renewal. This property, when considered with their abundance relative to stem cells in adult tissue, has led some researchers to postulate that progenitor cells could be a source of CSCs.32,33

Hypothesis #3: Cancer Cells Arise from Differentiated Cells.

Some researchers have suggested that cancer cells could arise from mature, differentiated cells that somehow de-differentiate to become more stem celllike. In this scenario, the requisite oncogenic (cancer causing) genetic mutations would need to drive the de-differentiation process as well as the subsequent self-renewal of the proliferating cells. This model leaves open the possibility that a relatively large population of cells in the tissue could have tumorigenic potential; a small subset of these would actually initiate the tumor. Specific mechanisms to select which cells would de-differentiate have not been proposed. However, if a tissue contains a sufficient population of differentiated cells, the laws of probability indicate that a small portion of them could, in principle, undergo the sequence of events necessary for de-differentiation. Moreover, this sequence may contain surprisingly few steps; researchers have recently demonstrated that human adult somatic cells can be genetically “re-programmed” into pluripotent human stem cells by applying only four stem-cell factors (see the chapter, “Alternate Methods for Preparing Pluripotent Stem Cells” for detailed discussion of inducing pluripotent stem cells).28,29

How Cancer Stem Cells Could Support Metastasis

Metastasis is a complex, multi-step process that involves a specific sequence of events; namely, cancer cells must escape from the original tumor, migrate through the blood or lymph to a new site, adhere to the new site, move from the circulation into the local tissue, form micrometastases, develop a blood supply, and grow to form macroscopic and clinically relevant metastases.9,34,35 Perhaps not surprisingly, metastasis is highly inefficient.9 It has been estimated that less than 2% of solitary cells that successfully migrate to a new site are able to initiate growth once there.34,36,37 Moreover, less than 1% of cells that initiate growth at the secondary site are able to maintain this growth sufficiently to become macroscopic metastases.36These observations suggest that a small, and most likely specialized, subset of cancer cells drives the spread of disease to distant organs.

Some researchers have proposed that these unique cells may be CSCs.9,30,32,33,38 In this hypothesis, metastatic inefficiency may reflect the relative rarity of CSCs combined with the varying compatibilities of these cells with destination microenvironments. Researchers have demonstrated that stem cells and metastatic cancer cells share several properties that are essential to the metastatic process, including the requirement of a specific microenvironment (or “niche”) to support growth and provide protection, the use of specific cellular pathways for migration, enhanced resistance to cell death, and an increased capacity for drug resistance.9There is emerging, albeit limited, evidence that these properties may also hold for CSCs.9 Metastatic sites for a given cancer type could therefore represent those tissues that provide or promote the development of a compatible CSC niche, from which CSCs could expand through normal or dysregulated cellular signaling. Moreover, normal stem cells tend to be quiescent unless activated to divide.39 If the CSC hypothesis holds true, then undifferentiated, dormant CSCs would be relatively resistant to chemotherapeutic agents, which act mainly on dividing cells.10 As such, this subpopulation could form the kernel of cells responsible for metastasis and cancer recurrence following treatment and remission.

How The CSC Model Could Affect Cancer Therapy

As noted previously, most contemporary cancer treatments have limited selectivity — systemic therapies and surgeries remove or damage normal tissue in addition to tumor tissue. These methods must therefore be employed judiciously to limit adverse effects associated with treatment. Moreover, these approaches are often only temporarily effective; cancers that appear to be successfully eliminated immediately following treatment may recur at a later time and often do so at a new site. Agents that target molecules implicated in cancer pathways have illustrated the power of a selective approach, and many researchers and drug developers are shifting toward this paradigm. If the CSC hypothesis proves to be correct, then a strategy designed to target CSCs selectively could potentially stop the “seeds” of the tumor before they have a chance to germinate and spread.

The CSC hypothesis accounts for observed patterns of cancer recurrence and metastasis following an apparently successful therapeutic intervention. In clinical practice, however, some cancers prove quite aggressive, resisting chemotherapy or radiation even when administered at relatively early stages of tumor progression. These tumors therefore have an increased likelihood of metastasizing, confounding further treatment strategies while compromising the cancer patient’s quality of life. The presence of CSC in some malignancies may account for some of these metastases. So why do some tumors succumb to therapy, while others resist it? Some scientists have suggested that the tumor aggressiveness may correlate with the proportion of CSCs within a corresponding tumor.40–42 In this scenario, less aggressive cancers contain fewer CSCs and a greater proportion of therapy-sensitive non-CSCs.9

There is also some evidence to suggest that CSCs may be able to selectively resist many current cancer therapies, although this property has yet to be proven in the clinic.9 For example, normal stem cells and metastatic cancer cells over-express several common, known drug-resistance genes.43 As a result, breast cancer CSCs express increased levels of several membrane proteins implicated in resistance to chemotherapy 17 These cells have also been shown to express intercellular signaling molecules such as Hedgehog and Bmi-1,44 which are essential for promoting self-renewal and proliferation of several types of stem cells.45 Moreover, experiments in cell lines from breast cancer46 and glioma40 have shown that CSCs (as identified by cell-surface markers) are more resistant to radiotherapy than their non-CSC counterparts. In the face of radiation, the CSCs appear to survive preferentially, repair their damaged DNA more efficiently, and begin the process of self-renewal.

These discoveries have led researchers to propose several avenues for treating cancer by targeting molecules involved in CSC renewal and proliferation pathways. Potential strategies include interfering with molecular pathways that increase drug resistance, targeting proteins that may sensitize CSCs to radiation, or restraining the CSCs’ self-renewal capacity by modifying their cell differentiation capabilities.9 In each case, successful development of a therapy would require additional basic and clinical research. Researchers must characterize the CSCs associated with a given tumor type, identify relevant molecules to target, develop effective agents, and test the agents in pre-clinical models, such as animals or cell lines. However, by targeting fundamental CSC cellular signaling processes, it is possible that a given treatment could be effective against multiple tumor types.


Cancer represents a major health challenge for the 21st century. Governed by an intricate, complex interplay of molecular signals, cancers often resist systemic treatments. Yet the uncontrolled cellular growth that characterizes cancers may paradoxically hold the key to understanding the spread of disease. It has long been postulated that tumors form and proliferate from the actions of a small population of unique cells. The observation that metastatic cancer cells exhibit experimental and clinical behaviors highly reminiscent of the classical properties of stem cells has led researchers to search for and to characterize “cancer stem cells” believed to be implicated in the cancer process.

The discovery of CSCs in some tumor types has ushered in a new era of cancer research. Cancer stem cell science is an emerging field that will ultimately impact researchers’ understanding of cancer processes and may identify new therapeutic strategies. However, much remains to be learned about these unique cells, which as of yet have not been identified in all tumor types. At present, evidence continues to mount to support a CSC Hypothesis—that cancers are perpetuated by a small population of tumor-initiating cells that exhibit numerous stem cell-like properties. Whether or not the Hypothesis ultimately proves true in all cases, understanding the similarities between cancer cells and stem cells will illuminate many molecular pathways that are triggered in carcinogenesis. Thus, the question, “Are stem cells involved in cancer?” has no simple answer. However, the characterization of CSCs will likely play a role in the development of novel targeted therapies designed to eradicate the most dangerous tumor cells, that may be resistant to current chemotherapy regimens, thereby providing researchers and clinicians with additional targets to alleviate the burden of cancer.


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Invasive Fungal Infections in Acute Leukemia

Content Source ~ NIH/NCBI – Invasive Fungal Infections in Acute Leukemia

Invasive fungal infection (IFI) is among the leading causes for morbidity, mortality, and economic burden for patients with acute leukemia. In the past few decades, the incidence of IFI has increased dramatically. The certainty of diagnosis of IFI is based on host factors, clinical evidence, and microbiological examination. Advancement in molecular diagnostic modalities (e.g. non-culture-based serum biomarkers such as β-glucan or galactomannan assays) and high-resolution radiological imaging has improved our diagnostic approach. The early use of these diagnostic tests assists in the early initiation of preemptive therapy. Nonetheless, the complexity of IFI in patients with leukemia and the limitations of these diagnostic tools still mandate astute clinical acumen. Its management has been further complicated by the increasing frequency of infection by non-Aspergillus molds (e.g. zygomycosis) and the emergence of drug-resistant fungal pathogens. In addition, even though the antifungal armamentarium has expanded rapidly in the past few decades, the associated mortality remains high. The decision to initiate antifungal treatment and the choice of anti-fungal therapy requires careful consideration of several factors (e.g. risk stratification, local fungal epidemiologic patterns, concomitant comorbidities, drug-drug interactions, prior history of antifungal use, overall cost, and the pharmacologic profile of the antifungal agents). In order to optimize our diagnostic and therapeutic management of IFI in patients with acute leukemia, further basic research and clinical trials are desperately needed.

Invasive fungal infections in acute leukemia-10.1177_2040620711410098

Fungemia and Leukemia – Like or Look-Alike?

Fungemia in patients with leukemia ~ NIH-PubMed ~ A nine-year retrospective study on fungemia in patients with leukemia was conducted. A total of 79 episodes of fungemia in 77 patients with leukemia were documented.

Candidemia in acute leukemia patients ~ NIH-PubMed

Candidemia in patients with acute leukemia ~ Fungal infections are not uncommon in patients with hematological malignancies, but they are rarely micro-biologically documented. A fast and reliable means of diagnosis of invasive fungal infections is urgently needed.