Infantile digital fibromatosis (IDF), also termed inclusion body fibromatosis, Reye tumor, or Reye's tumor, usually occurs as a single, small,

asymptomatic In medicine, any disease is classified asymptomatic if a patient tests as carrier for a disease or infection but experiences no symptoms. Whenever a medical condition fails to show noticeable symptoms after a diagnosis it might be considered asy ...

, nodule in the

dermis The dermis or corium is a layer of skin between the epidermis (with which it makes up the cutis) and subcutaneous tissues, that primarily consists of dense irregular connective tissue and cushions the body from stress and strain. It is divided i ...

on a

finger A finger is a limb of the body and a type of digit, an organ of manipulation and sensation found in the hands of most of the Tetrapods, so also with humans and other primates. Most land vertebrates have five fingers ( Pentadactyly). Chambers ...

toe Toes are the digits (fingers) of the foot of a tetrapod. Animal species such as cats that walk on their toes are described as being ''digitigrade''. Humans, and other animals that walk on the soles of their feet, are described as being ''plant ...

Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). Page 989. McGraw-Hill. . of infants and young children. IMF is a rare disorder with approximately 200 cases reported in the medical literature as of 2021. The World Health Organization, 2020, classified these nodules as a specific benign tumor type in the category of

fibroblastic and myofibroblastic tumors Fibroblastic and myofibroblastic tumors (FMTs) develop from the mesenchymal stem cells which differentiate into fibroblasts (the most common cell type in connective tissue) and/or the myocytes/myoblasts that differentiate into muscle cells. FMTs ...

. IDF was first described by the

Australia Australia, officially the Commonwealth of Australia, is a Sovereign state, sovereign country comprising the mainland of the Australia (continent), Australian continent, the island of Tasmania, and numerous List of islands of Australia, sma ...

pathologist Pathology is the study of the causal, causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when us ...

Douglas Reye Ralph Douglas Kenneth Reye ( "rye"; 5 April 1912 – 16 July 1977) was an Australian pathologist. In 1958, he discovered a muscular disease that was later named nemaline myopathy. A brain disease he and his colleagues described in 1963 is epony ...

, in 1965. IDF consists of an overgrowth of spindle-shaped cells in a

collagen Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...

fiber-rich background located in the dermis (i.e. the layer of skin between the

epidermis The epidermis is the outermost of the three layers that comprise the skin, the inner layers being the dermis and hypodermis. The epidermis layer provides a barrier to infection from environmental pathogens and regulates the amount of water rele ...

and

subcutaneous tissue The subcutaneous tissue (), also called the hypodermis, hypoderm (), subcutis, superficial fascia, is the lowermost layer of the integumentary system in vertebrates. The types of cells found in the layer are fibroblasts, adipose cells, and macr ...

) but may extend into the subcutaneous tissue. These spindle-shaped cells contain distinctive

inclusion bodies Inclusion bodies are aggregates of specific types of protein found in neurons, a number of tissue cells including red blood cells, bacteria, viruses, and plants. Inclusion bodies of aggregations of multiple proteins are also found in muscle cells ...

within their

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...

that greatly help in distinguishing IDF from other fibrous skin diseases. These inclusions are composed of densely packed

vimentin Vimentin is a structural protein that in humans is encoded by the ''VIM'' gene. Its name comes from the Latin ''vimentum'' which refers to an array of flexible rods. Vimentin is a type III intermediate filament (IF) protein that is expressed ...

and

actin Actin is a family of globular multi-functional proteins that form microfilaments in the cytoskeleton, and the thin filaments in muscle fibrils. It is found in essentially all eukaryotic cells, where it may be present at a concentration of over ...

filaments IDF lesions are usually painless and have a tendency to regress spontaneously. Consequently, the current recommended treatment for IDF nodules is conservative observation. If the lesions cause local deformities and/or functional impairments or continue to increase in size over long observation periods, surgical removal is recommended. However, surgically removed IDF lesions have had high rates of recurrence and this surgery may cause post-operative digital deformities.

Presentation

IDF typically presents as a solitary painless, smooth, flesh-colored to red, dome-shaped nodule located on the dorsal or lateral aspect of a finger or toe but sparing the thumb or great toe; they occur principally in the first two years of life with about 1/3 of cases having a lesion since birth. However: 1) lesions with appearances similar to, and diagnosed as, IPF have been described in extra digital sites such as the arm, breast, tongue, thigh, and chest; 2) unusual cases have presented with multiple lesions, i.e. 2–3, uncommonly 7–15, and one case with 74 lesions in a 2018 review study; 3) cases have been reported in children up to the age 10 and one case was reported in a 52-year-old adult; 4) the lesions are typically smaller than 2 cm in maximum diameter but rarely have been tumor-sized, e.g. 4.5 cm; 5) the lesions, particularly when larger-sized, may be painful and/or compromise the functions of nearby joints and digits; and 6) the lesions occasionally invade the

periosteum The periosteum is a membrane that covers the outer surface of all bones, except at the articular surfaces (i.e. the parts within a joint space) of long bones. Endosteum lines the inner surface of the medullary cavity of all long bones. Structure ...

and erode a nearby bone.

Pathology

Microscopic

histopathological Histopathology (compound of three Greek words: ''histos'' "tissue", πάθος ''pathos'' "suffering", and -λογία ''-logia'' "study of") refers to the microscopic examination of tissue in order to study the manifestations of disease. Spec ...

analyses of appropriately dye-stained IDF tissues typically show a non-encapsulated small tumor composed of bundles of uniform spindle-shaped cells that combine physical features of

fibroblasts A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells o ...

(the most common cell type in connective tissue) with those of

myofibroblast A myofibroblast is a cell phenotype that was first described as being in a state between a fibroblast and a smooth muscle cell. Structure Myofibroblasts are contractile web-like fusiform cells that are identifiable by their expression of α-sm ...

s (contractile, spindle-shaped cells that are identifiable by their expression of α-smooth muscle actin) in a background of collagen fibers. In hematoxylin and eosin-stained tissues, the spindle-shaped cells have pale eosinophilic (i.e. red or pink due to uptake of eosin) cytoplasm with plump and elongated nuclei composed of granulated (i.e. having many small, distinct parts)

chromatin Chromatin is a complex of DNA and protein found in eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important roles in r ...

. The most

pathognomonic Pathognomonic (rare synonym ''pathognomic'') is a term, often used in medicine, that means "characteristic for a particular disease". A pathognomonic sign is a particular sign whose presence means that a particular disease is present beyond any doub ...

(i.e. indicative of a particular disease) feature of these cells is the presence of

cytoplasmic In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. Th ...

perinuclear inclusion bodies which usually are small, round, pale pink bodies on hematoxylin and eosin staining that often indent their parent cells' nuclei. These inclusions are composed of densely packed

and

filaments. Newer tumors show relatively abundant inclusion bodies and scarce collagen fibers while older tumors show few or no detectable inclusion bodies and abundant collagen fibers. Immunohistochemical analyses show that the spindle-shaped cells typically express α-smooth muscle actin,

calponin Calponin is a calcium binding protein. Calponin tonically inhibits the ATPase activity of myosin in smooth muscle. Phosphorylation of calponin by a protein kinase, which is dependent upon calcium binding to calmodulin, releases the calponin's ...

desmin Desmin is a protein that in humans is encoded by the ''DES'' gene. Desmin is a muscle-specific, type III intermediate filament that integrates the sarcolemma, Z disk, and nuclear membrane in sarcomeres and regulates sarcomere architecture. Str ...

, and

CD99 CD99 antigen (Cluster of differentiation 99), also known as MIC2 or single-chain type-1 glycoprotein, is a heavily O-glycosylated transmembrane protein that is encoded by the ''CD99'' gene in humans. The protein has a mass of 32 kD. Unusually for ...

proteins but not

S100 protein The S100 proteins are a family of low molecular-weight proteins found in vertebrates characterized by two calcium-binding sites that have helix-loop-helix ("EF-hand-type") conformation. At least 21 different S100 proteins are known. They are enc ...

glial fibrillary acidic protein Glial fibrillary acidic protein (GFAP) is a protein that is encoded by the ''GFAP'' gene in humans. It is a type III intermediate filament (IF) protein that is expressed by numerous cell types of the central nervous system (CNS), including astroc ...

Diagnosis

The diagnosis of IDF is usually based on its presentation in newborn or young infants and

biopsy A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a diseas ...

fine needle aspirate Fine-needle aspiration (FNA) is a diagnostic procedure used to investigate lumps or masses. In this technique, a thin (23–25 gauge (0.52 to 0.64 mm outer diameter)), hollow needle is inserted into the mass for sampling of cells that, aft ...

analyses of the tumors' pathology. These analyses should show the presence of spindle-shaped cells bearing eosinophilic paranuclear inclusions consisting of actin and vimentin filaments, which, if necessary, can be confirmed by

immunofluorescence Immunofluorescence is a technique used for light microscopy with a fluorescence microscope and is used primarily on microbiological samples. This technique uses the specificity of antibodies to their antigen to target fluorescent dyes to specif ...

staining of the filaments. Inclusions may not be evident in older lesions stained with hematoxylin and eosin but may be apparent when stained with other reagents such as the

Masson's trichrome stain Masson's trichrome is a three-colour staining procedure used in histology. The recipes evolved from Claude L. Pierre Masson's (1880–1959) original formulation have different specific applications, but all are suited for distinguishing cells f ...

phosphotungstic acid-haematoxylin stain Phosphotungstic acid haematoxylin (PTAH) is a mix of haematoxylin with phosphotungstic acid, used in histology for staining. It stains some tissue in contrasting colors in a way similar to haematoxylin and eosin stain, as phosphotungstic acid b ...

, elastic

Van Gieson's stain Van Gieson's stain is a mixture of picric acid and acid fuchsin. It is the simplest method of differential staining of collagen and other connective tissue. It was introduced to histology by American neuropsychiatrist and pathologist Ira Van ...

, or Lendrum's phloxine-tartrazine stain. Demonstration of these filaments is not necessary for a diagnosis of IMF if the clinical picture and other histological findings are consistent with the disorder. Findings of one or a few usually small lesions centered in the dermis of a digit consisting of spindle-shaped cells and expressing α-smooth muscle actin, desmin, and calponin proteins would support the diagnosis of IDF.

Infantile myofibromatosis Infantile myofibromatosis (IMF) is a rare tumor found in 1 in 150,000 to 1 in 400,000 live births. It is nonetheless the most common tumor derived from fibrous connective tissue that occurs primarily in infants and young children. IMF tumors are b ...

(IMF) is, like IDF, a disease in which benign tumors develop primarily in the fingers and toes of newborns and infants and consists of spindle-shaped cells in a collagen fibrous background. IDF was once regarded as a sub-type of infantile myofibromatosis. However, IMF tumors can be far more aggressinve than IDF lesions and consist of cells that do not have paranuclear inclusions. The

World Health Organization The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...

(2020) classification includes IPF but not IMF as a tumor in the category of benign fibroblastic and myofibroblastic tumors.

Treatment

Infantile digital fibroma lesions were once thought to be potentially malignant and therefore treated with surgical excision and even digital amputations. Currently, these tumors are known to be benign, may spontaneously regress, and often recur after surgical removal. Consequently, IDF lesions are usually treated by a

watchful waiting Watchful waiting (also watch and wait or WAW) is an approach to a medical problem in which time is allowed to pass before medical intervention or therapy is used. During this time, repeated testing may be performed. Related terms include ''expec ...

observation approach with surgical resections limited to cases with functional impairment, significant symptoms, or progressive, long-term growth. Alternate or supplemental treatments used to treat IDF include injection of the

glucocorticoid Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebr ...

triamcinolone Triamcinolone is a glucocorticoid used to treat certain skin diseases, allergies, and rheumatic disorders among others. It is also used to prevent worsening of asthma and COPD. It can be taken in various ways including by mouth, injection into ...

, or the

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

drug,

5-fluorouracil Fluorouracil (5-FU), sold under the brand name Adrucil among others, is a cytotoxic chemotherapy medication used to treat cancer. By intravenous injection it is used for treatment of colorectal cancer, oesophageal cancer, stomach cancer, pancrea ...

, directly into the lesions. Since these injection treatments have not been evaluated in large studies to date, surgical resection is the most accepted treatment of highly symptomatic or progressively enlarging IDF lesions. Overall, the prognosis for IDF is excellent.

References

External links