Case 19-2006 — A 22-Month-Old Boy with the Rapid Growth of Subcutaneous Nodules
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《新英格兰医药杂志》
Presentation of Case
Dr. Richard Chou (Rheumatology): A 22-month-old boy was seen in the pediatric rheumatology clinic because of enlarging subcutaneous nodules on the head, legs, and right hand. The patient had been well until six weeks earlier, when his mother noticed a firm, nontender bump on his medial right shin. Two weeks later, she noticed three new bumps in a line on the left pretibial area. She took the child to his pediatrician's office. The mother could recall no specific trauma to his legs, and the bumps had not been red or tender. Radiographs of both lower legs showed a soft-tissue density on the left side, but none on the right, with no bony abnormalities or soft-tissue calcifications.
During the next three weeks, the lesions on the left leg grew from between 6 and 10 mm in diameter to nearly 20 mm. Laboratory evaluation showed normal levels of serum electrolytes and normal results of renal-function tests. Results of other laboratory tests are shown in Table 1. A palpable lesion appeared on the left index finger overlying the proximal interphalangeal joint, and the patient was referred to the pediatric rheumatology clinic for further evaluation.
Table 1. Laboratory Data.
When seen in the clinic, the patient had been coughing for two days, without dyspnea. He had no fever, chills, alopecia, weight loss, dysphagia, nausea, emesis, abdominal pain, change in bowel habits, epistaxis or other type of bleeding, or cold-associated changes in color in the digits. His appetite was good, and he slept through the night.
The patient had been born at 38 weeks' gestation by a spontaneous vertex vaginal delivery, with a birth weight of 3.1 kg. He had met all developmental motor milestones and played normally, but he was believed to be delayed in appropriate verbalization. At the age of 6 weeks and again at 7 months, he had had episodes of bronchiolitis, and when he was 13 months old, he had had a transient, flat, serpiginous rash on the abdomen and torso, presumed to be of viral origin. At 16 months of age, he was seen by a cardiologist because of a murmur that had been present since birth. The harsh, nonradiating (grade 2 of 6) systolic murmur was best heard at the left sternal border. Electrocardiography showed a sinus rhythm with potential right ventricular hypertrophy and incomplete right bundle-branch block, suggestive of a right ventricular volume overload. His QT interval corrected for heart rate was 401 msec, with a PRT axis of 41, 51, and 18, respectively. The cardiologist diagnosed a flow murmur and deferred echocardiographic examination. Another respiratory tract infection three months before the initial presentation was accompanied by some wheezing, requiring the transient use of an albuterol inhaler.
When the patient's mother was nine years of age, she had had reddish purple bumps arrayed semicircularly on the dorsum of each foot and extending below the medial and lateral malleoli. These skin lesions had developed during the summer and were thought to be tinea corporis; they resolved after two months of treatment with topical corticosteroids. Both of the patient's parents had had equivocal results on skin testing for tuberculosis with purified protein derivative eight years earlier, at the time of their marriage. The patient's mother and maternal grandmother had heart murmurs. A first cousin of the patient had a ventricular septal defect and hypoplastic left heart syndrome, which had required heart transplantation. There was no history of cancer in other relatives occurring early in life, thyroid disorder, or juvenile arthritis. The patient lived with his parents and a healthy four-year-old brother. His father worked as a physical therapist, and his mother cared for the children at home. The family had no pets, and the patient had no recent exposure to domesticated animals. The entire immediate family had been born in the United States and had not traveled in the preceding year.
On physical examination, the patient was afebrile, the pulse was 102 beats per minute, and the respirations were normal. His weight was 13.2 kg (29 lb) (75th percentile for his age). He was alert, playful, and occasionally cooperative. His mouth and eyes were normal. There were areas of patchy malar eczema bilaterally. He had full cervical motion, with no lymphadenopathy. A firm, oval, nontender, slightly mobile subcutaneous nodule, approximately 10 by 20 mm, with indistinct edges was palpable in the left postauricular area of the scalp (Figure 1). The cardiac rhythm was normal, with a grade 1 of 6 systolic murmur at the base. The chest was clear on auscultation, and there was no vertebral or paravertebral tenderness. The abdomen was normal. There was no palpable axillary, periclavicular, inguinal, or popliteal lymphadenopathy.
Figure 1. Lesion on the Scalp.
A raised, round, nonpigmented subcutaneous lesion is present in the left postauricular area of the scalp (arrow).
There was full, painless range of motion of all the large joints of the arms and legs. Three nodules, ranging from 8 to 15 mm in diameter, were present on the midanterior tibial regions, two on the left side and one on the right side. Another nodule, approximately 10 mm in diameter, was present on the dorsum of the right hand. Palpation elicited no discomfort, and all the nodules were firm and relatively nonmobile. They appeared to be subcutaneous, with a slight blue tint of the overlying skin, without erythema or other change in the epidermis. The small joints of the hands and feet were normal, and the nodule on the left index finger was no longer evident. There was no rash. The neurologic examination was normal.
Radiographs of the chest showed mild prominence of the pulmonary interstitium without focal consolidation or pleural effusion. The mediastinal contours were normal with no definite hilar or mediastinal lymphadenopathy.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. J. Patrick Whelan: When I saw this 22-month-old boy in the clinic, he had five nontender subcutaneous nodules that were widely distributed and that had been present for more than a month. The occurrence of superficial masses in patients who are one to four years of age (the toddler age group) brings to mind a differential diagnosis focused on inflammatory, infectious, and neoplastic causes. Five physical characteristics of superficial nodules merit attention, to narrow the diagnosis: the number (single vs. multiple), the location, and the presence or absence of tenderness, pigmentation or erythema, and firmness (Table 2).
Table 2. Differential Diagnosis of Cutaneous and Subcutaneous Nodules.
Erythema Nodosum
Because the first lesions were on the patient's shin, we initially considered a diagnosis of erythema nodosum (septal panniculitis), which commonly affects areas overlying the shins, ankles, and knees. Multiple causes of erythema nodosum related to infection have been described, including streptococcal infection, tuberculosis, coccidioidomycosis, and histoplasmosis, as well as infections caused by species of bartonella, yersinia, salmonella, mycoplasma, chlamydia, and leptospira.1 The history of equivocal results on tuberculin skin testing in both parents raised the possibility of emerging mycobacterial infection,2 although the child appeared well, with no constitutional symptoms, and the result of his tuberculin skin test was negative. Since tuberculosis is rare in the United States, it is an uncommon cause of erythema nodosum in the United States. However, it continues to be an important cause of erythema nodosum in the developing world.3 The patient did not have a recent history of pharyngitis due to group A -hemolytic streptococcus. When causative, this illness usually precedes the onset of erythema nodosum by two to three weeks. There had been no cat scratch or bite to suggest the possibility of bartonella infection, no history of gram-negative bacterial enteritis, no evidence of deep fungal infection, and no obvious sources of leptospira, such as exposure to rats or domesticated animals. The lesions of erythema nodosum do not ulcerate, can persist for several weeks, can involve the arms, and can occur in clusters — the patient had all these characteristics. But militating against erythema nodosum in this case was the normal erythrocyte sedimentation rate (elevated in more than three quarters1 of cases) and the absence of the characteristic tenderness and erythema.
Rheumatoid Nodules
Nodules are a classic feature of both rheumatic fever and adult-type rheumatoid arthritis. The absence of evidence in this case of preceding streptococcal infection or any of the other major criteria (besides subcutaneous nodules) — namely, arthritis, carditis, chorea, and the erythema marginatum rash — made the diagnosis of rheumatic fever unlikely.4 Nodules almost never develop in the pauciarticular form of juvenile rheumatoid arthritis that is common in the toddler age group. However, the rheumatoid-factor–positive polyarticular form, much less common in toddlers, is accompanied by the development of firm, nontender nodules similar to the ones seen in this child in 5 to 10 percent of patients, particularly those treated with methotrexate.5 The absence of arthritis and constitutional symptoms essentially ruled out these rheumatologic diagnoses.
Malignant Tumors
Cancer was a central concern of the family, and we considered an array of malignant and benign tumors that can present with subcutaneous nodules.6,7 In one large survey of superficial childhood tumors, only 1 to 2 percent were malignant.8 Hodgkin's disease very rarely occurs before a child reaches school age, and like most types of non-Hodgkin's lymphoma, it very rarely is manifested initially in the skin.9 Mycosis fungoides, a cutaneous T-cell lymphoma, usually presents as scaly or atrophic patches, rather than in a nodular form.10 An important consideration in a young child is precursor B-lymphoblastic lymphoma or leukemia, which may present as single or multiple cutaneous nodules.11
As children pass from infancy to the toddler age, the frequency of sarcomas increases.6 These soft-tissue tumors of mesodermal origin typically present as enlarging masses with indistinct borders, which when found on the arms and legs, are often affixed to the underlying muscle and fascia. The majority are rhabdomyosarcomas, but fibrosarcoma, tendon-sheath synovial sarcoma, and tumor of the peripheral-nerve sheath (a sarcoma that occasionally arises in neurofibromatosis) are also seen. Rhabdomyosarcomas on the arms and legs are mostly seen in adolescents as single, painful lesions. The alveolar form is seen in toddlers and is manifested by multiple nodular primary or metastatic lesions, but these are usually found on the face or trunk. Neither type fits the pattern of multiple, painless nodules seen in this patient.
Metastatic neuroblastoma can present as multiple, painless, firm cutaneous nodules on the trunk, arms, and legs, but this presentation is more commonly associated with disease in newborns than in toddlers. Children with advanced disease usually have an identifiable primary lesion, such as an abdominal or thoracic mass, and appear to have systemic illness.12
Dendritic-cell tumors of the skin, also known as Langerhans'-cell histiocytosis or eosinophilic granuloma, can present as a solitary mastoid or scalp nodule that is asymptomatic and often found incidentally.13 Cases of eosinophilic granuloma, or chronic focal Langerhans'-cell histiocytosis, only rarely involve the arms and legs. Eosinophilic granuloma can cause osteolysis of underlying bone and can also ulcerate superficially. When multiple lesions are found, it signifies a more malignant syndrome called multifocal Langerhans' histiocytosis (either multifocal unisystem disease or multifocal multisystem disease ). Letterer–Siwe disease is usually characterized by multiple skin lesions, often associated with fever, bone lesions, and hepatosplenomegaly.14 Although the occipital nodule in this patient could have been compatible with Langerhans'-cell disease, the multiple nodules on the arms and legs without osteolysis, ulceration, or systemic symptoms made the diagnosis unlikely.
Benign Tumors and Cysts
Benign tumors that warrant consideration include cutaneous benign fibrous histiocytomas, or dermatofibromas, which are small, solitary or polypoid nodules that have a yellow tint, unlike the skin-colored nodules seen in this patient.15 This patient's nodules were too firm to be lipomas, which are often multilobulated and much less common in young children than in older persons, or lipoblastomas, which are most often seen in the toddler age group but are similarly multilobular. Neurofibromas are usually soft and compressible and occur in the context of the clinically apparent syndrome of neurofibromatosis.
Myofibromatosis, once known as congenital fibrosarcoma, can occur during infancy as a colorless, subcutaneous or deep soft-tissue mass.16 Although toddlers can present with multiple myofibromas, the tumors often involve not only the skin but also bony and visceral lesions. Infantile desmoid-type fibromatosis usually presents as a single expanding mass on the head, neck, or thigh, with rapid growth that requires excision.
When lesions such as those in this patient are seen in infants, they may suggest several kinds of cysts.17 Dermoid cysts are deep, painless nodules that are typically distributed on the head and neck or, occasionally, down the spine. Thyroglossal-duct and branchial-duct cysts are distinguished by their principal location about the neck. Epidermal cysts occur bimodally and are usually found in the early teenage years or, occasionally, in the newborn (in association with Gardner's syndrome). Pilomatrixomas can be found as painless, skin-colored nodules in the toddler age group. These benign lesions are usually singular and located on the face, scalp, or upper trunk. When superficial, they can have a bluish gray or erythematous appearance.18 None of these conditions explain the findings in this case.
Granuloma Annulare
As its name suggests, granuloma annulare most commonly presents with rings of papules that have a characteristic granulomatous histologic appearance. But the toddler and preschool age groups are particularly susceptible to the subcutaneous form of granuloma annulare.19 The lesions in these children are most commonly pretibial, but they are also found on the buttocks, hands, and scalp. The subcutaneous form is associated in a minority of cases with the coincident presence of classic, ringed papular lesions. Granuloma annulare is usually sporadic, but familial cases have been reported. In this case, the patient's mother had had prominent lesions at the age of nine years that were, in retrospect, consistent with localized granuloma annulare. Since this patient's lesions were firm, nontender, nonpigmented, and not associated with systemic illness, the diagnosis of subcutaneous granuloma annulare seemed very likely. The localization of the lesions to the pretibia, dorsum of the hand, and occipital scalp, which are three of the most typical anatomical distributions for this disorder, supported the clinical diagnosis of granuloma annulare.20
The pathophysiology of this disease has been thought for many years to be driven by T cells.21 Unlike the granulomas seen in leprosy, the lesions of granuloma annulare have no evidence of infiltration by natural killer T cells or of clonal expansion of T cells bearing particular T-cell antigen receptors.22 The lesions of granuloma annulare bear a superficial resemblance to rheumatoid nodules, and the cytokine pattern in both disorders appears to be distinctly that of the type 1 helper T cell immune response,23 akin to that seen in the joints of children with juvenile arthritis.24 However, the recent demonstration that the major genetic risk factor for rheumatoid arthritis, termed the "shared epitope" of HLA-DRB1, does not predispose patients to the development of rheumatoid nodules suggests a pathogenesis independent of the systemic inflammation in these cases.25
To confirm the diagnosis, I arranged for Dr. Allan Goldstein of Pediatric Surgery to perform an excisional biopsy of a lesion on the left lower leg.
Dr. J. Patrick Whelan's Diagnosis
Subcutaneous granuloma annulare.
Pathological Discussion
Dr. Artur Zembowicz: At surgery, the lesion was circumscribed, appeared cystic, and extended to the periosteum of the tibia. It was dissected free of this and surrounding tissues and submitted for pathological examination. On gross examination, it was an irregular soft nodule, 1.9 by 1.5 by 0.7 cm, that contained a central cystic area with an irregular lining. Examination of histologic sections revealed a subcutaneous cystic cavity surrounded by large, irregularly shaped zones of necrobiotic collagen bordered by a rim of histiocytes and chronic inflammatory cells that formed finger-like projections into the cavity (Figure 2A). The cavity was devoid of epithelial lining, was focally covered by fibrin, and resembled synovium (Figure 2B).
Figure 2. Photomicrographs of the Lesion on the Left Lower Leg.
At low magnification, the subcutaneous tissue (Panel A, hematoxylin and eosin) contains an irregular pseudocystic cavity (arrow) with finger-like intraluminal projections and foci of bright pink fibrin. The adjacent tissue contains irregularly shaped areas of degenerating acellular collagen (necrobiosis) (outlined by arrowheads) surrounded by a zone (palisade) of histiocyte-rich inflammatory infiltrate and granulation tissue. At higher magnification (Panel B, hematoxylin and eosin), the cystic cavity does not have an epithelial lining. These features are consistent with a metaplastic synovial pseudocyst. The necrobiotic center of the lesions (Panel C, arrow) has a bluish hue suggestive of extracellular mucin (hematoxylin and eosin). At higher magnification of the zone of the inflammatory rim around an area of necrobiosis (Panel D, hematoxylin and eosin), most of the cells are histiocytes characterized by medium-sized nuclei with vesicular nuclei and abundant eosinophilic cytoplasm, which are arrayed in palisading fashion around the necrobiotic area. A stain for colloidal iron (Panel E) shows mucin deposition (blue) in the area of necrobiosis.
These features define a pseudocyst, rather than a true epithelial-lined cyst, and because of their resemblance to synovium, lesions such as this are referred to as metaplastic synovial pseudocysts.26 They are not related to joints or synovium and may be found in areas subjected to repeated trauma and surgical scars and in patients with the Ehlers–Danlos syndrome and other conditions associated with connective-tissue fragility and disintegration. In this case, metaplastic synovial pseudocyst formation was due to the necrobiosis of the adjacent collagen.
The primary pathologic process in this case is necrobiotic granulomatous dermatitis.27 Necrobiosis is a term applied to a form of degeneration of collagen that occurs as a result of local ischemia. Necrobiotic granulomas consist of irregular, sometimes stellate, acellular, light pink central areas of degenerating (necrobiotic) collagen surrounded by a zone of histiocyte-rich inflammatory infiltrate and granulation tissue (Figure 2C and 2D). Histiocytes typically form a rim, or palisade, around the areas of necrobiosis, as they did in this case. Hence, necrobiotic granulomas are sometimes referred to as palisading granulomas (Figure 2D).
The causes of palisading necrobiotic dermatitis are limited to five diseases: subcutaneous granuloma annulare, rheumatoid nodule, rheumatic fever nodule, necrobiosis lipoidica, and necrobiotic xanthogranuloma. Occasionally, tumor necrosis in a sarcoma or, rarely, a carcinoma can mimic necrobiosis.27 The last three conditions could easily be ruled out in this case on histologic grounds alone.
The cells surrounding areas of necrobiosis did not have malignant characteristics, thus ruling out a diagnosis of sarcoma. In contrast to the findings in this case, necrobiosis lipoidica is characterized by horizontal layers of cutaneous and subcutaneous necrobiosis with a plasma-cell–rich inflammatory infiltrate and necrobiotic centers that contain lipid. Necrobiotic xanthogranuloma contains large areas of subcutaneous necrobiosis with cholesterol clefts and numerous multinucleated giant cells with hyperchromatic nuclei. Most cases are associated with monoclonal IgG light-chain paraproteinemia.
Nodules associated with rheumatic fever are very rarely subjected to biopsy, but their histologic appearance can be very similar to that of rheumatoid nodules. They are usually small and are frequently associated with a mixed inflammatory infiltrate including neutrophils and multinucleated giant cells. These features were absent in this case.
Thus, the histologic differential diagnosis in this case was between subcutaneous granuloma annulare and rheumatoid nodule. On routine examination of sections, the two conditions can appear very similar. Necrobiotic centers in rheumatoid nodules are typically denser in appearance, fibrotic, and eosinophilic, whereas the areas of necrobiosis in granuloma annulare typically have a bluish appearance. The key differentiating histologic feature is the presence or absence of mucin in necrobiotic zones. Mucin is typically present in granuloma annulare and is responsible for the bluish appearance of the central zones on staining with hematoxylin and eosin.28 Staining with colloidal iron in this case confirmed the presence of abundant deposits of mucin (Figure 2E). Thus, in the context of the clinical findings, examination of the biopsy specimen favored the diagnosis of subcutaneous granuloma annulare.
Dr. Nancy Lee Harris (Pathology): Dr. Whelan, will you comment on your management and follow-up of this case?
Dr. Whelan: No intervention is needed in such cases, and no treatment was given. One year after the onset of symptoms, the patient had a persistent lesion on the left shin, and other lesions had appeared and disappeared on the occiput, the paravertebral region, and the dorsum of the right hand. Interestingly, a year after the initial diagnosis, a ring-shaped lesion developed on his right foot, reminiscent of the lesions his mother had had as a child. Now, two years since the onset, all the nodules have resolved.
A Physician: Did you think that the boy's mother had this disease as a child?
Dr. Whelan: We did not have that history at the first office visit. But when I called the family to report the pathological findings, the mother replied, "Oh, I had that when I was a kid." The rash that she described having at the age of nine years was characteristic of localized granuloma annulare, with ringed papules on the dorsum of both feet, initially treated as tinea corporis. All her lesions were superficial and resolved within three months, whereas this patient's lesions were deep and persisted for more than a year.
A Physician: Should children with granuloma annulare be followed more closely than other children for the development of diabetes?
Dr. Whelan: There have not been any prospective studies to my knowledge. But in a retrospective case series from the Mayo Clinic,20 two patients received a diagnosis of diabetes within a month either before or after the diagnosis of granuloma annulare was made. However, diabetes did not develop in any of the other 32 children during the mean follow-up of five years. Although some recent evidence suggests that children with granuloma annulare may have low insulin levels and impaired glucose tolerance as compared with children without granuloma annulare,25 the consensus in the literature is that this disease does not appear to presage the development of diabetes.
Anatomical Diagnosis
Subcutaneous granuloma annulare, with secondary metaplastic synovial pseudocyst.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Pediatric Rheumatology Service (J.P.W.) and the Department of Pathology (A.Z.), Massachusetts General Hospital; and the Departments of Pediatrics (J.P.W.) and Pathology (A.Z.), Harvard Medical School.
References
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Dr. Richard Chou (Rheumatology): A 22-month-old boy was seen in the pediatric rheumatology clinic because of enlarging subcutaneous nodules on the head, legs, and right hand. The patient had been well until six weeks earlier, when his mother noticed a firm, nontender bump on his medial right shin. Two weeks later, she noticed three new bumps in a line on the left pretibial area. She took the child to his pediatrician's office. The mother could recall no specific trauma to his legs, and the bumps had not been red or tender. Radiographs of both lower legs showed a soft-tissue density on the left side, but none on the right, with no bony abnormalities or soft-tissue calcifications.
During the next three weeks, the lesions on the left leg grew from between 6 and 10 mm in diameter to nearly 20 mm. Laboratory evaluation showed normal levels of serum electrolytes and normal results of renal-function tests. Results of other laboratory tests are shown in Table 1. A palpable lesion appeared on the left index finger overlying the proximal interphalangeal joint, and the patient was referred to the pediatric rheumatology clinic for further evaluation.
Table 1. Laboratory Data.
When seen in the clinic, the patient had been coughing for two days, without dyspnea. He had no fever, chills, alopecia, weight loss, dysphagia, nausea, emesis, abdominal pain, change in bowel habits, epistaxis or other type of bleeding, or cold-associated changes in color in the digits. His appetite was good, and he slept through the night.
The patient had been born at 38 weeks' gestation by a spontaneous vertex vaginal delivery, with a birth weight of 3.1 kg. He had met all developmental motor milestones and played normally, but he was believed to be delayed in appropriate verbalization. At the age of 6 weeks and again at 7 months, he had had episodes of bronchiolitis, and when he was 13 months old, he had had a transient, flat, serpiginous rash on the abdomen and torso, presumed to be of viral origin. At 16 months of age, he was seen by a cardiologist because of a murmur that had been present since birth. The harsh, nonradiating (grade 2 of 6) systolic murmur was best heard at the left sternal border. Electrocardiography showed a sinus rhythm with potential right ventricular hypertrophy and incomplete right bundle-branch block, suggestive of a right ventricular volume overload. His QT interval corrected for heart rate was 401 msec, with a PRT axis of 41, 51, and 18, respectively. The cardiologist diagnosed a flow murmur and deferred echocardiographic examination. Another respiratory tract infection three months before the initial presentation was accompanied by some wheezing, requiring the transient use of an albuterol inhaler.
When the patient's mother was nine years of age, she had had reddish purple bumps arrayed semicircularly on the dorsum of each foot and extending below the medial and lateral malleoli. These skin lesions had developed during the summer and were thought to be tinea corporis; they resolved after two months of treatment with topical corticosteroids. Both of the patient's parents had had equivocal results on skin testing for tuberculosis with purified protein derivative eight years earlier, at the time of their marriage. The patient's mother and maternal grandmother had heart murmurs. A first cousin of the patient had a ventricular septal defect and hypoplastic left heart syndrome, which had required heart transplantation. There was no history of cancer in other relatives occurring early in life, thyroid disorder, or juvenile arthritis. The patient lived with his parents and a healthy four-year-old brother. His father worked as a physical therapist, and his mother cared for the children at home. The family had no pets, and the patient had no recent exposure to domesticated animals. The entire immediate family had been born in the United States and had not traveled in the preceding year.
On physical examination, the patient was afebrile, the pulse was 102 beats per minute, and the respirations were normal. His weight was 13.2 kg (29 lb) (75th percentile for his age). He was alert, playful, and occasionally cooperative. His mouth and eyes were normal. There were areas of patchy malar eczema bilaterally. He had full cervical motion, with no lymphadenopathy. A firm, oval, nontender, slightly mobile subcutaneous nodule, approximately 10 by 20 mm, with indistinct edges was palpable in the left postauricular area of the scalp (Figure 1). The cardiac rhythm was normal, with a grade 1 of 6 systolic murmur at the base. The chest was clear on auscultation, and there was no vertebral or paravertebral tenderness. The abdomen was normal. There was no palpable axillary, periclavicular, inguinal, or popliteal lymphadenopathy.
Figure 1. Lesion on the Scalp.
A raised, round, nonpigmented subcutaneous lesion is present in the left postauricular area of the scalp (arrow).
There was full, painless range of motion of all the large joints of the arms and legs. Three nodules, ranging from 8 to 15 mm in diameter, were present on the midanterior tibial regions, two on the left side and one on the right side. Another nodule, approximately 10 mm in diameter, was present on the dorsum of the right hand. Palpation elicited no discomfort, and all the nodules were firm and relatively nonmobile. They appeared to be subcutaneous, with a slight blue tint of the overlying skin, without erythema or other change in the epidermis. The small joints of the hands and feet were normal, and the nodule on the left index finger was no longer evident. There was no rash. The neurologic examination was normal.
Radiographs of the chest showed mild prominence of the pulmonary interstitium without focal consolidation or pleural effusion. The mediastinal contours were normal with no definite hilar or mediastinal lymphadenopathy.
A diagnostic procedure was performed.
Differential Diagnosis
Dr. J. Patrick Whelan: When I saw this 22-month-old boy in the clinic, he had five nontender subcutaneous nodules that were widely distributed and that had been present for more than a month. The occurrence of superficial masses in patients who are one to four years of age (the toddler age group) brings to mind a differential diagnosis focused on inflammatory, infectious, and neoplastic causes. Five physical characteristics of superficial nodules merit attention, to narrow the diagnosis: the number (single vs. multiple), the location, and the presence or absence of tenderness, pigmentation or erythema, and firmness (Table 2).
Table 2. Differential Diagnosis of Cutaneous and Subcutaneous Nodules.
Erythema Nodosum
Because the first lesions were on the patient's shin, we initially considered a diagnosis of erythema nodosum (septal panniculitis), which commonly affects areas overlying the shins, ankles, and knees. Multiple causes of erythema nodosum related to infection have been described, including streptococcal infection, tuberculosis, coccidioidomycosis, and histoplasmosis, as well as infections caused by species of bartonella, yersinia, salmonella, mycoplasma, chlamydia, and leptospira.1 The history of equivocal results on tuberculin skin testing in both parents raised the possibility of emerging mycobacterial infection,2 although the child appeared well, with no constitutional symptoms, and the result of his tuberculin skin test was negative. Since tuberculosis is rare in the United States, it is an uncommon cause of erythema nodosum in the United States. However, it continues to be an important cause of erythema nodosum in the developing world.3 The patient did not have a recent history of pharyngitis due to group A -hemolytic streptococcus. When causative, this illness usually precedes the onset of erythema nodosum by two to three weeks. There had been no cat scratch or bite to suggest the possibility of bartonella infection, no history of gram-negative bacterial enteritis, no evidence of deep fungal infection, and no obvious sources of leptospira, such as exposure to rats or domesticated animals. The lesions of erythema nodosum do not ulcerate, can persist for several weeks, can involve the arms, and can occur in clusters — the patient had all these characteristics. But militating against erythema nodosum in this case was the normal erythrocyte sedimentation rate (elevated in more than three quarters1 of cases) and the absence of the characteristic tenderness and erythema.
Rheumatoid Nodules
Nodules are a classic feature of both rheumatic fever and adult-type rheumatoid arthritis. The absence of evidence in this case of preceding streptococcal infection or any of the other major criteria (besides subcutaneous nodules) — namely, arthritis, carditis, chorea, and the erythema marginatum rash — made the diagnosis of rheumatic fever unlikely.4 Nodules almost never develop in the pauciarticular form of juvenile rheumatoid arthritis that is common in the toddler age group. However, the rheumatoid-factor–positive polyarticular form, much less common in toddlers, is accompanied by the development of firm, nontender nodules similar to the ones seen in this child in 5 to 10 percent of patients, particularly those treated with methotrexate.5 The absence of arthritis and constitutional symptoms essentially ruled out these rheumatologic diagnoses.
Malignant Tumors
Cancer was a central concern of the family, and we considered an array of malignant and benign tumors that can present with subcutaneous nodules.6,7 In one large survey of superficial childhood tumors, only 1 to 2 percent were malignant.8 Hodgkin's disease very rarely occurs before a child reaches school age, and like most types of non-Hodgkin's lymphoma, it very rarely is manifested initially in the skin.9 Mycosis fungoides, a cutaneous T-cell lymphoma, usually presents as scaly or atrophic patches, rather than in a nodular form.10 An important consideration in a young child is precursor B-lymphoblastic lymphoma or leukemia, which may present as single or multiple cutaneous nodules.11
As children pass from infancy to the toddler age, the frequency of sarcomas increases.6 These soft-tissue tumors of mesodermal origin typically present as enlarging masses with indistinct borders, which when found on the arms and legs, are often affixed to the underlying muscle and fascia. The majority are rhabdomyosarcomas, but fibrosarcoma, tendon-sheath synovial sarcoma, and tumor of the peripheral-nerve sheath (a sarcoma that occasionally arises in neurofibromatosis) are also seen. Rhabdomyosarcomas on the arms and legs are mostly seen in adolescents as single, painful lesions. The alveolar form is seen in toddlers and is manifested by multiple nodular primary or metastatic lesions, but these are usually found on the face or trunk. Neither type fits the pattern of multiple, painless nodules seen in this patient.
Metastatic neuroblastoma can present as multiple, painless, firm cutaneous nodules on the trunk, arms, and legs, but this presentation is more commonly associated with disease in newborns than in toddlers. Children with advanced disease usually have an identifiable primary lesion, such as an abdominal or thoracic mass, and appear to have systemic illness.12
Dendritic-cell tumors of the skin, also known as Langerhans'-cell histiocytosis or eosinophilic granuloma, can present as a solitary mastoid or scalp nodule that is asymptomatic and often found incidentally.13 Cases of eosinophilic granuloma, or chronic focal Langerhans'-cell histiocytosis, only rarely involve the arms and legs. Eosinophilic granuloma can cause osteolysis of underlying bone and can also ulcerate superficially. When multiple lesions are found, it signifies a more malignant syndrome called multifocal Langerhans' histiocytosis (either multifocal unisystem disease or multifocal multisystem disease ). Letterer–Siwe disease is usually characterized by multiple skin lesions, often associated with fever, bone lesions, and hepatosplenomegaly.14 Although the occipital nodule in this patient could have been compatible with Langerhans'-cell disease, the multiple nodules on the arms and legs without osteolysis, ulceration, or systemic symptoms made the diagnosis unlikely.
Benign Tumors and Cysts
Benign tumors that warrant consideration include cutaneous benign fibrous histiocytomas, or dermatofibromas, which are small, solitary or polypoid nodules that have a yellow tint, unlike the skin-colored nodules seen in this patient.15 This patient's nodules were too firm to be lipomas, which are often multilobulated and much less common in young children than in older persons, or lipoblastomas, which are most often seen in the toddler age group but are similarly multilobular. Neurofibromas are usually soft and compressible and occur in the context of the clinically apparent syndrome of neurofibromatosis.
Myofibromatosis, once known as congenital fibrosarcoma, can occur during infancy as a colorless, subcutaneous or deep soft-tissue mass.16 Although toddlers can present with multiple myofibromas, the tumors often involve not only the skin but also bony and visceral lesions. Infantile desmoid-type fibromatosis usually presents as a single expanding mass on the head, neck, or thigh, with rapid growth that requires excision.
When lesions such as those in this patient are seen in infants, they may suggest several kinds of cysts.17 Dermoid cysts are deep, painless nodules that are typically distributed on the head and neck or, occasionally, down the spine. Thyroglossal-duct and branchial-duct cysts are distinguished by their principal location about the neck. Epidermal cysts occur bimodally and are usually found in the early teenage years or, occasionally, in the newborn (in association with Gardner's syndrome). Pilomatrixomas can be found as painless, skin-colored nodules in the toddler age group. These benign lesions are usually singular and located on the face, scalp, or upper trunk. When superficial, they can have a bluish gray or erythematous appearance.18 None of these conditions explain the findings in this case.
Granuloma Annulare
As its name suggests, granuloma annulare most commonly presents with rings of papules that have a characteristic granulomatous histologic appearance. But the toddler and preschool age groups are particularly susceptible to the subcutaneous form of granuloma annulare.19 The lesions in these children are most commonly pretibial, but they are also found on the buttocks, hands, and scalp. The subcutaneous form is associated in a minority of cases with the coincident presence of classic, ringed papular lesions. Granuloma annulare is usually sporadic, but familial cases have been reported. In this case, the patient's mother had had prominent lesions at the age of nine years that were, in retrospect, consistent with localized granuloma annulare. Since this patient's lesions were firm, nontender, nonpigmented, and not associated with systemic illness, the diagnosis of subcutaneous granuloma annulare seemed very likely. The localization of the lesions to the pretibia, dorsum of the hand, and occipital scalp, which are three of the most typical anatomical distributions for this disorder, supported the clinical diagnosis of granuloma annulare.20
The pathophysiology of this disease has been thought for many years to be driven by T cells.21 Unlike the granulomas seen in leprosy, the lesions of granuloma annulare have no evidence of infiltration by natural killer T cells or of clonal expansion of T cells bearing particular T-cell antigen receptors.22 The lesions of granuloma annulare bear a superficial resemblance to rheumatoid nodules, and the cytokine pattern in both disorders appears to be distinctly that of the type 1 helper T cell immune response,23 akin to that seen in the joints of children with juvenile arthritis.24 However, the recent demonstration that the major genetic risk factor for rheumatoid arthritis, termed the "shared epitope" of HLA-DRB1, does not predispose patients to the development of rheumatoid nodules suggests a pathogenesis independent of the systemic inflammation in these cases.25
To confirm the diagnosis, I arranged for Dr. Allan Goldstein of Pediatric Surgery to perform an excisional biopsy of a lesion on the left lower leg.
Dr. J. Patrick Whelan's Diagnosis
Subcutaneous granuloma annulare.
Pathological Discussion
Dr. Artur Zembowicz: At surgery, the lesion was circumscribed, appeared cystic, and extended to the periosteum of the tibia. It was dissected free of this and surrounding tissues and submitted for pathological examination. On gross examination, it was an irregular soft nodule, 1.9 by 1.5 by 0.7 cm, that contained a central cystic area with an irregular lining. Examination of histologic sections revealed a subcutaneous cystic cavity surrounded by large, irregularly shaped zones of necrobiotic collagen bordered by a rim of histiocytes and chronic inflammatory cells that formed finger-like projections into the cavity (Figure 2A). The cavity was devoid of epithelial lining, was focally covered by fibrin, and resembled synovium (Figure 2B).
Figure 2. Photomicrographs of the Lesion on the Left Lower Leg.
At low magnification, the subcutaneous tissue (Panel A, hematoxylin and eosin) contains an irregular pseudocystic cavity (arrow) with finger-like intraluminal projections and foci of bright pink fibrin. The adjacent tissue contains irregularly shaped areas of degenerating acellular collagen (necrobiosis) (outlined by arrowheads) surrounded by a zone (palisade) of histiocyte-rich inflammatory infiltrate and granulation tissue. At higher magnification (Panel B, hematoxylin and eosin), the cystic cavity does not have an epithelial lining. These features are consistent with a metaplastic synovial pseudocyst. The necrobiotic center of the lesions (Panel C, arrow) has a bluish hue suggestive of extracellular mucin (hematoxylin and eosin). At higher magnification of the zone of the inflammatory rim around an area of necrobiosis (Panel D, hematoxylin and eosin), most of the cells are histiocytes characterized by medium-sized nuclei with vesicular nuclei and abundant eosinophilic cytoplasm, which are arrayed in palisading fashion around the necrobiotic area. A stain for colloidal iron (Panel E) shows mucin deposition (blue) in the area of necrobiosis.
These features define a pseudocyst, rather than a true epithelial-lined cyst, and because of their resemblance to synovium, lesions such as this are referred to as metaplastic synovial pseudocysts.26 They are not related to joints or synovium and may be found in areas subjected to repeated trauma and surgical scars and in patients with the Ehlers–Danlos syndrome and other conditions associated with connective-tissue fragility and disintegration. In this case, metaplastic synovial pseudocyst formation was due to the necrobiosis of the adjacent collagen.
The primary pathologic process in this case is necrobiotic granulomatous dermatitis.27 Necrobiosis is a term applied to a form of degeneration of collagen that occurs as a result of local ischemia. Necrobiotic granulomas consist of irregular, sometimes stellate, acellular, light pink central areas of degenerating (necrobiotic) collagen surrounded by a zone of histiocyte-rich inflammatory infiltrate and granulation tissue (Figure 2C and 2D). Histiocytes typically form a rim, or palisade, around the areas of necrobiosis, as they did in this case. Hence, necrobiotic granulomas are sometimes referred to as palisading granulomas (Figure 2D).
The causes of palisading necrobiotic dermatitis are limited to five diseases: subcutaneous granuloma annulare, rheumatoid nodule, rheumatic fever nodule, necrobiosis lipoidica, and necrobiotic xanthogranuloma. Occasionally, tumor necrosis in a sarcoma or, rarely, a carcinoma can mimic necrobiosis.27 The last three conditions could easily be ruled out in this case on histologic grounds alone.
The cells surrounding areas of necrobiosis did not have malignant characteristics, thus ruling out a diagnosis of sarcoma. In contrast to the findings in this case, necrobiosis lipoidica is characterized by horizontal layers of cutaneous and subcutaneous necrobiosis with a plasma-cell–rich inflammatory infiltrate and necrobiotic centers that contain lipid. Necrobiotic xanthogranuloma contains large areas of subcutaneous necrobiosis with cholesterol clefts and numerous multinucleated giant cells with hyperchromatic nuclei. Most cases are associated with monoclonal IgG light-chain paraproteinemia.
Nodules associated with rheumatic fever are very rarely subjected to biopsy, but their histologic appearance can be very similar to that of rheumatoid nodules. They are usually small and are frequently associated with a mixed inflammatory infiltrate including neutrophils and multinucleated giant cells. These features were absent in this case.
Thus, the histologic differential diagnosis in this case was between subcutaneous granuloma annulare and rheumatoid nodule. On routine examination of sections, the two conditions can appear very similar. Necrobiotic centers in rheumatoid nodules are typically denser in appearance, fibrotic, and eosinophilic, whereas the areas of necrobiosis in granuloma annulare typically have a bluish appearance. The key differentiating histologic feature is the presence or absence of mucin in necrobiotic zones. Mucin is typically present in granuloma annulare and is responsible for the bluish appearance of the central zones on staining with hematoxylin and eosin.28 Staining with colloidal iron in this case confirmed the presence of abundant deposits of mucin (Figure 2E). Thus, in the context of the clinical findings, examination of the biopsy specimen favored the diagnosis of subcutaneous granuloma annulare.
Dr. Nancy Lee Harris (Pathology): Dr. Whelan, will you comment on your management and follow-up of this case?
Dr. Whelan: No intervention is needed in such cases, and no treatment was given. One year after the onset of symptoms, the patient had a persistent lesion on the left shin, and other lesions had appeared and disappeared on the occiput, the paravertebral region, and the dorsum of the right hand. Interestingly, a year after the initial diagnosis, a ring-shaped lesion developed on his right foot, reminiscent of the lesions his mother had had as a child. Now, two years since the onset, all the nodules have resolved.
A Physician: Did you think that the boy's mother had this disease as a child?
Dr. Whelan: We did not have that history at the first office visit. But when I called the family to report the pathological findings, the mother replied, "Oh, I had that when I was a kid." The rash that she described having at the age of nine years was characteristic of localized granuloma annulare, with ringed papules on the dorsum of both feet, initially treated as tinea corporis. All her lesions were superficial and resolved within three months, whereas this patient's lesions were deep and persisted for more than a year.
A Physician: Should children with granuloma annulare be followed more closely than other children for the development of diabetes?
Dr. Whelan: There have not been any prospective studies to my knowledge. But in a retrospective case series from the Mayo Clinic,20 two patients received a diagnosis of diabetes within a month either before or after the diagnosis of granuloma annulare was made. However, diabetes did not develop in any of the other 32 children during the mean follow-up of five years. Although some recent evidence suggests that children with granuloma annulare may have low insulin levels and impaired glucose tolerance as compared with children without granuloma annulare,25 the consensus in the literature is that this disease does not appear to presage the development of diabetes.
Anatomical Diagnosis
Subcutaneous granuloma annulare, with secondary metaplastic synovial pseudocyst.
No potential conflict of interest relevant to this article was reported.
Source Information
From the Pediatric Rheumatology Service (J.P.W.) and the Department of Pathology (A.Z.), Massachusetts General Hospital; and the Departments of Pediatrics (J.P.W.) and Pathology (A.Z.), Harvard Medical School.
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