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Familial Occurrence of Infantile Myofibromatosis Matej Brac’ko, MD,* Lada Cindro, MD,t and Rastko Golouh, MD, PhD*
Two brothers with multicentric infantile myofibromatosis (IM) are reported. In both, tumors were present at birth; the tumors regressed spontaneously, hut new lesions developed throughout the follow-up periods of 15 and 8 years. Immunohistochemically, the nodules were found to be positive for vimentin and actin, but negative for desmin and S-100 protein; these findings support the myofibrohlastic nature of IM. A literature review revealed nine additional families with IM in more than one family member. Although the occurrence of IM in eight sets of siblings, with consanguinity in two of them, favors an autosomal recessive mode of inheritance, the disorder also has been well documented in half-sisters and in successive generations, which makes autosomal dominant inheritance a more plausible explanation. Cancer 1992; 691294-1299. Infantile myofibromatosis (IM) is an uncommon mesenchymal disorder characterized by the formation of tumors in the skin, subcutaneous tissue, skeletal muscle, bone, and visceral organs. It was first properly documented in 1954 by Stout,’ who called the condition congenital generalized fibromatosis. Subsequent reports of this disease emphasized the multicentric variety of the disorder, for which a number of various terms have been applied. In 1965, Kauffman and Stout2 grouped their cases of congenital fibromatosis into two categories: a multiple form, with lesions restricted to skin, soft tissue, and bone; and a generalized form, with visceral involvement as well. That a solitary form of this condition exists was not fully appreciated until the late 1 9 7 0 ~however, ~; Chung and E n ~ i n g e rwho , ~ presented the only substantial series of this entity and renamed it infantile fibromatosis, found that the solitary form was more common than the multicentric type of the disease.
From the *Department of Pathology, Institute of Oncology, and the tDepartment of Neurology, Pediatric Clinic, Ljubljana, Slovenia. Address for reprints: Matej BraEko, MD, Institute of Oncology, ZaloSka 2, 61000 Ljubljana, Slovenia. Accepted for publication May 31, 1991.
The etiology of IM is uncertain. Although evidence that the disorder may be a heritable condition was presented as early as 1961; additional reports of familial cases have been relatively few, and different types of inheritance have been p~stulated.~*”” In the current study, we report another two cases of IM occumng in one family and review the literature on familial IM.
Case Reports
Patient 1 A 3250-g boy was delivered by cesarean section at full term of an uneventful pregnancy. The initial physical examination of the infant showed multiple subcutaneous nodules on the right thigh, left axilla, occiput, both temporal regions, and left lower eyelid. When the child was 4 months old, the axillary mass was excised and histologically diagnosed as neurofibroma. By the time the child was 1 year old, the lesion in the eyelid completelyregressed, whereas the remainder of lesions persisted, the largest measuring 1 to 2 cm.The patient presented again at the age of 6 years with signs of left brachial plexus lesion. There was completeclinical regression after conservative treatment, and an electromyography performed 1 year later showed conspicuous reinnervation. When seen again at the age of 12 years, the patient was well except for a few subcutaneous nodules that had developed during the past years on his trunk and extremities. On physical examination 1 year later, nodules measuring 1 to 2 cm in diameter were palpated on the right shoulder, left forearm, and right thigh. After a year, a new nodule appeared on the left thoracic wall while other lesions remained unchanged. At 15 years of age, the patient presented with partial Homer’s syndrome consisting of minimal left-sided ptosis and myosis. A computed tomography (CT) scan revealed multiple expanding lytic lesions in the posterior elements of the C3 and T2 vertebrae and first right rib (Fig. 1).A fine-needle aspiration biopsy of the rib lesion was performed, but no diagnostic material was obtained. A subcutaneousnodule on the left lower leg was excised, and histopathologic examination disclosed IM. A bone radiograph survey showed cortical osteolytic lesions in the left humerus and right tibia. The routine laboratory investigationswere negative, as were the chest radiograph, echocardiogram,abdomen echography, CT scan
Familial Myofibromatosis/BraEko et al.
1295
were stained with hematoxylin and eosin and by Masson’s trichromemethod. Additionalsectionswere evaluated immunohistochemically using monoclonal antibodies against vimentin (Dakopatts, Copenhagen, Denmark; dilution 1:loo), desmin (Dakopatts, dilution 1:2000), and muscle-specific actin (BioGenex, San Ramon, CA; dilution 1:200), all revealed by the avidinbiotin peroxidase complex method, and polyclonal antiserum against S-100 protein (Dakopatts, dilution 1:300), revealed by the peroxidase-antiperoxidase method. Results Figure 1. CT scan of the thoracic region showing osteolytic expanding lesions in the rib and the posterior segment of thoracic vertebra.
of the head, electroencephalography, and ophthalmologicexamination.
Patient 2 A full-term male infant, the brother of Patient 1,at birth had a subcutaneous mass on his left thigh. Additional nodules were found a few weeks later on the neck and tongue, and a skull radiograph examination showed an osteolytic lesion in the parietal bone. The lingual mass increased in size during the following months, and surgical removal was considered but was canceled because the lesion began to regress spontaneously when the child was 4 months old. The patient was again admitted to hospital at 3 years of age because of limited motion ability of the right upper extremity. Neurologic examination revealed left-sided latent hemiparesis. No soft tissue masses were noticed on physical examination; the left side of the tongue was atrophic, and the skin overlying the sites of previous nodules was €um and pale. A biopsy of one of these sites revealed only scar tissue. During the next 4 years, new subcutaneous nodules developed on the patient’s neck, chest wall, and axilla, some of them undergoing spontaneous regression. The neurologic status remained slightly pathologic, but a CT scan of the head performed when the child was 7 years old showed no abnormalities. The diagnosis of IM in his brother was established when Patient 2 was 8 years old; at that time, he underwent a skeletal radiograph survey that showed a solitary osteolytic cortical lesion in the diaphysis of the left humerus. There was no evidence of consanguinity or history of nodules in the parents. A blood-related uncle reportedly had two subcutaneous nodules excised from the eyelid and the scalp. Histology of these lesions could not be obtained.
A biopsy of the lesion in the left axillary region showed a well-circumscribed nonencapsulated 1.5-cm nodule occupying the reticular dermis and subcutaneous fat, composed of elongated cells with rather copious eosinophilic cytoplasm. These cells were arranged in whorled or interlacing fascicles separated in places by conspicuous collagen. The more cellular central area showed a prominent vascular pattern with thin-walled arborizing vessels (Fig. 2). Mitotic figures were not found. The second nodule, which was excised from the lower leg 15 years later, measured 2.5 cm in largest diameter and was situated within skeletal muscle. It showed extensive central necrosis, with a rim of viable tissue at the periphery being composed of bundles and well-delineated whorls formed by spindle cells with fibrillary eosinophilic cytoplasm intimately associated with varying amounts of collagen. Immunohistochemical findings were similar in both lesions. Most tumor cells showed strong cytoplasmic positivity for vimentin and, to a lesser degree, for actin, whereas none reacted positively for either desmin or S-100 protein (Fig. 3).
Materials and Methods
Two formalin-fixed, paraffin-embeddedexcision specimens from Patient 1 were available for review. They
Figure 2. The central portion of IM nodule composed of spindle cells arranged around thin-walled vessels in a pericytomatous pattern (H & E, original magnification X200).
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CANCER March 2,2992, Volume 69, No. 5
Figure 3. Cells of the IM lesion. (Left) Strongly positive for vimentin. (Middle) Showing a weaker positivity for actin. (Right) Negative for desmin, which is present only in an entrapped arrector muscle (ABC, original magnification X200).
in childhood4 or even adulthood’ but usually are limited to soft tissue. In rare instances, IM may undergo an aggressive course with protracted, slow, continuous, deAlthough the diagnosis of IM was not c o n h e d histostructive proliferation of the subcutaneous nodules.’6 logically in Patient 2, his clinical features, which are Neurologic symptomshave been rarely observed in nearly identical to his brother’s, are typical of the multiIM. Because the involvement of the central nervous centric form of infantile myofibromatosis, and an addisystem parenchyma is exceptional,” neurologic symptional biopsy was considered unnecessary. toms usually develop because of compression of neural The clinical manifestations and clinical course of structures by the nodules present in the dura mater,I8 IM depend upon the number and localization of the soft tissue, or bones, as seems to be the case in our lesions. The number of tumors, which range in size patients. from 0.5 to 7 cm, varies from 1 to more than 100, and The histology of IM is quite characteristic and apparently any organ or tissue may be involved. In the usually shows a distinct zoning phenomen~n.~,’’The multicentric type, the most common sites of involveperipheral areas of IM nodules consist of plump spindle ment, apart from the soft tissue and bone, are the lung, cells with eosinophilic cytoplasm arranged in well-deheart, and gastrointestinal tract.” The tumors usually marcated short bundles, fascicles or whorls resembling are present at birth and are almost always detected dursmooth muscle, whereas the central portions frequently ing the lirst year of life; however, about 20% of solitary are made up of less-differentiated cells arranged lesions, which are found most often in the skin, muscle, prominent vascular spaces in a hemangioperior subcutaneous tissue, appear in older i n d i v i d ~ a l s . ~ ~ ’around ~ cytoma-likepattern. Occasionally, the lesions show foci Of the 170 patients with IM reported until 1988,25 of coagulative necrosis, which may at times occupy the have died,” mostly through complications from viswhole central area and undergo calcification. ceral lesions in the multicentric form of disease, of While the histologic features of IM are well estabwhich pulmonary involvement seems to cany the most lished, there is some debate as to its histogenesis. Inigave progn~sis.’~ The one fatality in a case without tially, the cells forming the nodules in IM were regarded visceral involvement was due to spinal cord compresas fibroblastic in origin; however, their marked resemsion secondary to a lesion involving a cervical verteblance to smooth muscle was noticed by some early bra.14 Provided no vital organs are involved, the proginvestigator^.^ Later electron microscopic” and histonosis of IM is excellent: the recurrence rate after excichemical4 studies led to the conclusion that this lesion sion of solitary tumors is less than 10%,4,’’ and the was a tumor of myofibroblasts and to the introduction majority of multicentric lesions undergo spontaneous r e g r e s s i ~ n . ~However, ~ ’ ~ ~ ’ ~ new growths may occur later of its current name. The myofibroblasticcomposition of Discussion
Familial Myofibromatosis/BraEko et al.
1297
I
1
2
ca 3
4
5
6
mid m .a 7 8
Figure 4. Pedigrees of the families with IM in two or more kindred members. The numbers correspond to the patient numbers in Table 1; members with history of having nodules excised but no histologic or clinical c o n h a t i o n are designated as possible IM.
z x 13
14
15
18
(m!GId 19
20
IM is supported by our immunohistochemicalfindings and those of other investigators who studied a limited number of cases of classic IM’l or soft tissue tumors histologically indistinguishable from IM but occurring in adults.” In all of these studies, the lesions labeled for vimentin and muscle-specific adin but not for desmin or S-100 protein. However, the myofibroblastic nature of IM recently was questioned by Fletcher et aZ.,19 who found some of their cases to be desmin positive and who thought that IM was a tumor of primitive smooth muscle cells. It has now been shown that in certain pathologic settings, apart from vimentin and actin, myofibroblasts also may express de~min.’~ The exact cause of IM is not clear, but genetic factors are likely to pray an important role in its etiology. We have been able to trace nine well-documented family reports in which IM has been recorded in more than one kindred member.&” The pedigrees of these families are shown in Figure 4, and the clinical data of the affected family members are summarized in Table 1. Additional possible examples of familial IM, which are not included in this review because of lack of histologic c o n h a t i o n or pertinent clinical data, include a brother and sister with congenital generalized fibromatosis briefly mentioned by Teng et d , l 5 a brother and sister with congenital solitary fibromatosis reported by Kauffman and Stout,’ and an infant and his blood-reIated uncle observed by Jennings et aL9 IM also was reported in a patient whose family members had palmar-plantar fibromat~sis.’~ The true incidence of IM occurring in a familial setting is probably much higher than it seems to be when judged by the paucity of reports in the medical literature because most of the published single cases provide
910
% 24
25
minimal or no data on family history. Because the lesions of IM frequently are small and asymptomatic and tend to disappear spontaneously, milder expressions of the disease in the relatives can easily be overlooked. As seen in Table 1,familial IM has no sex predilection and shows the same wide spectrum of presentation as observed in sporadic cases. The occurrence of cases of multicentric IM with or without visceral involvement and of solitary IM in the same families supports the concept that these are forms of the same disease. There are insufficient data to allow any firm conclusions regarding the genetics of IM. In six famifies4,5.7,10.11 the disease was reported in siblings, and in at least two of them5p7first cousins also were affected; parents of two sets of affected siblings were consang u i n e ~ ~ ~These . ~ , ”data strongly support an autosomal recessive mode of inheritance. However, autosomal recessive inheritance does not explain the cases of IM occurring in half-sisters6 and in successive generat i o n ~ , ~for , ~ which autosomal dominant inheritance with reduced penetrance, as proposed by Jennings et aZ.? seems to be the most plausible explanation. Although a mechanism under genetic influence appears to be the major etiologic factor in IM, its variable presentation and course indicate that this probably is modulated by some other factors. Several investigators suggested a relationship to estrogenic hormones, evidenced by the fact that nodules morphologically similar to those seen in IM can be produced in guinea pigs treated with large and prolonged doses of estrogenic s~bstances’~ and that lesions of IM usually develop in u tero, possibly under estrogenic stimulation. However, with the notable exception of a patient in whom new nodules developed soon after childbirth? there is no
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CANCER March 1,1992, Volume 69, No. 5
Table 1. Reported Familial Cases of Infantile Myofibromatosis Initial presentation
Site Reference Bartlett e f aL5
Hower et aL6 Baird and Worth7
Pfliiger e f d8* Chung and Enzinger4 Chung and Enzinger' Jennings e f al? Venencie e f al." Salamah e f al."
Current report
Patient no./sex
1/F 2/M 3/M 4/F 5/F 6/F 7/M 8/M 9/F 10/M 11/F 12/F 13/M 14/F 15/M 16/F 17/M 18/F 19/M 20/M 21/M 22/F 23/F 24/M 25/M
Time
Type
MC NB NB MC NB MC lmo MC NB MC NB MC NB MC NB MC NB MC 10mo MC Infancy MC 16yr S NB MC NB MC 8 yr S NB MC NB S NB MC NB MC NB MC NB MC 3mo ,MC ? S NB MC NB MC
SS
B
V
+ + + + + + + + + + + + + +
+
+ + +
+
+
+ + +
+ + + + + + + + + + + + +
+
Follow-up Diedat 2days New growths (SS) at 2 to 4 mo; alive and well at 3 yr New growth (SS) at 3 mo; alive and well at 2 yr Excision; alive and well at 18 mo Diedat 8 wk Partial regression of bone lesions; alive at 7 wk New growths until 5 yr; complete regression; alive at 16 yr New growths until 18 mo; complete regression; alive at 14 yr Regression; alive at 19 mo Excision of both lesions; no recurrence; alive at 19 mo New growths (breasts, SS) at 21 and 23 yr; alive and well Excision of large bowel lesion; new growth (SS) at 17 yr; alive Alive and well at 5 yr NO follow-~p New growths (SS, B) at 9, 10.5, and 11.5 yr; alive Alive and well at 10 yr New growth (SS) at 25 yr; alive New growths (SS) at 7, 12, and 13 wk; alive Complete regression (SS) at 2 yr; alive and well at 7 yr Complete (SS) and partial (B) regression; alive and well at 5 yr New growths (SS, brain) at 2 mo and 2 yr; alive Excisions; alive and well at 1 yr Excision; no follow-up New growths (SS, B) until 15 yr; alive and well New growths (SS) until 8 yr; alive and well
S S skin and/or soft tissues; B bone; V: viscera; N B newborn; MC: multicentric; S solitary.
* No data provided for the remaining five affected family members.
evidence of any hormonal dysfunction in those patients who develop the lesions later in life. Moreover, the few cases of IM analyzed thus far contained no estrogen receptor protein.21
References 1. Stout AP. Juvenile fibromatoses. Cancer 1954; 7:953-978. 2. Kauffman SL, Stout AP. Congenital mesenchymal tumors. Cancer 1965; 18:460-476. 3. Kindblom L-G, Termen G, Save-Soderbergh J et al. Congenital solitary fibromatosis of soft tissues, a variant of congenital generalized fibromatosis. Two case reports. Acfa Pafhol Microbiol Scand (A) 1977; 85:640-648. 4. Chung EB, Enzinger FM. Infantile myofibromatosis. Cancer 1981; 48~1807-1818. 5. Bartlett RC, Otis RD, Laakso AO. Multiple congenital neoplasms of soft tissues. Report of 4 cases in 1 family. Cancer 1961; 14~913-920. 6. Hower J, Gobel FJ, Riittner JR, Wurster K. Familiare kongenitale generalisierte Fibromatose bei zwei Halbschwestem. Schweiz Med Wochenschr 1971; 101:1381-1385.
7. Baird PA, Worth AJ. Congenital generalized fibromatosis: An autosomal recessive condition? Clin Genet 1976; 9:488-494. 8. Pfliiger VH, Kolb R, Mayr WR. Kongenitale Polyfibromatose: Klinische und genetische Untersuchungen. Wien Klin WochenS C ~ Y1976; 88:92-94. 9. Jennings TA, Duray PH, Collins FS, Sabetta J, Enzinger FS. Infantile myofibromatosis. Evidence for an autosomal-dominant disorder. Am J Surg Pathol 1984; 8:529-538. 10. Venencie PY, Bigel P, Desgruelles C, Lortat-JacobS, Dufier JL, Saurat JH. Infantile myofibromatosis. Report of two cases in one family. Br I D e n a f o l 1987; 117255-259. 11. Salamah MM, Hammoudi SM, Sadi ARM. Infantile myofibromatosis. J Pediafr Surg 1988; 23:975-977. 12. Wiswell TE, Davis J, Cunningham BE, Solenberger R, Thomas PJ. Infantile myofibromatosis: The most common fibrous tumor of infancy. Ped Surg 1988; 23:314-318. 13. Roggli VL, Kim H-S, Hawkins E. Congenital generalized fibromatosis with visceral involvement. A case report. Cancer 1980; 45:954-960. 14. Christensen E, Hojgaard K, Smith CC. Congenital malignant mesenchymal tumors in a two month old child. Acta Pafhol Microbiol Scand 1961; 53:237-242. 15. Teng P, Warden J, Cohn WL. Congenital generalized fibromatosis (renal and skeletal) with complete spontaneous regression. J Pediafr 1963; 42748-753.
Familial Myofibromatosis/BracXo et al. 16. Molnar P, Olah E, Miko TL, Gomba S. Aggressive infantiIe myofibromatosis. Report of a case of a clinicallyprogressive congenital multiple fibromatosis. Med Pediafr Oncol 1986; 14:332-337. 17. Bernard JL, Gentet JC, Scheiner C, Theveniau D, Coze C, Raybaud C. Disseminated multivisceral fibromatosis in an infant. An unusual case with favourable outcome (Abstr). Med Pediafr Oncol 1990; 18:427. 18. Altemani AM, Amstalden EI, Fdho JM. Congenital generalized fibromatosis causing spinal cord compression. Hum Pafholl985; 163063-1065. 19. Fletcher CDM, Achu P, Van Noorden S, McKee PH. Infantile myofibromatosis: A light microscopic, histochemical and immunohistochemical study suggesting true smooth muscle differentiation. Histopathology 1987; 11:245-258.
20. Benjamin SP, Mercer RD, Hawk WA. Myofibroblastic contrac-
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21.
22.
23.
24. 25.
tion in spontaneous regression of multiple congenital mesenchyma1 hamartomas. Cancer 1977; 40:2343-2352. Kennedy S, Yunis E, Smith S, Locker J. Morphologicand molecular analysis of congenital myofibromatosis and fibromatosis (Abstr). Mod Pafhol 1990; 3:4P. Daimaru Y, Hashimoto H, Enjoji M. Myofibromatosis in adults (adult counterpart of infantile myofibromatosis). Am J Surg Pathol 1989; 13~859-865. Skalli 0, Schiirch W, Seemayer T et al. Myofibroblasts from diverse pathologic settings are heterogenous in their content of actin isoforms and intermediate filament proteins. Lab Invest 1989; 60:275-285. Young ID, Fortt RW. Familial fibromatosis. Clin Genet 1981; 20:211-216. Nadel EN. Histopathology of estrogen-induced tumors in guinea pigs. J Natl Cancer Insf 1950; 10:1043-1065.
Familial Occurrence of Infantile Myofibromatosis Matej Brac’ko, MD,* Lada Cindro, MD,t and Rastko Golouh, MD, PhD*
Two brothers with multicentric infantile myofibromatosis (IM) are reported. In both, tumors were present at birth; the tumors regressed spontaneously, hut new lesions developed throughout the follow-up periods of 15 and 8 years. Immunohistochemically, the nodules were found to be positive for vimentin and actin, but negative for desmin and S-100 protein; these findings support the myofibrohlastic nature of IM. A literature review revealed nine additional families with IM in more than one family member. Although the occurrence of IM in eight sets of siblings, with consanguinity in two of them, favors an autosomal recessive mode of inheritance, the disorder also has been well documented in half-sisters and in successive generations, which makes autosomal dominant inheritance a more plausible explanation. Cancer 1992; 691294-1299. Infantile myofibromatosis (IM) is an uncommon mesenchymal disorder characterized by the formation of tumors in the skin, subcutaneous tissue, skeletal muscle, bone, and visceral organs. It was first properly documented in 1954 by Stout,’ who called the condition congenital generalized fibromatosis. Subsequent reports of this disease emphasized the multicentric variety of the disorder, for which a number of various terms have been applied. In 1965, Kauffman and Stout2 grouped their cases of congenital fibromatosis into two categories: a multiple form, with lesions restricted to skin, soft tissue, and bone; and a generalized form, with visceral involvement as well. That a solitary form of this condition exists was not fully appreciated until the late 1 9 7 0 ~however, ~; Chung and E n ~ i n g e rwho , ~ presented the only substantial series of this entity and renamed it infantile fibromatosis, found that the solitary form was more common than the multicentric type of the disease.
From the *Department of Pathology, Institute of Oncology, and the tDepartment of Neurology, Pediatric Clinic, Ljubljana, Slovenia. Address for reprints: Matej BraEko, MD, Institute of Oncology, ZaloSka 2, 61000 Ljubljana, Slovenia. Accepted for publication May 31, 1991.
The etiology of IM is uncertain. Although evidence that the disorder may be a heritable condition was presented as early as 1961; additional reports of familial cases have been relatively few, and different types of inheritance have been p~stulated.~*”” In the current study, we report another two cases of IM occumng in one family and review the literature on familial IM.
Case Reports
Patient 1 A 3250-g boy was delivered by cesarean section at full term of an uneventful pregnancy. The initial physical examination of the infant showed multiple subcutaneous nodules on the right thigh, left axilla, occiput, both temporal regions, and left lower eyelid. When the child was 4 months old, the axillary mass was excised and histologically diagnosed as neurofibroma. By the time the child was 1 year old, the lesion in the eyelid completelyregressed, whereas the remainder of lesions persisted, the largest measuring 1 to 2 cm.The patient presented again at the age of 6 years with signs of left brachial plexus lesion. There was completeclinical regression after conservative treatment, and an electromyography performed 1 year later showed conspicuous reinnervation. When seen again at the age of 12 years, the patient was well except for a few subcutaneous nodules that had developed during the past years on his trunk and extremities. On physical examination 1 year later, nodules measuring 1 to 2 cm in diameter were palpated on the right shoulder, left forearm, and right thigh. After a year, a new nodule appeared on the left thoracic wall while other lesions remained unchanged. At 15 years of age, the patient presented with partial Homer’s syndrome consisting of minimal left-sided ptosis and myosis. A computed tomography (CT) scan revealed multiple expanding lytic lesions in the posterior elements of the C3 and T2 vertebrae and first right rib (Fig. 1).A fine-needle aspiration biopsy of the rib lesion was performed, but no diagnostic material was obtained. A subcutaneousnodule on the left lower leg was excised, and histopathologic examination disclosed IM. A bone radiograph survey showed cortical osteolytic lesions in the left humerus and right tibia. The routine laboratory investigationswere negative, as were the chest radiograph, echocardiogram,abdomen echography, CT scan
Familial Myofibromatosis/BraEko et al.
1295
were stained with hematoxylin and eosin and by Masson’s trichromemethod. Additionalsectionswere evaluated immunohistochemically using monoclonal antibodies against vimentin (Dakopatts, Copenhagen, Denmark; dilution 1:loo), desmin (Dakopatts, dilution 1:2000), and muscle-specific actin (BioGenex, San Ramon, CA; dilution 1:200), all revealed by the avidinbiotin peroxidase complex method, and polyclonal antiserum against S-100 protein (Dakopatts, dilution 1:300), revealed by the peroxidase-antiperoxidase method. Results Figure 1. CT scan of the thoracic region showing osteolytic expanding lesions in the rib and the posterior segment of thoracic vertebra.
of the head, electroencephalography, and ophthalmologicexamination.
Patient 2 A full-term male infant, the brother of Patient 1,at birth had a subcutaneous mass on his left thigh. Additional nodules were found a few weeks later on the neck and tongue, and a skull radiograph examination showed an osteolytic lesion in the parietal bone. The lingual mass increased in size during the following months, and surgical removal was considered but was canceled because the lesion began to regress spontaneously when the child was 4 months old. The patient was again admitted to hospital at 3 years of age because of limited motion ability of the right upper extremity. Neurologic examination revealed left-sided latent hemiparesis. No soft tissue masses were noticed on physical examination; the left side of the tongue was atrophic, and the skin overlying the sites of previous nodules was €um and pale. A biopsy of one of these sites revealed only scar tissue. During the next 4 years, new subcutaneous nodules developed on the patient’s neck, chest wall, and axilla, some of them undergoing spontaneous regression. The neurologic status remained slightly pathologic, but a CT scan of the head performed when the child was 7 years old showed no abnormalities. The diagnosis of IM in his brother was established when Patient 2 was 8 years old; at that time, he underwent a skeletal radiograph survey that showed a solitary osteolytic cortical lesion in the diaphysis of the left humerus. There was no evidence of consanguinity or history of nodules in the parents. A blood-related uncle reportedly had two subcutaneous nodules excised from the eyelid and the scalp. Histology of these lesions could not be obtained.
A biopsy of the lesion in the left axillary region showed a well-circumscribed nonencapsulated 1.5-cm nodule occupying the reticular dermis and subcutaneous fat, composed of elongated cells with rather copious eosinophilic cytoplasm. These cells were arranged in whorled or interlacing fascicles separated in places by conspicuous collagen. The more cellular central area showed a prominent vascular pattern with thin-walled arborizing vessels (Fig. 2). Mitotic figures were not found. The second nodule, which was excised from the lower leg 15 years later, measured 2.5 cm in largest diameter and was situated within skeletal muscle. It showed extensive central necrosis, with a rim of viable tissue at the periphery being composed of bundles and well-delineated whorls formed by spindle cells with fibrillary eosinophilic cytoplasm intimately associated with varying amounts of collagen. Immunohistochemical findings were similar in both lesions. Most tumor cells showed strong cytoplasmic positivity for vimentin and, to a lesser degree, for actin, whereas none reacted positively for either desmin or S-100 protein (Fig. 3).
Materials and Methods
Two formalin-fixed, paraffin-embeddedexcision specimens from Patient 1 were available for review. They
Figure 2. The central portion of IM nodule composed of spindle cells arranged around thin-walled vessels in a pericytomatous pattern (H & E, original magnification X200).
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CANCER March 2,2992, Volume 69, No. 5
Figure 3. Cells of the IM lesion. (Left) Strongly positive for vimentin. (Middle) Showing a weaker positivity for actin. (Right) Negative for desmin, which is present only in an entrapped arrector muscle (ABC, original magnification X200).
in childhood4 or even adulthood’ but usually are limited to soft tissue. In rare instances, IM may undergo an aggressive course with protracted, slow, continuous, deAlthough the diagnosis of IM was not c o n h e d histostructive proliferation of the subcutaneous nodules.’6 logically in Patient 2, his clinical features, which are Neurologic symptomshave been rarely observed in nearly identical to his brother’s, are typical of the multiIM. Because the involvement of the central nervous centric form of infantile myofibromatosis, and an addisystem parenchyma is exceptional,” neurologic symptional biopsy was considered unnecessary. toms usually develop because of compression of neural The clinical manifestations and clinical course of structures by the nodules present in the dura mater,I8 IM depend upon the number and localization of the soft tissue, or bones, as seems to be the case in our lesions. The number of tumors, which range in size patients. from 0.5 to 7 cm, varies from 1 to more than 100, and The histology of IM is quite characteristic and apparently any organ or tissue may be involved. In the usually shows a distinct zoning phenomen~n.~,’’The multicentric type, the most common sites of involveperipheral areas of IM nodules consist of plump spindle ment, apart from the soft tissue and bone, are the lung, cells with eosinophilic cytoplasm arranged in well-deheart, and gastrointestinal tract.” The tumors usually marcated short bundles, fascicles or whorls resembling are present at birth and are almost always detected dursmooth muscle, whereas the central portions frequently ing the lirst year of life; however, about 20% of solitary are made up of less-differentiated cells arranged lesions, which are found most often in the skin, muscle, prominent vascular spaces in a hemangioperior subcutaneous tissue, appear in older i n d i v i d ~ a l s . ~ ~ ’around ~ cytoma-likepattern. Occasionally, the lesions show foci Of the 170 patients with IM reported until 1988,25 of coagulative necrosis, which may at times occupy the have died,” mostly through complications from viswhole central area and undergo calcification. ceral lesions in the multicentric form of disease, of While the histologic features of IM are well estabwhich pulmonary involvement seems to cany the most lished, there is some debate as to its histogenesis. Inigave progn~sis.’~ The one fatality in a case without tially, the cells forming the nodules in IM were regarded visceral involvement was due to spinal cord compresas fibroblastic in origin; however, their marked resemsion secondary to a lesion involving a cervical verteblance to smooth muscle was noticed by some early bra.14 Provided no vital organs are involved, the proginvestigator^.^ Later electron microscopic” and histonosis of IM is excellent: the recurrence rate after excichemical4 studies led to the conclusion that this lesion sion of solitary tumors is less than 10%,4,’’ and the was a tumor of myofibroblasts and to the introduction majority of multicentric lesions undergo spontaneous r e g r e s s i ~ n . ~However, ~ ’ ~ ~ ’ ~ new growths may occur later of its current name. The myofibroblasticcomposition of Discussion
Familial Myofibromatosis/BraEko et al.
1297
I
1
2
ca 3
4
5
6
mid m .a 7 8
Figure 4. Pedigrees of the families with IM in two or more kindred members. The numbers correspond to the patient numbers in Table 1; members with history of having nodules excised but no histologic or clinical c o n h a t i o n are designated as possible IM.
z x 13
14
15
18
(m!GId 19
20
IM is supported by our immunohistochemicalfindings and those of other investigators who studied a limited number of cases of classic IM’l or soft tissue tumors histologically indistinguishable from IM but occurring in adults.” In all of these studies, the lesions labeled for vimentin and muscle-specific adin but not for desmin or S-100 protein. However, the myofibroblastic nature of IM recently was questioned by Fletcher et aZ.,19 who found some of their cases to be desmin positive and who thought that IM was a tumor of primitive smooth muscle cells. It has now been shown that in certain pathologic settings, apart from vimentin and actin, myofibroblasts also may express de~min.’~ The exact cause of IM is not clear, but genetic factors are likely to pray an important role in its etiology. We have been able to trace nine well-documented family reports in which IM has been recorded in more than one kindred member.&” The pedigrees of these families are shown in Figure 4, and the clinical data of the affected family members are summarized in Table 1. Additional possible examples of familial IM, which are not included in this review because of lack of histologic c o n h a t i o n or pertinent clinical data, include a brother and sister with congenital generalized fibromatosis briefly mentioned by Teng et d , l 5 a brother and sister with congenital solitary fibromatosis reported by Kauffman and Stout,’ and an infant and his blood-reIated uncle observed by Jennings et aL9 IM also was reported in a patient whose family members had palmar-plantar fibromat~sis.’~ The true incidence of IM occurring in a familial setting is probably much higher than it seems to be when judged by the paucity of reports in the medical literature because most of the published single cases provide
910
% 24
25
minimal or no data on family history. Because the lesions of IM frequently are small and asymptomatic and tend to disappear spontaneously, milder expressions of the disease in the relatives can easily be overlooked. As seen in Table 1,familial IM has no sex predilection and shows the same wide spectrum of presentation as observed in sporadic cases. The occurrence of cases of multicentric IM with or without visceral involvement and of solitary IM in the same families supports the concept that these are forms of the same disease. There are insufficient data to allow any firm conclusions regarding the genetics of IM. In six famifies4,5.7,10.11 the disease was reported in siblings, and in at least two of them5p7first cousins also were affected; parents of two sets of affected siblings were consang u i n e ~ ~ ~These . ~ , ”data strongly support an autosomal recessive mode of inheritance. However, autosomal recessive inheritance does not explain the cases of IM occurring in half-sisters6 and in successive generat i o n ~ , ~for , ~ which autosomal dominant inheritance with reduced penetrance, as proposed by Jennings et aZ.? seems to be the most plausible explanation. Although a mechanism under genetic influence appears to be the major etiologic factor in IM, its variable presentation and course indicate that this probably is modulated by some other factors. Several investigators suggested a relationship to estrogenic hormones, evidenced by the fact that nodules morphologically similar to those seen in IM can be produced in guinea pigs treated with large and prolonged doses of estrogenic s~bstances’~ and that lesions of IM usually develop in u tero, possibly under estrogenic stimulation. However, with the notable exception of a patient in whom new nodules developed soon after childbirth? there is no
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CANCER March 1,1992, Volume 69, No. 5
Table 1. Reported Familial Cases of Infantile Myofibromatosis Initial presentation
Site Reference Bartlett e f aL5
Hower et aL6 Baird and Worth7
Pfliiger e f d8* Chung and Enzinger4 Chung and Enzinger' Jennings e f al? Venencie e f al." Salamah e f al."
Current report
Patient no./sex
1/F 2/M 3/M 4/F 5/F 6/F 7/M 8/M 9/F 10/M 11/F 12/F 13/M 14/F 15/M 16/F 17/M 18/F 19/M 20/M 21/M 22/F 23/F 24/M 25/M
Time
Type
MC NB NB MC NB MC lmo MC NB MC NB MC NB MC NB MC NB MC 10mo MC Infancy MC 16yr S NB MC NB MC 8 yr S NB MC NB S NB MC NB MC NB MC NB MC 3mo ,MC ? S NB MC NB MC
SS
B
V
+ + + + + + + + + + + + + +
+
+ + +
+
+
+ + +
+ + + + + + + + + + + + +
+
Follow-up Diedat 2days New growths (SS) at 2 to 4 mo; alive and well at 3 yr New growth (SS) at 3 mo; alive and well at 2 yr Excision; alive and well at 18 mo Diedat 8 wk Partial regression of bone lesions; alive at 7 wk New growths until 5 yr; complete regression; alive at 16 yr New growths until 18 mo; complete regression; alive at 14 yr Regression; alive at 19 mo Excision of both lesions; no recurrence; alive at 19 mo New growths (breasts, SS) at 21 and 23 yr; alive and well Excision of large bowel lesion; new growth (SS) at 17 yr; alive Alive and well at 5 yr NO follow-~p New growths (SS, B) at 9, 10.5, and 11.5 yr; alive Alive and well at 10 yr New growth (SS) at 25 yr; alive New growths (SS) at 7, 12, and 13 wk; alive Complete regression (SS) at 2 yr; alive and well at 7 yr Complete (SS) and partial (B) regression; alive and well at 5 yr New growths (SS, brain) at 2 mo and 2 yr; alive Excisions; alive and well at 1 yr Excision; no follow-up New growths (SS, B) until 15 yr; alive and well New growths (SS) until 8 yr; alive and well
S S skin and/or soft tissues; B bone; V: viscera; N B newborn; MC: multicentric; S solitary.
* No data provided for the remaining five affected family members.
evidence of any hormonal dysfunction in those patients who develop the lesions later in life. Moreover, the few cases of IM analyzed thus far contained no estrogen receptor protein.21
References 1. Stout AP. Juvenile fibromatoses. Cancer 1954; 7:953-978. 2. Kauffman SL, Stout AP. Congenital mesenchymal tumors. Cancer 1965; 18:460-476. 3. Kindblom L-G, Termen G, Save-Soderbergh J et al. Congenital solitary fibromatosis of soft tissues, a variant of congenital generalized fibromatosis. Two case reports. Acfa Pafhol Microbiol Scand (A) 1977; 85:640-648. 4. Chung EB, Enzinger FM. Infantile myofibromatosis. Cancer 1981; 48~1807-1818. 5. Bartlett RC, Otis RD, Laakso AO. Multiple congenital neoplasms of soft tissues. Report of 4 cases in 1 family. Cancer 1961; 14~913-920. 6. Hower J, Gobel FJ, Riittner JR, Wurster K. Familiare kongenitale generalisierte Fibromatose bei zwei Halbschwestem. Schweiz Med Wochenschr 1971; 101:1381-1385.
7. Baird PA, Worth AJ. Congenital generalized fibromatosis: An autosomal recessive condition? Clin Genet 1976; 9:488-494. 8. Pfliiger VH, Kolb R, Mayr WR. Kongenitale Polyfibromatose: Klinische und genetische Untersuchungen. Wien Klin WochenS C ~ Y1976; 88:92-94. 9. Jennings TA, Duray PH, Collins FS, Sabetta J, Enzinger FS. Infantile myofibromatosis. Evidence for an autosomal-dominant disorder. Am J Surg Pathol 1984; 8:529-538. 10. Venencie PY, Bigel P, Desgruelles C, Lortat-JacobS, Dufier JL, Saurat JH. Infantile myofibromatosis. Report of two cases in one family. Br I D e n a f o l 1987; 117255-259. 11. Salamah MM, Hammoudi SM, Sadi ARM. Infantile myofibromatosis. J Pediafr Surg 1988; 23:975-977. 12. Wiswell TE, Davis J, Cunningham BE, Solenberger R, Thomas PJ. Infantile myofibromatosis: The most common fibrous tumor of infancy. Ped Surg 1988; 23:314-318. 13. Roggli VL, Kim H-S, Hawkins E. Congenital generalized fibromatosis with visceral involvement. A case report. Cancer 1980; 45:954-960. 14. Christensen E, Hojgaard K, Smith CC. Congenital malignant mesenchymal tumors in a two month old child. Acta Pafhol Microbiol Scand 1961; 53:237-242. 15. Teng P, Warden J, Cohn WL. Congenital generalized fibromatosis (renal and skeletal) with complete spontaneous regression. J Pediafr 1963; 42748-753.
Familial Myofibromatosis/BracXo et al. 16. Molnar P, Olah E, Miko TL, Gomba S. Aggressive infantiIe myofibromatosis. Report of a case of a clinicallyprogressive congenital multiple fibromatosis. Med Pediafr Oncol 1986; 14:332-337. 17. Bernard JL, Gentet JC, Scheiner C, Theveniau D, Coze C, Raybaud C. Disseminated multivisceral fibromatosis in an infant. An unusual case with favourable outcome (Abstr). Med Pediafr Oncol 1990; 18:427. 18. Altemani AM, Amstalden EI, Fdho JM. Congenital generalized fibromatosis causing spinal cord compression. Hum Pafholl985; 163063-1065. 19. Fletcher CDM, Achu P, Van Noorden S, McKee PH. Infantile myofibromatosis: A light microscopic, histochemical and immunohistochemical study suggesting true smooth muscle differentiation. Histopathology 1987; 11:245-258.
20. Benjamin SP, Mercer RD, Hawk WA. Myofibroblastic contrac-
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22.
23.
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tion in spontaneous regression of multiple congenital mesenchyma1 hamartomas. Cancer 1977; 40:2343-2352. Kennedy S, Yunis E, Smith S, Locker J. Morphologicand molecular analysis of congenital myofibromatosis and fibromatosis (Abstr). Mod Pafhol 1990; 3:4P. Daimaru Y, Hashimoto H, Enjoji M. Myofibromatosis in adults (adult counterpart of infantile myofibromatosis). Am J Surg Pathol 1989; 13~859-865. Skalli 0, Schiirch W, Seemayer T et al. Myofibroblasts from diverse pathologic settings are heterogenous in their content of actin isoforms and intermediate filament proteins. Lab Invest 1989; 60:275-285. Young ID, Fortt RW. Familial fibromatosis. Clin Genet 1981; 20:211-216. Nadel EN. Histopathology of estrogen-induced tumors in guinea pigs. J Natl Cancer Insf 1950; 10:1043-1065.
