Hemihypertrophy and a Poorly Differentiated Embryonal Rhabdomyosarcoma of the Pelvis
David P. Samuel, MB, ChB,1* Maria Tsokos, MD,2 and Michael R. DeBaun, MD, MPH3,4
Background. Asymmetry of the limbs (con- ventionally known as hemihypertrophy) is one of the overgrowth syndromes occurring spo- radically in the general population at a fre- quency of approximately 1:86,000. Hemihy- pertrophy is also reported as part of the Beck- with-Wiedemann syndrome which has as its cardinal features omphalocele, macroglossia and gigantism with hypoglycemia, organo- megaly, renal anomalies, hemihypertrophy, and embryonal tumors occurring less fre- quently. Various neoplasms are also associated with isolated hemihypertrophy. Wilms tumor, adrenocortical carcinoma, and hepatoblastoma are the most frequent. Rhabdomyosarcoma, neuroblastoma, phaeochromocytoma, and un- differentiated sarcoma of the lung are encoun- tered only rarely. Loss of heterozygosity (LOH) of chromosome 11p15.5 is strongly associated with childhood embryonal tumors, particularly Wilms tumor, hepatoblastoma, and rhabdo- myosarcoma. Procedure and Results. In this ar- ticle, we describe an adolescent male with con-
genital asymmetry of the lower limbs who pre- sented with a large poorly differentiated pelvic sarcoma. Conventional histologic, immunohis- tochemical, and ultrastructural studies of this tumor were insufficient for accurate subclassfi- cation. However, positive staining for MyoD1 (a recently identified embryonically expressed marker of muscle differentiation) and LOH at the tyrosine hydroxylase locus of chromosome 11p15.5 by molecular analysis favored the di- agnosis of embryonal rhabdomyosarcoma over an undifferentiated sarcoma. Conclusions. This case stresses the importance of pursuing clini- cal findings when they occur in conditions with an increased risk of developing cancer, which in this case was asymmetry of a limb. Also il- lustrated by this patient is the need for early consideration of molecular diagnostic tests where available, to refine an uncertain patho- logic diagnosis that may ultimately have an impact on treatment and prognosis. Med. Pedi- atr. Oncol. 32:38-43, 1999. Published 1999 Wiley-Liss, Inc.+
Key words: hemihypertrophy; sarcoma; rhabdomyosarcoma; LOH; 11p15.5; MyoD1
INTRODUCTION
Asymmetry of the human body has been recognized for centuries by ancient Greek and Roman sculptors and by the early Egyptians. The earliest clinical report of asymmetry of the body is that of Wagner in 1839 [1] who described hemihypertrophy of the right chest and right upper extremity, especially the hand and finger. Since then, many cases have been reported in the world litera- ture and have been the subject of reviews by several authors [2-6], most recently by Cohen [7]. Sporadic cases in the normal population are estimated to occur at a frequency of approximately 1:86,000 [5]. The associa- tion of hemihypertrophy with neoplasms is well known, the most common being Wilms tumor [8], with adreno- cortical carcinoma [9] and hepatoblastoma [10] also be- ing reported. Other tumors have also been noted rarely, namely neuroblastoma [11,12], testicular carcinoma [13], adrenal adenoma [14], phaeochromocytoma [15], rhab- domyosarcoma [16], leiomyosarcoma [17], and undiffer- entiated sarcoma of the lung [6]. We encountered an adolescent male with asymmetry of the lower limbs who developed a histologically poorly differentiated sarcoma
Published 1999 Wiley-Liss, Inc. +This article is a US Govern- ment work and, as such, is in the public domain in the United States of America.
of the pelvis with features of an embryonal rhabdomyo- sarcoma.
A 15-year-old African American adolescent male with congenital left-sided hemihypertrophy of the leg and foot (Fig. 1) was referred to the pediatric branch of the Na- tional Cancer Institute (NCI) with a 3-month history of left leg pain. It was intermittent, localized to the mid- thigh, and occasionally felt in the knee. One month after the onset of leg pain, the patient developed a lump in his left buttock with progressive weakness in that leg and
1Pediatric Branch, National Cancer Institute, Bethesda, Maryland
2Laboratory of Pathology, National Cancer Institute, Bethesda, Mary- land
3Genetic Epidemiology Branch, Division of Cancer Etiology, National Cancer Institute, Bethesda, Maryland
4Department of Pediatrics, Washington University Medical School, St. Louis, Missouri
*Correspondence to: David Samuel, M.B. Ch.B, Pediatric Branch, Na- tional Cancer Institute, National Institute of Health, Bethesda, MD 20895. E-mail: samueld@exchange.nih.gov
Received 9 September 1997; Accepted 25 June 1998
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significant limping. When medical attention was sought, hesitancy of urine along with straining and the passing of small thin stool had developed.
Plain X-ray films of the pelvis revealed a lytic lesion in the left ischium. Magnetic resonance imaging (Fig. 2) showed a pelvic mass of 22 cm in the cephalocaudad dimension, 12 × 12 cm in the anteroposterior and trans- verse dimensions, respectively, with an isthmus extend- ing through the obturator foramen into the adductors of the left hip. The superior extent of the tumor was to the level of the first sacral vertebra and the inferior extent was to the floor of the pelvis invading the root of the penis. Computed tomography of the chest showed nu- merous lesions consistent with metastatic pulmonary nodules and a bone scan highlighted a mass arising out of the floor of the pelvis. Bilateral bone marrow aspirates and biopsy revealed no evidence of marrow involvement. Cytogenetic evaluation by G-banding analysis of five analyzable metaphases of the patient showed the 46, XY karyoptype of a normal male.
The patient had been born at full term by spontaneous vaginal delivery with a birth weight of 7 lb 4 oz (50th centile). Apart from noting the left-sided hemihypertro- phy, no perinatal problems were reported. An umbilical hernia resolved without intervention. Development was normal, with independent walking at 10 months and speech developing at the expected time. Despite body asymmetry, physical activity was normal.
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General examination was significant for icthyosis vul- garis in a slender adolescent of weight 60.7 kg (50th centile), height 172 cm (50th centile), and head circum- ference 54 cm (25th centile). There were no dysmorphic features. No lymphadenopathy was noted with normal head and neck, cardiovascular, respiratory, and abdomi- nal examination. A left buttock mass measuring 16 × 7.5 cm of firm consistency was noted with gait significant for left leg circumduction but normal power tone and re- flexes. Limb measurements revealed differences between the left and right sides. The left leg measured 99 cm and the right 97.5 cm in length. Foot length on the left side 31 cm and on the right 27 cm. Girth of the left foot was
26 cm whereas the right measured 24 cm. The patient was entered on the NCI treatment protocol for high-risk pediatric sarcomas (NCI 86-C-169). Chemotherapy con- sisted of standard chemotherapeutic agents active against sarcoma, namely, vincristine, etoposide, ifosfamide, doxorubicin, and cyclophosphamide. Radiotherapy to the pelvis (50 Gy) was given between weeks 18 and 24. On completion of chemotherapy and radiotherapy, no evi- dence of metastases or of pulmonary or pelvic disease was noted. Four months after completing his initial therapy, a pulmonary mass was found. Treatment using a phase one agent (paclitaxel), for a total of three cycles, was given every 3 weeks. This was discontinued because of disease progression. Another phase one agent (9 cis- retinoic acid) was commenced, but the disease pro- gressed and he died 24 months from the time of diagno- sis.
Family Evaluation
All five half-siblings of the patient were evaluated for body asymmetry and features associated with Beckwith- Wiedemann syndrome. A male half-sibling demonstrated a left ear dimple and pit. A female half-sibling was found to have a generous sized tongue but not macroglossia and a leg length discrepancy of 1 cm. We believe neither of these findings to be strong enough indicators to suggest the diagnosis of Beckwith-Wiedemann syndrome. The remaining members of the family had a normal pheno- type.
PATHOLOGY
Needle core biopsy of the buttock mass was per- formed at the referring institution. The diagnosis of high- grade sarcoma was rendered based on histopathologic evaluation of several pieces of cylindrical segments mea- suring 0.5 × 0.3 × 0.1 cm. Further diagnostic work-up was not possible due to limited material.
A repeat needle core biopsy was done at the NCI in preference to an open biopsy in view of impending bowel and bladder obstruction. The specimen in aggregate was 0.9 × 0.7 × 0.3 cm. Histologically, very little tumor ex- hibited hyper- and hypocellular areas, the latter in a myx- oid background. The tumor cells were predominantly spindle shaped with scant cytoplasm. Extensive necrosis was present (Fig. 3a). Immunohistochemical staining was negative for keratin, epithelial membrane antigen (EMA), and muscle-specific and smooth muscle actin. Rare cells were positive for desmin and S-100 protein. Neuron-specific enolase was diffusely positive. Further immunohistochemical analysis with an antibody against MyoD1 protein (Novocastra Laboratories Ltd., New- castle upon Tyne, UK) revealed extensive staining of tumor nuclei (Fig. 3b). Ultrastructurally, the tumor cells were poorly differentiated with variably developed rough
endoplasmic reticulum and high nuclear/cytoplasmic ra- tio. These cells also lacked cytoplasmic filaments and rarely had cytoplasmic glycogen (Fig. 3c,d).
Polymerase chain reaction (PCR)-based studies using polymorphic short tandem repeats at the tyrosine hydrox- ylase (TH) locus have been used to detect loss of het- erozygosity (LOH) at the chromosome 11p15.5 region in human embryonal rhabdomyosarcoma [18]. When ana- lyzed using this technique, tumor material from this pa- tient demonstrated LOH at the TH locus when compared to his normal tissue. Based on the histology of the tumor, ultrastructural findings, and desmin positivity, a rhabdo- myosarcoma can only be inferred. However, together with the expression of MyoD1 and the detection of LOH at the TH locus of the 11p15.5 region, a diagnosis of embryonal rhabdomyosarcoma was favored.
DISCUSSION
The present case represents a rare association of spo- radic hemihypertrophy and embryonal rhabdomyosarco- ma. In a series of 151 patients [17], other embryonal tumors such as Wilms tumor, hepatoblastoma, and neu- roblastoma occurred with isolated hemihypertrophy at a frequency of approximately 6%. However, the Inter- group Rhabdomyosarcoma Study Committee reported only one case of hemihypertrophy in a series of 115 patients with rhabdomyosarcoma who were autopsied [16] and no other individual cases have been reported. The classification of hemihypertrophy remains contro- versial without an internationally accepted definition. Several authors [3,19-22] discuss the need to distinguish true from “pseudo” hemihypertrophy and highlight the association of hemihypertrophy with other conditions. The most notable among them are are Beckwith- Wiedemann syndrome, Klippell-Trenaunay-Weber syn- drome, neurofibromatosis, and Proteus syndrome [7]. Asymmetry of the body is regarded by some as a distinct entity, defined as unilateral overgrowth of the body in- cluding structures of the head for which no cause can be found, thus excluding disorders of vascular origin and neurofibromatosis [23,24]. An attempt at the subclassfi- cation of hemihypertrophy is offered by Rowe [25], whereby complex hemihypertrophy involves an entire half of the body or at least an arm and a leg. When the enlarged parts are on the same side, it is classified as complex ipsilateral; when they are crossed, it is referred to as complex contralateral hemihypertrophy. Also in this classification, simple hemihypertrophy involves a single limb and hemifacial hypertrophy involves one side of the face. The working definition of hemihypertrophy in the NCI Beckwith-Wiedemann Registry is a discrepancy of at least 10% in limb length or girth measurement, which has been used in this case report, although by convention a 10% difference in girth alone is sufficient.
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It has also been suggested that hemihypertrophy is an underappreciated diagnostic feature of the overgrowth syndrome of Beckwith-Wiedemann [26]. When probands with Beckwith-Wiedemann syndrome were followed
prospectively for risk of malignancy, hemihypertrophy was associated with the greatest relative risk of 4.6 (range 1.5-14.2, confidence interval 95%) [27]. In spite of a left ear crease and pit in a male half-sibling, which
may be observed in patients with Beckwith-Wiedemann syndrome [28], as well as a leg length discrepancy of 1 cm and a generous sized tongue (but not macroglossia) in a female half-sibling, these findings are insufficient to make a diagnosis of Beckwith-Wiedemann syndrome.
The tumor in our patient was not easily classifiable and the traditional histologic and ultrastructural features supported a poorly differentiated sarcoma. The initial dif- ferential diagnosis, in addition to an embryonal rhabdo- myosarcoma, included other spindle cell sarcomas of the soft tissue as well as an extrarenal Wilms tumor which may present as a monophasic poorly differentiated vari- ant. Limited tumor tissue availability by needle core bi- opsy was an additional limiting factor for the correct diagnosis. However, the technique of needle core biopsy has been prospectively studied by Barth et al. [29] for its diagnostic utility in soft tissue masses and was expected to yield a definitive diagnosis with the least amount of morbidity. In our patient, the risk of further morbidity from impending bowel and bladder obstruction following laparotomy precluded an open biopsy.
Molecular diagnostic testing on the patient’s paraffin- embedded tumor tissue revealed LOH at the 11p15.5 region, as has been reported for Wilms tumor, rhabdo- myosarcoma, and hepatoblastoma [30,31]. The same chromosomal region has also been implicated in Beck- with-Wiedemann syndrome with two kindreds showing linkage of the syndrome with the insulin gene located at 11p15.5 [32,33]. Further pedigree analysis of Beckwith- Wiedemann families suggested a pattern of autosomal dominant inheritance with greater penetrance in female offspring, which implies genomic imprinting [34,35]. None of our patient’s family members had the constel- lation of features that is sufficient for the diagnosis of Beckwith-Wiedemann syndrome.
Immunohistochemical studies of the paraffin- embedded tumor tissue revealed positivity for MyoD1 protein. Nuclear staining of MyoD1 is a specific marker for rhabdomyosarcoma [36,37]. Studies by Scrabble et al. [38] on primary tumor and nude mouse xenograft tumor tissue using both the LOH of chromosome 11p15.5 as a molecular marker and MyoD1 positivity showed strong correlation with the diagnosis of embryo- nal rhabdomyosarcoma. In recent studies, LOH of chro- mosome 11p15.5 has been observed in a small percent of alveolar rhabdomyosarcomas [39]. However, the com- bined consideration of histology, MyoD1 staining, and LOH at the 11p15.5 region in this patient’s poorly dif- ferentiated sarcoma almost undoubtedly supports the di- agnosis of embryonal rhabdomyosarcoma.
Hemihypertrophy is a clinical finding associated with cancer predisposition. When present in a child with a mass, it should raise the possibility of an embryonal tu- mor. LOH at the 11p15.5 region in our patient’s tumor together with the positive staining for the early myo-
genous marker MyoD1 enabled a definitive diagnosis, highlighting the value of considering a patient’s pheno- type and tumor genotype for an accurate pathologic di- agnosis.
ACKNOWLEDGMENTS
We are grateful to Dr. Arleen Thom, M.D. for refer- ring this patient to our institution and to Joanne Derdak, A.N.P. for her help in patient care.
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