Cardiovascular Pathology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Cardiovascular Pathology
Case Report
Primary cardiac malignant peripheral nerve sheath tumor in a 23-month-old infant Jihong Sun, Shaoxiong Chen, Rong Fan ⁎ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 350 W 11th St, Indianapolis, IN 46202
a r t i c l e
i n f o
Article history: Received 17 February 2014 Received in revised form 28 March 2014 Accepted 31 March 2014 Available online xxxx
a b s t r a c t We report the second case of primary cardiac malignant peripheral nerve sheath tumor in pediatric population. © 2014 Elsevier Inc. All rights reserved.
Keywords: Heart Malignant peripheral nerve sheath tumor Cardiac tumor Pediatric tumor
1. Introduction
2.1. Pathology findings
Primary cardiac malignant peripheral nerve sheath tumor (MPNST) is exceedingly rare. Excluding cases occurring in the background of neurofibromatosis Type 1 and pericardium cases, MPNST has only rarely been reported in adult patients; most arose from the left atrium, but one case was from the left ventricle; [1–4] in one most recent case, it arose in the right atrium and protruded into the right ventricle through the tricuspid valve [5].
Gross examination of the surgical specimen showed a large (4.1 cm) lobulated “lipomatous” tumor (Fig. 1A); however, the impression under the microscope was quite different, demonstrating a somewhat wavy hyperchromatic spindle cell lesion with variable cellularity. The lesion had some sort of biphasic appearance, showing higher cellularity around many slit-like vasculatures. Neither Antoni A and B zonation nor the hyaline vessels of a schwannoma were identified. A mild to moderate degree of atypia was noted, but mitotic activity was considered low (Fig. 1B, C). Immunohistochemistry workup revealed that the lesional cells were convincingly positive for S100 (Fig. 1D), GFAP, and PGP 9.5 and negative for HMB-45 and pancytokeratin. The diagnosis of low-grade MPNST was unequivocally established with further confirmation by authoritative tumor pathologists. Finally, the lesion is also extensively positive for p53, which further consolidated our diagnosis.
2. Case report Our patient, a 23-month-old previously healthy infant male with significant family history, was noticed to have generalized swelling. He was first taken to urgent care, diagnosed with bilateral otitis media, and treated with antibiotics. However, the generalized swelling persisted. An echocardiogram demonstrated a large mitral valve mass causing some degree of inflow obstruction. Intraoperatively, a multilobulated mass was filling the mitral orifice, which was based off what appeared to be the posterior mitral annulus. The mass was resected and submitted for pathological examination. Funding: This research received no specific grand from any funding agency, commercial, or not-for-profit sectors. Financial Support: This research received no specific grand from any funding agency, commercial, or not-for-profit sectors. Conflicts of Interest: None. ⁎ Corresponding author at: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Riley Hospital for Children at IU Health, 702 Barnhill Dr, Rm 2536, Indianapolis, IN 46202-5200, USA. Tel.: +1 -317 944 2616; fax: +1 317 944 2810. E-mail address: [email protected] (R. Fan).
2.2. Followup The patient is doing well, without any signs of tumor recurrence 2 years after surgical resection of this intracardiac mass. 3. Discussion 3.1. Epidemiology The vast majority of pediatric heart tumors are benign. Different reviews concur that the most common benign entity for the location is rhabdomyoma. The second place in the ranking is debatable, either fibroma or teratoma; but, without doubt, the perinatal period
http://dx.doi.org/10.1016/j.carpath.2014.03.008 1054-8807/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Sun J, et al, Primary cardiac malignant peripheral nerve sheath tumor in a 23-month-old infant, Cardiovasc Pathol (2014), http://dx.doi.org/10.1016/j.carpath.2014.03.008
2
J. Sun et al. / Cardiovascular Pathology xxx (2014) xxx–xxx
Fig. 1. (A) Large (4.1cm) lobulated lipomatous tumor on gross examination; (B and C) Histologically, the spindle cell lesion showed variable cellularity featuring biphasic “marbleized” appearance, with higher cellularity around many slit-like vasculatures. The asymmetric spindle cells in the lesion were typically showing buckled nuclei. A mild to moderate degree of atypia was noted, but mitotic activity was low. (D) Immunohistochemistry workup was positive for S100.
teratoma is more common than fibroma. The other benign entities include myxoma, hemangioma, lipoma, and histiocytoid nodule, also known as Purkinje cell tumor or oncocytic cardiomyopathy [6–8]. Primary cardiac malignant tumors are uncommon, consisting of about 25% of all primary cardiac tumors, among which 75% are sarcomas. For pediatric population, only 10% of cardiac tumors are malignant, with no reliable statistics available for exact frequencies. The most common entity in this category, as in adults, is angiosarcoma. The other pediatric primary malignant heart tumors reported included rhabdomyosarcoma, ranking perhaps the second, and fibrosarcoma, lymphoma, pheochromocytoma, primitive neuroectodermal tumor, and undifferentiated sarcoma [6,7,9]. It is worth mentioning that secondary tumors (i.e., metastatic) are 10–20 times more common in pediatric hearts. Rare cases of both primary and secondary MPNSTs have been reported before, mostly in adults. To our knowledge, this is the second primary MPNST case in the pediatric population. 3.2. Location of tumor Most of cardiac sarcomas are located in the left atrium. The location of primary cardiac MPNST from the general (adult) population appears to be on the left side, while the primary cardiac rhabdomyosarcoma has no predilection site. The recent reported case, however, was located at the right side of the heart. The histology description of the case appeared to be quite typical of MPNST; however, the figure illustration in the article is not quite convincing [5]. 3.3. Diagnostic caveats Admittedly, the definite diagnosis of MPNST is difficult and often elusive, even among the experts due to lack of specific confirmatory markers and consensus of standard set of criteria. In the past, some pathologists took a more liberal approach to diagnose MPNST; some included any atypical spindle cell lesions with collagen production as MPNST. With the evolution of immunohistochemistry tools and our understanding of this entity and its close mimickers, however, the diagnosis has become more and more consistent, especially among
the top experts in the field. To diagnose MPNST, a malignant tumor arising from peripheral nerve or showing nerve sheath differentiation is required, with the exception of tumors originating from epineurium or peripheral nerve vasculature. The documented association of Von Recklinghausen disease, also known as neurofibromatosis I, is not mandatory. But if the malignant tumor arising from prior benign nerve sheath tumor is mostly neurofibroma, then the diagnosis is nearly conclusive. In addition, with advancement of immunohistochemistry techniques, it also becomes clear that fibrosarcoma is rare, and by definition S100, epithelial membrane antigen, and keratin should be completely negative, and therefore, some of the undifferentiated sarcoma or fibrosarcoma cases in the literature may actually be MPNST. On the microscopic level, according to the authoritative comments of Dr. Sharon Weiss, alternating dense and less cellular fascicles, spindle cell cells with irregular buckled nuclei, and peculiar patterns frequently encountered in Schwann cell tumors, such as nuclear palisading, vague whorled structures, curlicue arrangement of cells, and perivascular density are highly suggestive features [10]. The most effective immunohistochemical stains to document nerve sheath derivation are S100, PGP9.5, and myelin basic protein. Among these markers, the S100 stain is most widely used and should stain positive in the majority of the cases; it has the peculiarity of being patchy and less strong than various benign entities. It is also worth pointing out that this tendency persists in the different grades of MPNST; that is, low-grade MPNST has stronger S100 and more diffuse staining than high-grade MPNST. Importantly, besides atypical features, extensive p53 staining supports the diagnosis of MPNST, as this p53 immunoreactivity, a marker suggesting the malignant transition, was present in less than 5% of neurofibromas [11]. Hence, when compared with these discussed diagnostic benchmarks, our case is close to a perfect match for a classic low-grade MPNST. 4. Conclusion This is, to our knowledge, among the rare documented intracardiac MPNST cases, confirming its preferred location within left atrium and the first or second intracardiac MPNST case in a pediatric patient. It is
Please cite this article as: Sun J, et al, Primary cardiac malignant peripheral nerve sheath tumor in a 23-month-old infant, Cardiovasc Pathol (2014), http://dx.doi.org/10.1016/j.carpath.2014.03.008
J. Sun et al. / Cardiovascular Pathology xxx (2014) xxx–xxx
speculated that some of the undifferentiated sarcoma or fibrosarcoma cases of the heart reported in the early medical literature were in fact MPNST. Acknowledgments The authors want to thank Dr. Christopher Fletcher, Professor, Department of Pathology, Brigham and Women's Hospital, Harvard University, for confirming our diagnosis. References [1] D'Amato N, Correale M, Ireva R, Di Biase M. A rare cause of acute heart failure: malignant schwannoma of the pericardium. Congest Heart Fail 2010;16:82–4. [2] Pauwels P, Dal Cin P, Sciot R, et al. Primary malignant peripheral nerve sheath tumour of the heart. Histopathology 1999;34:56–9.
3
[3] Rahman M, Cook DS, Ellis G, O'Keefe PA. Malignant peripheral nerve sheath tumor of the heart. Asian Cardiovasc Thorac Ann 2006;14:425–7. [4] Cho WC, Jung SH, Lee SH, et al. Malignant peripheral nerve sheath tumor arising from the left ventricle. J Card Surg 2012;27:567–70. [5] Prifti E, Baboci A, Ikonomi M. A giant cardiac malignant peripheral nerve sheath tumor presenting with total obstruction of the superior vena cava. Ann Thorac Surg 2014;97:e7–9. [6] Isaacs H. Fetal and neonatal cardiac tumors. Pediatr Cardiol 2004;25:252–73. [7] Uzun O, Wilson DG, Vujanic GM, Parsons JM, De Giovanni JV. Cardiac tumours in children. Orphanet J Rare Dis 2007;2:11. [8] Kumar N, Agarwal S, Ahuja A, et al. Spectrum of cardiac tumors excluding myxoma: experience of a tertiary center with review of the literature. Pathol Res Pract 2011;207:769–74. [9] Simcha A, Wells BG, Tynan MJ, Waterston DJ. Primary cardiac tumours in childhood. Arch Dis Child 1971;46:508–14. [10] Weiss SW, Goldblum JR, Enzinger FM. Enzinger and Weiss' soft tissue tumors. 5th ed. Philadelphia, PA: Mosby Elsevier; 2008. [11] Halling KC, Scheithauer BW, Halling AC, et al. p53 expression in neurofibroma and malignant peripheral nerve sheath tumor. An immunohistochemical study of sporadic and NF1-associated tumors. Am J Clin Pathol 1996;106:282–8.
Please cite this article as: Sun J, et al, Primary cardiac malignant peripheral nerve sheath tumor in a 23-month-old infant, Cardiovasc Pathol (2014), http://dx.doi.org/10.1016/j.carpath.2014.03.008
Contents lists available at ScienceDirect
Cardiovascular Pathology
Case Report
Primary cardiac malignant peripheral nerve sheath tumor in a 23-month-old infant Jihong Sun, Shaoxiong Chen, Rong Fan ⁎ Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 350 W 11th St, Indianapolis, IN 46202
a r t i c l e
i n f o
Article history: Received 17 February 2014 Received in revised form 28 March 2014 Accepted 31 March 2014 Available online xxxx
a b s t r a c t We report the second case of primary cardiac malignant peripheral nerve sheath tumor in pediatric population. © 2014 Elsevier Inc. All rights reserved.
Keywords: Heart Malignant peripheral nerve sheath tumor Cardiac tumor Pediatric tumor
1. Introduction
2.1. Pathology findings
Primary cardiac malignant peripheral nerve sheath tumor (MPNST) is exceedingly rare. Excluding cases occurring in the background of neurofibromatosis Type 1 and pericardium cases, MPNST has only rarely been reported in adult patients; most arose from the left atrium, but one case was from the left ventricle; [1–4] in one most recent case, it arose in the right atrium and protruded into the right ventricle through the tricuspid valve [5].
Gross examination of the surgical specimen showed a large (4.1 cm) lobulated “lipomatous” tumor (Fig. 1A); however, the impression under the microscope was quite different, demonstrating a somewhat wavy hyperchromatic spindle cell lesion with variable cellularity. The lesion had some sort of biphasic appearance, showing higher cellularity around many slit-like vasculatures. Neither Antoni A and B zonation nor the hyaline vessels of a schwannoma were identified. A mild to moderate degree of atypia was noted, but mitotic activity was considered low (Fig. 1B, C). Immunohistochemistry workup revealed that the lesional cells were convincingly positive for S100 (Fig. 1D), GFAP, and PGP 9.5 and negative for HMB-45 and pancytokeratin. The diagnosis of low-grade MPNST was unequivocally established with further confirmation by authoritative tumor pathologists. Finally, the lesion is also extensively positive for p53, which further consolidated our diagnosis.
2. Case report Our patient, a 23-month-old previously healthy infant male with significant family history, was noticed to have generalized swelling. He was first taken to urgent care, diagnosed with bilateral otitis media, and treated with antibiotics. However, the generalized swelling persisted. An echocardiogram demonstrated a large mitral valve mass causing some degree of inflow obstruction. Intraoperatively, a multilobulated mass was filling the mitral orifice, which was based off what appeared to be the posterior mitral annulus. The mass was resected and submitted for pathological examination. Funding: This research received no specific grand from any funding agency, commercial, or not-for-profit sectors. Financial Support: This research received no specific grand from any funding agency, commercial, or not-for-profit sectors. Conflicts of Interest: None. ⁎ Corresponding author at: Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Riley Hospital for Children at IU Health, 702 Barnhill Dr, Rm 2536, Indianapolis, IN 46202-5200, USA. Tel.: +1 -317 944 2616; fax: +1 317 944 2810. E-mail address: [email protected] (R. Fan).
2.2. Followup The patient is doing well, without any signs of tumor recurrence 2 years after surgical resection of this intracardiac mass. 3. Discussion 3.1. Epidemiology The vast majority of pediatric heart tumors are benign. Different reviews concur that the most common benign entity for the location is rhabdomyoma. The second place in the ranking is debatable, either fibroma or teratoma; but, without doubt, the perinatal period
http://dx.doi.org/10.1016/j.carpath.2014.03.008 1054-8807/© 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Sun J, et al, Primary cardiac malignant peripheral nerve sheath tumor in a 23-month-old infant, Cardiovasc Pathol (2014), http://dx.doi.org/10.1016/j.carpath.2014.03.008
2
J. Sun et al. / Cardiovascular Pathology xxx (2014) xxx–xxx
Fig. 1. (A) Large (4.1cm) lobulated lipomatous tumor on gross examination; (B and C) Histologically, the spindle cell lesion showed variable cellularity featuring biphasic “marbleized” appearance, with higher cellularity around many slit-like vasculatures. The asymmetric spindle cells in the lesion were typically showing buckled nuclei. A mild to moderate degree of atypia was noted, but mitotic activity was low. (D) Immunohistochemistry workup was positive for S100.
teratoma is more common than fibroma. The other benign entities include myxoma, hemangioma, lipoma, and histiocytoid nodule, also known as Purkinje cell tumor or oncocytic cardiomyopathy [6–8]. Primary cardiac malignant tumors are uncommon, consisting of about 25% of all primary cardiac tumors, among which 75% are sarcomas. For pediatric population, only 10% of cardiac tumors are malignant, with no reliable statistics available for exact frequencies. The most common entity in this category, as in adults, is angiosarcoma. The other pediatric primary malignant heart tumors reported included rhabdomyosarcoma, ranking perhaps the second, and fibrosarcoma, lymphoma, pheochromocytoma, primitive neuroectodermal tumor, and undifferentiated sarcoma [6,7,9]. It is worth mentioning that secondary tumors (i.e., metastatic) are 10–20 times more common in pediatric hearts. Rare cases of both primary and secondary MPNSTs have been reported before, mostly in adults. To our knowledge, this is the second primary MPNST case in the pediatric population. 3.2. Location of tumor Most of cardiac sarcomas are located in the left atrium. The location of primary cardiac MPNST from the general (adult) population appears to be on the left side, while the primary cardiac rhabdomyosarcoma has no predilection site. The recent reported case, however, was located at the right side of the heart. The histology description of the case appeared to be quite typical of MPNST; however, the figure illustration in the article is not quite convincing [5]. 3.3. Diagnostic caveats Admittedly, the definite diagnosis of MPNST is difficult and often elusive, even among the experts due to lack of specific confirmatory markers and consensus of standard set of criteria. In the past, some pathologists took a more liberal approach to diagnose MPNST; some included any atypical spindle cell lesions with collagen production as MPNST. With the evolution of immunohistochemistry tools and our understanding of this entity and its close mimickers, however, the diagnosis has become more and more consistent, especially among
the top experts in the field. To diagnose MPNST, a malignant tumor arising from peripheral nerve or showing nerve sheath differentiation is required, with the exception of tumors originating from epineurium or peripheral nerve vasculature. The documented association of Von Recklinghausen disease, also known as neurofibromatosis I, is not mandatory. But if the malignant tumor arising from prior benign nerve sheath tumor is mostly neurofibroma, then the diagnosis is nearly conclusive. In addition, with advancement of immunohistochemistry techniques, it also becomes clear that fibrosarcoma is rare, and by definition S100, epithelial membrane antigen, and keratin should be completely negative, and therefore, some of the undifferentiated sarcoma or fibrosarcoma cases in the literature may actually be MPNST. On the microscopic level, according to the authoritative comments of Dr. Sharon Weiss, alternating dense and less cellular fascicles, spindle cell cells with irregular buckled nuclei, and peculiar patterns frequently encountered in Schwann cell tumors, such as nuclear palisading, vague whorled structures, curlicue arrangement of cells, and perivascular density are highly suggestive features [10]. The most effective immunohistochemical stains to document nerve sheath derivation are S100, PGP9.5, and myelin basic protein. Among these markers, the S100 stain is most widely used and should stain positive in the majority of the cases; it has the peculiarity of being patchy and less strong than various benign entities. It is also worth pointing out that this tendency persists in the different grades of MPNST; that is, low-grade MPNST has stronger S100 and more diffuse staining than high-grade MPNST. Importantly, besides atypical features, extensive p53 staining supports the diagnosis of MPNST, as this p53 immunoreactivity, a marker suggesting the malignant transition, was present in less than 5% of neurofibromas [11]. Hence, when compared with these discussed diagnostic benchmarks, our case is close to a perfect match for a classic low-grade MPNST. 4. Conclusion This is, to our knowledge, among the rare documented intracardiac MPNST cases, confirming its preferred location within left atrium and the first or second intracardiac MPNST case in a pediatric patient. It is
Please cite this article as: Sun J, et al, Primary cardiac malignant peripheral nerve sheath tumor in a 23-month-old infant, Cardiovasc Pathol (2014), http://dx.doi.org/10.1016/j.carpath.2014.03.008
J. Sun et al. / Cardiovascular Pathology xxx (2014) xxx–xxx
speculated that some of the undifferentiated sarcoma or fibrosarcoma cases of the heart reported in the early medical literature were in fact MPNST. Acknowledgments The authors want to thank Dr. Christopher Fletcher, Professor, Department of Pathology, Brigham and Women's Hospital, Harvard University, for confirming our diagnosis. References [1] D'Amato N, Correale M, Ireva R, Di Biase M. A rare cause of acute heart failure: malignant schwannoma of the pericardium. Congest Heart Fail 2010;16:82–4. [2] Pauwels P, Dal Cin P, Sciot R, et al. Primary malignant peripheral nerve sheath tumour of the heart. Histopathology 1999;34:56–9.
3
[3] Rahman M, Cook DS, Ellis G, O'Keefe PA. Malignant peripheral nerve sheath tumor of the heart. Asian Cardiovasc Thorac Ann 2006;14:425–7. [4] Cho WC, Jung SH, Lee SH, et al. Malignant peripheral nerve sheath tumor arising from the left ventricle. J Card Surg 2012;27:567–70. [5] Prifti E, Baboci A, Ikonomi M. A giant cardiac malignant peripheral nerve sheath tumor presenting with total obstruction of the superior vena cava. Ann Thorac Surg 2014;97:e7–9. [6] Isaacs H. Fetal and neonatal cardiac tumors. Pediatr Cardiol 2004;25:252–73. [7] Uzun O, Wilson DG, Vujanic GM, Parsons JM, De Giovanni JV. Cardiac tumours in children. Orphanet J Rare Dis 2007;2:11. [8] Kumar N, Agarwal S, Ahuja A, et al. Spectrum of cardiac tumors excluding myxoma: experience of a tertiary center with review of the literature. Pathol Res Pract 2011;207:769–74. [9] Simcha A, Wells BG, Tynan MJ, Waterston DJ. Primary cardiac tumours in childhood. Arch Dis Child 1971;46:508–14. [10] Weiss SW, Goldblum JR, Enzinger FM. Enzinger and Weiss' soft tissue tumors. 5th ed. Philadelphia, PA: Mosby Elsevier; 2008. [11] Halling KC, Scheithauer BW, Halling AC, et al. p53 expression in neurofibroma and malignant peripheral nerve sheath tumor. An immunohistochemical study of sporadic and NF1-associated tumors. Am J Clin Pathol 1996;106:282–8.
Please cite this article as: Sun J, et al, Primary cardiac malignant peripheral nerve sheath tumor in a 23-month-old infant, Cardiovasc Pathol (2014), http://dx.doi.org/10.1016/j.carpath.2014.03.008
