VOLUME
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2015
JOURNAL OF CLINICAL ONCOLOGY
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O N C O L O G Y
U/mL], CA19-9, 24 U/mL [normal range, 0 to 33 U/mL]) were negative. Speculum and colposcopic examinations revealed a cervical polypoid mass protruding within the vagina. This suggested a clinical diagnosis of botryoid rhabdomyosarcoma, which was corroborated by positron emission tomography– computed tomography (CT) images that demonstrated intense [18F]fluorodeoxyglucose uptake within the cervical mass (Fig 1A) in axial view and intense [18F]fluorodeoxyglucose uptake within bilateral iliac lymph nodes in the coronal view (Fig 1B). Few fragments were obtained by incisional biopsy of the mass. Histologically, the lesion consisted of a major proliferation of stellate and polygonal large cells with eosinophilic or finely
Uterine Inflammatory Myofibroblastic Tumor in a 10-Year-Old Girl Presenting As Polypoid Mass Case Report A 10-year-old girl was referred for evaluation of menorrhagia, malaise, abdominal discomfort, and pelvic pain. Her medical history was unremarkable. Tumor markers (CA-125, 8.38 U/mL [normal range, 0 to 21 U/mL], carcinoembryonic antigen, 1.74 ng/mL [normal range, 0 to 5 ng/mL], CA15-3, 17.2 U/mL [normal range, 0 to 43
A
B
C
D
Fig 1. Journal of Clinical Oncology, Vol 33, No 2 (January 10), 2015: pp e7-e10
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Harvard Libraries on April 21, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 128.103.105.244
e7
Fraggetta et al
vacuolated, foamy cytoplasm and plump, round nuclei with prominent nucleolus, embedded in a variable amount of myxoid matrix (Fig 1C). Minor, albeit clearly recognizable, components were represented by focal, fascicular proliferation of spindle cells and chronic inflammatory cells mostly consisting of small lymphocytes and plasma cells. Overall mitotic activity was scant (0 to 4 mitoses per 10 high-power fields, without atypical figures). Necrosis was absent. The cells composing the lesion were diffusely immunoreactive for vimentin, a smooth muscle actin, and anaplastic lymphoma kinase (ALK) protein. Focal immunoreactivity for desmin and cytokeratin AE1/AE3 was present as well. Immunoreactions for S-100 protein, CD34, CD31, myogenin, CD99, CD45, CD30, HMB-45, NB84, chromogranin A, CD56, synaptofisin, neuron-specific enolase, epithelial membrane antigen, and h-caldesmon were negative. Both morphologic and immunohistochemical results led to a diagnosis of inflammatory myofibroblastic tumor (IMT) with prominent epithelioid and foamy cell components. Fluorescent in situ hybridization analysis highlighted ALK translocation (Fig 1D). On the basis of the features described, a hysterectomy with pelvic lymphadenectomy was performed. Gross examination of the uterus revealed a polypoid mass measuring 8 cm in greatest diameter arising from the endocervix and protruding through the ostium into the vaginal cavity. Histologic examination of the surgical specimen confirmed the findings that were seen in the incisional biopsy. Two pelvic lymph nodes were metastatic, showing the typical fascicular pattern of IMT. Distant metastases were ruled out by a total-body CT scan. A watch-and-wait strategy without any therapy was chosen, and the patient is currently disease free after a 20-month follow-up period, as confirmed by clinical examination and a CT scan. Discussion IMT is a mesenchymal neoplasm that was originally described in the lung and previously referred to as an inflammatory pseudotumor, plasma cell granuloma, xanthomatous pseudotumor, xanthoma, or histiocytoma.1-5 Although IMT preferentially occurs in the lung, mesentery, omentum, and retroperitoneum of children, adolescents, and young adults, this neoplasm may be ubiquitous.3,6,7 Only a few other cases of IMT have been reported in the female genital tract.8-17 Because of its rarity and nonspecific symptoms, clinicians rarely recognize IMT before performing surgery or biopsy and, in addition, pathologic diagnosis is challenging as well. Notwithstanding these difficulties, a correct diagnosis is critical so that patients can be offered appropriate management and treatment. Although previously regarded as a reactive lesion,3 IMT is now considered a neoplastic process,3,7,17-23 owing in part to the identification of translocations involving the ALK receptor tyrosine kinase at chromosome 2p23, which have been detectable in approximately 50% of patients. The receptor tyrosine kinase that is encoded by the ALK gene is expressed under normal conditions only in neural tissue. Clonal abnormalities of ALK were first described in anaplastic large cell lymphoma. Several ALK fusion patterns have since been identified, including TPM3 at 1p23, TPM4 at 19p13, ATIC at 2q35, CLTC at 17q23, CARS at 11p15, RANBP2 at 2q13, and SEC31L1 at 4q21.3,17,18,22,23 Histologically, a basic feature of IMT is usually a mesenchymal spindle cell proliferation that is accompanied by reactive lymphocytic/plasmacytic infiltrate in a myxoid background.7 Three histologic patterns could variably coexist within the same tumor: myxoid/vascular, compact spindle cell, and a fibrous hypocellular pattern.3,6,7,15,21,24 Consistent with its myofibroblastic differentiation, IMT shows immunoreactivity for smooth muscle actin and, e8
© 2014 by American Society of Clinical Oncology
focally, desmin and calponin; approximately 50% of IMTs do stain for ALK. These tumors are considered neoplasms with intermediate biologic potential because of their trend toward local recurrence and a low, albeit present, risk of distant metastasis.3,7 The recurrence rate of IMT varies according to the anatomic site of development, ranging from less than 2% for lung tumors to 25% for extrapulmonary lesions.3 Distant metastases are rare, occurring in less than 5% of patients. The most common distant metastatic sites include lung and brain, followed by liver and bone.3 To date, no morphologic parameters that are predictive of aggressive behavior have been identified.3,24 An unequivocal prognostic impact played by ALK expression in IMT is questionable.3,18 In fact, some studies suggest that patients with ALK positivity have a low risk of metastasis, but ALK immunoreactivity does not seem to correlate with recurrence rates.18,24 In the patient described here, for instance, despite ALK expression, regional lymph nodes metastases were present. Histopathologic differential diagnosis varies according to the prevalence of various histologic patterns and includes sarcomatoid carcinoma, spindle cell melanoma, dedifferentiated liposarcoma, desmoid fibromatosis, nodular fasciitis, GI stromal tumor, leiomyosarcoma, rhabdomyosarcoma, and urogenital tract pseudosarcomatous spindle cell lesions.3,7,11,15,17,25 In addition, if IMT arises in an unusual site such as the female genital tract, its morphologic appearance (ie, spindle cells in a myxoid background) and immunoprofile (ie, variable staining for both epithelial and smooth muscle markers) create problems in the differential diagnosis with the relatively more common spindle cells tumors of this anatomic region, which include benign counterparts such as leiomyoma with hydropic change and myxoid leiomyoma and, on the malignant side, myxoid and inflammatory leiomyosarcoma and botryoid and spindle cell rhabdomyosarcoma. In this context, immunohistochemistry plays only a supportive role in confirming myofibroblastic differentiation of neoplastic cells, given that the available markers show variable expression and lack of specificity. ALK immunoreactivity, if present, is helpful, although its absence does not exclude the diagnosis, especially in adults, because this marker is more commonly expressed in younger patients.3,6,7,18,24 Equally important, ALK immunoreactivity has been occasionally reported to overlap in other soft tissue tumors, some of which enter into the differential diagnosis with IMT (ie, leiomyosarcoma, rhabdomyosarcoma, Ewing sarcoma, extraskeletal myxoid chondrosarcoma, benign and malignant adipocytic tumors).3,25 To date, considering only the female genital tract, ALK expression has been shown to be specific for IMT.17 Above all, only the detection of ALK gene rearrangements by fluorescent in situ hybridization may aid in distinguishing IMT from its mimics and allow a definitive diagnosis to be reached, in particular in those cases that are not immunoreactive for ALK.3,15,17 The treatment of IMT primarily involves surgery26; among more than 100 reported cases in the literature in various anatomic sites that were treated predominantly with surgical excision, recurrence ranged from 12% to 45% depending on the site and the completeness of resection.15 When excision is complete, recurrences are substantially avoided.27 Long-term follow-up is important, given that recurrent tumors have been reported as long as 11 years after resection.28 No guidelines exist for locally aggressive or recurrent forms.29 In a few cases, when IMT was not resectable (for instance, because of the patient’s status or distant metastases), nonsteroidal anti-inflammatory drugs, anti–tumor necrosis factor ␣ antibody, and corticosteroids JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at Harvard Libraries on April 21, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 128.103.105.244
Diagnosis in Oncology
have been used, with conflicting results.27,30-32 In addition, chemotherapeutic regimens including methotrexate-vinblastine followed by ifosfamide-doxorubicin, ifosfamide alone, or carboplatinpaclitaxel33,34 have been proposed, mainly in the pediatric population. An appealing approach is represented by testing ALK inhibitors in those patients with IMT who present with an aggressive form of the disease.34 A phase I dose-escalation trial of the selective MET/ALK inhibitor crizotinib showed a long-term partial response in one patient with IMT who carried an ALK translocation, although resistance to crizotinib therapy developed later, during progression of the disease.35 In cases arising within the female genital tract, IMT can be treated conservatively and have a more favorable prognosis.15 Despite the absence of necrosis, marked atypia, and a high mitotic index, our patient’s disease demonstrated a locally aggressive clinical course that was represented by the occurrence of two metastatic regional lymph nodes. This feature, in light of the 20 months of follow-up, during which a watch-and-wait approach has been used, suggests that IMT may require strict follow-up rather than immediate treatment. Accordingly, oncologists should be aware of the fact that IMT may occur, albeit rarely, in the genital tract of young females, to avoid a misdiagnosis of full-blown malignancy and, most importantly, to guarantee both proper therapeutic decisions and an accurate prognosis.
Filippo Fraggetta Cannizzaro Hospital, Catania, Italy
Claudio Doglioni San Raffaele Scientific Institute, Milano, Italy
Paolo Scollo Cannizzaro Hospital, Catania, Italy
Lorenza Pecciarini San Raffaele Scientific Institute, Milano, Italy
Massimo Ippolito Cannizzaro Hospital, Catania, Italy
Paolo Amico Umberto I Hospital, Enna, Italy
Giuseppe Pelosi National Cancer Institute, Milano, Italy
Maurilio Ponzoni San Raffaele Scientific Institute, Milano, Italy
ACKNOWLEDGMENT
F.F. and C.D. contributed equally to this article. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Bahadori M, Liebow AA: Plasma cell granulomas of the lung. Cancer 31:191-208, 1973 2. Corrin B: Pathology of the Lungs. London, United Kingdom, Churchill Livingstone, 2000, pp 587-590 3. Gleason BC, Hornick JL: Inflammatory myofibroblastic tumours: Where are we now? J Clin Pathol 61:428-437, 2008 4. Janik JS, Janik JP, Lovell MA, et al: Recurrent inflammatory pseudotumors in children. J Pediatr Surg 38:1491-1495, 2003 5. Wu JP, Yunis EJ, Fetterman G, et al: Inflammatory pseudo-tumours of the abdomen: Plasma cell granulomas. J Clin Pathol 26:943-948, 1973 www.jco.org
6. Coffin CM, Watterson J, Priest JR, et al: Extrapulmonary inflammatory myofibroblastic tumor (inflammatory pseudotumor): A clinicopathologic and immunohistochemical study of 84 cases. Am J Surg Pathol 19:859-872, 1995 7. Coffin CM, Fletcher JA: Inflammatory myofibroblastic tumor, in Fletcher CD, Unni KK, Mertens F (eds): World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon, France, IARC Press, 2002, pp 91-93 8. Abenoza P, Shek YH, Perrone T: Inflammatory pseudotumor of the cervix. Int J Gynecol Pathol 13:80-86, 1994 9. Azuno Y, Yaga K, Suehiro Y, et al: Inflammatory myoblastic tumor of the uterus and interleukin-6. Am J Obstet Gynecol 189:890-891, 2003 10. Gu¨cer F, Altaner S, Mu¨layim N, et al: Invasive inflammatory pseudotumor of uterine cervix: A case report. Gynecol Oncol 98:325-328, 2005 11. Gupta N, Mittal S, Misra R: Inflammatory pseudotumor of uterus: An unusual pelvic mass. Eur J Obstet Gynecol Reprod Biol 156:118-119, 2011 12. Kargi HA, Ozer E, Gokden N: Inflammatory pseudotumor of the uterus: A case report. Tumori 81:454-456, 1995 13. Olgan S, Saatli B, Okyay RE, et al: Hysteroscopic excision of inflammatory myofibroblastic tumor of the uterus: A case report and brief review. Eur J Obstet Gynecol Reprod Biol 157:234-236, 2011 14. Shintaku M, Fukushima A: Inflammatory myofibroblastic tumor of the uterus with prominent myxoid change. Pathol Int 56:625-628, 2006 15. Rabban JT, Zaloudek CJ, Shekitka KM, et al: Inflammatory myofibroblastic tumor of the uterus: A clinicopathologic study of 6 cases emphasizing distinction from aggressive mesenchymal tumors. Am J Surg Pathol 29:13481355, 2005 16. Gilks CB, Taylor GP, Clement PB: Inflammatory pseudotumor of the uterus. Int J Gynecol Pathol 6:275-286, 1987 17. Fuehrer NE, Keeney GL, Ketterling RP, et al: ALK-1 protein expression and ALK gene rearrangements aid in the diagnosis of inflammatory myofibroblastic tumors of the female genital tract. Arch Pathol Lab Med 136:623-626, 2012 18. Coffin CM, Patel A, Perkins S, et al: ALK1 and p80 expression and chromosomal rearrangements involving 2p23 in inflammatory myofibroblastic tumor. Mod Pathol 14:569-576, 2001 19. Cook JR, Dehner LP, Collins MH, et al: Anaplastic lymphoma kinase (ALK) expression in the inflammatory myofibroblastic tumor: A comparative immunohistochemical study. Am J Surg Pathol 25:1364-1371, 2001 20. Griffin CA, Hawkins AL, Dvorak C, et al: Recurrent involvement of 2p23 in inflammatory myofibroblastic tumors. Cancer Res 59:2776-2780, 1999 21. Hussong JW, Brown M, Perkins SL, et al: Comparison of DNA ploidy, histologic, and immunohistochemical findings with clinical outcome in inflammatory myofibroblastic tumors. Mod Pathol 12:279-286, 1999 22. Li XQ, Hisaoka M, Shi DR, et al: Expression of anaplastic lymphoma kinase in soft tissue tumors: An immunohistochemical and molecular study of 249 cases. Hum Pathol 35:711-721, 2004 23. Lawrence B, Perez-Atayde A, Hibbard MK, et al: TPM3-ALK and TPM4-ALK oncogenes in inflammatory myofibroblastic tumors. Am J Pathol 157:377-384, 2000 24. Coffin CM, Hornick JL, Fletcher CD: Inflammatory myofibroblastic tumor: Comparison of clinicopathologic, histologic, and immunohistochemical features including ALK expression in atypical and aggressive cases. Am J Surg Pathol 31:509-520, 2007 25. Brooks SE, Zhan M, Cote T: Surveillance, epidemiology, and end results analysis of 2677 cases of uterine sarcoma 1989-1999. Gynecol Oncol 93:204208, 2004 26. Fabre D, Fadel E, Singhal S, et al: Complete resection of pulmonary inflammatory pseudotumors has excellent long-term prognosis. J Thorac Cardiovasc Surg 137:435-440, 2009 27. Bertocchini A, Lo Zupone C, Callea F, et al: Unresectable multifocal omental and peritoneal inflammatory myofibroblastic tumor in a child: Revisiting the role of adjuvant therapy. J Pediatr Surg 46:e17-e21, 2011 28. Weinberg PB, Bromberg PA, Askin FB: “Recurrence” of a plasma cell granuloma 11 years after initial resection. South Med J 80:519-521, 1987 29. Karnak I, Senocak ME, Ciftci AO, et al: Inflammatory myofibroblastic tumor in children: Diagnosis and treatment. J Pediatr Surg 36:908-912, 2001 30. Applebaum H, Kieran MW, Cripe TP, et al: The rationale for nonsteroidal anti-inflammatory drug therapy for inflammatory myofibroblastic tumors: A Children’s Oncology Group study. J Pediatr Surg 40:999-1003, 2005 31. Lee MH, Lee HB, Lee YC, et al: Bilateral multiple inflammatory myofibroblastic tumors of the lung successfully treated with corticosteroids. Lung 189:433-435, 2011 32. Schaeffer CJ, Minai OA, Sharma N, et al: Inflammatory myofibroblastic tumor of the lung: Recurrence after steroid treatment. J Thorac Imaging
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Harvard Libraries on April 21, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 128.103.105.244
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23:191-193, 2008 33. Kubo N, Harada T, Anai S, et al: Carboplatin plus paclitaxel in the successful treatment of advanced inflammatory myofibroblastic tumor. Intern Med 51:23992401, 2012 34. Tothova Z, Wagner AJ: Anaplastic lymphoma kinase-directed therapy in inflammatory myofibroblastic tumors. Curr Opin Oncol 24:409-413, 2012
35. Butrynski JE, D’Adamo DR, Hornick JL, et al: Crizotinib in ALKrearranged inflammatory myofibroblastic tumor. N Engl J Med 363:17271733, 2010
DOI: 10.1200/JCO.2013.48.8304; published online ahead of print at www.jco.org on March 3, 2014
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33
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U/mL], CA19-9, 24 U/mL [normal range, 0 to 33 U/mL]) were negative. Speculum and colposcopic examinations revealed a cervical polypoid mass protruding within the vagina. This suggested a clinical diagnosis of botryoid rhabdomyosarcoma, which was corroborated by positron emission tomography– computed tomography (CT) images that demonstrated intense [18F]fluorodeoxyglucose uptake within the cervical mass (Fig 1A) in axial view and intense [18F]fluorodeoxyglucose uptake within bilateral iliac lymph nodes in the coronal view (Fig 1B). Few fragments were obtained by incisional biopsy of the mass. Histologically, the lesion consisted of a major proliferation of stellate and polygonal large cells with eosinophilic or finely
Uterine Inflammatory Myofibroblastic Tumor in a 10-Year-Old Girl Presenting As Polypoid Mass Case Report A 10-year-old girl was referred for evaluation of menorrhagia, malaise, abdominal discomfort, and pelvic pain. Her medical history was unremarkable. Tumor markers (CA-125, 8.38 U/mL [normal range, 0 to 21 U/mL], carcinoembryonic antigen, 1.74 ng/mL [normal range, 0 to 5 ng/mL], CA15-3, 17.2 U/mL [normal range, 0 to 43
A
B
C
D
Fig 1. Journal of Clinical Oncology, Vol 33, No 2 (January 10), 2015: pp e7-e10
© 2014 by American Society of Clinical Oncology
Information downloaded from jco.ascopubs.org and provided by at Harvard Libraries on April 21, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 128.103.105.244
e7
Fraggetta et al
vacuolated, foamy cytoplasm and plump, round nuclei with prominent nucleolus, embedded in a variable amount of myxoid matrix (Fig 1C). Minor, albeit clearly recognizable, components were represented by focal, fascicular proliferation of spindle cells and chronic inflammatory cells mostly consisting of small lymphocytes and plasma cells. Overall mitotic activity was scant (0 to 4 mitoses per 10 high-power fields, without atypical figures). Necrosis was absent. The cells composing the lesion were diffusely immunoreactive for vimentin, a smooth muscle actin, and anaplastic lymphoma kinase (ALK) protein. Focal immunoreactivity for desmin and cytokeratin AE1/AE3 was present as well. Immunoreactions for S-100 protein, CD34, CD31, myogenin, CD99, CD45, CD30, HMB-45, NB84, chromogranin A, CD56, synaptofisin, neuron-specific enolase, epithelial membrane antigen, and h-caldesmon were negative. Both morphologic and immunohistochemical results led to a diagnosis of inflammatory myofibroblastic tumor (IMT) with prominent epithelioid and foamy cell components. Fluorescent in situ hybridization analysis highlighted ALK translocation (Fig 1D). On the basis of the features described, a hysterectomy with pelvic lymphadenectomy was performed. Gross examination of the uterus revealed a polypoid mass measuring 8 cm in greatest diameter arising from the endocervix and protruding through the ostium into the vaginal cavity. Histologic examination of the surgical specimen confirmed the findings that were seen in the incisional biopsy. Two pelvic lymph nodes were metastatic, showing the typical fascicular pattern of IMT. Distant metastases were ruled out by a total-body CT scan. A watch-and-wait strategy without any therapy was chosen, and the patient is currently disease free after a 20-month follow-up period, as confirmed by clinical examination and a CT scan. Discussion IMT is a mesenchymal neoplasm that was originally described in the lung and previously referred to as an inflammatory pseudotumor, plasma cell granuloma, xanthomatous pseudotumor, xanthoma, or histiocytoma.1-5 Although IMT preferentially occurs in the lung, mesentery, omentum, and retroperitoneum of children, adolescents, and young adults, this neoplasm may be ubiquitous.3,6,7 Only a few other cases of IMT have been reported in the female genital tract.8-17 Because of its rarity and nonspecific symptoms, clinicians rarely recognize IMT before performing surgery or biopsy and, in addition, pathologic diagnosis is challenging as well. Notwithstanding these difficulties, a correct diagnosis is critical so that patients can be offered appropriate management and treatment. Although previously regarded as a reactive lesion,3 IMT is now considered a neoplastic process,3,7,17-23 owing in part to the identification of translocations involving the ALK receptor tyrosine kinase at chromosome 2p23, which have been detectable in approximately 50% of patients. The receptor tyrosine kinase that is encoded by the ALK gene is expressed under normal conditions only in neural tissue. Clonal abnormalities of ALK were first described in anaplastic large cell lymphoma. Several ALK fusion patterns have since been identified, including TPM3 at 1p23, TPM4 at 19p13, ATIC at 2q35, CLTC at 17q23, CARS at 11p15, RANBP2 at 2q13, and SEC31L1 at 4q21.3,17,18,22,23 Histologically, a basic feature of IMT is usually a mesenchymal spindle cell proliferation that is accompanied by reactive lymphocytic/plasmacytic infiltrate in a myxoid background.7 Three histologic patterns could variably coexist within the same tumor: myxoid/vascular, compact spindle cell, and a fibrous hypocellular pattern.3,6,7,15,21,24 Consistent with its myofibroblastic differentiation, IMT shows immunoreactivity for smooth muscle actin and, e8
© 2014 by American Society of Clinical Oncology
focally, desmin and calponin; approximately 50% of IMTs do stain for ALK. These tumors are considered neoplasms with intermediate biologic potential because of their trend toward local recurrence and a low, albeit present, risk of distant metastasis.3,7 The recurrence rate of IMT varies according to the anatomic site of development, ranging from less than 2% for lung tumors to 25% for extrapulmonary lesions.3 Distant metastases are rare, occurring in less than 5% of patients. The most common distant metastatic sites include lung and brain, followed by liver and bone.3 To date, no morphologic parameters that are predictive of aggressive behavior have been identified.3,24 An unequivocal prognostic impact played by ALK expression in IMT is questionable.3,18 In fact, some studies suggest that patients with ALK positivity have a low risk of metastasis, but ALK immunoreactivity does not seem to correlate with recurrence rates.18,24 In the patient described here, for instance, despite ALK expression, regional lymph nodes metastases were present. Histopathologic differential diagnosis varies according to the prevalence of various histologic patterns and includes sarcomatoid carcinoma, spindle cell melanoma, dedifferentiated liposarcoma, desmoid fibromatosis, nodular fasciitis, GI stromal tumor, leiomyosarcoma, rhabdomyosarcoma, and urogenital tract pseudosarcomatous spindle cell lesions.3,7,11,15,17,25 In addition, if IMT arises in an unusual site such as the female genital tract, its morphologic appearance (ie, spindle cells in a myxoid background) and immunoprofile (ie, variable staining for both epithelial and smooth muscle markers) create problems in the differential diagnosis with the relatively more common spindle cells tumors of this anatomic region, which include benign counterparts such as leiomyoma with hydropic change and myxoid leiomyoma and, on the malignant side, myxoid and inflammatory leiomyosarcoma and botryoid and spindle cell rhabdomyosarcoma. In this context, immunohistochemistry plays only a supportive role in confirming myofibroblastic differentiation of neoplastic cells, given that the available markers show variable expression and lack of specificity. ALK immunoreactivity, if present, is helpful, although its absence does not exclude the diagnosis, especially in adults, because this marker is more commonly expressed in younger patients.3,6,7,18,24 Equally important, ALK immunoreactivity has been occasionally reported to overlap in other soft tissue tumors, some of which enter into the differential diagnosis with IMT (ie, leiomyosarcoma, rhabdomyosarcoma, Ewing sarcoma, extraskeletal myxoid chondrosarcoma, benign and malignant adipocytic tumors).3,25 To date, considering only the female genital tract, ALK expression has been shown to be specific for IMT.17 Above all, only the detection of ALK gene rearrangements by fluorescent in situ hybridization may aid in distinguishing IMT from its mimics and allow a definitive diagnosis to be reached, in particular in those cases that are not immunoreactive for ALK.3,15,17 The treatment of IMT primarily involves surgery26; among more than 100 reported cases in the literature in various anatomic sites that were treated predominantly with surgical excision, recurrence ranged from 12% to 45% depending on the site and the completeness of resection.15 When excision is complete, recurrences are substantially avoided.27 Long-term follow-up is important, given that recurrent tumors have been reported as long as 11 years after resection.28 No guidelines exist for locally aggressive or recurrent forms.29 In a few cases, when IMT was not resectable (for instance, because of the patient’s status or distant metastases), nonsteroidal anti-inflammatory drugs, anti–tumor necrosis factor ␣ antibody, and corticosteroids JOURNAL OF CLINICAL ONCOLOGY
Information downloaded from jco.ascopubs.org and provided by at Harvard Libraries on April 21, 2015 from Copyright © 2015 American Society of Clinical Oncology. All rights reserved. 128.103.105.244
Diagnosis in Oncology
have been used, with conflicting results.27,30-32 In addition, chemotherapeutic regimens including methotrexate-vinblastine followed by ifosfamide-doxorubicin, ifosfamide alone, or carboplatinpaclitaxel33,34 have been proposed, mainly in the pediatric population. An appealing approach is represented by testing ALK inhibitors in those patients with IMT who present with an aggressive form of the disease.34 A phase I dose-escalation trial of the selective MET/ALK inhibitor crizotinib showed a long-term partial response in one patient with IMT who carried an ALK translocation, although resistance to crizotinib therapy developed later, during progression of the disease.35 In cases arising within the female genital tract, IMT can be treated conservatively and have a more favorable prognosis.15 Despite the absence of necrosis, marked atypia, and a high mitotic index, our patient’s disease demonstrated a locally aggressive clinical course that was represented by the occurrence of two metastatic regional lymph nodes. This feature, in light of the 20 months of follow-up, during which a watch-and-wait approach has been used, suggests that IMT may require strict follow-up rather than immediate treatment. Accordingly, oncologists should be aware of the fact that IMT may occur, albeit rarely, in the genital tract of young females, to avoid a misdiagnosis of full-blown malignancy and, most importantly, to guarantee both proper therapeutic decisions and an accurate prognosis.
Filippo Fraggetta Cannizzaro Hospital, Catania, Italy
Claudio Doglioni San Raffaele Scientific Institute, Milano, Italy
Paolo Scollo Cannizzaro Hospital, Catania, Italy
Lorenza Pecciarini San Raffaele Scientific Institute, Milano, Italy
Massimo Ippolito Cannizzaro Hospital, Catania, Italy
Paolo Amico Umberto I Hospital, Enna, Italy
Giuseppe Pelosi National Cancer Institute, Milano, Italy
Maurilio Ponzoni San Raffaele Scientific Institute, Milano, Italy
ACKNOWLEDGMENT
F.F. and C.D. contributed equally to this article. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest. REFERENCES 1. Bahadori M, Liebow AA: Plasma cell granulomas of the lung. Cancer 31:191-208, 1973 2. Corrin B: Pathology of the Lungs. London, United Kingdom, Churchill Livingstone, 2000, pp 587-590 3. Gleason BC, Hornick JL: Inflammatory myofibroblastic tumours: Where are we now? J Clin Pathol 61:428-437, 2008 4. Janik JS, Janik JP, Lovell MA, et al: Recurrent inflammatory pseudotumors in children. J Pediatr Surg 38:1491-1495, 2003 5. Wu JP, Yunis EJ, Fetterman G, et al: Inflammatory pseudo-tumours of the abdomen: Plasma cell granulomas. J Clin Pathol 26:943-948, 1973 www.jco.org
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DOI: 10.1200/JCO.2013.48.8304; published online ahead of print at www.jco.org on March 3, 2014
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