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Year : 2015  |  Volume : 58  |  Issue : 4  |  Page : 509-512
Anaplastic lymphoma kinase-positive pulmonary inflammatory myofibroblastic tumor with sarcomatous morphology and distant metastases: An unusual histomorphology and behavior

1 Department of Pathology, Tata Memorial Centre, Mumbai, Maharashtra, India
2 Sri Venkateswara Medical Colleges, Tirupati, Andhra Pradesh, India

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Date of Web Publication4-Nov-2015


Inflammatory myofibroblastic tumor (IMT), an intermediate-grade neoplasm of myofibroblastic/fibroblastic differentiation, occurs commonly in children and young adults. It is characterized by anaplastic lymphoma kinase (ALK) gene rearrangement and overexpression of ALK-protein. However, aggressive behavior is more commonly associated with ALK-negativity rather than ALK-positivity. Pulmonary involvement is most common visceral location and carries minimal potential for distant metastasis. We present a case of 49-year-old female with pulmonary IMT of spindle cell sarcomatous histomorphology. Frequent mitoses and necrosis with characteristic cytoplasmic immunoreactivity for ALK-1 protein and ALK-gene rearrangement on fluorescence in-situ hybridization were noted. This case is unusual for occurrence in higher age-group of fifth decade, sarcomatous histomorphology at presentation (rather than transformation) and metastases to distant sites despite ALK-protein overexpression and gene rearrangement.

Keywords: Anaplastic lymphoma kinase gene, anaplastic lymphoma kinase-protein, crizotinib, fluorescence in-situ hybridization, inflammatory myofibroblastic sarcoma

How to cite this article:
Sethi B, Pai T, Allam A, Epari S. Anaplastic lymphoma kinase-positive pulmonary inflammatory myofibroblastic tumor with sarcomatous morphology and distant metastases: An unusual histomorphology and behavior. Indian J Pathol Microbiol 2015;58:509-12

How to cite this URL:
Sethi B, Pai T, Allam A, Epari S. Anaplastic lymphoma kinase-positive pulmonary inflammatory myofibroblastic tumor with sarcomatous morphology and distant metastases: An unusual histomorphology and behavior. Indian J Pathol Microbiol [serial online] 2015 [cited 2022 Jul 7];58:509-12. Available from: https://www.ijpmonline.org/text.asp?2015/58/4/509/168866

   Introduction Top

Inflammatory myofibroblastic tumors (IMTs) are intermediate-grade histologically diverse soft tissue tumors of fibroblastic/myofibroblastic differentiation.[1] Recurrence-rate varies from 2% for pulmonary to 25% for extrapulmonary lesions with very rare distant metastasis.[2] Though the incidence of pulmonary IMT (pIMT) is reported to be 0.04-1% of all pulmonary neoplasms, it is the most common site of occurrence.[3] IMTs have shown overexpression of anaplastic lymphoma kinase (ALK)-protein secondary to ALK-gene (2p23) rearrangement in 50-60% cases.[1] We present an unusual case of pIMT in 49-year-old female with sarcomatous histomorphology, ALK-gene rearrangement, and protein-overexpression with distant metastases.

   Case Report Top

A 49-year-old female, on investigation for persistent cough for 2 months and weight loss during this period with no documentation of hemoptysis, detected to have a radiopaque mass near the left lung hilar region on chest-X-ray. Computed tomography (CT) scan (using 70 ml optiray 350 mg) showed a well-defined hypodense mass measuring 3.8 cm × 3.7 cm × 3.0 cm, which revealed active disease (max-SUV 12.9) on F18-Fluorodeoxyglucose positron-emission-tomography-CT (PET-CT) [Figure 1]a. Rest of the lung parenchyma, pleura, and abdominopelvic organs were normal.
Figure 1: Positron-emission-tomography-computed tomography (a) Depicting active mass in left lower lobe. Photomicrographs (H and E, b-f) Spindle-cell-neoplasm with pushing-margins, geographic-necrosis (black-arrow) (b, ×40), Entrapped native-alveoli at periphery (c, ×100), Sheeting and storiform architectures (d, ×200), Admixed eosinophils (e, ×400), pleomorphism and mitoses (f, ×400)

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Left-lower lung lobectomy with hilar lymphadenectomy was done, which revealed a well-defined, gray-white, soft-firm mass measuring 4 cm × 4 cm × 3.5 cm in the lung parenchyma, near hilum. Microscopy showed a spindle cell neoplasm with interspersed geographic areas of necrosis and few entrapped-distorted alveoli at the periphery [Figure 1]b and [Figure 1]c. The spindle-shaped tumor cells were arranged in sheets with focal fascicular and storiform architectures [Figure 1]d, had plump elongated nuclei with occasional pleomorphic-bizarre forms. No unequivocal epithelioid morphology identified. Admixed neutrophils, eosinophils, and lymphocytes (at places forming microabscesses) were noted [Figure 1]e. However, plasma cells were notably inconspicuous. Frequent mitoses (20-25/10 high-power-fields in highest proliferating-areas) with rare atypical-forms noted [Figure 1]f. On immunohistochemistry (IHC), the tumor was positive for vimentin (Dako-V9;1:600 dilution), ALK-1 (Dako-ALK1;1:100), and p53 protein (Dako-DO7;1:400) [Figure 2]a and [Figure 2]b, and negative for pancytokeratin (Dako-MNF116;1:300), p63 (Biocare medical-BC4A4;1:250), smooth muscle actin (SMA) (Dako-1A4;1:1200), S100-protein (Dako-polyclonal;1:1800) [Figure 2]c,[Figure 2]d,[Figure 2]e, h-caldesmon (Dako-h.CD;1:200), CD117 (Dako-polyclonal;1:1000), CD34 (Dako-QBEnd10;1:200), CD21 (Dako-1F8;1:40), and CD23 (Leica-1B12;1:400). Interphase-fluorescence in-situ hybridization analysis using Vysis Locus Specific Identifiable ALK dual-color break-apart-probe demonstrated split-signals in approximately 25-30% tumor cells suggesting ALK-gene rearrangement [Figure 2]f. Thus, the diagnosis of ALK-positive IMT with sarcomatous morphology was made. Bronchial and hilar blood vessels cut margins, and four hilar lymph nodes were all free of tumor. Postoperative period was uneventful.{Figure 1}
Figure 2: Immunohistochemistry photomicrographs showing cytoplasmic immunoreactivity for anaplastic lymphoma kinase (ALK)-1 (a, ×400), Focal immunoreactivity for p53 (b, ×400), Immunonegativity for smooth muscle actin (c, ×200), S-100-protein (d, ×400), And p63 (e, ×200) And ALK-1 gene rearrangement in the form of split signals on interphase-fluorescence in-situ hybridization with dual-color break-apart-probe (f, ×1000)

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After 4-month, CT-scan thorax and abdomen were done for the complaints of chest pain, which showed pleural thickening with minimal pleural effusion and metastasis in the right anterior-end of third-rib and right adrenal gland [Figure 3]a,[Figure 3]b [Figure 3]c. Biopsy from these lesions, histologically confirmed the metastases [Figure 3]d. The patient was treated with crizotinib (ALK-inhibitor) and had a clinico-radiological response for 6-month with the subsequent reappearance of symptoms and CT-enhanced lesions [Figure 3]e and [Figure 3]f. PET-CT also revealed hypermetabolic left pleural-based (maximum standardized uptake value [max-SUV 21.28]), right adrenal (max-SUV 32.04), right chest wall (max-SUV 7.2), and left-lateral abdominal wall lesions (max-SUV 17). She is presently on doxorubicin and ifosfamide.
Figure 3: Representative computed tomography (CT) contrast images of pleural-based recurrences (a) Right chest wall (b) And adrenal metastases (c) Histology (d, H, and E, ×40) Showing needle tissue cores comprising spindle cells and inflammatory cells (d-inset; H and E, ×400). 6-month post crizotinib contrast-CT showing enhancing left-lung (e) And right adrenal (f) Deposits

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   Discussion Top

Inflammatory myofibroblastic tumors are intermediate-grade neoplasms of myofibroblastic/fibroblastic differentiation in the current World Health Organization histological classification of soft tissue tumors.[1] They can locally recur but rarely metastasize and can also occur in viscera-more commonly in the lung, orbit, retroperitoneum or abdominopelvic region.[1] pIMTs are known to occur commonly in children and young adults, with few exceptions.[3],[4],[5] In contrast to extrapulmonary sites, pIMTs are usually slow growing and present with symptoms such as cough, dyspnea, chest pain, hemoptysis, fever, weight loss, clubbing and/or fatigue.[3] On the contrary, the present case is a pIMT presented in a fifth decade with cough and weight loss without any documented hemoptysis.

Inflammatory myofibroblastic tumors have diverse histomorphology with myofibroblastic/fibroblastic immunoprofile and distinctive 2p23 chromosomal alterations. Histologically, they show admixture of mixed inflammatory cells, histiocytes, and fibroblasts, in various proportions in three described patterns-spindled, fibroblastic-myofibroblastic, and inflammatory-cells' type. Cyto-nuclear pleomorphism, necrosis, and mitoses are uncommon.[1] Occasionally, ganglion-like cells, epithelioid/round cell or sarcomatous morphology have been observed.[1],[2],[6],[7] None of the histological features are known to correlate with biological behavior.[1] The present case was of spindled-sarcomatous morphology with no significant plasma cells. And more interestingly, the case under discussion had the biological behavior of a high-grade sarcoma akin to the histomorphological features, which was not considered to be of any prognostic relevance in IMTs.

On IHC, IMTs may show variable positivity for SMA, desmin, CD30, CD68, and keratin with negativity for epithelial membrane antigen, caldesmon, CD117, CD1a, CD23, CD21, CD34, S-100 protein, and myogenin.[1],[7],[8] Cytoplasmic ALK-protein positivity has been detected in 50-60% of cases and correlates with the presence of ALK-gene rearrangement-the diagnostic feature of IMTs.[1] ALK-rearrangements are associated with younger age and indolent behavior. Several fusion gene partners including ATIC, CARS, TPM3, TMP4, TPM3, and TPM4, CLTC, RANBP2, and SEC31 L have been identified.[2] Corresponding chimeric proteins result in distinct immunostaining patterns due to distinct subcellular location. Local recurrence was reported in IMTs irrespective of ALK-alterations however the distant metastases were predominantly reported in ALK-negative cases.[1] RANBP2-ALK fusion (commonly in extra pIMTs) is known to have aggressive behavior and usually show nuclear-membrane/perinuclear immunoreactivity, which is unlikely in the present case, as ALK immunostaining was cytoplasmic.[2],[3],[6]

In the present case, the histological differentials of pleomorphic undifferentiated sarcoma (malignant fibrous histiocytoma), sarcomatoid carcinoma, dendritic cell sarcoma, leiomyosarcoma, rhabdomyosarcoma, gastrointestinal stromal tumor, neural, and fibrohistiocytic tumors were excluded due to characteristic ALK-protein overexpression on IHC and negativity for the other relevant markers. ALK-1 positivity has been detected in >50% cases of IMT and has not been demonstrated in any other sarcomas.[7]

To the best of authors' knowledge, this case is only the second report of metastasizing de novo sarcomatous pIMT with a vivid illustration of ALK-gene rearrangement occurring in the middle age-group. The only other reported case of metastasizing ALK-positive pIMT was by Moon et al. in 47-year-old male, but without documentation of genetic alteration.[9] Rest of the reports of aggressive PIMTs were in younger age group and/or were ALK-negative.[3],[4],[5] This case challenges the accepted belief of relative indolent behavior of ALK-positive IMTs, and also demonstrates the occurrence of ALK-gene alterations and distant metastases with high-grade histomorphology. Thus, raising a question about the need for histological grading of IMTs and possibly to classify these sarcomatous tumors as "inflammatory myofibroblastic sarcomas," rather than only tumors; however, these findings need to substantiate in a larger series.

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Conflicts of interest

There are no conflicts of interest.

   References Top

Coffin CM, Fletcher JA. Inflammatory myofibroblastic tumor. In: Fletcher CD, Bridge JA, Hogendoorn PC, Mertens F, editors. WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon: IARC; 2013. p. 83-4.  Back to cited text no. 1
Li J, Yin WH, Takeuchi K, Guan H, Huang YH, Chan JK. Inflammatory myofibroblastic tumor with RANBP2 and ALK gene rearrangement: A report of two cases and literature review. Diagn Pathol 2013;8:147.  Back to cited text no. 2
Carillo C, Anile M, De Giacomo T, Venuta F. Bilateral simultaneous inflammatory myofibroblastic tumor of the lung with distant metastatic spread. Interact Cardiovasc Thorac Surg 2011;13:246-7.  Back to cited text no. 3
Melloni G, Carretta A, Ciriaco P, Arrigoni G, Fieschi S, Rizzo N, et al. Inflammatory pseudotumor of the lung in adults. Ann Thorac Surg 2005;79:426-32.  Back to cited text no. 4
Gallego L, Santamarta TR, Blanco V, García-Consuegra L, Cutilli T, Junquera L. Inflammatory myofibroblastic tumor of the lung and the maxillary region: A benign lesion with aggressive behavior. Case Rep Dent 2013;2013:879792.  Back to cited text no. 5
Mariño-Enríquez A, Wang WL, Roy A, Lopez-Terrada D, Lazar AJ, Fletcher CD, et al. Epithelioid inflammatory myofibroblastic sarcoma: An aggressive intra-abdominal variant of inflammatory myofibroblastic tumor with nuclear membrane or perinuclear ALK. Am J Surg Pathol 2011;35:135-44.  Back to cited text no. 6
Sukov WR, Cheville JC, Carlson AW, Shearer BM, Piatigorsky EJ, Grogg KL, et al. Utility of ALK-1 protein expression and ALK rearrangements in distinguishing inflammatory myofibroblastic tumor from malignant spindle cell lesions of the urinary bladder. Mod Pathol 2007;20:592-603.  Back to cited text no. 7
Jacob SV, Reith JD, Kojima AY, Williams WD, Liu C, Vila Duckworth L. An unusual case of systemic inflammatory myofibroblastic tumor with successful treatment with ALK-inhibitor. Case Rep Pathol 2014;2014:470340.  Back to cited text no. 8
Moon CH, Yoon JH, Kang GW, Lee SH, Baek JS, Kim SY, et al. A case of recurrent pulmonary inflammatory myofibroblastic tumor with aggressive metastasis after complete resection. Tuberc Respir Dis (Seoul) 2013;75:165-9.  Back to cited text no. 9

Correspondence Address:
Dr. Sridhar Epari
Department of Pathology, Tata Memorial Centre, Mumbai, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.168866

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