Clinicopathological features of atypical lipomatous tumors of the laryngopharynx

Clinicopathological features of atypical lipomatous tumors of the laryngopharynx 1 first-author †E-mail:shihuaiyin@sina.com †E-mail:shihuaiyin@sina.com shihuaiyin@sina.com 1 2 1 Department of Pathology, Chinese PLA General Hospital, Beijing 100853, China Department of Pathology, Chinese PLA General Hospital, Beijing 100853, China Department of Otorhinolaryngology, Chinese PLA General Hospital, Beijing 100853, China Department of Otorhinolaryngology, Chinese PLA General Hospital, Beijing 100853, China Atypical lipomatous tumor (ALT) of the laryngopharynx is rare. Here we report five cases to demonstrate their clinicopathological features. The patients were four males and one female, aged 41 to 69 years (median 53.6 years). All tumors (two in the hypopharynx and three in the larynx) presented as a slowly growing, painless mass. Symptoms included dysphagia (2/5), dysphonia (3/5), and the feeling of a foreign body in the throat (5/5). Tumors were well circumscribed or focally infiltrative, ranging from 2.0 to 5.0 cm (median, 3.4 cm) in size, and microscopically showed the typical features of lipoma-like ALT. Immunohistochemically, tumor cells were stained with S-100, vimentin, murine double minute 2 (MDM-2), and cyclin-dependent kinase 4 (CDK4). Two patients had local tumor recurrences at 6 and 14 months after initial surgery during follow-up. ALT of laryngopharynx is an indolent tumor. Immunohistochemical staining for MDM-2 and CDK4 is helpful in pathological diagnosis. Atypical lipomatous tumor (ALT) Laryngopharynx Immunohistochemistry Introduction 1 Liposarcoma is a malignancy of adipocytic cells that occurs mostly in limbs and retroperitoneum. Liposarcoma is classified into four subtypes according to the World Health Organization (WHO) classification of soft tissue tumors (Fletcher et al., 2002 2002 ), including atypical lipomatous tumor (ALT)/well-differentiated liposarcoma, myxoid/round cell liposarcoma, dedifferentiated liposarcoma, and pleomorphic liposarcoma. ALTs are those well-differentiated liposarcomas located in the superficial parts of the body, and bear a favorable prognosis if completely excised (Fletcher et al., 2002 2002 ). The proportion of ALT among all liposarcomas is about 40%–45%, and ALTs are further subclassified into three variants, namely the lipoma-like, sclerosing, inflammatory, and spindle cell variants. Liposarcoma of the laryngopharynx is very rare (Wenig et al., 1990 1990 ; Wenig and Heffner, 1995 1995 ; Wambeek and Mendelson, 1996 1996 ; Fahmy et al., 1998 1998 ; Mestre de Juan and Fernández-Aceñero, 1999 1999 ; Mouret, 1999 1999 ; Brauchle et al., 2001 2001 ; Lippert et al., 2002 2002 ; Powitzky et al., 2007 2007 ; Luna-Ortiz et al., 2009 2009 ). The largest series of laryngopharyngeal liposarcoma is reported by Wenig et al. ( 1990 1990 ) and Wenig and Heffner ( 1995 1995 ), in which ten cases were clinicopathologically analyzed. ALT is the most common variant of liposarcoma in the laryngopharynx (Wenig et al., 1990 1990 ; Wenig and Heffner, 1995 1995 ; Mandell et al., 1999 1999 ). The prognosis of ALT is favorable and local recurrences may occur occasionally, but metastasis of ALT is very rare. In this study, we report five additional ALT cases of the laryngopharynx and their morphological features, immunohistochemical staining profile, and differential diagnosis, as well as follow-up data. Materials and methods 1 The five ALT cases of the laryngopharynx were from the Department of Pathology, Chinese PLA General Hospital, its two affiliated hospitals, and the consultation files of one author (Dr. Huai-yin SHI). Hematoxylin and eosin (H&E) sections were available for all the five cases and the representative blocks were selected for immunohistochemical staining. Antibodies used in this study included cyclin-dependent kinase 4 (CDK4; DC9-31, 1:400 dilution, Biosource), murine double minute 2 (MDM-2; IF2, 1:200, Invitrogen), S-100 protein (polyclonal, 1:6000, Dako), vimentin (clone V9, 1:50, Dako), and Ki-67 (MIB-1, 1:50, Dako). Positive controls were used for all antibodies in immunohistochemical staining of the tumors. The staining was scored as negative (no tumor cells stained), diffuse (at least 50% tumor cells stained), or focal (less than 50% tumor cells stained). Follow-up data were available for all the five patients. Results 1 Clinical and follow-up findings 2 The clinical features of the patients are summarized in Table 1 1 . The five patients were one female and four males, with an age ranging from 41 to 69 years (median 53.6 years). Two tumors arose at the posterior wall of the hypopharynx and three from the larynx (two from the epiglottis and one from the vestibule). All tumors were surgically removed by pharyngolaryngectomy with supplementary CO 2 laser resection. The period of follow-up was from 26 to 96 months, median 56 months. The follow-up data revealed local recurrences in two cases at 6 and 14 months after initial surgical resection. The other three tumors did not recur during the follow-up. The second surgical resection of the recurrent tumors was performed, with a surgery procedure identical to the first, and the patients were negative for disease thereafter. All the five cases were alive during the follow-up period. M: male; F: female; NED: no evidence of disease Case No. Sex Age (year) Tumor site Size (cm) Histology Symptoms Follow-up (month) Follow-up data 1 F 45 Vestibule of larynx 3.0 Lipoma-like Dysphonia 56 NED 2 M 41 Hypopharynx 4.5 Sclerosing Dysphonia 42 Recur at 6 months 3 M 56 Epiglottis 2.5 Lipoma-like Dysphagia 60 NED 4 M 58 Hypopharynx 5.0 Lipoma-like Dysphonia 26 Recur at 14 months 5 M 69 Epiglottis 2.0 Lipoma-like Dysphagia 96 NED Gross and microscopical examinations 2 Grossly, the tumors were yellow or grey-white in color and lobulated on cut surface, with no grossly visible necrosis noted. The tumors were covered by intact squamous mucosa in all cases (Fig. 1 1 ). Microscopically, three tumors were well circum scribed, but not encapsulated. Other two tumors were partly well demarcated with focal infiltration of the surrounding soft tissue. The tumors were covered by intact squamous mucosa on one side (Fig. 2a 2a ), were lobular in arrangement, and were mainly consisted of adipocytes of different sizes and shapes showing hyperchromatic nuclei (Fig. 2b 2b ). Univacuolar and multivacuolar lipoblasts were noted in all tumors (Fig. 2c 2c ). Four tumors showed features of lipoma-like ALT, and were intermixed with little sclerosing fibrous tissue. In one case, prominent interstitial sclerosis was in accordance with the diagnosis of sclerosing ALT (Fig. 2d 2d ). Mitotic activity was very low and no pathological mitoses were noted in all tumors. Necrosis and dedifferentiation of the tumor cells were absent. Grossly, the tumors were yellow and grey-white in color and lobulated on the cut surface. The tumors were covered by intact squamous mucosa on one side The tumors were covered by intact squamous mucosa (H&E) (a), were lobular in arrangement, and were composed of adipocytes of different sizes and shapes showing hyperchromatic nuclei (H&E) (b). Univacuolar and multivacuolar lipoblasts were present in every case (H&E) (c). In one case, prominent interstitial sclerosis and little adipose were in accordance with the diagnosis of sclerosing ALT (H&E) (d) Immunohistochemical staining 2 The tumor cells were diffusely stained with vimentin (5/5), S-100 (4/5), MDM-2 (3/5), and CDK4 (3/5) (Fig. 3 3 ). Focal positivity for MDM-2 (2/5) and CDK4 (2/5) was noted in two tumors. Ki-67 was focally positive in no more than 5% of tumor cells in all the tumors. The results of immunohistochemical staining are summarized in Table 2 2 . The tumor cells stained diffusely or focally with vimentin (a), S-100 (b), MDM-2 (c), and CDK4 (d) Case No. Vimentin S-100 MDM-2 CDK4 Ki-67 1 Diffusely (+) Diffusely (+) Focally (+) Focally (+) Focally, less than 5% 2 Diffusely (+) Focally (+) Diffusely (+) Focally (+) Focally, less than 5% 3 Diffusely (+) Diffusely (+) Focally (+) Diffusely (+) Focally, less than 5% 4 Diffusely (+) Focally (+) Diffusely (+) Diffusely (+) Focally, less than 5% 5 Diffusely (+) Diffusely (+) Diffusely (+) Diffusely (+) Focally, less than 5% Discussion 1 Liposarcoma, mostly occurring in the retroperitoneum and extremities, is the most common malignant mesenchymal tumor of adulthood. However, its occurrence in the laryngopharynx is relatively rare. Mandell et al. ( 1999 1999 ) had reviewed 39 cases of liposarcoma of upper aerodigestive tract, among which 26 were located in the larynx, 7 in the hypopharynx, and 6 in the esophagus. These patients had a mean age of 55.8 years, and most of the patients were males. A total of 86% of the tumors in the above-mentioned review were histologically low-grade and only half of them had local recurrence after tumor excision. Distant metastases occurred in only three patients and two patients died of the disease. It was argued that whether or not the tumor had been completely removed seemed to be more closely correlated with the tumor recurrence than with the histological subtype (Mandell et al., 1999 1999 ). For anatomical reasons, the extensiveness of surgery for laryngopharyngeal tumors, including ALT, is usually restricted to some extent and the surgical margins are relatively close to the tumor. Thus pharyngolaryngectomy with supplementary laser resection is the optimal choice for laryngopharyngeal ALT in order to remove the tumor as completely as possible. Most laryngopharyngeal liposarcomas are well differentiated, located in the submucosal area, and covered by intact mucosa. They usually have morphological features of lipoma-like subtype, and the sclerosing subtype is only occasionally or focally noted (Wenig et al., 1990 1990 ; Wenig and Heffner, 1995 1995 ; Mandell et al., 1999 1999 ). Other variants of liposarcoma such as myxoid liposarcoma or pleomorphic liposarcoma are very rare in the laryngopharynx. Immunohistochemically, the tumor cells of ALT were permanently labelled with vimentin and S-100 proteins. Other antigens frequently present in ALT include MDM-2, CDK4, and high mobility group protein isoform I-C (HMGI-C) (Xiao et al., 1995 1995 ; Rogalla et al., 1996 1996 ; Dei Tos et al., 2000 2000 ). These antigens are coded by the genes located in 12q13–15, which are present in more than 90% ALT cases (Dal Cin et al., 1993 1993 ; Fletcher et al., 1996 1996 ; Rosai et al., 1996 1996 ; Pedeutour et al., 1999 1999 ). In this study, we performed immunohistochemical staining of MDM-2 and CDK4 and found that the tumor cells were diffusely or focally positive for these two antigens in all the five cases. Thus, it was concluded that MDM-2 and CDK4 may be useful in the differential diagnosis between lipoma and ALT of the laryngopharynx. ALT of the laryngopharynx should be differentiated from other benign lipomatous tumors such as classical lipoma, spindle cell lipoma, and pleomorphic lipoma (Arista-Nasr et al., 1998 1998 ; Jungehülsing et al., 2000 2000 ; Cantarella et al., 2001 2001 ; Persaud et al., 2002 2002 ). However, the adipocytic cells in classical lipoma do not show hyperchromatic nuclei, a typical histological feature of ALT. Otherwise, the adipocytes of lipoma are more uniform in size and shape and lipoblasts are absent. Spindle cell/pleomorphic lipoma (SC/PL), although rare in the laryngopharynx, can occasionally occur (Arista-Nasr et al., 1998 1998 ; Cantarella et al., 2001 2001 ). Likewise, SC/PL is usually composed of mature adipose and the size and shape of the adipocytic cells are relatively uniform. In addition, SC/PL is characterized by the presence of thick rope-like collagen bundles, without cells having atypical hyperchromatic nuclei as seen in the ALT, and immunohistochemically the spindle tumor cells are not stained with MDM-2 and CDK4. Although most ALTs can be diagnosed microscopically based on H&E sections, sometimes it may be difficult to make the differential diagnosis between ALT and lipoma or between ALT and SC/PL. In these cases, immunohistochemical staining of MDM-2 and CDK4 may be very useful as an aid in the differential diagnosis. Considering the indolent biological behavior, we think that ALT is a more suitable term for these laryngopharyngeal tumors than well-differentiated liposarcoma in order to avoid excessive treatment. 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Interaction between the retinoblastoma protein and the oncoprotein MDM2 The authors thank En-ping BA, Wei CHEN, Xin SONG, and Ling-hong CHEN (technicians of Department of Pathology, Chinese PLA General Hospital) for their technical assistance. 10.1631/jzus.B1000164 2010-05-02 2010-11-16 2010-08-29 2022-01-05 Copyright © Zhejiang University and Springer-Verlag Berlin Heidelberg 2010 2010 Journal of Zhejiang University-SCIENCE B (Biomedicine and Biotechnology) 12 11