Well-Differentiated/Dedifferentiated Liposarcoma Arising in the Upper Aerodigestive Tract: 8 Cases Mimicking Non-adipocytic Lesions

Abstract

Well-differentiated (WDL) and dedifferentiated liposarcomas (DL) of the pharynx, larynx and oral cavity are rare, often mimicking benign lipomatous neoplasms or non-lipogenic mesenchymal tumors. Cases of WDL/DL arising in the upper aerodigestive tract, exclusive of the cervical esophagus, were reviewed. Morphologic features, ancillary studies, including fluorescence in situ hybridization (FISH) studies for CPM/MDM2, and clinical data was catalogued. Eight WDL/DL (4 WDL, 4 DL); were identified in patients ranging from 32 to 77 years (median 52.5 years; 6 males, 2 females) with sites of origin including hypopharynx (5 cases), larynx (2 cases) and oral cavity (1 case). Six of the 8 cases were received for expert consultation, and the remaining 2 cases were initially misdiagnosed as benign lymphangiomatous or fibroepithelial polyps. Morphologically, 4 tumors had areas mimicking various non-lipomatous soft tissue tumors including nodular fasciitis, mammary-type myofibroblastoma, low-grade myofibroblastic sarcoma and undifferentiated pleomorphic sarcoma, 2 cases simulated benign hypopharyngeal polyps, and 1 lesion was notable for a dense lymphoplasmacytic infiltrate suggestive of hematolymphoid neoplasm or IgG4-related sclerosing disease. FISH showed amplification of CPM/MDM2 (8/8 cases). All cases (4/4) with longer than 1-year of follow-up recurred (45–118 months) with 1 tumor showing progression to DL. WDL/DL presenting in the upper aerodigestive tract are rare and diagnostically challenging. Awareness of the morphologic spectrum of WDL/DL coupled with appropriate use of MDM2 FISH is essential for accurate classification and management, as these tumors appear to have a high risk for local recurrence and eventual dedifferentiation in these anatomical locations.

Introduction

Atypical lipomatous tumor/well-differentiated liposarcoma (WDL) and dedifferentiated liposarcoma (DL), the most commonly encountered sarcomas in adulthood, usually arise in the extremities and retroperitoneum. When these tumors occur in the head and neck region, they typically involve the soft tissue of the neck rather than submucosal sites. Prompted by the recent recognition that the majority of giant fibrovascular polyps of the esophagus are WDL/DL [1], we wondered whether liposarcomas arising at other upper aerodigestive tract sites might also present similar diagnostic challenges, especially cases without a well-defined adipocytic component. Herein we detail our experience with a cohort of 8 WDL/DL arising in upper aerodigestive locations, highlighting unusual morphologic features to raise awareness of these rare neoplasms and aid in their appropriate classification and management.

Methods

The Institutional Review Board of the Mayo Clinic approved this study. The consultation and institutional anatomic pathology archives of our hospital were searched for cases of WDL and DL arising in the upper aerodigestive tract, exclusive of the cervical esophagus, from January 1, 1992 to November 30, 2019. Clinicopathologic information, including patient age and sex, tumor size, and anatomic location was collected. The available H&E slides were reviewed for morphologic patterns, as well as quantitation of the adipocytic component (< 10%, minimal; 10 to 25%, focal). Immunostains and fluorescence in situ hybridization studies (FISH) for MDM2 or CPM, a diagnostic surrogate for MDM2 [2], were catalogued. Treatment data and clinical follow-up information, when available, was acquired through the institutional electronic medical records or the submitting pathologist.

Results

A total of 8 cases of WDL/DL (4 WDL; 4 DL) were identified in 6 males and 2 females (32 to 77 years; median 52.5 years) with sites of origin including hypopharynx (5 cases), larynx (2 cases) and oral cavity (1 case) and sizes ranging from 2.8 to 6 cm (n = 4) (Table 1). Presenting symptoms included dysphagia, foreign sensation, choking and difficulty breathing.

Table 1.

Clinicopathologic features of cohort

Case	Dx	Age/sex	Site	Initial diagnosis	Expert consultation requested	IHC performed (number)	Intralesional fat	Morphologic ddx	Outcome
1	WDL	32/F	Left lateral pharyngeal wall/pyriform sinus	Lymphangiomatous polyp	No	No	Minimal	Lymphangiomatous polyp	Recurrence (93 mo)
2	DL	41/M	Supraglottis	DL	Yes	Yes (9)	Minimal	Undifferentiated pleomorphic sarcoma	NA
3	WDL+	42/M	Hyopharynx	Fibroepithelial polyp	No	No	Focal	Fibroepithelial polyp	Recurrence (118 mo)
4	WDL	50/M	Buccal mass	WDL	Yes	Yes (6)	Minimal	Lymphoma, IgG4-related disease or fibroinflammatory proliferation	NA
5	DL	55/M	Pyriform sinus	Low-grade myofibroblastic sarcoma	Yes	Yes (8)	Mimimal	Myofibroblastic sarcoma, perineurioma	Recurrence (45 mo)
6	WDL	66/F	Epiglottis	WDL	Yes	Yes (5)	Minimal	Mammary-type myofibroblastoma	Recurrence (96 mo)
7	DL	71/M	Pyriform sinus	DL	Yes	Yes (18)	Focal	Nodular fasciitis	NA
8	DL	77/M	Hypopharynx	DL	Yes	Yes (16)	Minimal	Nodular fasciitis	NED (4 mo)

Dx diagnosis, Ddx differential diagnosis, F female, M male, WDL well-differentiated liposarcoma, DL dedifferentiated liposarcoma, NA not available, NED no evidence of disease, mo months

⁺Recurrence harbored areas of dedifferentiation

The majority of cases in our cohort (n = 6) were consultation cases that were sent for second opinion either at the time of primary diagnosis or after recurrence. Diagnoses and differential diagnoses from the submitting pathologists included: “reactive,” “bland spindle cell proliferation,” “fibroblastic/myofibroblastic proliferation,” “smooth muscle lesion,” IgG4-related sclerosing disease, nodular fasciitis, inflammatory myofibroblastic tumor, low-grade myofibroblastic sarcoma, and “malignant spindle cell neoplasm.” The final 2 cases were originally diagnosed as benign lymphangiomatous and fibroepithelial polyps, respectively, and only correctly classified upon review of the recurrences when the patient presented for care at our institution.

Histologic examination of all cases showed a component of mature adipose tissue and varying numbers of atypical spindled or multinucleated cells with hyperchromatic and smudgy nuclei, as seen in well-differentiated liposarcoma (Fig. 1). However, the adipocytic component was always a minor component of the mass with areas of mature fat ranging from focal (n = 2) to minimal (n = 6). Furthermore, a wide spectrum of other morphologic patterns was appreciated.

Fig. 1.

All cases showed at least a small adipocytic component composed of mature fat and atypical hyperchromatic stromal cells within areas of fibrosis

Histologic examination of 2 cases (Cases 1 and 3) revealed a polypoid submucosal proliferation of spindled cells with features reminiscent of esophageal lesions previously termed ‘giant fibrovascular polyps. ’ The spindled cell population was deposited within a minimally to focally fibrofatty background admixed with ectatic lymphatic and vascular spaces (Fig. 2). Only subtle cytologic atypia and subtle hyperchromasia were present in the lesional cells, and mitotic figures were difficult to identify.

Fig. 2.

Case 1 showed an exophytic and polypoid mass composed of ectactic vascular spaces (a, b). The surrounding stroma contained spindle cells with only minimal atypia and areas of mature fat (c)

Case 2 presented as a supraglottic mass which was superficially biopsied at first. The initial biopsy showed a spindle cell proliferation with myxoid changes in the background. Spindled cells with hyperchromatic nuclei were also seen. The significance of the atypia was uncertain at this time and the differential diagnosis of a mesenchymal neoplasm versus reactive changes was considered. A second, deeper biopsy was then performed which showed spindled cells with marked nuclear pleomorphism and brisk mitotic activity. Amplification of the MDM2 gene was detected by FISH, which in conjunction with the morphologic findings, supported the diagnosis of dedifferentiated liposarcoma. In retrospect, the spindle cells seen in the earlier biopsy were also present in the deeper biopsy and considered to be part of the same tumor.

Case 4 harbored features suggestive of an inflammatory process or hematolymphoid neoplasm. In addition to a small focus of mature fat, microscopic examination revealed a densely hyalinized stroma with a prominent nodular lymphoplasmacytic infiltrate (Fig. 3). Admixed spindled cells with mild cytologic atypia and rare enlarged multinucleated cells with hyperchromatic nuclei could be appreciated with careful examination, and a focus of metaplastic bone was noted. A battery of hematolymphoid markers including CD3, CD20, IgG, IgG4 and kappa and lambda studies failed to show evidence of lymphoma, plasma cell neoplasm or increased numbers of IgG4-positive cells.

Fig. 3.

Histologic sections of Case 4 showed a prominent lymphoplasmacytic infiltrate (a). The inflammatory cells were deposited in a hyalinized background with thick bands of collagen (b). Rare atypical hyperchromatic stromal cells were noted (c), and a focus of metaplastic bone was also appreciated (d)

The dominant histologic feature in the remaining 4 cases (Cases 5–8) was a spindle cell proliferation with atypia varying from mild to severe, although the mitotic rate was generally low, ranging from 1 to 5 mitotic figures/10 high power fields. A single case harbored markedly pleomorphic epithelioid cells and multinucleated cells, while perineurial-like nodules (Case 5) and meningothelial-like whorls (Case 7) were noted in a single case each (Fig. 4). The spindle cell component in Cases 7 and 8 was focally arranged in a loose storiform pattern, raising the possibility of myofibroblastic lesions such as nodular fasciitis (Fig. 5a). Case 7 showed patchy staining for actin and STAT6 (Fig. 5b), and the spindle cells of Case 8 were focally immunoreactive for actin, calponin and desmin. Examination of the recurrence of Case 6 revealed small foci of spindle cells with minimal atypia admixed with variably sized bundles of ropy collagen reminiscent of mammary-type myofibroblastoma, and these spindle cells showed staining for CD34 and desmin (Fig. 6),

Fig. 4.

Other morphologic patterns included markedly atypical epithelioid and spindled cells (a), perineurial-like areas (b), and meningothelial-like whorls (c)

Fig. 5.

Case 6 had areas containing a loose arrangement of spindled cells resembling nodular fasciitis (a), and focal nuclear expression of STAT6 (b) was also noted in this case

Fig. 6.

The recurrent tumor from Case 5 showed a paucicellular proliferation of relatively bland spindled cells admixed with dense ropey collagen bundles, suggestive of mammary-type myofibroblastoma (a). The tumor cells also demonstrated staining for CD34 (b) with focal desmin expression (c)

FISH studies performed either on the primary tumor or recurrence material was positive for CPM (1/1 case) or MDM2 (7/7 cases) amplification in all cases. Florescence in situ hybridization for USP6 performed on Case 8 was negative.

Follow-up was available on 5 patients (4 to 212 months, median 96 months), and all 4 tumors (3 WDL, 1 DL) with longer than 1-year of follow-up recurred (at 45, 93, 96 and 118 months). Progression to dedifferentiated liposarcoma was observed in a single tumor (Case 3) during recurrence at 118 months. No metastases have been reported to date.

Discussion

Atypical lipomatous tumor/well-differentiated liposarcoma is an adipocytic neoplasm composed of mature adipose tissue and irregular widened fibrous septa containing diagnostic atypical hyperchromatic stromal cells (and less commonly lipoblasts). Occasionally, the degree of cytologic atypia in these tumors may be mild and/or the characteristic atypical hyperchromatic stromal cells sparse. However, given the frequency of this tumor within deep somatic soft tissue or at deep central sites such as the retroperitoneum or mediastinum, pathologists have learned to recognize these pitfalls and utilize MDM2 studies when unequivocal cytologic atypia is absent. Dedifferentiated liposarcoma, on the other hand, is a biphasic malignancy with a predilection for the retroperitoneum, composed either of areas of well-differentiated liposarcoma juxtaposed to (usually) non-lipogenic spindle cell sarcoma, or consisting only of non-lipogenic spindle cell sarcoma in the recurrence of a previous WDL. In fact, the vast majority of pleomorphic sarcomas in the retroperitoneum are now felt to represent dedifferentiated liposarcomas [3]. Consequently, even when tumors lack an adipocytic component or harbor heterologous elements, pathologists are able to appropriately classify these sarcomas given their classic clinical presentation. Our group recently reported a series of WDL/DL of the esophagus and found that the majority was misclassified as benign polyps, and we suspected that these tumors may be similarly misdiagnosed at other upper aerodigestive tract sites given their morphologic diversity [1].

We identified a total of 8 cases of WDL/DL in our institutional and consultation archives in 6 males and 2 females ranging in age from 32 to 77 years with sites including the hypopharynx, lateral pharyngeal wall/pyriform sinus, supraglottis, epiglottis and buccal region. Six of the 8 cases were sent for expert consultation, and the remaining 2 cases were initially misdiagnosed as benign polyps. Furthermore, 5 of the 6 cases sent for expert consultation underwent an extensive immunohistochemical/molecular work-up before a diagnosis of WDL/DL was rendered. Cases of WDL/DL presenting in the oral cavity, larynx and pharynx are rare and most often harbor a well-differentiated lipomatous component [4–44]. Even though a subset of these tumors may be initially misdiagnosed as benign lipomas or fibrolipomas, pathologists often can recognize them as adipocytic neoplasms. Conversely, cases in our cohort had minimal amounts of mature fat, resulting in diagnostic difficulty. Based on the morphologic features cataloged in our series, the most common morphologic mimics included benign polyps, inflammatory processes and non-lipogenic mesenchymal spindle cell neoplasms.

Two cases in our series were originally felt to represent simply fibroepithelial or lymphangiomatous polyps and were only correctly diagnosed after the patients experienced recurrence. Morphologically, these tumors were composed of a variably cellular proliferation of spindled cells with minimal cytologic atypia deposited in a fibrofatty background. The majority of lymphangiomatous polyps are reported to occur in the tonsil. Microscopically, lymphangiomatous polyps are composed of a combination of lymphatic channels, fibrous and/or adipose stroma, and lymphoid tissue [45]. Fibroepithelial or lymphangiomatous polyps in adults in the larynx and hypopharynx may represent well-differentiated liposarcoma in some cases, and caution should be exercised before rendering these diagnoses. Careful morphologic examination with attention to cytologic atypia in the form of atypical hyperchromatic stromal cells, as well as MDM2 studies, will help to confirm or exclude a diagnosis of well-differentiated liposarcoma in this setting.

It is well recognized that retroperitoneal well-differentiated liposarcomas may contain a significant inflammatory component (so-called inflammatory variant) [46]. One case in our series consisted largely of densely hyalinized fibroconnective tissue containing a prominent lymphoplasmacytic infiltrate which largely obscured the scattered enlarged, hyperchromatic stromal cells of WDL, simulating some type of hematolymphoid process, such as lymphoma, plasma cell neoplasm, or IgG4-related sclerosing disease. As hematolymphoid neoplasms and IgG4-relating sclerosing disease outnumber WDL/DL in the head and neck, pathologists must maintain high degree of suspicion for the latter diagnosis in this anatomic location. Helpful morphologic clues to the diagnosis of inflammatory WDL in the upper aerodigestive tract include the presence of fat in unusual locations, as well as the presence of a spindled cell population with cytologic atypia, and these findings should prompt MDM2 studies.

Dedifferentiated liposarcomas are notorious for their morphologic complexity. Not only are these malignancies capable of harboring heterologous elements, the degree of atypia in the dedifferentiated areas may be minimal, potentially mimicking reactive processes or benign neoplasms. As these tumors may contain a population of low-grade spindle cells arranged in fascicles with some combination of actin and/or desmin staining, the morphologic findings overlap with numerous myofibroblastic lesions such as reactive proliferations, nodular fasciitis or low-grade myofibroblastic sarcoma. The presence of cytologic atypia would exclude the first two possibilities. Furthermore, cases of nodular fasciitis arising in the larynx and hypopharynx are rare, and confirmation with USP6 gene rearrangement should be pursued [47–49]. Low-grade myofibroblastic sarcoma, as well as undifferentiated pleomorphic sarcoma, may be impossible to differentiate from DL by histologic examination alone. Before making a diagnosis of these two entities, the pathologist should search diligently for areas of well-differentiated liposarcoma or correlate with imaging findings which may show areas of fat. When a well-differentiated lipomatous component is not identified, the presence of MDM2 expression by immunohistochemistry or MDM2 amplification will help support the diagnosis of DL. Finally, a myoepithelial neoplasm can be excluded by absence of biphasic appearance, ductal elements and/or keratin/S100-protein staining.

Interestingly, one case in our study showed expression of STAT6, a marker which has been shown to be a sensitive and relatively specific surrogate for the characteristic NAB2-STAT6 fusion that drives the pathogenesis of solitary fibrous tumors [50–53]. While the pleura is the most common anatomic site for this tumor, solitary fibrous tumors may arise in the head and neck region [54]. Furthermore, solitary fibrous tumors occasionally harbor areas of mature fat [55–58]. Doyle and colleagues found that STAT6 immunoreactivity may rarely be seen in dedifferentiated liposarcoma, likely reflecting the close proximity of the STAT6 gene to genes frequently amplified in WDL/DL (e.g., MDM2, CDK4) [53]. Pathologists should be aware of this pitfall when interpreting STAT6 staining in spindle cell lesions with lipomatous differentiation in the upper aerodigestive tract.

All patients (4 of 4) with significant follow-up experienced local recurrence, similar to the behavior of WDL/DL at other deep central sites, and a single case in our cohort also progressed to DL on recurrence. Although there is evidence that dedifferentiated liposarcomas have a better prognosis than other high grade pleomorphic sarcomas, these tumors still have high rates of recurrence if not completely excised [54, 59, 60]. These findings underscore the need for accurate classification of these tumors, complete tumor resection, and close follow-up of these patients.

In conclusion, well-differentiated and dedifferentiated liposarcomas arising in the upper aerodigestive tract are rare and diagnostically challenging, often resulting in expert consultation, extensive immunohistochemical/molecular workup and/or incorrect diagnosis. Additionally, the morphologic spectrum of DL is broad, further complicating appropriate classification. Consequently, pathologists should be aware that these tumors arise at sites such as the oral cavity, larynx and hypopharynx. Careful morphologic examination and appropriate use of MDM2 studies should aid in correct diagnosis and clinical management.

Author Contributions

TG helped with data acquisition and manuscript preparation. DS-W helped with manuscript preparation. MR helped with project design, data acquisition and manuscript preparation. AR helped with data acquisition and manuscript preparation. RG helped with manuscript preparation. AF helped with manuscript preparation. KF helped with project design, data acquisition and manuscript preparation. WDL/DL presenting in the upper aerodigestive tract are rare and diagnostically challenging. Awareness of the morphologic spectrum of WDL/DL coupled with appropriate use of MDM2 FISH is essential for accurate classification and management, as these tumors appear to have a high risk for local recurrence and eventual dedifferentiation in these anatomical locations.

Funding

No funding obtained.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

The Institutional Review Board of the Mayo Clinic approved this study.