Differential diagnosis of laryngeal spindle cell carcinoma and inflammatory myofibroblastic tumor – report of two cases with similar morphology
© Völker et al; licensee BioMed Central Ltd. 2007
Received: 04 December 2006
Accepted: 09 January 2007
Published: 09 January 2007
Spindle cell tumors of the larynx are rare. In some cases, the dignity is difficult to determine. We report two cases of laryngeal spindle cell tumors.
Case 1 is a spindle cell carcinoma (SPC) in a 55 year-old male patient and case 2 an inflammatory myofibroblastic tumor (IMT) in a 34 year-old female patient. A comprehensive morphological and immunohistochemical analysis was done. Both tumors arose at the vocal folds. Magnified laryngoscopy showed polypoid tumors. After resection, conventional histological investigation revealed spindle cell lesions with similar morphology. We found ulceration, mild atypia, and myxoid stroma. Before immunohistochemistry, the dignity was uncertain. Immunohistochemical investigations led to diagnosis of two distinct tumors with different biological behaviour. Both expressed vimentin. Furthermore, the SPC was positive for pan-cytokeratin AE1/3, CK5/6, and smooth-muscle actin, whereas the IMT reacted with antibodies against ALK-1, and EMA. The proliferation (Ki67) was up to 80% in SPC and 10% in IMT. Other stainings with antibodies against p53, p21, Cyclin D1, or Rb did not result in additional information. After resection, the patient with SPC is free of disease for seven months. The IMT recurred three months after first surgery, but no relapses were found eight months after resurgery.
Differential diagnosis can be difficult without immunohistochemistry. Therefore, a comprehensive morphological and immunohistochemical analysis is necessary, but markers of cell cycle (apart from the assessment of proliferation) do not help.
The most common type of malignant laryngeal tumors is the classical squamous cell carcinoma (SCC). Benign tumors of the larnyx are divided in two groups: mesenchymal and epithelial lesions. The latter harbours particular papillomas, whereas simple vocal cord polyps, Reinke edema, or e.g. leiomyomas have a mesenchymal origin. A further group are tumorous inflammatory lesions, such as granulomatous polyps. Most of these different entities show a characteristic histomorphology, so that the diagnosis might be unproblematic for the histopathologist.
Spindle cell lesions of the larynx are rare (1.3%) . Such tumors usually require immunohistochemical investigations for detailed histopathological specification. In some cases, the dignity is difficult to determine.
We demonstrate a spindle cell carcinoma (SPC) and an inflammatory myofibroblastic tumor (IMT), two laryngeal spindle cell tumors with complete different dignity, and discuss the differential diagnosis focusing on the immunohistochemical results.
A 55 year-old male patient with relapsing dyspnoe and five pneumonias within the last four years was referred to our ENT hospital with progressive dyspnoe and dysphonia for five months. The patient was a smoker with 30 pack years, no alcohol abuse. He did not show any other systemic symptoms. Flexible transnasal laryngoscopy showed a laryngeal mass without visible glottis. Subsequently, microlaryngoscopy with laser resection of the ulcerated tumor (diameter 3 cm) was performed. The tumor originated from the right vocal fold. Histologically, a spindle cell carcinoma (SPC) was diagnosed. In a second surgery no remnants were found. The cervical lymph nodes were unsuspicious in ultrasound and computertomographic investigation. Therefore, neck dissection was not carried out. The patient is free of disease seven months after surgery.
A 34 year-old female patient with increasing dysphonia for one month was referred to our ENT hospital. She had neither a history of smoking nor alcohol abuse. Magnified laryngoscopy showed a polyp (0.8 cm) of the right vocal fold. Examination was followed by microlaryngoscopy with macroscopically complete resection. In a postoperative control ten days after surgery, a small nodule was found and suspected as a granulomatous polyp. Logopedic therapy led to a subjective voice improvement within the next three months. However, further magnified laryngoscopy showed an increasing size of the nodule. The following resection of a round tumor with 1.2 cm diameter was macroscopically and histologically complete. Eight months after surgery the patient is free of disease.
Histopathological and immunohistochemical methods
After surgical resection, routinely processed paraffin blocks were cut at 2 μm and put on 3-aminopropyltriethoxysilane (APES) coated slides. Sections were first stained with hematoxylin-eosin (HE) and periodic acid Schiff (PAS) reaction.
Expression in SPC
Expression in IMT
DAKO, mouse, 1:800
PanCytokeratin AE1/3 *
DAKO, mouse, 1:100
+ (weak only)
LOXO, mouse, 1:20
DAKO, mouse, 1:20
smooth muscle Actin
Beckman Coulter, mouse, 1:20
DAKO, mouse, 1:400
DAKO, rabbit, 1:2000
DAKO, mouse, 1:100
DAKO, mouse, 1:100
DAKO, mouse, 1:200
PanCytokeratin KL1 *
Beckman Coulter, mouse, 1:40
NR (but epithelium +)
DAKO, mouse, 1:50
+ (weak only)
DAKO, mouse, 1:50
DAKO, mouse, 1:20
Kiel, ascites, 1:20000
DAKO, mouse, 1:5
DAKO, mouse, 1:10
DAKO, rabbit, 1:100
DAKO, mouse, 1:10
DAKO, mouse, 1:10
DAKO, mouse, 1:20
Neomarkers, mouse, 1:200
Dianova, rat, 1:20
LOXO, mouse, 1:20
+ (weak cytoplasmatic)
DAKO, mouse, 1:400
Neomarkers, mouse 1:50
Tebu, rat, 1:200
Virofem, mouse conc.
All stainings are used in routine investigations and the antibodies were tested in suitable positive controls.
Apart from the diagnostic areas shown, both cases contained distended spindle cell components with a high degree of overlapping histomorphology in conventional HE stain.
We demonstrated two cases of laryngeal spindle cell tumors with complete different dignity. The first case was a spindle cell carcinoma (SPC), the second an inflammatory myofibroblastic tumor (IMT). Because of similar morphology, only comprehensive immunohistochemical investigations allowed the correct final diagnoses and the aligned assessment of biological behaviour.
According to the recent WHO definition, laryngeal SPCs represent biphasic tumors, composed of a squamous cell carcinoma (SCC), either in situ or invasive, and a malignant spindle cell component with mesenchymal appearance , but of an evident monoclonal epithelial origin . Obsolete synonyms are sarcomatoid carcinoma, carcinosarcoma, collision tumor, or pseudosarcoma. Males in the 6th and 7th decade are predisposed (reported male to female ratio is 10:1) [4, 5]. The vocal fold is the most common site of involvement . Risk factors correspond to common SCC: cigarette smoking and alcohol abuse . Some SPCs seem to develop after radiation [5, 6], but a strong evidence of this hypothesis is missing. The prognosis of SPCs is discussed controversially. One quarter metastasizes in regional lymph nodes, distant metastases occur in 5–15% . These often contain usual SCC with or without spindle cell component. Rarely, only the spindle cell component occurs . Five year survival is reported to be 65–95% [1, 5]. Low tumor stage and absence of previous irradiation indicate a better prognosis. Besides, improved survival rates are associated with a low level of cytokeratin expression .
The differential diagnosis includes, apart from rare laryngeal sarcomas, reactive or benign spindle cell proliferations, such as nodular fasciitis, IMT, or low grade myofibroblastic sarcoma.
Synopsis of all 19 laryngeal inflammatory myofibroblastic tumors published in the English literature.
M, 62 
Hoarseness, dysphonia, systemic manifestations (fever and weight loss) for 3 months
True vocal cord
FD 24 months
vim +, actin +, NR: desmin, CK, S100, Alk-1
M, 2 
Snoring, apneic events
R 7 months
F, 52 
Voice change for 12 months
FD 4 years
vim +, sm-actin +, NR: S100, desmin
F, 49 
Dyspnoea, stridor for 4 month, 15 month after road accident
Persistence for 1 months after surgery, resurgery with persistence for 12 months, 2nd resurgery, FD 15 months after resurgery
sm-actin patchy +, NR: desmin, CK, EMA
M, 51 
Hoarseness for 6 months
FD 12 months
vim+, sm-actin+, NR: CK, desmin, S100, CD34
M, 74 
Hoarseness, foreign body sensation, dyspnoe for several months
True vocal cord
FD 2 months, death on cardiac failure
vim +, actin +, NR: S100, desmin, CK
M, 57 
Hoarseness, dyspnoe, disphonia for 5 months
R 2 months, after resurgery FD 12 months
vim +, actin +
M, 72 
Dysphonia for 2 months
True vocal cord
FD 6 months
vim +, sm-actin +, CD68 focally +, NR: CK, S100, desmin, CD34, LMP
5 M, 3 F with age median of 59 (19–69) 
Hoarseness, stridor, dysphonia, foreign body sensations from 10 days up to 4 months
7 cases FD, one case with 4 relapses in 24 months
All: vim +, sm-actin +, NR: CK, S100, desmin, myoglobin, CD34
3 further cases, 
2 cases FD, one R 12 months
The etiology of IMTs is unknown. The idea of a reactive lesion was refuted by genetic studies. The clonal origin is evident [13, 14] and chromosomal abnormalities involving 2p23 [15, 16], and fusion of the ALK gene with tropomyosin 3 (TPM3-ALK) or tropomyosin 4 (TPM4-ALK) is found in a subset . Gene rearrangement and gene activation are restricted to the myofibroblastic component. Some authors assume an association with a trauma. Alaani et al. have documented a causal relation between local laryngeal trauma and IMT , Wenig et al. found an IMT after traumatic intubation . Furthermore, immunosuppression, unspecific infections, infections of HHV8  and EBV  were identified in IMT and an overexpression of IL-6 and cyclin D1 (confirmed by our investigations) have been reported . In the case we have presented, we could not affirm any infectious genesis.
Clinically, IMT can mimic a neoplastic process. Patients suffer from hoarseness, dysphonia, or foreign body sensations in the troath. Constitutional or systemic signs (fever, weight loss, anaemia) are usually missing in extrapulmonary IMTs. Systemic alterations are only reported in one laryngeal IMT .
The diagnosis of IMTs can be difficult due to the wide morphological spectrum. Coffin et al. have described three morphologic patterns:
1. spindle cells in a myxoid background with a vascular and inflammatory component (nodular fasciitis like)
2. compact spindle cells in a solid confluent area or as irregular foci in areas of dense collagen (fibrous histiocytoma like)
3. collagen dense pattern similar to desmoid fibromatosis .
Our case of IMT first presented as variant one with relapse as variant two. Alaani et al. described in a relapsed IMT a progressive diminution of inflammatory cells, reduction of atypia and more collagenous, less myxoid stroma up to osteoblastic changes . A transformation of an IMT to higher malignancy is possible, especially in cases with repeated recurrences.
According to Coffin et al., immunohistochemical investigations could reveal an expression of vimentin in 99%, sm-actin in 92%, focally desmin in 69%, cytokeratins in 36%, CD68 in 24%, and CD30 in 6% . The reported laryngeal IMT expressed consistently vimentin and actin, but none of the other markers. Anaplastic lymphoma kinase (ALK) gene expression is detectable in IMTs, often in children and young adults under 40 [14–17, 21]. Only two laryngeal IMTs (including our case) have a reported staining with antibodies against ALK-1. The importance of ALK expression regarding the prognosis is controversially discussed. Chun et al. found a better prognosis in cases with ALK expression , whereas Coffin et al. found a recurrence in 45% of ALK-positive and 20% of ALK-negative IMTs . The malignant transformation seems independent of ALK expression .
The differential diagnosis of IMT comprises low grade myofibroblastic sarcomas as well as a long list of benign, reactive, or neoplastic spindle cell lesions, such as leiomyoma, solitary fibrous tumor, spindle cell carcinoma, nodular fasciitis, and peripheral nerve sheet tumor . Morphology and immunohistochemical profile help to rule out these entities, whereby low grade myofibroblastic sarcoma can be difficult to distinguish due to the low or mild atypia and low proliferations index . The best discrimination of this malignant neoplasm with favorable prognosis is the occurrence of local infiltrative growth [20, 23].
As mentioned above, SPC is also an important differential diagnosis. But if the diagnosis cannot be made on the basis of conventional histomorphology, it becomes even more difficult. Typically, SPCs contain pleomorphic malignant spindle cells with mitoses (including atypical mitoses). Most of them are associated with epithelial dysplasia or common SCC . Our case of SPC showed similarities with IMT in some areas. We found only mild atypia, hypocellular myxoid degeneration and no association with dysplasia of the surface epithelium. So we were not able to diagnose a SPC with HE staining alone. However, immunohistochemistry was evident for SPC/IMT (SPC: cytokeratin and vimentin positive, ALK-1 negative versus IMT: ALK-1 and vimentin positive, cytokeratins negative). Problems arise in an ambiguous staining pattern: SPCs express cytokeratins only in 40–85% and IMTs in up to 75% [5, 7, 8, 24–26]. In our SPC, not all pan-cytokeratins (MNF 116) were expressed. In such cases, the p63 antibody is helpful . An expression of sm-actin is reported in SPC and IMT [1, 7, 8], we found it only in SPC. In contrast to that, all laryngeal IMTs in literature expressed actin (table 2). An expression of ALK-1 is typical, but only one half of IMT are positive. And interestingly, positivity in patients over 40 years is less likely (whereas IMTs of the head and neck occurs in the 5th/6th decade) [28, 29]. Therefore, even comprehensive immunohistochemical analysis could fail in revealing the right diagnosis.
Hussong et al. described an overexpression of p53 in one of six IMT with recurrence and in one of two with malignant transformation, but in none without . Even if Ledet et al. found p53 only in malignancies but not in IMTs . But an expression of p53 seems to be not a sure sign of malignant behavior. Yamamoto et al. described p53 positivity in 6.7% of all IMTs , Brooks et al. detected it in an oral IMT without recurrence or malignancy . However, the highest number of investigated IMTs is a study of 24 cases (including six recurrences and two malignant IMTs) . Therefore, p53 seems to be not sufficient criterion for differential diagnosis. Bcl-2 expression is reported in 38% of IMT without relation to recurrence or malignant transformation . Expression of cyclin D1 and Rb was described [18, 28], the value of p21 is not assessed. The degree of cellularity, mitoses, and the extent of inflammatory cells showed no correlation to more aggressive behavior , but the presence of aneuploidy , atypia and ganglion-like cells do . Reliable criteria with a high predictive value regarding the biological behavior of IMTs do not exist so far.
In summary, the differential diagnosis of SPC and IMT can be difficult, particularly in cases with uncommon immunohistochemical profile. Therefore, a comprehensive morphological and immunohistochemical analysis is necessary, but markers of cell cycle (apart from assessment of proliferation) do not help.
We thank Petra Stempfle and Erwin Schmitt for their excellent technical assistance.
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