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Intrapulmonary tumour showing recent growth
  1. Juan Laforga1,
  2. Luis Andreo2
  1. 1 Pathology, Hospital de Denia, Denia, Alicante, Spain
  2. 2 Radiology, Hospital de Denia, Denia, Alicante, Spain
  1. Correspondence to Dr Juan Laforga, Pathology, Hospital de Denia, Denia, Alicante, Spain; jblaforga{at}gmail.com

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Clinical question

A 68-year-old man presented with a well-delimited tumour measuring 31×28 mm in the right upper lobe of the lung (figure 1A) that had been detected by chest CT 5 years earlier. A recent CT scan showed that the tumour had grown to 42×36 mm (figure 1B). A core biopsy was performed followed by tumour excision with an atypical wedge resection segmentectomy and intraoperative cytology touch imprint examination.

Figure 1

CT scan of the thorax. (A) Initially the tumour measured 31×28 mm. (B) The tumour now measuring 42×36 mm.

What is your diagnosis?

  1. Dedifferentiated liposarcoma.

  2. Biphasic synovial sarcoma.

  3. Biphasic malignant mesothelioma.

  4. Metastatic CD34+ spindle cell tumour (GIST, Kaposi sarcoma, mammary-type myofibroblastoma).

  5. Atypical solitary fibrous tumour.

Discussion

Solitary fibrous tumours (SFTs) were originally described in the pleura, but they have since been reported at virtually all anatomic sites. The vast majority of SFTs are clinically and morphologically benign, but around 5% show malignant behaviour, including metastasis. An even smaller proportion have morphological features associated with aggressive behaviour, namely, increased mitotic activity (>4 mitoses/10 high-power fields (HPFs)), nuclear atypia, hypercellularity and necrosis.1 2 This more aggressive variant, known as atypical SFT, resembles conventional SFT, but it has atypical histological features that are each suggestive of malignancy (box 1). Its immunohistochemical characteristics are also analogous to those of conventional SFTs (CD34 and STAT6 positivity). As prognosis is unpredictable, long-term follow-up is recommended. Nuclear expression of STAT6 is a surrogate marker for the NAB2–STAT6 fusion gene, located in region 12q 13. Immunohistochemical expression of STAT6 has high sensitivity and specificity for SFT and increases diagnostic certainty. Intraoperative cytology touch imprints were very useful, as they showed a biphasic population consisting of a single layer of two-dimensional structures and a population of giant pleomorphic cells with morphological features suggestive of malignancy (figure 2A,B). Obviously, the single-layer component corresponded to normal alveolar epithelial cells forming cleft-like spaces that may occasionally be trapped by growing spindle cells. This feature may be a source of misinterpretation with biphasic synovial sarcoma (BSS).

Box 1

Histopathological criteria for atypical/malignant SFT

  • Increased mitotic activity (>4/10 HPFs).

  • Necrosis.

  • Pleomorphism.

  • Increased cellularity.

  • It resembles conventional SFT, but the above atypical features are each suggestive of malignancy. HPFs, high-power fields; SFT, solitary fibrous tumour.

Figure 2

Cytological features. (A) Cytology touch imprints showing a single layer of benign epithelial cells and isolated atypical giant cells (Papanicolaou ×200). (B) Large atypical mononuclear cells with a microvacuolated cytoplasm and hyperchromatic nuclei together with a pleomorphic multinucleated giant cell with coarse chromatin (Papanicolaou ×400).

Microscopically, the tumour had a predominantly spindle cell appearance, with hypocellular collagenous areas alternating with hypercellular areas showing mild nuclear atypia and increased mitotic activity (3 mitoses/10 HPFs) (figure 3A,B). There were focal nests of clearly atypical pleomorphic cells with hyperchromatic nuclei and coarse chromatin (figure 3C,D). No foci of necrosis were observed. The tumour cells showed strong diffuse immunoreactivity to CD34 and STAT6 (figure 4A,B). Cytokeratin, S-100 protein, smooth muscle actin (SMA), desmin, epithelial membrane antigen (EMA), murine double minute 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) were all negative. There was also an interspersed epithelial component lining a series of cleft-like spaces that gave an adenofibromatous appearance and stained diffusely with EMA and thyroid transcription factor 1 (TTF-1) (figure 4C,D). The presence of pleomorphic cells requires consideration of malignant SFT, which should show an abrupt transition from a typical SFT to a clearly malignant tumour in the form of a small-blue-round-cell tumour, fibrosarcoma or pleomorphic sarcoma.

Figure 3

Histological features. (A) The tumour showed an adenofibromatous pattern with hypercellular areas at the top and hypocellular collagenous areas at the bottom (H&E ×40). (B) Hypercellular areas consisting of spindle cells with ovoid nuclei. Mitotic figure (H&E ×400). (C, D) Multinucleated giant cells with cytoplasmic vacuolation and marked nuclear pleomorphism (H&E ×200).

Figure 4

Immunohistochemical features. (A) Strong diffuse staining of tumour cells with CD34 (CD34 ×100). (B) Strong diffuse nuclear immunoreactivity with STAT6 (STAT6 ×100). (C) EMA positivity in the epithelial component (EMA ×200). (D) Intense nuclear staining with TTF-1 in the intratumoral alveolar epithelial cells (TTF-1 ×200). EMA, epithelial membrane antigen; TTF-1, thyroid transcription factor 1.

The somewhat ‘biphasic’ appearance of the SFT in our case can be explained by its location. Because the tumour was exclusively intrapulmonary, as it grew, it would have incorporated alveolar elements that express epithelial markers (cytokeratins and e abbreviations 'EMA', 'MDM2' and 'CDK4' at its first mentioEMA) and stain positively for nuclear TTF-1, causing certain confusion with other biphasic tumours.

Observation of the epithelial component made it necessary to establish the differential diagnosis with other biphasic tumours such as BSS, biphasic mesothelioma and dedifferentiated liposarcoma (DLPS). Biphasic mesothelioma shows a diffuse growth pattern, but it can also grow locally. It has a mixed spindle cell and epithelial pattern and is diagnosed by positive staining for pan-cytokeratin, calretinin, CK 5/6, podoplanin and WT1.

The negative results for S-100, MDM2 and CDK4 ruled out DLPS.

Because of its high specificity, STAT6 is very useful for ruling out tumours with a similar morphology to SFT.3 It should be noted, however, that STAT6 amplification was recently demonstrated in a subset comprising nearly 1% of DLPS. As these tumours also express STAT6 by immunohistochemistry (although with less intensity than SFT), care should be taken when distinguishing between DLPS and SFT.4

It was also necessary to rule out CD34+ spindle cell tumours that can mimic SFTs when they occur in the lung. These include (a) lung metastasis from gastrointestinal stromal tumour, which shows strong diffuse staining with CD117 and/or Delay of germination-1 (DOG-1); (b) Kaposi sarcoma of the lung, which can occur in patients with AIDS and stains positively with human herpesvirus 8 (HHV8) and (c) mammary-type myofibroblastoma, which stains positively for desmin, h-caldesmnon, estrogen receptor, progesterone receptor and androgen receptor and negatively for retinoblastoma protein. SFT can be ruled out in all these cases because of the absence of STAT6 expression.

Correct answer

E. Atypical solitary fibrous tumour.

Take home messages

  • Atypical SFT resembles conventional solitary fibrous tumour (SFT), but it shows atypical histological features each suggestive of malignancy. Its immunohistochemical characteristics are also analogous to those of conventional SFTs (positivity for CD34 and STAT6).

  • Intraoperative touch imprint cytology is useful for identifying giant pleomorphic cells suggestive of malignancy.

  • Intrapulmonary growth leading to incorporation of alveolar elements expressing epithelial markers (cytokeratins and EMA) and TTF-1 can lead to confusion with biphasic tumours.

  • Normal alveolar epithelial cells form cleft-like spaces that may occasionally be trapped by growing spindle cells. Pathologists need to be aware of this possibility to avoid misdiagnosis of biphasic synovial sarcoma.

  • Dedifferentiated liposarcoma (DLPSs) is ruled out by S-100, MDM2 and CDK4 negativity. Note that 1% of DLPSs are STAT6+.

  • STAT6 positivity rules out other CD34+ spindle cell tumours.

Ethics statements

Acknowledgments

The author would like to thank Dr Christopher D.M. Fletcher (Brigham and Women’s Hospital, Boston, MA) for reviewing the case and for his helpful comments.

References

Footnotes

  • Handling editor Iskander Chaudhry.

  • Contributors JL made the diagnosis, prepared the manuscript, recorded clinical information and provided the figures. LA diagnosed and provided CT scans.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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