May 2013

A 62-year-old man with constipation and abnormal urinary bladder function

J.T. Stuelpnagel, MD and K.A. Gyure, MD

Overview

A 62-year-old man presented with a one month history of inability to have a bowel movement and a several week history of inability to pass urine easily. He complained of dull sacral pain without significant sensory changes and had good strength of his lower extremities.

Gross Description

An MRI showed a large, erosive sacral mass extending into the retroperitoneum as well as a small right renal cortical cystic lesion and an enlarged prostate. No lesions were present on colonoscopy. A biopsy of the lesion retrieved gray-white, mucoid tissue admixed with bone fragments. Microscopic images are provided below (Figures 1 and 2):

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Figure 1 : Tumor cells are present within bone.
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Figure 2 : The cells are round to oval with a central nucleus and have abundant, light ly eosinophilic, and somewhat vacuolated cytoplasm.

Diagnosis

What is the diagnosis ?

Answer

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Discussion

Chordoma is a midline malignant tumor which typically occurs at the two poles of the vertebral column, the skull base and the sacrum. It arises in the axial skeleton from notochordal embryologic remnant cells and represents approximately one percent of malignant primary bone tumors.[1-3] Lesions derived from notochordal remnants can range from the benign ecchordosis physaliphora to destructive malignant chordomas.[4] Chordomas may be divided into conventional or chondroid variants.[5]

Chordomas are more common in men (2:1) with a typical age of incidence between 40 and 70 years, but they can occur at any age with an incidence rate of < 0.1 per 100,000 per year.[3,5,6] In adults, chordoma is more common in the sacrococcygeal region, and in children, it is more common in the spheno-occipital region followed by the thoracolumbar spine. Approximately 50% of tumors are destructive intrasacral lesions that present with pain, bladder dysfunction, and constipation as in this case. The spheno-occipital tumors account for approximately 35% of cases and typically involve the clivus.[1,3,5] Patients with these lesions present with cranial nerve deficits such as facial numbness, dysphagia, or diplopia and with hypopituitarism. Erosive lesions very rarely may cause epistaxis or cerebrospinal fluid rhinorrhea.[5] The somewhat controversial chondroid variant of chordoma has a predilection for the skull base and may have a worse prognosis than conventional chordoma. The remainder of chordomas occur in the cervical and lumbar regions [15%]. Chordomas can have life-threatening local invasion with occasional metastasis to the lungs, bone, liver, lymph nodes, and skin.[5] Late metastasis has been reported in up to 43% of cases.[5] These tumors tend to recur after surgical resection and have a mean survival of four years for skull base lesions and less than 10 years for sacral lesions.[1,3]

Chordomas are extradural lesions which may not be visualized on plain x-rays. At diagnosis, there is usually radiologic evidence of osteolytic bone destruction with occasional extrasosseous extension. By conventional plain film x-ray, chordomas will classically show expansion of surrounding thin trabecular bone with focal calcification within the tumor.[1,4,5,6] On magnetic resonance imaging, tumors are heterogeneous due to the mucoid extracellular matrix. CT or MR imaging are the preferred modalities for pre-surgical analysis. As in this case, sacrococcygeal chordomas may destroy bone and directly extend into the retroperitoneum, presenting as a palpable extrarectal mass. It may be difficult by imaging studies alone to differentiate chordomas from a metastatic lesion or an aggressive nerve sheath tumor.[1-3,5,6]

Chordomas are soft, lobulated, gray-red, translucent, gelatinous, and hemorrhagic lesions with gritty calcifications and fragments of thin overlying bone. Microscopically, they are characterized by large physaliferous cells with vacuolated or bubbly cytoplasm separated by thin fibrous septa and extracellular myxoid stroma.[2] The cells grow in lobules, cords, or sheets. The extracellular mucus contains hyaluronidase-resistant, sulfated mucopolysaccharide material.

Classic chordomas have distinctive phyasliphorous cells in a mucoid matrix, and, in conjunction with radiographic and clinical history, do not typically require additional staining. Brachyury, a transcription factor, is a recently identified, highly sensitive and specific marker for all chordomas and benign notochordal remnant cells, but it can be negative in high-grade regions. Brachyury is nearly always negative in chondrosarcomas and carcinomas.[7] The tumor cells in chordomas are also immunoreactive for cytokeratins (CK 8/18, AE1/AE3), epithelial membrane antigen (EMA), and S-100 protein.

Investigation into the genetic abnormalities of chordoma has been limited by the rare nature of the tumor. The lack of 1p36 loss of heterozygosity or the presence of TNFRSF8 expression has been suggested to correlate with a better prognosis.[6] Chordomas may have mutations of the c-MET proto oncogene as well as expression of cathepsin B and K and urokinase type plasminogen activator [8], which are thought to be related to invasive potential. Up regulation of N-cadherin, p53 protein, and MDM2, and down regulation of E-cadherin may also be poor prognostic factors.[6] Interestingly, there is some evidence that losses at the TSC1 (9q34) or TSC2 (16p13) gene loci may play a role in the coexistence of sacrococcygeal chordomas and tuberous sclerosis.[9] Loss of heterozygosity of the retinoblastoma (RB) gene has also been found in several chordomas.[1,5]

Treatment for chordomas includes aggressive surgery. However, because of the tumor’s location and invasive nature, complete resection is often difficult.[1,5,9] For skull based tumors in children, external radiation is often successful, but in general chordomas are considered radioresistant and have not been reported to be sensitive to chemotherapy.[3,5] Poor prognostic factors include large tumor size, extensive necrosis, positive surgical margins, high mitotic activity, areas of dedifferentiation to high grade spindle cell sarcomas, and metastasis. This slow growing, frequently recurrent tumor may have distant metastases to unexpected locations such as skin, bone, and ovaries. After distant metastasis has occurred, the median survival is less than 12 months.[5] Wide surgical excision offers the best chance for a cure.

References

  1. Burger, P., Scheithauer, B. Tumors of the Central Nervous System. Washington, DC: American Registry of Pathology, 2007.
  2. Yamaguchi T, Watanabe-Ishiiwa H, Suzuki S, Igarashi Y, Ueda Y. Incipient chordoma: A report of two cases of early-stage chordoma arising from notochordal cell remnants. Mod Pathol 2005;18:1005–1010.
  3. Rosai, J. Rosai and Ackerman’s Surgical Pathology, 10th edition. Philadelphia, PA: Elsevier Health Sciences, 2011.
  4. Yamaguchi, T Iwata, J., Sugihara, S., et al. Distinguishing benign notochordal cell tumors from vertebral chordoma. Skeletal Radiol 2008; 37:291-299.
  5. Chugh, R., Tawbi, H., Lucas, D., et al. Chordoma: The nonsarcoma primary bone tumor. Oncologist 2007;12:1344-1350.
  6. Longoni, M., Orzan, F., Stroppi, M., et al. Evaluation of 1p36 markers and clinical outcome in a skull base chordoma study. Neuro-Oncology 2008;10:52-60.
  7. Oakley, G., Fuhrer, K.,Seethala, R., Brachyury, SOX-9 and podplanin, new markers in the skull base chordoma vs chondrosarcoma differential: a tissue microarray-based comparative analysis. Mod Pathol 2008;21:1461-1469.
  8. Naka, T. Invasive ability in chordoma. Austral - Asian Journal of Cancer 2012;11:255-260.
  9. Lee-Jones, L., Aligianis, I., Davies, P. Sacrococcygeal chordomas in patients with tuberous sclerosis complex show somatic loss of TSC1 or TSC2. Genes Chromosomes Cancer 2004:41; 80-85.