Thymic Carcinoma: Should Biology Dictate Therapy

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Thymic Carcinoma Should Biology Dictate Therapy

• Jeff Bednarski, M.D., Ph.D

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Case Presentation

• 16 yo boy presented with 1-2 month history of
  pain and swelling in joints, including kness,
  ankles, elbows, wrists, fingers, and shoulders.
  Decreased energy. Chills and night sweats often
  soaking the sheets. 20-25 lb wt loss. Also
  notes chest pain with some difficulty breathing
  and coughing.
• PMH Exercise-induced asthma accidental
  amputation of distal phalanx of right index
  finger
• Meds ibuprofen and aleve
• FH maternal cousin died of leukemia 2 yrs ago
  (age 20).
• PE Digital clubbing. Swollen, warms knees,
  ankles, and wrists with effusion. Small
  lymphadenopathy of anterior cervical chain and
  bilateral groins (all lt 1 cm). Lungs clear.
  Heart regular rate and rhythm

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Case Presentation

• Labs
• WBC 22.7 with normal diff.
• Hgb 10.5
• Plt 637,000
• LDH 174
• Uric acid 3.6
• ESR 52 (nl lt 20)
• CRP 7.4 (nl lt 0.3)
• ANA neg.
• Anti-dsDNA neg.
• C3 and C4 normal
• CMV IgM and IgG neg
• EBV IgM neg
• EBV IgG postive
• ACE 18 (nl 10-55)

• Radiology
• CXR Anterior and mediastinal lymphadenopathy
• Wrists and Knees diffuse periosteal reaction
• CT scan 11.4 x 5.8 cm mediastinal mass with
  compression of SVC. Plus nodular thickening of
  pleura. Some thoracic lymphadenopathy but
  nothing noted outside of chest.

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Case Presentation

• Mass was biopsied and was consistent with
  thymoma.
• Returned for surgical excision and found to have
  involvement of the innominate vein, SVC and right
  internal jugular vein as well as phrenic nerve
  and pericardium. Had complete excision with
  reconstruction of vessels, plication of right
  diaphragm and removal of pericardium.
• Final pathology lymphoepithelioma-like carcinoma
  arising from thymus tumor seen in 4 of 13
  associated LNs and 3 of 3 LN from right mammary
  region LNs from left mammary region were
  negative. EBER positive and EBV-LMP negative.

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Thymic Carcinoma

• Thymic epithelial tumors
• Thymoma
• Thymic Carcinoma
• Thymic Carcinoid
• Thymic epithelial tumors are more common in the
  4th to 5th decade of life
• Constitute 1.5 of mediastinal masses in
  children
• Carcinomas constitute 4-14 of cases
• Less than 20 reported cases of thymic carcinoma
  under 18 years of age.
• Thymic carcinoma obvious cytological anaplasia,
  extensive infiltraion of surrounding tissues and
  extrathoracic metastasis. Generally, poor
  prognosis.

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Thymic Carcinoma

• Various histological subtypes
• Squamous cell carcinoma (majority of cases)
• Lymphoepithelioma-like carcinoma
• Clear-cell carcinoma
• Undifferentiated carcinoma
• Paraneoplastic syndromes can occur but are
  present much less frequently than in thymoma
• Myasthenia gravis, lupus, scleroderma and
  hypertrophic osteoarthropathy
• Staging (Masaoka)
• Stage I completely encapsulated
• Stage II focally infiltrates capsule or
  mediastinal fat
• Stage III direct extension into adjacent
  structures
• Stage IVa separate tumore nodules on pericardium
  or pleura
• Stage IVb lymph node or distant metastases

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Thymic LELC

• 12-32 of all thymic carcinomas
• More aggressive
• 20-25 have involvement of pleura, diaphragm and
  pericardium
• 67 have extrathoracic mets
• 46 have lymphatic mets
• Sites of metastasis lungs (43), liver (46),
  bones (29), kidneys (18), and brain (11).
• Poorest prognosis with average survival 20 mon.
• Associated with EBV
• EBV not seen in other thymic tumors
• bears resemblance to nasopharyngeal carcinoma
• In adults, 47 of thymic LELC were EBV-associated
• All pediatric cases tested are postitive for EBV

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Thymic Carcinoma Treatment

• Surgery has been the backbone of therapy
• Complete surgical resection has the best
  prognosis
• Chemotherapy and radiation therapy have been
  added to make unresectable lesions more amenable
  to surgery and to improve outcomes in subtotal
  resection.
• In general, the therapy for thymic carcinoma has
  evolved out of treatment for thymomas.
• Very rare disease, making large prospective
  trials difficult.

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Thymic Carcinoma Radiation

• Eng and Thomas, 2005
• Thymomas are radiosensitive
• Thymoma, stage II, resected recurrence was 29
  w/o radiation vs. 8 with radiation
• Thymoma, stage III/IV, resected risk of
  recurrent decreased from 50 to 20
• Thymic carcinoma no survival benefit has been
  shown but there is improved local control of
  disease
• Toxicities to heart, lungs, ribs and spine are
  concerns.

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Thymic Carcinoma Chemotherapy

• Yoh, et al 2003 retrospectively reviewed 12
  patients with thymic carcinoma treated with
  cisplatin, vincristine, doxorubicin, and
  etoposide (CODE)
• 11 of 12 had stage IV disease
• Given 6 cycles of chemo
• Overall response rate was 42
• Median PFS was 5.6 months OS at 1 yr. 80 and at
  2 yrs. 58

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Thymic Carcinoma Chemotherapy

• Koizumi, et al. (2002) retrospectively review 8
  cases with stage IV disease treated with
  cisplatin, doxorubicin, vincristin and
  cyclophosphamide (ADOC)
• PR in 75 of patients (no CR)
• Median survival 19 months
• Other regimens attempted included
• Cisplatin, doxorubicin, cyclophosphamide
• Cisplatin, epirubicin, etoposide /- prednisone

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Thymic Carcinoma Treatment
Survival based on Stage

• Kondo and Monden (2003) reviewed 1,320 cases of
  thymic epithelial tumors from across Japan
• Adjuvant therapy does not improve prognosis
• Stage and surgical resection are best predictors
  of overal survival

I/II
III
IV
Survival in Stage III/IV based on Resection
Survival in Stage III/IV based on Therapy
CT
None
Complete
RT
Partial
CTRT
unresect
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Thymic Carcinoma in Children

• Yaris, et al (2006) reported a 16 yo with Stage
  IVb LELC
• Treated with neoadjuvant chemo consisting of
  cisplatin (100 mg/m2), etoposide (120 mg/m2) and
  doxorubicin (20 mg/m2)
• Had decrease in mass size but develop metastases
• Chemo changed to cisplatin, vincristine,
  ifosfamide, doxorubicin
• Died at 15 mons due to progressive disease

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Thymic Carcinoma in Children

• Hsueh, et al (2006) reported on LELC in children.
  Reported 2 cases and reviewed 7 additional cases
  from literature.
• 14 yo boy with unresectable mass treated with
  cisplatin, cyclophosphamide, epirubicin and
  prednisone plus RT. Developed metastases and
  died at 10 mon.
• 10 yo boy with partial resection then treated
  with chemo plus RT. Developed metastases and
  died at 11 mon.
• All tumors were EBER positive and LMP-1 was
  detected in case 2.
• Review
• Malefemale 54
• Four had hypertrophic osteoarthropathy at
  presentation
• In all cases studied, EBV was identified.
• Most patients died by 2 years. 2 patients
  survived to 3 and 12 years

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Other LELC tumors

• Nasopharyngeal carcinoma in children
• Highly EBV associated
• Very responsive to cisplatin and 5-FU based
  chemotherapy.
• Mertens, et al (2005) reported on a multicenter
  trial with methotrexate (120 mg/m2), cisplatin
  (100 mg/m2) and 5-FU (1000 mg/m2) followed by
  radiation and subsequently with INF-beta
• 59 patients 95 had response after chemo (14
  had CR and 86 had PR)
• 72 in CR after chemo and RT
• DFS 91 and OFS 95 at 9 years.
• Lung LELC (Chan, et al 1998)
• 71 with PR to cisplatin and 5-FU therapy (no CR)
  
• One literature case report of thymic LELC treated
  with oxaloplatin and 5-FU

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Biology and Therapy

• Thymomas had high expression of mRNA for
  thymidylate synthase (TS) and dihydropyrimidine
  dehydrogenase (DPD). Sasaki, et al (2003)
• TS converts dUMP to dTMP. 5-FU exerts its effect
  by forming a complex between TS and
  methylene-tetrahydrofolate resulting in
  inhibition of TS and blockage of DNA synthesis.
  Overexpression of TS confers resistance to 5-FU
• DPD degrades 5-FU. Increased expression confers
  resistance.
• Thus, 5-FU may not be useful in treating thymomas
• Topoisomerase 2alpha is overexpressed in thymic
  carcinoma Liu, et al (2006). All patients with
  overexpression responded to CAP (cisplatin,
  adriamycin, cyclophosphamide) therapy whereas
  those patients with no detectable expression
  progressed on treatment.

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Hypertrophic Osteoarthropathy

• Syndrome of digital clubbing and periosteal
  proliferation along tubular bones. Other
  manifestations include painful swelling of
  exremities and arthralgias.
• In adults, 92 of cases are associated with
  malignancy (most commonly intrathoracic).
• In children, only 12 are associated with
  malignancy.
• Pathogenesis remains unclear
• VEGF is induced by hypoxia through COX-2
  up-regulation. VEGF is endothelial cell mitogen
  and vascular permeability factor.
• COX-2 upregulation may increase prostaglandins.
  Prostaglandins normally in-activated by
  first-pass through the lungs by a prostaglandin
  dehydrogenase
• Typically resolves once tumor is removed.

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Conclusions

• Complete resection is the most important
  prognostic factor
• Uncertain role of chemotherapy or radiation
  therapy in completed resected masses.
• Chemotherapy and radiation likely play an
  important role in unresectable and partially
  resected masses
• Most chemotherapy regimens achieve PR but few
  CRs.
• There may be benefit in tailoring therapy to
  subtypes of thymic carcinomas and in exploring
  therapies outside of those designed for thymomas.

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Back to Case

• Is chemo warranted? If disease is still present,
  yes. But unclear whether its beneficial in the
  absence of radiation therapy.
• Can we watch and wait? If no identifiable
  disease, may be reasonable.

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References

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• Koizumi, T Takabayashi, Y Yamagishi, S
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