1. health and fitness
2. disease
3. cancer

1
This practice algorithm has been specifically developed for MD Anderson using a multidisciplinary approach and taking into consideration circumstances particular to MD Anderson,
including the following: MD Anderson’s specific patient population; MD Anderson’s services and structure; and MD Anderson’s clinical information. Moreover, this algorithm is not
intended to replace the independent medical or professional judgment of physicians or other health care providers. This algorithm should not be used to treat pregnant women.
Note: Consider Clinical Trials as treatment options for eligible patients.
EVALUATION
FURTHER WORK-UP
FINDINGS
Ultrasound
● FNA or Core needle
biopsy (preferred)3
● CT scan of head and
neck
● Consider PET/CT
TREATMENT
Head and Neck Surgery:
● Triple endoscopy
● Consider tonsillectomy
●
History and physical including
pelvic, rectal and hemoccult
exam
● Complete Blood Count, Liver
Function Tests/chemistry
profile, Prostate Surface
Antigen, other directed serum
tumor markers1
● CT scan of chest, abdomen and
pelvis and mammogram
● Endoscopy when indicated
● MRI of the brain and bone scan
if symptomatic
● PET/CT (optional)
●
Metastatic
cervical
adenopathy
Squamous
cell1
carcinoma
(5%)
Fine Needle
Aspiration or core
biopsy (preferred) of
most accessible lesion2
Metastatic
inguinal
adenopathy
Disseminated,
visceral
metastases
Undifferentiated carcinoma,
neuroendocrine carcinoma,
undifferentiated neoplasm
(30% all included)
Copyright 2014 The University of Texas MD Anderson Cancer Center
Yes
No, disseminated disease
Perineal exam, anoscopy if needed
3
● Pelvic examination in a woman
● PET/CT optional
● Cystoscopy/urologic evaluation if indicated
●
For neuroendocrine carcinoma:
● Octreotide scan
● Bone scan and
● Neuroendocrine markers as
indicated
If localized, lymph node dissection or local
radiation therapy (or both in selected cases)
● Neoadjuvant chemotherapy in selected cases
●
Low grade/
intermediate
High grade
Chemotherapy if good performance status
●
●
Directed invasive tests as needed
Chemotherapy if good performance status
Radiation therapy as indicated
Octreotide when indicated
Systemic therapy
● Radiation therapy
● Surgery when indicated
●
●
Chemotherapy with etoposide/
cisplatin or irinotecan/cisplatin
Refer to
Neuroendocrine
Service when
indicated
Serum and immunohistochemical markers to
exclude extragonadal germ cell
● Chemotherapy in good-performance status patients
● Surgery and radiation therapy if indicated
●
1
Refer to Appendix A for MD Anderson
approved biomarkers.
2
The biopsied lesion may be the
primary site.
3
If suspecting Head and Neck ,Cervical,
or Anal malignancy, consider testing
for HPV in situ hybridization.
Localized
to head and
neck?
Refer to Head and
Neck Service for
further treatment
recommendations
Undifferentiated carcinoma,
undifferentiated neoplasm
Adenocarcinoma1, poorly differentiated
carcinoma (65%) – See Page 2
Department of Clinical Effectiveness V4
Approved by Executive Committee of the Medical Staff 07/29/2014
1
This practice algorithm has been specifically developed for MD Anderson using a multidisciplinary approach and taking into consideration circumstances particular to MD Anderson,
including the following: MD Anderson’s specific patient population; MD Anderson’s services and structure; and MD Anderson’s clinical information. Moreover, this algorithm is not
intended to replace the independent medical or professional judgment of physicians or other health care providers. This algorithm should not be used to treat pregnant women.
Note: Consider Clinical Trials as treatment options for eligible patients.
FINDINGS
FURTHER
WORK-UP
ADDITOINAL FINDINGS
Disseminated cancer, two
or more sites involved
Immunohistochemical
markers to help suggest
“most likely” primary
● Estrogen Receptor/
Progesterone Receptor
in women
● Alpha Fetoprotein and
beta -human chorionic
gonadotropin for poorly
differentiated
carcinoma to rule out
germ cell (See Table 1,
Figure 1)
See Notes below
TREATMENT
Chemotherapy if good performance status
●
Adenocarcinoma1,
poorly
differentiated
carcinoma (65%)
If suggestive of primary peritoneal cancer, refer to
ovarian cancer algorithm. Palliative measures, as
needed, for small bowel obstruction.
Women with peritoneal carcinoma
(typically, serous papillary pathology) in
the presence of normal ovaries: check
Cancer Antigen-125
If resectable, resect with or without prior chemotherapy,
chemoradiation.
If unresectable, chemotherapy, radiation or chemoradiation
PET/CT recommended.
Solitary site of metastasis
Isolated axillary
nodes in women
Breast Magnetic
Resonance Imaging (MRI)
if mammogram and
ultrasound are negative
●
●
MRI negative, no surgery, consider radiation
Chemotherapy for breast cancer
Refer to Breast
Cancer Algorithm
MRI positive, breast surgery or
● Radiation therapy and chemotherapy
●
1
Refer to Appendix A for MD Anderson approved biomarkers.
NOTES:
● Gene Expression Profiling to identify the putative primary cancer profile (tissue of origin) is an
emerging diagnostic test; currently experimental and studies are ongoing.
● Appropriate mutation analysis studies where indicated. (E.g. in a lung profile patient, EGFR mutation
analysis when appropriate.
Copyright 2014 The University of Texas MD Anderson Cancer Center
Department of Clinical Effectiveness V4
Approved by Executive Committee of the Medical Staff 07/29/2014
This practice algorithm has been specifically developed for MD Anderson using a multidisciplinary approach and taking into consideration circumstances particular to MD Anderson,
including the following: MD Anderson’s specific patient population; MD Anderson’s services and structure; and MD Anderson’s clinical information. Moreover, this algorithm is not
intended to replace the independent medical or professional judgment of physicians or other health care providers. This algorithm should not be used to treat pregnant women.
Note: Consider Clinical Trials as treatment options for eligible patients.
TABLE 1: Commonly utilized immunoperoxidase stains to assist in the differential diagnosis of poorly diferentiated neoplasms
Likely Primary Site
Stain
Breast Cancer
Estrogen receptor (ER), Gross cystic disease fluid fibrous protein-15 (GCDFP-15), mammaglobin, Her-2 neu, GATA-3
Lung Cancer
Thyroid transcription factor (TTF-1), surfactant protein A, Napsin A
Prostate Cancer
PSA, PAP, Alpha-methylacyl CoA racemase/P504S (AMACR/P504S), Prostein
Lymphoma
Leukocyte common antigen (LCA), CD3, CD 4, CD 5, CD10, CD20, CD45, PAX5, Bcl-2, Bcl-6,cyclin D1
Mullerian/Ovarian
Estrogen receptor (ER), WT-1, PAX8
Sarcoma
Desmin1, factor VIII2, CD31, Smooth muscle actin for Leiomyosarcoma, MyoD1, myogenin for Rhabdomyosarcoma
Neuroendocrine Tumor
Chromogranin, Synaptophysin, CD56
Germ Cell Tumor
βHCG, αFP, OCT¾, CKIT, SALL4, CD30 (embryonal)
Urothelial Malignancies
CK7, CK20, Thrombomodulin, GATA-3
Colorectal Cancer
CK7, CK20, CDX-2, carcinoembryonic antigen (CEA)
Renal
RCC, CD10, PAX8
Hepatoma
HepPar-1, CD10, Glypican-3
Melanoma
S100, Vimentin, HMB-45, Tyrosinase and Melan-A
Thyroid
Thyroglobulin, TTF-1
1
2
Copyright 2014 The University of Texas MD Anderson Cancer Center
Positive in desmoid tumors, rhabdomyosarcomas, and leiomyosarcomas
Positive in angiosarcomas
Department of Clinical Effectiveness V4
Approved by Executive Committee of the Medical Staff 07/29/2014
This practice algorithm has been specifically developed for MD Anderson using a multidisciplinary approach and taking into consideration circumstances particular to MD Anderson,
including the following: MD Anderson’s specific patient population; MD Anderson’s services and structure; and MD Anderson’s clinical information. Moreover, this algorithm is not
intended to replace the independent medical or professional judgment of physicians or other health care providers. This algorithm should not be used to treat pregnant women.
Note: Consider Clinical Trials as treatment options for eligible patients.
Approach to Cytokeratin (CK7 and CK20) markers used in Cancer of Unknown Primary
FIGURE 1
CK7
CK20
CK7 positive, CK20 positive
CK7 positive, CK20 negative
CK7 negative, CK20 positive
CK7 negative, CK20 negative
Urothelial tumors
Ovarian mucinous adenocarcinoma
Pancreatic adenocarcinoma
Cholangiocarcinoma
Stomach carcinoma
Lung adenocarcinoma
Breast carcinoma
Thryoid carcinoma
Endometrial carcinoma
Cervical carcinoma
Salivary gland carcinoma
Cholangiocarcinoma
Pancreatic carcinoma
Stomach carcinoma
Esophageal carcinoma
Colorectal carcinoma
Merkel cell carcinoma
(dot-like pattern)
Hepatocellular carcinoma
Renal cell carcinoma
Prostate carcinoma
Squamous cell and small cell lung carcinoma
Head and neck carcinoma
Department of Clinical Effectiveness V4
Approved by Executive Committee of the Medical Staff 07/29/2014
Copyright 2014 The University of Texas MD Anderson Cancer Center
This practice algorithm has been specifically developed for MD Anderson using a multidisciplinary approach and taking into consideration circumstances particular to MD Anderson,
including the following: MD Anderson’s specific patient population; MD Anderson’s services and structure; and MD Anderson’s clinical information. Moreover, this algorithm is not
intended to replace the independent medical or professional judgment of physicians or other health care providers. This algorithm should not be used to treat pregnant women.
Note: Consider Clinical Trials as treatment options for eligible patients.
APPENDIX A: Unknown Primary Molecular Markers – MD ANDERSON APPROVED1
BIOMARKER
DISEASE SITE
Unknown Primary
CELL TYPE
FISH
Breast,
Gastric Profile
HER2/neu
Lung Profile
ALK rearrangement
IMMUNOHISTOCHEMISTRY
HER2/neu
Small Bowel, Colon
Profile
1
Literature
support for MD Anderson approved Biomarkers is available and can be found under Clinical Management Algorithms
1
Literature support for MD Anderson approved Biomarkers is available and can be found under Clinical Management Algorithms
Copyright 2014 The University of Texas MD Anderson Cancer Center
MOLECULAR
EGFR mutation
KRAS mutation
“Biomarkers – MD Anderson Approved”
“Biomarkers – MD Anderson Approved”
Department of Clinical Effectiveness V4
Approved by Executive Committee of the Medical Staff 07/29/2014
This practice algorithm has been specifically developed for MD Anderson using a multidisciplinary approach and taking into consideration circumstances particular to MD Anderson,
including the following: MD Anderson’s specific patient population; MD Anderson’s services and structure; and MD Anderson’s clinical information. Moreover, this algorithm is not
intended to replace the independent medical or professional judgment of physicians or other health care providers. This algorithm should not be used to treat pregnant women.
Note: Consider Clinical Trials as treatment options for eligible patients.
SUGGESTED READINGS
Briasoulis E, Kalofonos H, Bafaloukos D, et al. (2000). Carboplatin plus paclitaxel in unknown primary carcinoma: a phase II Hellenic Cooperative Oncology Group Study.
J Clin Oncol; 18:3101-7.
Bugat R, et al. (2003). Summary of the Standards, Options and Recommendations for the management of patients with carcinoma of unknown primary site. Br J Cancer; 89 Suppl 1:S59-66.
Culine S, Lortholary A, Voigt JJ, et al. Cisplatin in combination with either gemcitabine or irinotecan in carcinomas of unknown primary site: results of a randomized phase II study--trial for
the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01). J Clin Oncol 2003;21:3479-82.
Olson JA Jr, et al. (2000). Magnetic resonance imaging facilitates breast conservation for occult breast cancer. Ann Surg Oncol; 7(6): 411-505.
Olson JA, Jr., Morris EA, Van Zee KJ, et al. (2000). Magnetic resonance imaging facilitates breast conservation for occult breast cancer. Ann Surg Oncol; 7:411-5.
Greco FA, Hainsworth JD. (1997). One-hour paclitaxel, carboplatin, and extended-schedule etoposide in the treatment of carcinoma of unknown primary site. Semin Oncol; 24:S19-101-S19-05.
Hainsworth JD. (2006). Bevacizumab plus erlotinib in patients (pts) with carcinoma of unknown primary site: a phase II trial fo the Minnie Pearl Cancer Research Network.
J Clin Oncol; 24:3033.
Kende AI, et al. (2003). Expression of cytokeratins 7 and 20 in carcinomas of the gastrointestinal tract. Histopathology; 42(2):137-140.
Koch WM, Bhatti N, Williams MF, et al. (2001). Oncologic rationale for bilateral tonsillectomy in head and neck squamous cell carcinoma of unknown primary source.
Otolaryngol Head Neck Surg; 124:331-3.
Nanni C, Rubello D, Castellucci P, et al. (2005). Role of 18F-FDG PET-CT imaging for the detection of an unknown primary tumour: preliminary results in 21 patients.
Eur J Nucl Med Mol Imaging; 32:589-92.
Pavlidis N, Fizazi K. (2005). Cancer of unknown primary (CUP). Crit Rev Oncol Hematol; 54(3): 243-250.
Regelink G, Brouwer J, de Bree R, et al. (2002). Detection of unknown primary tumours and distant metastases in patients with cervical metastases: value of FDG-PET versus conventional
modalities. Eur J Nucl Med Mol Imaging; 29:1024-30.
Rusthoven KE, Koshy M, Paulino AC. (2004). The role of fluorodeoxyglucose positron emission tomography in cervical lymph node metastases from an unknown primary tumor.
Cancer; 101:2641-9.
Roh MS, Hong SH. (2002). Utility of thyroid transcription factor-1 and cytokeratin 20 in identifying the origin of metastatic carcinomas of cervical lymph nodes.
J Korean Med Sci; 17:512-7.
Tan D, Li Q, Deeb G, et al. (2003). Thyroid transcription factor-1 expression prevalence and its clinical implications in non-small cell lung cancer: a high-throughput tissue microarray and
immunohistochemistry study. Hum Pathol; 34:597-604.
Tothill RW, Kowalczyk A, Rischin D, et al. (2005). An expression-based site of origin diagnostic method designed for clinical application to cancer of unknown origin.
Cancer Res; 65:4031-40.
Varadhachary GR, et al. (2004). Diagnostic strategies for unknown primary cancer. Cancer 100(9): 1776-1785.
Varadhachary GR, Talantov D, Raber MN, et al. (2008). Molecular profiling of carcinoma of unknown primary and correlation with clinical evaluation. J Clin Oncol
26(27):4442-8.
Department
of Clinical Effectiveness V4
Approved by Executive Committee of the Medical Staff 07/29/2014
Copyright 2014 The University of Texas MD Anderson Cancer Center
This practice algorithm has been specifically developed for MD Anderson using a multidisciplinary approach and taking into consideration circumstances particular to MD Anderson,
including the following: MD Anderson’s specific patient population; MD Anderson’s services and structure; and MD Anderson’s clinical information. Moreover, this algorithm is not
intended to replace the independent medical or professional judgment of physicians or other health care providers. This algorithm should not be used to treat pregnant women.
Note: Consider Clinical Trials as treatment options for eligible patients.
DEVELOPMENT CREDITS
This practice consensus algorithm is based on majority expert opinion of the Gastrointestinal Faculty at the University of Texas MD Anderson Cancer
Center. It was developed using a multidisciplinary approach that included input from the following medical, radiation and surgical oncologists.
Beth Chasen MD
Renato Lenzi MD
Aurelio Matamoros MD
Martin Raber MD
Nelson Ordonez MD
Asif Rashid MD
Gauri Varadhachary MD Ŧ
Ŧ Core Development Team
Department of Clinical Effectiveness V4
Approved by Executive Committee of the Medical Staff 07/29/2014
Copyright 2014 The University of Texas MD Anderson Cancer Center