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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]

Synonyms and keywords: Occult cancer; CUP; Metastases of unknown primary origin; Unknown primary origin neoplasm; cancers of unknown primary site; neoplasms of unknown primary site

Historical Perspective

• Cancer of unknown primary origin was first discovered by [scientist name], a [nationality + occupation], in [year] during/following [event].
• In [year], [gene] mutations were first identified in the pathogenesis of cancer of unknown primary origin.
• In [year], the first [discovery] was developed by [scientist] to treat/diagnose cancer of unknown primary origin.

Classification

• Cancer of unknown primary origin may be classified according to [classification method] into [number] subtypes/groups:

• [group1]
• [group2]
• [group3]

• Other variants of cancer of unknown primary origin include [disease subtype 1], [disease subtype 2], and [disease subtype 3].

Pathophysiology

• The pathogenesis of Cancer of unknown primary origin is characterized by [feature1], [feature2], and [feature3].
• The [gene name] gene/Mutation in [gene name] has been associated with the development of cancer of unknown primary origin, involving the [molecular pathway] pathway.
• On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of Cancer of unknown primary origin.
• On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of Cancer of unknown primary origin.

Causes

• Cancer of unknown primary origin may be caused by either [cause1], [cause2], or [cause3].
• Cancer of unknown primary origin is caused by a mutation in the [gene1], [gene2], or [gene3] gene[s].
• There are no established causes for cancer of unknown primary origin.

Differentiating Cancer of Unknown Primary Origin from Other Diseases

• Cancer of unknown primary origin must be differentiated from other diseases that cause [clinical feature 1], [clinical feature 2], and [clinical feature 3], such as:

• [Differential dx1]
• [Differential dx2]
• [Differential dx3]

Epidemiology and Demographics

• The prevalence of cancer of unknown primary origin is approximately [number or range] per 100,000 individuals worldwide.
• In [year], the incidence of Cancer of unknown primary origin was estimated to be [number or range] cases per 100,000 individuals in [location].

Age

• Patients of all age groups may develop cancer of unknown primary origin.

• Cancer of unknown primary origin is more commonly observed among patients aged [age range] years old.
• Cancer of unknown primary origin is more commonly observed among [elderly patients/young patients/children].

Gender

• Cancer of unknown primary origin affects men and women equally.

• [Gender 1] are more commonly affected with cancer of unknown primary origin than [gender 2].
• The [gender 1] to [Gender 2] ratio is approximately [number > 1] to 1.

Race

• There is no racial predilection for cancer of unknown primary origin.

• Cancer of unknown primary origin usually affects individuals of the [race 1] race.
• [Race 2] individuals are less likely to develop Cancer of unknown primary origin.

Risk Factors

• Common risk factors in the development of cancer of unknown primary origin are [risk factor 1], [risk factor 2], [risk factor 3], and [risk factor 4].

Natural History, Complications and Prognosis

• The majority of patients with cancer of unknown primary origin remain asymptomatic for [duration/years].
• Early clinical features include [manifestation 1], [manifestation 2], and [manifestation 3].
• If left untreated, [#%] of patients with Cancer of unknown primary origin may progress to develop [manifestation 1], [manifestation 2], and [manifestation 3].
• Common complications of Cancer of unknown primary origin include [complication 1], [complication 2], and [complication 3].
• Prognosis is generally [excellent/good/poor], and the [1/5/10­year mortality/survival rate] of patients with Cancer of unknown primary origin is approximately [#%].

Diagnosis

Diagnostic Criteria

• The diagnosis of cancer of unknown primary origin is made when at least [number] of the following [number] diagnostic criteria are met:

• [criterion 1]
• [criterion 2]
• [criterion 3]
• [criterion 4]

Symptoms

• Cancer of unknown primary origin is usually asymptomatic.
• Symptoms of cancer of unknown primary origin may include the following:

• [symptom 1]
• [symptom 2]
• [symptom 3]
• [symptom 4]
• [symptom 5]
• [symptom 6]

Physical Examination

• Patients with cancer of unknown primary origin usually appear [general appearance].
• Physical examination may be remarkable for:

• [finding 1]
• [finding 2]
• [finding 3]
• [finding 4]
• [finding 5]
• [finding 6]

Laboratory Findings

• There are no specific laboratory findings associated with cancer of unknown primary origin.

• A [positive/negative] [test name] is diagnostic of cancer of unknown primary origin.
• An [elevated/reduced] concentration of [serum/blood/urinary/CSF/other] [lab test] is diagnostic of Cancer of unknown primary origin.
• Other laboratory findings consistent with the diagnosis of Cancer of unknown primary origin include [abnormal test 1], [abnormal test 2], and [abnormal test 3].

Imaging Findings

• There are no [imaging study] findings associated with cancer of unknown primary origin.

• [Imaging study 1] is the imaging modality of choice for cancer of unknown primary origin.
• On [imaging study 1], Cancer of unknown primary origin is characterized by [finding 1], [finding 2], and [finding 3].
• [Imaging study 2] may demonstrate [finding 1], [finding 2], and [finding 3].

Other Diagnostic Studies

• Cancer of unknown primary origin may also be diagnosed using [diagnostic study name].
• Findings on [diagnostic study name] include [finding 1], [finding 2], and [finding 3].

Treatment

Medical Therapy

• There is no treatment for cancer of unknown primary origin; the mainstay of therapy is supportive care.

• The mainstay of therapy for cancer of unknown primary origin is [medical therapy 1] and [medical therapy 2].
• [Medical therapy 1] acts by [mechanism of action1].
• Response to [medical therapy 1] can be monitored with [test/physical finding/imaging] every [frequency/duration].

Surgery

• Surgery is the mainstay of therapy for cancer of unknown primary origin.
• [Surgical procedure] in conjunction with [chemotherapy/radiation] is the most common approach to the treatment of Cancer of unknown primary origin.
• [Surgical procedure] can only be performed for patients with [disease stage] Cancer of unknown primary origin.

Prevention

• There are no primary preventive measures available for cancer of unknown primary origin.

• Effective measures for the primary prevention of cancer of unknown primary origin include [measure1], [measure2], and [measure3].

• Once diagnosed and successfully treated, patients with Cancer of unknown primary origin are followed-up every [duration]. Follow-up testing includes [test 1], [test 2], and [test 3].

References

Solitary Pulmonary Nodule Detected

Step 1: Assess likelihood of cancer ❑ Mayo Clinic Malignancy Risk Calculator

Step 2: Review prior films Is there a growth?

No previous films *Refer to step 2A

Yes, growing

No, stable

Step 2A Enhanced Computed Tomography

Step 2B Surveillance

Imaging evaluation

Location ❑ Upper lobe ❑ Lower lobe ❑ Middle lobe Size ❑ < 8mm ❑ > 8mm Lesion characteristics ❑ Margins (irregular/regular) ❑ Shape (spiculated/rounded) ❑ Attenuation

Other Diagnostic Studies ❑ PET/CT scan

Low risk ❑ < 5%

Intermediate risk ❑ 5-65%

High risk ❑ > 65%

Serial CT scans

Non-surgical biopsy *Refer to Step 3: Treatment

Surgical resection *Refer to Step 3: Treatment

Step 3: Treatment

Step 1: Assess likelihood of cancer ❑ Clinical judgment ❑ Mayo Clinic Malignancy Risk Calculator

Step 2: Review prior films Is there a growth?

Yes

No

Enhanced Computed Tomography

Surveillance

Imaging evaluation

Location ❑ Upper lobe ❑ Lower lobe ❑ Middle lobe Size ❑ < 8mm ❑ > 8mm Lesion characteristics ❑ Margins (irregular/regular) ❑ Shape (spiculated/rounded) ❑ Attenuation

Other Diagnostic Studies ❑ PET/CT scan ❑ Bronchoscopy ❑ Mediastinoscopy

Biopsy

Step 3 Treatment