What is the approach to diagnosing and treating suspected pathology?

Diagnostic Approach to Suspected Pathology

When evaluating suspected pathology, begin with a systematic three-step diagnostic formulation: (1) determine the functional status or severity of the condition, (2) characterize the clinical syndrome pattern, and (3) establish the most likely underlying disease or cause. 1

Initial Diagnostic Framework

Step 1: Form and Test Your Diagnostic Hypothesis

• Generate a diagnostic hypothesis based on available clinical information and estimate its likelihood before ordering tests 1, 2
• Determine how certain the diagnosis must be based on disease severity and the consequences of missing or delaying treatment 1, 2
• Reassess the probability of your suspected diagnosis and select appropriate diagnostic tests based on this revised probability 1, 2
• Evaluate your post-test confidence and decide whether additional testing or treatment is warranted 1, 2

Step 2: Classify Diagnostic Confidence Level

• Categorize cases into "high confidence," "low confidence/indeterminate," or "alternative diagnosis" based on initial findings 1, 2
• For indeterminate cases, assign a provisional diagnosis while pursuing further evaluation, recognizing that this diagnosis may change as new data emerge 1, 2
• Document the confidence level explicitly to guide subsequent testing decisions and prevent overutilization of invasive procedures in high-confidence cases 1, 2

Tissue Acquisition and Pathologic Evaluation

Obtaining Adequate Tissue

• Prioritize core needle biopsy over fine needle aspiration to obtain adequate tissue for both diagnosis and molecular testing 1
• Consult with the pathologist before the procedure to determine if additional biopsy material will be necessary 1
• When multiple sites are involved, biopsy the pathology conferring the highest stage (e.g., suspected metastasis or lymph node rather than the primary lesion) 1

Key Factors in Selecting Diagnostic Procedures

Consider these factors when choosing the optimal diagnostic approach 1:

• Anticipated diagnostic yield (sensitivity) and accuracy including the reliability of negative results
• Adequate tissue volume for both histologic diagnosis and molecular testing
• Invasiveness and procedural risk
• Efficiency of evaluation and access to the procedure
• Concomitant staging capability to avoid additional procedures

Pathologic Examination Process

The pathologist follows a systematic approach 3:

1. Determine if a lesion is present, then whether it is neoplastic or non-neoplastic (neoplastic lesions consist of a single clonal cell type, while non-neoplastic conditions contain multiple cell types)
2. Distinguish epithelial from mesenchymal origin based on cell shape, growth pattern, stromal characteristics, and vascular arrangement 3
3. Assess for malignancy based on differentiation, growth rate, growth pattern (invasive vs. expansile), cellularity, necrosis, and nuclear alterations 3
4. Classify the specific tumor type using histologic features, supplemented by immunohistochemistry, molecular diagnostics, or electron microscopy when needed 1, 3

Specialized Testing Strategy

Tiered Approach to Additional Testing

• Avoid a "shotgun" approach to diagnostic testing; use a tiered strategy based on clinical complexity 1
• Tier 1 testing (basic laboratory studies and standard imaging) is sufficient for most typical presentations 1
• Reserve specialized biomarker testing, advanced imaging, and subspecialty evaluations for atypical presentations, complex cases, or when initial evaluation is inconclusive 1

When to Consider Neuropsychological or Specialized Assessment

Pursue specialized evaluation when 1:

• Symptoms are mild, unusual, or the presentation is atypical
• Educational extremes (very limited or extensive education) complicate interpretation
• Language or cultural considerations affect assessment
• Significant comorbidities (sensory impairments, movement disorders, stroke, psychiatric conditions, substance abuse) may confound the clinical picture

Immunohistochemical Panels

• Use directed, limited immunohistochemical panels rather than large, unfocused panels 1
• For distinguishing primary lung adenocarcinoma from metastatic colorectal cancer: TTF-1, CK7, CK20, and CDX-2 provide diagnostic clarity 1
• For tumors of unknown origin, CK7/CK20 patterns help narrow the differential (e.g., CK7+/CK20+ suggests urothelial origin; CK7-/CK20- suggests liver, kidney, or prostate) 1

Multidisciplinary Evaluation

When and How to Engage Multidisciplinary Teams

• Complex cases, atypical presentations, and cases with neuropsychiatric or sensorimotor dysfunction require multidisciplinary team involvement 1
• For suspected lung cancer, decisions should involve thoracic radiologists, interventional radiologists, and board-certified thoracic surgeons with significant thoracic oncology experience 1
• Review all available data collectively rather than in isolation to identify diagnostic patterns 1, 2

Integrating Clinical and Pathologic Information

• The pathologist must receive pertinent clinical information and radiographic findings to integrate with histopathologic evaluation 1
• Clinical formulation should be succinct and incorporated into an individualized care plan 1
• For example, distinguish between a patient with cognitive impairment alone versus one with cognitive impairment plus anxiety, sleep disturbance, and motor dysfunction, as these require different management approaches 1

Managing Diagnostic Uncertainty

The Iterative Diagnostic Process

• Recognize that diagnosis is iterative and should be revisited as additional data become available 1, 2
• Create a clear follow-up plan with specific timeframes for reassessment when diagnostic uncertainty persists 2
• Consider atypical presentations of common diseases before pursuing rare diagnoses 2

When to Stop Testing and Start Treatment

• Do not delay treatment while awaiting complete diagnostic workup in severe or progressive presentations 1, 2
• Clinical judgment about test-treatment thresholds should consider disease behavior and the impact of delayed treatment 1
• In some cases, diagnostic uncertainty may remain even after invasive procedures; in the absence of a predominant alternative cause, maintain a "provisional" diagnosis and proceed with treatment based on multidisciplinary consensus 1

Critical Pitfalls to Avoid

• Never perform preoperative bronchoscopy or separate staging procedures when intraoperative assessment is feasible, as this adds time, cost, coordination burden, and additional anesthetic risk 1
• Avoid overutilizing invasive diagnostic procedures (VATS, mediastinoscopy) in patients with high-confidence provisional diagnoses 1, 2
• Do not fail to obtain adequate tissue volume for molecular testing, as this may necessitate repeat procedures 1
• Never neglect to revisit and revise the working diagnosis when new information becomes available 1, 2
• Avoid using large, unfocused immunohistochemical panels when directed panels based on the differential diagnosis are more appropriate 1

Communication with Patients

• Explain that the diagnostic process is iterative and may require multiple assessments over time 2
• Provide clear information about suspected conditions and the rationale for the chosen diagnostic approach 2
• Discuss how diagnostic uncertainty affects treatment decisions and prognosis 2