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Signature ✍️
- “Cryptic cancers” refers to malignancies that commonly evade the detection of the diagnostician owing to…
- Radiologic challenges: usually the crux of localized, primary cancers (e.g. too small, incorrect study)
- Pathologic challenges: usually the crux of diffuse cancers (e.g. misleading findings, inadequate specimen, incomplete immunostaining)
- Context challenges: refers to the myriad complications that either mask the underlying malignancy completely (e.g. post-obstructive pneumonia of endobronchial tumor) or entrap the diagnostician’s center of gravity (e.g. autoimmune disease of AITL, paraneoplastic syndrome)
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DDx 🏳️🌈
Lymphoproliferative (Pathologic/Context > Radiologic)
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- Radiology ⊕: cryptic lymphoproliferative disorders usually come in the form of aggressive diseases that are radiographically-visualizable but extranodal in location (i.e. radiologic “fake out”. ) Many are pathologically accompanied by a prominent lymphohistiocytic backdrop that can be confused for a “reactive” histology, when in fact that finding may represent the disease itself (i.e. pathologic challenge). Finally, if a skin biopsy is used as a proxy (i.e. no nodal tissue is acquired), findings can be non-specific & reactive to systemic disease (e.g. granulomatous dermatitis)
- Lymphomas
- Lymphomatoid Granulomatosis: the predominant histologic feature is not the neoplastic B-cells, but instead the accompanying lymphohistiocytic infiltrate & angiocentric T-cells. (Key to Dx = demonstrating EBV-⊕ B-cells via FISH.)
- T-cell/Histiocyte Rich B-cell Lymphoma (T/HRBCL): of note, the histologic appearance mirrors that of a special Hodgkin’s lymphoma subtype (Nodular lymphocyte-predominant Hodgkin’s lymphoma i.e. NLPHL), & B-cells can look very similar to Reed-Sternberg cells. (They can be easily differentiated by their very different clinical courses.)
- Anaplastic Large Cell Lymphoma (ALCL): ~20% have atypical pathologic findings, of which “lymphohistiocytic” is a subtype. If compatible histology, immunostaining for CD30 to look for characteristically strong membrane & Golgi pattern, as well as immunostaining for ALK (proxy for ALK gene rearrangement) can confirm the Dx, although some patients are ALK ⊖
- Angioimmunoblastic T-cell Lymphoma (AITL): malignant follicular T helper cells only represent a minority of cells within the malignant node, which is "effaced" & devoid of follicles. Accompanying autoimmune diseases (with numerous ⊕ autoantibodies) as well as HLH present substantial context challenges
- Subcutaneous Panniculitis-like T-cell Lymphoma (SPTCL): deep subcutaneous nodular lesions representative of panniculitis are often missed on superficial skin biopsy given their depth (i.e. pathologic challenge). Similar to AITL, HLH as an initial presentation can also pose a context challenge
- Multicentric Castleman Disease (MCD): unlike the lymphomas above, MCD isn’t radiographically extranodal, but it often comes with a context challenge in the form of HLH at initial presentation, or autoantibody craze, as well as pathologic challenge (”reactive” histology)
- Histiocytoses: while most malignant histiocytoses have diffuse bone lesions, bone biopsies are notoriously ⊖. Diagnosis involves careful review of past & present slides ensuring immunostaining for CD1a, S100, CD68, CD163, CD207, & BRAF
- Radiology ⊖
- Intravascular Large B-cell Lymphoma (IVLBCL): as a disease confined to blood vessels, “intravascular lymphoma” itself is not radiographically-visualizable. However, its consequences are, & the aggressive complications often pose a context challenge (e.g. HLH of unknown origin, rapidly-progressive neurologic deficits). LPs are notoriously ⊖. (Key to Dx = numerous telescoping skin biopsy followed by affected tissue biopsy if skin biopsies ⊖.)
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- Unicentric Castleman Disease: radiographically-visualizable, regionally-localized expansion of a group of lymph nodes (not uncommonly, just one node) with pathology showing expansion of morphologically benign polyclonal lymphocyte in a “hyaline vascular” or “plasmacytic” pattern. Vast majority of adults are asymptomatic & labs are usually normal, but ~5% of adults do have B-symptoms & do have labs of multicentric disease (e.g. cytopenias), which make for rare context challenges. Pathologic challenges include 1) Lack of excisional specimen (needed for nodal architectural analysis) 2) Mischaracterization as reactive lymphoid hyperplasia (note enlargement of a single node as well as nodal size > 3 cm is unusual for reactive lymphadenopathy, which is usually diffuse & smaller)
Solid (Radiologic > Pathologic/Context)
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- Endobronchial lesion NOS: any small tumor resulting in intermittent vs. constitutive airway obstruction can result in recurrent post-obstructive pneumonia resulting in both context & radiologic issues
- Mucinous adenocarcinoma: a subtype of lung adenocarcinoma that secretes mucus & results in same issues as above
- Lepidic adenocarcinoma: another subtype of lung adenocarcinoma characterized by spread confined to the alveolar tree without adjacent distortion (i.e. without post-obstructive physiology, lepidic spread itself is a “pneumonia mimicker”)
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- Breast cancer NOS: if suspicion for breast cancer is absent, it can be missed on chest CT if you’re not looking for it. (The sensitivity of chest CT by trained radiologists specifically looking for it is ~85%, with slightly lower sensitivity if no IV contrast is given, compared to ~79% sensitivity of mammography, & compared to only ~54% when radiologist isn’t explicitly looking for it.)
- Inflammatory: often initially treated as mastitis (i.e. context issue). If signs of inflammatory breast cancer (i.e. rapidly progressive tender mass, skin changes), full-thickness skin biopsy should be pursued to evaluate for dermal lymphatic invasion
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- Luminal: early stage colon cancer is often missed on cross sectional imaging & requires colonoscopy, & it should be suspected if unexplained iron deficiency anemia, unexplained Gram ⊖ or polymicrobial bacteremia, or SBO without an explanation in the elderly (e.g. terminal ileum is collapsed). If colonoscopy is unrevealing, upper endoscopy should then be considered for upper tumors
- Hepatobiliary: intrahepatic cholangiocarcinoma is often read as “hepatic abscess” on cross sectional imaging due to its conformation to the epithelial lining of the liver, & it often leads to ultrahypercoagulability elsewhere, meaning it can also be read as “hepatic infarction” (i.e. radiologic/context issue)
- Peritoneal: malignant mesothelioma can present with cryptic, chronic non-portal hypertensive ascites with no cellular atypia on ascitic cytology, requiring direct tissue biopsy vs. specific cytopathologic analysis (including NGS) to detect
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- Urothelial carcinoma in situ: often presents as hematuria with ⊖ cross sectional imaging, but visualizable macroscopically via cystoscopy & microscopically via urine cytology
- Prostate: if boney metastasis is osteolytic rather than osteoblastic, & if PSA is lower than expected for metastatic disease burden, prostate cancer may not be considered. This is particularly a problem for the small cell variant
- Clear cell ovarian carcinoma: on CT may be described as a cystic mass & not considered a malignancy; however, solid & nodular components inside are concerning findings. Since ~50-70% arise from an endometriotic lesion, a history of known endometriotic lesion may pose a context challenge. Other context challenges include ultrahypercoagulability & hypercalcemia of malignancy
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- Laryngeal: laryngoscopy is superior to cross sectional imaging in the patient with chronic unexplained cough & hoarseness
- Sinonasal & Parapharyngeal: nasoscopy followed by dedicated MRI of the sinonasal & parapharyngeal space should be considered if recurrent epistaxis, subacute sinus pain/pressure unresponsive to empiric therapies, “chronic otitis media” (eustachian tube impingement), or unexplained cranial neuropathies. Cryptic culprits include SNUC (sinonasal undifferentiated carcinoma), ACC (adenoid cystic carcinoma), & melanoma (sinonasal mucosal melanoma)
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- Melanoma: can present as metastatic disease if the primary lesion is of routine aggressiveness but not recognized due to atypical features, or if the primary lesion is misdiagnosed due to overly rapid growth. The former issue can be a result of spontaneous immune-mediated regression (leaving behind only subtle scarring or hypopigmentation), amelanotic variants (mimicking benign lesions both visually & on pathology), & sneaky primary locations (e.g. scalp, nail bed, perineum/pelvis, mucosal, ocular). The latter issue is a problem for the “nodular” subtype, which does not obey the typical radial growth of superficially spreading melanoma, & which often grows so fast it can mimic an acute condition
- Eccrine porocarcinoma: similar to metastatic melanoma, rare aggressive variants of porocarcinoma can metastasize earlier than clinical detection at the primary site. As a cancer of sweat glands, the primary may be hidden on the scalp, which is a common site of origin
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- Mesothelioma: spreads diffusely along serosal surfaces rather than forming a focal mass. Radiographic findings may be subtle or interpreted as inflammatory or reactive (e.g. “chronic effusion,” “peritoneal thickening”), while cytology is frequently non-diagnostic due to bland-appearing mesothelial cells. Importantly, mesothelial cells are normally shed into pleural and peritoneal fluid, so their presence alone does not imply malignancy. The core diagnostic challenge is pathologic, not radiologic: immunostaining confirms mesothelial lineage but often cannot distinguish reactive from malignant mesothelium. Definitive diagnosis typically requires demonstration of tumor suppressor gene loss (e.g. BAP1 loss), or tissue biopsy showing unequivocal invasion. As a result, diagnosis is often delayed until nodal or extraserosal spread, identified after months-years of unexplained effusions
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- Any microscopic tumor with strong paraneoplastic signature (e.g. hypercortisolism of small cell, carcinoid of neuroendocrine syndrome, FUO of angiomatoid fibrous histiocytoma, thyrotoxicosis of choriocarcinoma, hypoglycemia 2/2 IGF-2)
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Principles❗️
The Diagnostic Arc ⛰️
- Suspicion for “cryptic cancer”?
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- Targeted visualization (e.g. mammogram, cystoscopy)?
- Pathology redo (reread vs. additional immunostaining vs. reacquisition vs. new site)?
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- “Cancer of Unknown Primary” DDx
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References 📚
