Final Diagnosis -- Collecting duct carcinoma
Collecting duct carcinoma
The overall morphologic and immunohistochemical features of this case support a diagnosis of collecting duct carcinoma (CDC). The differential diagnosis in this case includes a high-grade papillary renal cell carcinoma (RCC), and mucinous tubular and spindle cell carcinoma (MTSC). In particular, the presence of immunohistochemical staining for ulex europaeus-1 and absence of staining for racemase argue against papillary RCC and MTSC. In addition, the high-grade nuclear features and lack of predominating elongated tubules or definite spindle cell component argue against a diagnosis of MTSC. Regarding the patient's lung nodules, a subsequent fine-needle aspirate of the lung and hilar lymph node biopsy showed evidence of metastatic carcinoma favoring renal origin.
CDC is a rare, aggressive, high-grade neoplasm which arises from the renal medullary collecting ducts and from an embryologic standpoint, the mesonephros. It was previously subgrouped with the RCCs by the World Health Organization (WHO) in 1981 with the alternative name "Bellini duct carcinoma," but has since been recognized as a separate entity. It accounts for approximately 0.6-3.0% of all renal epithelial neoplasms, and occurs in patients in their second-fifth decades (average age 55 years) with a slight male preference (M:F 1.7-2:1). At the time of initial presentation, approximately 40% of patients have metastatic disease and may have generalized inflammatory symptoms (e.g. fever, general malaise, weight loss), flank pain, and a history of intermittent hematuria as this patient demonstrated.
Radiologically and grossly, CDC is generally poorly circumscribed and classically occupies a deep, central medullary location. It ranges in size from approximately 1-16 cm. Renal angiography will often show the mass to be hypovascular or avascular. The cut surface is classically firm, gray-white, and sometimes has areas of obvious necrosis. It often involves hilar structures and approximately 20% of cases show renal vein invasion.
Histologically, CDCs have a range of irregular architecture: tubulopapillary, pseudopapillary, cribriform, microcystic, ductal, and solid. The tumor consists of intermixed round-to-oval, clear eosinophilic and basophilic cells. The cytomorphology of the malignant cells is high-grade with marked nuclear atypia, hyperchromasia, prominent single nucleoli, and sometimes numerous atypical mitoses. Intracytoplasmic mucin can also be seen, and sarcomatoid change can be seen as a sign of dedifferentiation. Cells often protrude into lumens in a hobnail pattern. Marked atypia and dysplasia may be seen in adjacent collecting ducts, and there is usually marked desmoplasia often including granulocytes in the surrounding stroma. Prominent vascular and lymphatic invasion are common.
Immunohistochemically, CDC cells are commonly immunoreactive with markers of the distal nephron (ulex europaeus agglutinin-I, peanut agglutinin lectin, e-cadherin, epithelial membrane antigen (EMA)), high molecular weight keratins (34betaE12, cytokeratin 19), and low molecular weight keratins. Cells are usually negative for markers of proximal tubules (CD10, Leu-M1, RCC, N-cadherin, racemase). Vimentin may be present in tumor cytoplasm, and c-kit may also be positive. Aquaporin-3 (AQP-3), present in normal collecting duct and urothelial cells, as well as high-grade urothelial carcinoma, is also present in CDC.
Cytogenetic analyses often demonstrate monosomy of chromosomes 1, 6, 12, 15, 18, 21, and 22. Loss of heterozygosity (LOH) is seen in chromosome arms 1q (similar to urothelial carcinoma, 57-69%), 6p, 8p, 13q, and 21q. Molecular alterations also exist that suggest tumor heterogeneity, including loss of the Y chromosome; gains of chromosomes 7 and 17; and LOH of the von Hippel Lindau gene (3p), p16 (9p), and p53 (17p). In addition, one can see loss of DNA sequences involving chromosomes 1, 2, 9, 11, and 18; gains of DNA sequences affecting chromosomes 12, 16 and 20; and c-erb B2 oncogene amplification (45%).
The differential diagnosis of CDC includes papillary RCCs, medullary carcinoma, conventional RCC, urothelial carcinoma, and metastatic carcinoma. MTSC and tubulocystic carcinoma are also briefly discussed here due to the presence of mucin in this case as well as the overlap of these entities' nomenclature in the past.
- Papillary RCC: This is an important distinction as papillary RCC usually, but not always, has a more indolent prognosis compared to that of CDC. Both papillary RCC and CDC show papillary architecture and positive immunoreaction with distal nephron markers. Grossly, papillary RCC tends to be more well-demarcated and has a yellow to dark-brown cut surface; its epicenter should be in the renal cortex as opposed to the medulla. Microscopically, atypia in adjacent collecting duct cells, marked stromal desmoplasia, and the presence of mucin favor CDC although mucin can be seen in papillary RCC as well. Immunohistochemically, CK 7, CD10, racemase, RCC and N-cadherin positivity favor papillary RCC while ulex europaeus-1, e-cadherin, and high molecular weight keratin 34betaE1 positivity favor CDC. However the current case of CDC showed CK 7 positivity. Cytogenetically, trisomies of chromosome 7 and 17 and loss of Y chromosome tend to favor papillary RCC though rarely have also been reported in CDC.
- Renal medullary carcinoma: Renal medullary carcinoma often occurs in young black patients with sickle cell trait. Similar to CDC, it also presents as high-stage at the time of diagnosis with poor response to chemo- and radiation therapy. In addition, its tubulocystic pattern and marked inflammatory and desmoplastic stromal response can mimic CDC. However histologically, it has a loose reticular pattern of growth similar to yolk sac tumor, and is usually negative for ulex europaeus-1 and high molecular weight keratins. Some consider it to be a subtype of CDC.
- Conventional RCC: Grossly, the cut surface of conventional RCC is typically yellow. Microscopically, the neoplastic cells contain abundant glycogen and lipid droplets. Immunohistochemically, the cells frequently express low molecular weight cytokeratins (similar to CDC) and vimentin (negative to variable in CDC). Cytogenetically, deletion of chromosome arm 3p is often seen although this has been reported in CDC as well.
- Urothelial carcinoma: Urothelial carcinoma involving the renal pelvis and medulla can show urothelial carcinoma in-situ of adjacent collecting ducts which resembles the dysplasia seen next to CDC. In the absence of a gross intrarenal papillary lesion, distinguishing the two neoplasms can be difficult. Immunohistochemically, urothelial carcinoma is usually negative for vimentin, and positive for p63, CK7, and CK 13 whereas CDC usually shows the opposite staining pattern. However, few cases of CDC can show p63 positivity and conversely, some urothelial carcinomas show ulex europaeus positivity. Recently, carbonic anhydrase-9 (CA-9) has been shown to have diffuse strong membrane staining in 90% of urothelial carcinomas, and focal weak membrane staining in 60% of CDCs. Both neoplasms show positivity for high molecular weight keratins and e-cadherin, and CEA is variable in both as well. Of note, absence of urothelial carcinoma is a WHO major criterion for the diagnosis of CDC.
- Metastatic carcinoma: CDC should be differentiated from adenocarcinomas producing mucin, namely of the gastrointestinal tract and lung. In such cases, clinical and immunohistochemical differentiation (e.g. CDX2, thyroid transcription factor-1) is useful. In addition, metastatic tumors to the kidney are usually multiple, well-circumscribed, and usually not associated with dysplasia of collecting ducts.
- Mucinous tubular and spindle cell carcinoma (MTSC): This is generally an indolent neoplasm thought to arise from the collecting ducts or loop of Henle, however its immunoreactivity with CK7 and racemase also suggest a proximal nephron origin; it has been previously referred to in the past as low-grade CDC. It has a 4:1 female:male predominance and is associated with nephrolithiasis. Grossly, MTSC is usually well-circumscribed, may be cortical, and has a tan cut surface. MTSC has three core elements: tubules (which tend to be elongated and curvilinear), spindle-cell areas, and mucinous stroma. The nuclei are usually low-grade although there may be occasional areas of high nuclear grade, solid tubular growth, and necrosis. Foam cells, lymphocytic infiltrates, and small psammoma bodies may also be present. Immunohistochemically, MTSC is positive for low molecular weight cytokeratins, CK7, and racemase; high molecular weight keratins, ulex-europaeus-1, CD10, and RCC antigen are usually negative.
- Tubulocystic carcinoma: This is also referred to as low-grade CDC although its genetic profile is more similar to that of papillary RCCs (with gains in chromosomes 7 and 17) than of CDC. It has a 7:1 male:female predominance and grossly, is circumscribed with a spongy or "bubble-wrap" cut surface. It consists of tightly packed tubules and cysts separated by thin fibrous septae and bland fibrous stroma. Nuclear features are generally high grade but not as high grade as CDC. Hobnailing and extracellular mucin can be seen, also similar to CDC. However solid growth or desmoplasia is not seen. Immunohistochemically, tubulocystic carcinomas stain for a wide range of CKs, parvalbumin, CD10, and racemase; CK7 is usually positive but may be focal/weak; this tumor does not stain with high-molecular weight keratin (e.g. 34betaE12) unlike CDC.
Patients with CDC have a poor prognosis, with approximately 2/3 of patients dying within 2 years of the initial diagnosis (mean survival is 11.5 months). Metastases at the time of diagnosis are common in the regional lymph nodes (80%), adrenal glands (25%), lung (25%), liver (20%), and skin. Metastases have also been reported in the leptomeninges and bone which are usually osteoblastic although isolated osteolytic metastases have recently been reported. There is a high frequency of local recurrence and distant metastases even when a radical nephrectomy has been successfully performed. In addition, conventional treatments for renal cell carcinoma including radiation, chemotherapy, and immunotherapy are usually not effective. Recent studies show promising results with chemotherapy usually used for primary urothelial carcinomas, which may suggest biologic similarities between the two tumors.
In summary, this case demonstrates a collecting duct carcinoma in a 52-year-old female with classic symptoms of a renal cell carcinoma and lung metastasis at the time of diagnosis. Some histologic features overlap with those seen in high-grade papillary renal cell carcinoma and mucinous tubular and spindle cell carcinoma. Strong immunohistochemical staining for ulex europaeus-1 helped to make the final diagnosis.
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Contributed by Rashi Singhal, MD, MPH, and Anil Parwani, MD, PhD