Clinical History
FNA biopsy of lymph node. A 77-year-old male who presented with hematuria and enlarged
retroperitoneal lymph node, which was aspirated.
Case 10 - Slide 1
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Diagnosis:
Renal cell Carcinoma,Papillary (Chromophil) RCC
Incidence: RCC comprises approximately 90% of kidney tumors and about 2% of all visceral
malignancies. Men have a slightly higher frequency than women (M: F, 1.5:1). It is usually a tumor of
adults, peaking in the fifties; however it can occur in young adults.
Etiology: No definite carcinogens have been linked to RCC, but smoking, including tobacco,
pipes, and cigars have all been implicated. Genetic abnormalities are found in the majority of cases,
with chromosome 3 being the most frequently involved. Pre-existing cysts, congenital or acquired, are
found more frequently in patients with RCC. Familial cases are rare; associations include Von
Hippel-Lindau disease.
Presentation: The classic triad of hematuria, flank pain and abdominal mass is present in only
10-15% of patients with RCC. Hematuria usually occurs after the calyceal collecting system has been
infiltrated by the tumor. Other non-specific symptoms such as weakness, fatigue, fevers, varicocele may
be seen but it is not unusual that the tumor is discovered incidentally. Approximately a third of
patients present with paraneoplastic syndromes including hypercalcemia, polycythemia, hypertension,
anemia, virilization, and gynecomastia, Cushing's syndrome, amyloidosis and leukemoid reactions. Another
25-30% of patients present with metastatic disease in lung, bone, liver, lymph nodes, brain, adrenal or
the other kidney and rarely in soft tissue, thyroid, ovary, salivary gland and pancreas. RCC is the most
common tumor that "receives" other metastases; with lung, breast and prostate being the most common donor
malignancies. Patients with RCC have a relatively high incidence of a second primary tumor, especially
lung, gastric and colonic primaries.
Histogenesis: Traditionally, RCC has been thought to arise from the proximal renal tubule.
More recently, the concept of a progenitor cell origin has been favored. Features shared with the
proximal tubular cell include a long microvillous brush border, rich in mitochondria, lipid and glycogen.
Gross: RCC is usually solitary, but very variable in size. Less than 5% are multiple or
bilateral. The most common location is at the upper pole of the kidney. The gross appearance is solid
and /or cystic with areas of hemorrhage and necrosis.
Cytomorphology: Microscopically, clear cell RCC is the most common subtype followed by
papillary (chromophil) and the least common is sarcomatoid RCC. Other subtypes include collecting duct
carcinoma, medullary carcinoma and chromophobe RCC
Fine Needle Aspiration: Most renal lesions are not aspirated since they are diagnosed as
benign by radiologic features or are obviously malignant and resected. Indications for FNA include (1)
diagnosis for unresectable lesions (primary or metastatic), or diagnosis in a patient who is a poor
surgical risk (2) Radiologically indeterminate lesions, often cysts (3) Diagnosis of lesions where
partial nephrectomy is an option (oncocytoma, chromophobe RCC, angiomyolipoma). Subclassification of RCC
by FNA, is relatively accurate; however in a study performed in 1997, the most common error was to
misclassify papillary and sarcomatoid RCC as clear cell RCC.
Grading: Histologically Furhman's nuclear grading system is used; application to FNA is
inconsistently practiced.
Papillary (Chromophil) RCC
Definition: Histologically, papillary RCC is defined as an
RCC in which >50% of the tumor grows in well-formed papillae with a fibrovascular core; other subtypes
of RCC may have papillary or pseudopapillary areas focally.
Incidence: It accounts for about 10-15% of all RCC. On an
IVP, these tumors are typically hypovascular. In most tumors nuclear grade is low; when significant
nuclear atypia is present, the prognosis is similar to other RCC. The proportion of Type 1 and Type 2
(see below under subtypes), seems to be close to 2:1.
Clinical Behavior: Type 1 tumors have a smaller size, lower TNM
stage, and lower nuclear grade than Type 2 tumors. Type 2 tumors seem to be slightly more common in
patients younger than 40 years.
Subtypes: Two subtypes of papillary RCC have been described based
on clinico-pathologic and immunohistochemical findings (a) Type 1: composed of short papillae
covered by 1-2 layers of small epithelial cells with scant pale to clear cytoplasm. Many papillae are
edematous, giving a "cystic" appearance. Hemorrhage, necrosis, psammomatous calcification and foamy
histiocytes within cores of the papillae tend to be prominent features. The tumor cells stain for
cytokeratin 7 and negative for Ulex Europeaus. (b) Type 2: papillae are lined by cells with
abundant eosinophilic cytoplasm, and are arranged in a stratified or pseudostratified pattern. Dense
fibrous cores are seen, rather than cystic dilatation of papillae cores. Necrosis and hemorrhage along
with multinucleated giant cells are also common. Foamy histiocytes may be seen in the background but are
not present within the cores of the papillae. Nuclear grade tends to be higher. CK 7 and Ulex Europeas
are both negative.
Immunohistochemistry
Keratin (AE1/AE2): positive
CK 7: positive (in type 1)
Keratin HMW (34BE12): negative
EMA: positive
Vimentin: variable, +/-
Ulex Europeaus: negative
CD 68: negative
CD 10: positive
Inhibin: negative
Hales colloidal iron: negative
Cytogenetic abnormalities:
Loss of Y chromosome,
Trisomy 3q, 7, 8, 12, 16, 17, 20
FNA findings: Smears are cellular. Neoplastic cells form true
papillae containing fibrovascular cores, surrounded by tumor cells or rounded spherules of tumor cells.
Dyscohesion/ single cells are rare. The tumor cells are usually cuboidal to columnar, with low grade
nuclei, a high nuclear/cytoplasmic ratio, and minimal pleomophism of size or shape. The nuclear
chromatin is fine with small, inconspicuous nucleoli. Intranuclear cytoplasmic inclusions, nuclear
grooves, and psammomatous calcifications, features common to papillary lesions, may be seen. Cytoplasm
is scant and clear/pale in Type 1 and abundant/ eosinophilic in Type 2 and the tumor cells may contain
hemosiderin pigment. The fibrovascular stalks often contain histiocytes, with or without hemosiderin and
/or lipid. The background may also show numerous histiocytes. Necrosis can be seen in some cases.
Differential diagnosis
1) Normal distal
tubules: Seen as single cells, flat sheets. Cells have scant cytoplasm and no cytologic atypia,
but may contain cytoplasmic hemosiderin. They are keratin and EMA positive and CD 68 negative.
2) Histiocytes:
Seen as single cells, small groups with foamy cell cytoplasm with or without hemosiderin, and have
elongated nuclei with nuclear grooves. CD 68 positive; keratin and EMA negative
3) Conventional/ clear cell RCC: clear
cell RCC rarely has a papillary architecture; high vascularity causing pseudopapillae may be
misinterpreted as papillae. Morphologically more single cells, atypical, more cytoplasm with
vacuolization, and prominent nucleoli. Histiocytes and psammoma bodies are rare. Intracytoplasmic
hemosiderin and foamy histiocytes have been suggested as being the most sensitive markers of papillary
RCC morphology.
4) Collecting duct carcinoma:
cytomorphology is a mixed tubulo-papillary pattern and single cells are common. Some cases are mucin
positive, and resemble breast carcinoma. Immunohistochemistry: ulex Europeaus and keratin 34BE12 are
both immunoreactive in collecting duct ca and negative in papillary carcinoma.
5) Low grade papillary urothelial
carcinoma: the lining cells are more stratified, a high grade component may be present,
cercariform cells may be seen, and nuclear chromatin is dark. Mucin is +/-, uroplakin positive, CEA
positive
6) Metastatic papillary adenocarcinomas:
History and immunohistochemistry, mucin positivity are useful in making this distinction
7) Adrenal cortical neoplasm: Loosely
cohesive cells, stripped nuclei. Inhibin +, Melan A +, Keratin and EMA negative, Calretnin variable +/-.
References:
- Aspiration cytology: a pattern recognition approach. Renshaw AA. Elsiever Press; 2005.
- Modern Cytopathology. Geisinger K, Stanley M, Raab S, Silverman J, Abati A. Churchill Livingston. 2004
- The Art and Science of Cytopathology. DeMay R. ASCP Press; 1992.
- Granter SR, Perez-Atayde AR, Renshaw AA. Cytologic analysis of papillary renal cell carcinoma. Cancer 1998; 84(5): 303-308
- Delahunt B, Eble JN. Papillary renal cell carcinoma: a clinico-pathologic and immunohistochemical study of 105 tumors. Mod Pathol 1997; 10 (6): 537-544
- Renshaw AA, Corless CL. Papillary renal cell carcinoma: histology and immunohistochemistry. Am J Surg Pathol 1995; 19(7): 842-849
- Mai KT, Alhalouly T, Lamba M, et al. Distribution of subtypes of metastatic renal cell carcinoma: correlating findings of fine needle aspiration biopsy and surgical pathology. Diagn Cytopathol 2003; 28(2): 66-70
- Wang S, Filipowicz EA, Schnadig VJ. Abundant Intracytoplasmic hemosiderin in both histiocytes and neoplastic cells: a diagnostic pitfall in fine needle aspiration of cystic papillary carcinoma. Diagn Cytopathol 2001; 24(2): 82-85.
- Renshaw AA, Lee KR, Madge R. Accuracy of fine needle aspiration in distinguishing subtypes of renal cell carcinoma. Acta Cytol 1997; 41(4): 987-994.
- Dekmezian R, Sneige N, Shabb N. Papillar renal cell carcinoma: fine needle aspiration of 15 cases. Diagn Cytopathol 1991; 7(2): 198-203.
- Flint A, Cookingham C. Cytologic diagnosis of the papillary variant of renal cell carcinoma. Acta Cytol 1987; 31(3): 325-329.
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