Eble JN, Sauter G., Epstein JI, Sesterhenn IA - iarc

Fig. 1.08 Hereditary papillary renal cancer (HPRC)
with multiple, bilateral papillary RCC.
Fig. 1.09 Germline mutations of the MET oncogene
in hereditary papillary renal cell carcinoma (HPRC).
members develop the disease by the
ago of 55 years {2327}. Extrarenal manifestations
of HPRC have not been identified.
Papillary renal cell carcinoma
BHD patients develop myriad papillary
tumours, ranging from microscopic
lesions to clinically symptomatic carcinomas
{1979}. The histological pattern has
been termed papillary renal carcinoma
type 1 and is characterized by papillary
or tubulo-papillary architecture very
similar to papillary renal cell carcinoma,
type 1.
Genetics
Responsible for the disease are activating
mutations of the MET oncogene
which maps to chromosome 7q31. MET
codes for a receptor tyrosine kinase
{799,1212,1213,1570,2326,2327,2926,
2928}. Its ligand is hepatocyte growth
factor (HGFR). Mutations in exons 16
to 19, ie the tyrosine kinase domain causes
a ligand-independent constitutive
activation.
Duplication of the mutant chromosome 7
leading to trisomy is present in a majority
of HPRC tumours {768,845,1996,2032,
2937}.
Management
For patients with confirmed germline
mutation, annual abdominal CT imaging
is recommended.
Hereditary leiomyomatosis and
renal cell cancer (HLRCC)
Definition
Hereditary leiomyomatosis and renal cell
cancer (HLRCC, MIN no: 605839) is an
autosomal dominant tumour syndrome
caused by germline mutations in the FH
gene. It is characterized by predisposition
to benign leiomyomas of the skin and
the uterus. Predisposition to renal cell
carcinoma and uterine leiomyosarcoma
is present in a subset of families.
MIM No. 605839 {1679}.
Diagnostic criteria
The definitive diagnosis of HLRCC relies
on FH mutation detection. The presence
of multiple leiomyomas of the skin and
the uterus papillary type 2 renal cancer,
and early-onset uterine leiomyosarcoma
are suggestive {51,52,1330,1450,1469,
2632}.
Renal cell cancer
At present, 26 patients with renal carcinomas
have been identified in 11 families
out of 105 (10%) {52,1329,1450,1469,
2632}. The average age at onset is much
earlier than in sporadic kidney cancer;
median 36 years in the Finnish and 44
years in the North American patients,
(range 18-90 years). The carcinomas are
typically solitary and unilateral {1450,
2632}. The most patients have died of
metastatic disease within five years after
diagnosis. The peculiar histology of renal
cancers in HLRCC originally led to identification
of this syndrome {1450}.
Typically, HLRCC renal cell carcinomas
display papillary type 2 histology and
large cells with abundant eosinophilic
cytoplasm, large nuclei, and prominent
inclusion-like eosinophilic nucleoli. The
Fuhrman nuclear grade is from 3 to 4.
Most tumours stain positive for vimentin
and negative for cytokeratin 7. Recently,
three patients were identified having
either collective duct carcinoma or oncocytic
tumour {52,2632}. Regular screening
for kidney cancer is recommended,
but optimal protocols have not yet been
determined. Computer tomography and
abdominal ultrasound have been proposed
{1328,2632}. Moreover, as renal
cell carcinoma is present only in a subset
of families, there are no guidelines yet,
whether the surveillance should be carried
out in all FH mutation families.
A
Fig. 1.10 Hereditary papillary renal cell carcinoma (HPRC) A Tumours have a papillary or tubulo-papillary
architecture very similar to papillary renal cell carcinoma, type 1. Macrophages are frequently present in
the papillary cores. B Hereditary papillary renal cell carcinoma frequently react strongly and diffusely with
antibody to cytokeratin 7.
B
Leiomyomas of the skin and uterus
Leiomyomas of the skin and uterus are
the most common features of HLRCC,
the penetrance being approximately
85% {1328,2632}. The onset of cutaneous
leiomyomas ranges from 10-47
years, and uterine leiomyomas from 18-
52 years (mean 30 years) {2632}.
Clinically, cutaneous leiomyomas present
18
Tumours of the kidney