Discussion
In this paper, we report the case of recurrent phaeochromocytoma in a
middle-aged male patient with atypical clinical presentations that could
be well controlled with medication. The patient had already received two
adrenalectomies before his admission. According to the pathological
reports provided, all of the removed tumors underwent
immunohistochemistry analysis, and suggested a positive expression of
neuroendocrine markers (Syn and CgA). Ki-67 index was no more than 2%,
indicating a low proliferation capacity, and was consistent with the
slow progression of the disease. Laboratory results did not reveal any
endocrine abnormalities. However, there was always a local recurrence
following surgery and distant lesions appeared as disease developed.
Although we didn’t perform a biopsy of extra-adrenal lesions,
PET/CT showed catecholamine
hypermetabolism in right adrenal gland and several intra-abdominal
nodules, indicating the possibility of malignant phaeochromocytoma.
Currently, the World Health Organization (WHO) has replaced the previous
concept of ‘malignant PPGL’ with ‘metastatic PPGL’, and proposes that
all PPGL should have malignant potential.3 A definite
diagnosis of malignancy can only be validated by the presence of
metastasis in non-chromaffin tissues (such as brain, lung, liver, bones
or lymph nodes). There have already been several methods to predict
metastasis of PPGL. Some scoring systems, like PASS and GAPP, are
primarily based on histopathological features. Both systems have been
proved to be highly sensitive to metastatic potential, but lack
specificity.4, 5 Metastatic and non-metastatic PPGLs
are similar histologically and hard to distinguish from each other. It
may be more convincing to rule out the possibility of malignancy when
scores are low, rather than to make a metastatic prediction with high
scores. Analogously, it is also difficult to determine the metastatic
potential of PPGL by a single biomarker. Ki-67 is a proliferative marker
that has been shown to be predictive of metastases in PPGL. But some
studies indicate that Ki-67 index has a low sensitivity, and correlates
with progression-free survival rather than the occurrence of metastasis.
The recommended thresholds are also disputed. Another system, the COPPS
score, integrates clinic-pathological features and immunohistochemical
markers (PS100 losses, SDHB immunostaining) for risk assessment of
metastasis, and exhibits an excellent reproducibility (AUROC =
0.981).6 However, in our case, slides of primary tumor
were not available and immunohistochemical results were incomplete,
which limited the application of COPPS. Taking clinical features into
account, the primary tumor was large, and showed a strong tendency to
recurrence, but presented no rapid invasion with a biochemical silent
phenotype. It might be judged as a slowly progressing metastatic PPGL.
The preferred treatment for metastatic PPGL is tumor resection.
Conservative treatments include the following methods. Chemotherapy is
mainly used for rapid progressing metastatic PPGL. The common
chemotherapy regimen is CVD regimen, a combination of cyclophosphamide,
vincristine and dacarbazine. It is reported that the complete remission
rate of CVD regimen is 4%, while partial remission rate is 37%, and
the rate of stabilization is 14%, as assessed by tumor volume
reductions. 7However, it may cause severe adverse
reactions, such as marrow suppression and hypertensive
crisis. Nuclide therapy, including
metaiodobenzylguanidine (MIBG)
therapy and peptide receptor radionuclide therapy (PRRT), needs to
evaluate the nuclide uptake in tumor cells before treatment. The
conventional MIBG preparations has been shown to prolong survival with
an increased 5-year survival rate of 45%-68% and achieve stabilization
in 73%-79% of patients. However, the preparations contain large doses
of unlabeled MIBG that disrupt the norepinephrine-reuptake mechanism,
leading to very low specific activity and life-threatening side effects.
In comparison, high-specific-activity MIBG shows improved efficacy and
tolerability in vivo. 8So far, the new preparations
haven’t been available domestically. PRRT is considered as a viable
alternative to chemotherapy and MIBG therapy. Meta-analyses reported
PRRT remission rate and disease control rate of 25% and 84%,
respectively. 9MIBG treatment and PRRT are usually
applied to advanced systemic PPGL. Radiofrequency ablation and
embolization perform well in local control. Kohlenberg, J et ml.
reported an ablative efficacy of 86% local control on imaging, ang 92%
symptomatic remission with a low incidence of serious
complications.10 Targeted therapeutic agents, for
instance, tyrosine kinase inhibitors, also show potential efficacy,
especially in patients bearing SDHB gene mutations. Relevant clinical
trials are ongoing and there is still a lot to be done in this
area.11
In this case, due to multiorgan involvement, and intra-abdominal
adhesions caused by previous operations, surgery became risky. We turned
to conservative options for a safer solution. Chemotherapy could act on
the whole body and was usually used in the treatment of advanced PPGL.
However, chemotherapy-induced myelosuppression, and severe infection and
intracranial hemorrhage that may occur afterwards, might be fatal. It
was not a priority to take the hazard for a slow-progressing PPGL with
mild symptoms. Considering the life-threatening side effects of
conventional MIBG preparations, MIBG therapy was not preferred as well.
Furthermore, targeted therapy was costly and we had to take into account
the patient’s financial burden. Radiofrequency ablation and embolization
might be useful, but were rarely performed in PPGL in our hospital. The
efficacy was uncertain. We decided to wait and see under the close
observation of the multidisciplinary team.
PPGL is of great heterogeneity, progression and metastasis may occur
even 10 years after diagnosis. All PPGL patients need long-term
assessment, basically containing endocrine workup and imaging
examinations. MRI is preferred to reduce radiation. Genetic testing
should be completed early if possible, especially in patients with large
primary tumors (≥5-6cm), extra-adrenal tumors, positive family history,
recurrence, or young onset. For cost saving, screening for RET, VHL and
SDHx genes may be recommended. Ma, X et ml. reported a genetic profile
in Chinese PPGL patients in a single center study: SDHB mutation is the
most frequent, accounting for 20%, followed by RET (3.8%), VHL
(3.8%), SDHD (2.5%), SDHA (2.2%).12 Based on
genetic results, extra screening should be added. VHL patients have to
pay attention to VHL-associated tumors, and receive careful ophthalmic
examinations and MRI scans of the head and abdomen. At-risk relatives
should also undergo comprehensive screening and molecular genetic
testing early. 2For biochemical silent PPGLs, apart
from regular checkup, target organ management is also necessary, to
avoid complications. In our case, the patient underwent cardiovascular
and renal function screening, glucose level and lipid profile checkup
every 12 months. Interestingly, we observed no significant vascular
benefits with the use of α-adrenoceptor blocker. Given that the tumors
were non-functional, there was a probability that α-adrenoceptor blocker
application had a limited effect. Significant improvement occurred after
the initiation of overall target organ management.
In conclusion, some advanced phaeochromocytomas and paragangliomas are
unresectable. Therapeutic strategies are recommended to be selected
under the coordination of a multidisciplinary team according to concrete
situations. Watch and wait may become a choice when PPGL is inoperable
but slow-progressing. Symptom control and effective management of target
organ damage contribute to better clinical outcomes. Long-term benefits
still need to be confirmed. As the observation continues, we may learn
more.