|Year : 2015 | Volume
| Issue : 4 | Page : 1036
Very late recurrence of an apparently benign pheochromocytoma
Elena Thai1, Letizia Gnetti1, Annalisa Gilli2, Pietro Caruana1, Raffaele Dalla Valle3, Sebastiano Buti2
1 Unit of Pathology, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T.), Parma, Italy
2 Medical Oncology Unit, Department of Emergency and General and Specialistic Medical Area, University Hospital of Parma, Parma, Italy
3 Clinical and Transplantation Surgery, Department of General and Specialistic Surgery, University Hospital of Parma, Parma, Italy
|Date of Web Publication||15-Feb-2016|
L'Unità Operativa, Anatomia Patologica c/o Ospedale Maggiore, Viale A. Gramsci 14, Parma-43126
Source of Support: None, Conflict of Interest: None
Pheochromocytoma is a tumor that has the probability to relapse in about 10% of surgically treated cases. Currently, the only recognized criteria of malignancy in these neoplasms are the evidence of metastasis at non-chromaffin sites. No reliable clinical or histopathological parameter has been, so far, identified to predict malignancy in patients with diagnosis of primary pheochromocytoma. Several authors has attempted to propose morphologic features to detect potentially malignant pheochromocytomas, but there are still too many reported cases of recurrence, also after decades, in tumors that, according to the current knowledge, are considered "benign". Here we report a case of recurrence, after 25 years, of a pheochromocytoma that had not enough criteria to be considered as malignant.
Keywords: Follow-up, late recurrence, malignancy, pheochromocytoma
|How to cite this article:|
Thai E, Gnetti L, Gilli A, Caruana P, Valle RD, Buti S. Very late recurrence of an apparently benign pheochromocytoma. J Can Res Ther 2015;11:1036
| > Introduction|| |
Pheochromocytomas are neuroendocrine neoplasms that have been called "10% tumors", as they approximately are 10% malignant, 10% bilateral and 10% familial.  Several scoring systems, such as PASS (Pheochromocytoma of Adrenal gland Scaled Score)  have been proposed to assess their malignancy.
Recently, De Wailly et al.,  attempted to define new malignancy histologic criteria that included tumor size, weight, presence of necrosis, high mitotic rate [>3/10 high power field (HPF)], ki67 index > 4%, S100 absence.
Long term follow-up is moreover recommended in patients with inherited tumors, large size or multiple localizations. 
The WHO states that the only reliable criterion to define pheochromocytoma malignancy is the presence of loco-regional invasion or metastasis at non-chromaffin sites distant from the primary tumor. 
However, several cases of relapse, some after decades from the primary diagnosis, have been reported even in patients with no one of the proposed prognostic indicators. ,,,
| > Case report|| |
In 1987, a 39-year-old Italian woman came to clinicians attention for high blood pressure and the finding of a retroperitoneal mass (26 cm of diameter), above the right kidney, that was surgically removed.
Histological examination assessed the diagnosis of pheochromocytoma [Figure 1].
|Figure 1: The primary lesion was a classic pheochromocytoma (Hematoxylin and Eosin (H and E), ×40)|
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After surgery, pressure values returned to normal levels. No other lesions were detected in other organs with abdominal computed tomography (CT) scan. A few months later, a CT scan demonstrated a mass in the right liver, with normal levels of urinary catecholamines and vanilmandelic acid. However, pressure values were not altered. At laparotomic exploration, the lesion was ovoidal, soft and regular, with features of a hepatic hemangioma; hence, no intervention has been realized.
So, it was decided to continue only with clinical and instrumental follow-up. In 2008, 21 years later, ultrasound revealed only the already known liver hemangioma with sharp borders, measuring 5.4 cm.
In March 2012, she had recurring hypertensive crisis. Endocrinological analysis revealed that vanilmandelic acid, homovanillic acid, chromogranin A, nor-metanephrine, metanephrine and 3-methoxytyramine were increased. Comorbidities included: Hypothyroidism in multinodular goiter, in substitution treatment; hypertensive heart disease; aortic valve disease; chronic atrial fibrillation in oral anticoagulant treatment. Positron Emission Tomography (PET) scans relevead a single hepatic lesion of about 11 cm. A CT scan showed pulmonary thromboembolism and an inhomogeneous hypodense lesion in the right liver with irregular contrast enhancement, leading to the suspect of metastasis of the pheochromocytoma resected 25 years ago.
Therefore, after controlling pressure values, she underwent a right hepatectomy. During the surgical intervention, the mobilization of the right liver lobe caused important hypertensive crisis, but after the surgery, pressure values returned to normal levels.
The histological examination confirmed a hepatic metastasis of pheochromocytoma: A lesion with pleomorphic cellularity, consisting of neoplastic cells arranged in nests, with finely granular cytoplasms [Figure 2] and [Figure 3], a very low mitotic index (ki67 < 5%) [Figure 4]. Focal S100-positive substentacular cells were present [Figure 5]. Chromogranin A, synaptophysin [Figure 6] and NSE positive staining confirmed the diagnosis. Surgical margins were free of disease.
|Figure 2: The hepatic metastasis was a recurrence of pheochromocytoma, with pleomorphic neoplastic cells arranged in nests (H and E, ×40)|
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|Figure 3: Neoplastic cells had finely granular cytoplasms (H and E, × 40 and H and E, ×100)|
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|Figure 4: A very low mitotic index, ki67 < 5% (3,3' Diaminobenzidine (DAB), ×400) has been detected in the neoplasm|
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|Figure 5: Focal S100-positive substentacular cells were present in the metastasis (DAB, ×100)|
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|Figure 6: (a) Diffuse positivity for Chromogranin A (DAB, ×100) and (b) synaptophysin (DAB, ×100) confirmed the diagnosis|
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Post-operatory CT scan didn't point out recurrent disease and showed resolution of the previous pulmonary thromboembolism.
Collateraly, on September 2013, it is diagnosed chronic myeloid leukaemia, for which it is undertaken Imatinib.
After 17 months of follow-up, the patient is completely asymptomatic, in good general conditions, without signs or symptoms of new onset, except for a few laboratory alterations compatible with toxicity due to Imatinib.
| > Discussion|| |
Currently, it is still not possible to diagnose malignancy in pheochromocytoma with only pathological examination. To the best of our knowledge, the only accepted criteria to define malignancy in these tumors are the presence of tumor cells in areas where embryologically there is no paragangliar tissue (non-chromaffin sites) and the presence of local invasion or distant metastases.  Common metastatic sites include bone, liver and lymph nodes.
Risk factors universally accepted are size >5-6 cm, weight >8 g, an abnormal DNA ploidy patterns, high levels of dopamine circulating and its high concentration in tumor and persistent hypertension in the post-operative. 
After the diagnosis of recurrence of pheochromocytoma in our patient, we proceeded to the revaluation of the slides of the primary tumor.
The only "risky" feature of the primary lesion was the huge size of the mass (26 cm). Anyway, at the time of the first diagnosis, there were no enough criteria to assess the neoplasm as malignant.
The recurrent tumor had the same histological and immunohistochemical features of the previous lesion, with very low mitotic index (ki67 < 5%).
Several scoring systems have been defined, but they all failed to predict pheochromocytomas behavior in a reliable way.
Thompson's PASS score  uses histological parameters to distinguish benign from malignant neoplasms; these included: capsular invasion, vascular invasion, extension into peri-adrenal fat, presence of large nests or diffuse growth (in >10% of tumor volume), central necrosis, high cellularity, tumor cell spindling, cellular monotony, increased mitotic figures (<3/10 HPF), atypical mitosis, marked nuclear polymorphism and nuclear hyperchromasia. The cut-off value of 4 has been proposed to predict malignancy.  Basing on these criteria, the primary pheochromocytoma of our patient diagnosed in 1987 should have been labeled as benign. However, it relapsed, even if after decades.
The lack of S100-positive substentacular cells in malignant pheochromocytoma has been confirmed by different studies, but it's presence in some reported malignant pheochromocytomas (including ours), has weakened its utility. Unger et al.,  suggested S100-positive sustentacular cells in malignant and locally aggressive adrenal pheochromocytomas. Ki67 proliferation index is another interesting marker of malignancy, but has demonstrated a poor sensitivity. Our case had a very low expression of ki67 (<2%).
In literature there are only a few reports of "apparently benign" pheochromocytomas relapsed, even after decades; ,,, approximately, recurrence rates of up to 14% have been reported in pheochromocytomas and of up to 30% in extra-adrenal lesions; thereby, the need of long-term follow-up, though the lesion is diagnosed as benign. 
Pheochromocytoma is a tumor that should warn clinicians to a lifetime follow-up, even if completely excised and with no high risk criteria, until reliable predictors of malignancy will be defined.
| > References|| |
Thompson LD, Young WF Jr, Kawashima A, Komminoth P, Tischler AS. Malignant adrenal pheochromocytoma. In: De Lellis RA, Lloyd RV, Heitz PU, Eng C, editors. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Endocrine Organs. IARC Press Edition: Lyon; 2004; p. 147-50.
Thompson LD. Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: A clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol 2002;26:551-66.
de Wailly P, Oragano L, Radé F, Beaulieu A, Arnault V, Levillain P, et al
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Amar L, Servais A, Gimenez-Roqueplo AP, Zinzindohoue F, Chatellier G, Plouin PF. Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab 2005;90:2110-6.
Noshiro T, Shimizu K, Watanabe T, Akama H, Shibukawa S, Miura W, et al
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Poch E, Paz MA, Botey A, Fernández-Cruz L, Cases A, Revert L. Late recurrence in pheochromocytoma: Need for a long term follow up. Rev Clin Esp 1991;189:178-80.
van Heerden JA, Roland CF, Carney JA, Sheps SG, Grant CS. Long-term evaluation following resection of apparently benign pheochromocytoma (s)/paraganglioma (s). World J Surg 1990;14:325-9.
Unger P, Hoffman K, Pertsemlidis D, Thung S, Wolfe D, Kaneko M. S100 protein-positive sustentacular cells in malignant and locally aggressive adrenal pheochromocytomas. Arch Pathol Lab Med 1991;115:484-7.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]