Year :
2023
| Month :
November
| Volume :
17
| Issue :
11
| Page :
XR01 - XR05
Full Version
Triple Malignancy: A Series of Three Cases
Published: November 1, 2023 | DOI: https://doi.org/10.7860/JCDR/2023/65212.18758
Bhavya S Kumar, Prakash N Purushothaman, Parvathy Rajmohan, Sugeeth Mangalapilly Thambi, Balaji Krishnan
1. Senior Resident, Department of Medical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India.
2. Additional Professor, Department of Medical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India.
3. Senior Resident, Department of Medical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India.
4. Assistant Professor, Department of Medical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India.
5. Senior Resident, Department of Medical Oncology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India.
Correspondence Address :
Dr. Sugeeth Mangalapilly Thambi,
Assistant Professor, Department of Medical Oncology, Regional Cancer Centre, Thiruvananthapuram-695011, Kerala, India.
E-mail: sugeethmt@ymail.com
Abstract
Occurrence of Multiple Primary Malignancies (MPM) in an individual is an uncommon phenomenon. It can occur synchronously or metachronously, and the incidence ranges from 1 to 16%. There has been a dramatic increase in the incidence of multiple primaries in patients in the last few years. The diagnosis and treatment of these malignancies pose a clinical challenge as there is no consensus on the optimal management of this condition. It is important to distinguish this condition from the metastasis of an existing malignancy as it can alter the treatment and prognosis of these patients. So far, there have been few case reports published in the literature on triple malignancies, and to the best of authors knowledge, no series have been published yet. Here, authors report a series of three patients (one male and two females) who developed three primary malignancies either synchronously or metachronously. The management of all the patients was decided in a multidisciplinary board based on the stage of each disease and patient tolerance. Two of these patients are alive and on regular follow-up, while one patient was lost to follow-up during treatment. These cases highlight the importance of evaluating and closely following up patients, as well as considering histopathological examination of lesions in unusual sites of metastasis.
Keywords
Metachronous, Metastasis, Multiple primary malignancies, Synchronous
Introduction
The occurrence of Multiple Primary Malignancies (MPM) in a patient is not common. With advancements in screening methods, diagnosis, and treatment of malignancies, the number of patients with MPM is increasing (1). According to Surveillance, Epidemiology and End Results (SEER) data, the incidence of MPM varies from 1 to 16% depending on the primary malignancy (2). The management of these malignancies poses a clinical challenge as there is no consensus on their optimal treatment. Patients with a history of malignancy have a 14% increased risk of a second primary malignancy (3). Two primary malignancies in a person are relatively more common, but three or more primary malignancies are exceedingly rare. Here, authors report the clinical characteristics and treatment of three patients with triple malignancies.
Case Report
Case 1
A 29-year-old male with epidermodysplasia verruciformis has been receiving treatment since childhood. He presented with a rapidly enlarging swelling on the right eyelid, accompanied by ulceration lasting for two months. Examination revealed multiple verrucous lesions on the body and bilateral cervical lymphadenopathy. Histopathology {Haematoxylin and Eosin (H&E)} of the swelling confirmed cutaneous T-cell lymphoma. The diagnosis was T3N0M0 (stage IIB) disease. Cervical lymph node biopsy revealed Langerhans Cell Histiocytosis (LCH). The Computed Tomography (CT) images have been shown in (Table/Fig 1)a-c The patient underwent radiotherapy with 30 Gray in 15 fractions for the eyelid swelling and achieved complete remission. As he was asymptomatic for Langerhans Cell Histiocytosis (LCH), he was placed on follow-up.
One year later, he developed a scrotal ulcer measuring 5×5 cm and another ulceroproliferative lesion on the abdominal {Lower stage A2, Tumour Lymph node (TNM) stage III} wall measuring 8×7 cm. Biopsy from the scrotal ulcer indicated well-differentiated squamous cell carcinoma. He underwent wide excision of the ulcers along with right orchiectomy. Pathology confirmed the abdominal wall lesion as cutaneous T-cell lymphoma. Subsequently, he developed a new lesion in the interscapular region, which was biopsy-proven as cutaneous T-cell lymphoma. The patient was started on low-dose methotrexate, to which he initially responded, but later was lost to follow-up.
Case 2
A 46-year-old female with Neurofibromatosis (NF) was evaluated for a dull, aching pain radiating to her lower limbs, which had been present for six months. During the evaluation, a large pelvic mass was identified. She had multiple café-au-lait spots and neurofibromas. Her mother and brother also had NF. The Computed Tomography (CT) images have been shown in (Table/Fig 2)a,b The patient underwent an incomplete resection of the mass due to its encasement of the femoral vessels and nerves. Intraoperatively, another mass lesion measuring 6×4.5 cm was found in the proximal jejunum, which was completely resected. The pelvic tumour was histologically confirmed as a Malignant Peripheral Nerve Sheath Tumour (MPNST) with rhabdomyoblastic differentiation (Malignant Triton Tumour), and the jejunal tumour was suggestive of a Gastrointestinal Stromal Tumour (GIST). Postoperative imaging revealed a residual right adnexal lesion fixed to the lateral pelvic wall. The patient received six cycles of adjuvant chemotherapy with ifosfamide and adriamycin. Subsequent re-evaluation showed regression of the adnexal lesion. Additionally, she received adjuvant Imatinib 400 mg daily for three years. After a period of seven years, a soft tissue lesion measuring 5×4 cm in the right lower lobe of the lung was detected. The patient underwent a right lung lower lobectomy, and histopathology confirmed a malignant spindle cell neoplasm with clear margins. Currently, she is in the third cycle of six cycles of chemotherapy with gemcitabine and docetaxel.
Case 3
A 35-year-old unmarried lady underwent an evaluation for abdominal pain lasting two months. A CT scan revealed a 6×6×5.9 cm mass with necrosis in the lower pole of the right kidney, suggestive of renal cell carcinoma. She underwent laparoscopic right radical nephrectomy, and the histopathology confirmed clear cell renal cell carcinoma. The metastatic workup was negative, and she has been on regular follow-up. After six months, an ultrasound scan of the abdomen detected a right adnexal mass, leading to a right ovarian cystectomy. Histopathology showed an endometriotic cyst with marked atypia of the lining epithelial cells and stromal invasion, suggesting a diagnosis of borderline ovarian tumour (Table/Fig 3)a,b. Due to her preference against salpingo-oophorectomy, the patient was placed on close follow-up. After a disease-free survival of four years, she was investigated for right lower limb deep vein thrombosis and subsequently diagnosed with Philadelphia chromosome-positive acute B-lymphoblastic leukaemia (4). She was started on chemotherapy with the BFM-95 protocol and achieved complete remission with minimal residual disease negativity following induction. Currently, she is undergoing the reinduction phase of chemotherapy.
Discussion
It was Theodore Bilroth who first reported MPM about a century ago. In 1932, Warren and Gates analysed 1,259 patients from the literature with reasonably well-described MPMs (5). MPM can be categorised into synchronous (the occurrence of tumours at the same time) and metachronous (the occurrence of tumours one after the other at an interval of more than six months) (6).
The occurrence of MPM can be due to genetic or other modifiable factors. There has been a dramatic increase in the detection of MPM in the last 50 years (7). Better screening tests for cancers and advanced diagnostic imaging techniques have led to an increased detection of multiple primaries in patients. Increased exposure to radiation for diagnostic and therapeutic purposes may have also contributed to the increased incidence of MPMs (8). Lifestyle changes, including increased use of alcohol and tobacco, are also contributing factors.
The major challenge in diagnosing MPM is distinguishing it from the metastasis of an existing primary tumour. This is important as it affects the patient’s staging, treatment, and prognosis. Warren S and Gates D have established criteria for the diagnosis of MPM (5): (1) Each of the tumours must be histopathologically confirmed; (2) each must be geographically separated and distinct, and the lesions should be separated by normal mucosa; (3) the probability of one being the metastasis of the other must be excluded. Hence, a biopsy from all the lesions is essential to confirm their nature.
The treatment of MPM poses a clinical dilemma as there is no consensus on its optimal management. It is usually decided in a multidisciplinary board based on the patient’s age, performance status, and disease stage. Treatment modalities include chemotherapy, surgery, and radiotherapy, depending on the disease site and stage. Patients with MPM generally have a better outcome than those with metastatic disease (9).
Among authors’ three patients, case 1 and 2 had synchronous primaries, while case 3 had a metachronous presentation. Two patients were females. Literature reviews of MPM also show a female preponderance. Case 1 had epidermodysplasiaverruciformis, which is prone to non melanoma cutaneous malignancies. The malignancy index in these patients is around 60% (10). The patient had cutaneous T-cell lymphoma and squamous cell carcinoma, which are described associations of epidermodysplasiaverruciformis. LCH was an incidental diagnosis that could have been missed if the lymph node biopsy had not been performed. There has been a lot of debate on whether LCH is neoplastic or inflammatory. Identification of specific mutations, including those in the MAPK pathway, has established it to be malignant. The World Health Organisation included LCH in the group of histiocytic and dendritic cell neoplasms in the latest classification of haematologic malignancies in 2017 (11). Case 2 had NF. Patients with NF-1 have a 6-7% increased chance of developing GIST (12). While the most common site of GIST is the stomach in the general population, small intestinal GIST is common in NF-1 (13). The incidence of MPNST is also dramatically increased in patients with NF-1 (14). This case also highlights the importance of obtaining tissue diagnosis from all sites of disease, especially if the sites are unusual for metastasis. Both case 1 and 2 were prone to MPM, probably due to genetic predisposition. Genetic evaluation might have provided better insight into the pathogenesis of tumours in these patients.
Patient 3 was found to have metachronous lesions during regular follow-up. This case demonstrates the significance of regular imaging in detecting abnormalities early in patients with malignancy. This may sometimes lead to overdiagnosis and treatment; however, this patient developed another invasive malignancy later during the follow-up period.
All the patients’ details were discussed in a multidisciplinary board, and the treatment was determined based on the stage of each disease. All except one patient are undergoing regular follow-up.
While there are numerous case reports on multiple malignancies, this is likely the first case series on triple malignancies. In the literature, all the reported patients were over the age of 45 years. Gastrointestinal malignancy was the most commonly reported type. Ten reported patients had three gastrointestinal malignancies, each diagnosed at a different site. Two patients had triple malignancies confined to the genitourinary system. Haematological malignancy was the least commonly associated type. All of them received treatment based on the stage of each disease (Table/Fig 4) (15),(16),(17),(18),(19),(20),(21),(22),(23),(24),(25),(26),(27),(28),(29),(30),(31),(32),(33),(34),(35),(36),(37),(38),(39),(40),(41),(42),(43),(44),(45),(46),(47),(48). A case summary of all the cases has been provided in (Table/Fig 5).
The present cases emphasise the importance of closely evaluating and monitoring patients, as well as considering histopathological examination of lesions in unusual sites of metastasis.
Conclusion
Triple primary malignancies are uncommon, and only a few large studies describe this phenomenon. Regular surveillance and early suspicion are required in patients with a history of malignancy to promptly identify metachronous lesions. Biopsy from any unusual site of metastasis is also important in MPMs. Managing these patients poses a clinical challenge due to a lack of consensus. A multidisciplinary approach with patient-tailored treatment is necessary to achieve optimal outcomes.
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DOI: 10.7860/JCDR/2023/65212.18758
Date of Submission: May 05, 2023
Date of Peer Review: Aug 22, 2023
Date of Acceptance: Oct 11, 2023
Date of Publishing: Nov 01, 2023
AUTHOR DECLARATION:
• Financial or Other Competing Interests: None
• Was informed consent obtained from the subjects involved in the study? Yes
• For any images presented appropriate consent has been obtained from the subjects. Yes
PLAGIARISM CHECKING METHODS:
• Plagiarism X-checker: May 10, 2023
• Manual Googling: Oct 07, 2023
• iThenticate Software: Oct 09, 2023 (8%)
ETYMOLOGY: Author Origin
EMENDATIONS: 6
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