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Unusual occurrence of solid tumors with hematological malignancies
* Corresponding author: Dr. Basab Bagchi, DM in Clinical Haematology, Department of Clinical Haematology, Chittaranjan National Cancer Institute, Kolkata, West Bengal, 700156, India. bapuji25dr@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Aich R, Sen A, Kumar A, Das D, Hajra S, Mandal A, et al. Unusual occurrence of solid tumors with hematological malignancies. Asian J Oncol. 2025;11:12. doi: 10.25259/ASJO_58_2024
Abstract
The co-occurrence of multiple primary tumors in one person is not uncommon, with a reported prevalence of multiple primary malignancy (MPM) ranging between 0.73% and 11.7%, depending on the definition. But the combination of solid organ tumors with hematological malignancy is rare. Herein, we report five cases, one with therapy-related, one metachronous, and three synchronous hematological and non-hematological malignancies. The management of MPM is challenging as there is no therapeutic guideline for treating these rare presentations.
Keywords
Hematologic malignancy
Metachronous malignancy
Multiple primary malignancies
Synchronous malignancy
INTRODUCTION
Multiple primary malignancy (MPM) refers to two or more primary tumors occurring in the same patient either simultaneously or one after the other.[1] The diagnostic criteria proposed by Warren and Gates[2] are as follows: 1. The tumors should be clearly malignant and have different histopathological features.[2] 2. The tumors should be completely separate in distinct geographical locations.[3] 3. The probability that the second tumor is metastasized from the first should be excluded.[1–3]
Synchronous primary malignancy is defined as two tumors occurring simultaneously or within 6 months of each other.[1,3] Metachronous primary malignancies are two tumors separated by a time gap of more than 6 months.[3] International rules for MPMs are more detailed, and tumors arising in an organ or pair of organs or a tissue are usually considered a single tumor. However, there are two exceptions: systemic cancers involving many different organs should be counted once, and cancers with different histologies should be regarded as multiple cancers even if they are diagnosed simultaneously at the same site.[2] The causative factors behind MPMs are unclear but may be related to smoking, alcohol intake, viral infections, inflammations, familial predisposition, defects in DNA repair mechanisms, and exposure to radiation and chemotherapeutic agents.[1] Here we describe a case series of five MPM cases [Table 1].
| No | Age (year) | Sex | Hematological tumor | Year of dx | Treatment | Solid malignancy | Year of dx | Treatment |
|---|---|---|---|---|---|---|---|---|
| 1 | 73 | F | Myelodysplastic neoplasm | 2023 | HMA | Ductal carcinoma breast | 2016 | Mastectomy adjuvant chemo +RT |
| 2 | 76 | M | AML | 2024 | HMA | Urothelial ca-bladder | 2022 | TURBT |
| 3 | 49 | F | Granulocytic sarcoma | 2023 | HMA | Adenoca gallbladder | 2023 | ----- |
| 4. | 73 | M | Essential thrombocythemia | 2022 | HU, Aspirin | Papillary renal cell Ca | 2022 | Right nephrectomy |
| 5. | 71 | M | DLBCL | 2024 | R-CHOP | NSCLC | 2024 | Paclitaxel+ carboplatin |
HMA: Hypomethylating agent; RT: Radiotherapy; TURBT: Trans urethral resection of bladder tumor; HU: Hydroxyurea; DLBCL: Diffuse large B cell lymphoma; R-CHOP: Rituximab cyclophosphamide, doxorubicin vincristine prednisone, NSCLC: Non-small cell lung carcinoma, dx-diagnosis, AML: Acute myeloid leukemia, Ca: Carcinoma.
CASE SERIES
Case 1: Therapy-related myelodysplastic neoplasm (MDN) in a follow-up case of ductal carcinoma of the left breast
A 73-year-old hypertensive female, known case of invasive ductal carcinoma of left breast (pT2 N2 M0), presented with anemia, generalized weakness, and breathlessness for 2 months from November 2023
She was administered six cycles of adjuvant chemotherapy (fluorouracil, epirubicin, and cyclophosphamide) and radiation (40 Gy in 15 fractions). Her radiation and chemotherapy was completed on 13/8/16.
Hematological workup and ancillary testing eventually led to the diagnosis of MDN. Bone marrow was hypercellular with erythroid hyperplasia with dyserythropoesis and dysmegakaryopoesis. [Figure 1] Cytogenetics showed a complex karytotype. She has received 10 cycles of azacitidine so far uneventfully.
- Erythroid dysplasia in bone marrow at × 100 magnification. (Leishman-Giemsa). The dyspoietic erythroid precursors are shown with arrows.
- Dysmegakaryopoesis in bone marrow at ×100 magnification (Leishman-Giemsa). A dyspoietic hypolobated megakaryocyte is shown with an arrow.
Case 2: Metachronous urothelial carcinoma and acute myeloid leukemia (AML)
A 76-year-old male presented with fever, sternal tenderness, respiratory distress, and severe pancytopenia in January 2024. He is a known case of hypertension, chronic kidney disease (CKD), and post-renal transplant. He was diagnosed with a high-grade urothelial carcinoma of the bladder [Figure 2a and b] and underwent trans-urethral resection of bladder tumor (TURBT) in June 2022 with regular cystoscopic follow-up. He received no chemotherapy or immunotherapy. His bone marrow had 56% myeloid blasts [Figure 2c], which expressed CD34, HLA-DR, CD13, CD33, CD64, and CD19. Cytogenetic analysis revealed trisomy 16. He had received a short course (3 days) of inj Azacitidine. He gradually deteriorated and was shifted to the ICU. Culture done from the endotracheal suction sample showed the growth of Acinetobacter baumannii, and he ultimately succumbed to septic shock.
- Urothelial carcinoma (non myoinvasive) at ×10 (Hematoxylin and Eosin Stain). The malignant epithelial cells are invading the subepithelial tissue.
- Urothelial carcinoma at ×40 (Hematoxylin and Eosin Stain). The malignant cells have hyperchromatic nuclei and moderate amount of cytoplasm.
- Bone marrow showing myeloid blasts(arrow) at × 100 magnification (Leishman-Giemsa).
Case 3: Synchronous malignancy of granulocytic sarcoma and gallbladder adenocarcinoma
A 49-year-old female presented with a slowly growing, well-defined, mildly tender mass over the lateral aspect of the right knee for 6 months before consulting an oncologist in December, 2023. With a diagnosis of malignant mesenchymal neoplasm from outside, she was admitted for palliative radiotherapy. A repeat trucut biopsy from the thigh, followed by immunohistochemistry (IHC), led to the diagnosis of myeloid sarcoma (MS) (positive for vimentin, CD68, MPO), [Figure 3a and b].
- Myeloid sarcoma at 40× (Haematoxylin and Eosin stain). The undifferentiated cells have pleomorphic nuclei and moderate amount of cytoplasm.
- Tumor cells are CD68 positive ×10 magnification.
Positron emission tomography (PET) scan showed fluro deoxy glucose (FDG) avid a right lower thigh mass encasing the femur and knee joint, and an FDG avid necrotic space occupying lesion (SOL) in the liver with a thickened gallbladder wall. A subsequent biopsy done from the GB mass was consistent with poorly differentiated adenocarcinoma. [Figure 3c] IHC was positive for pan-CK and CK19 [Figure 3d and e].
- Gall bladder adenocarcinoma at 40x Haematoxylin and Eosin stain. The neoplastic cells have pleomorphic hyperchromatic nuclei, irregular nuclear outline and is invading the stroma.
- CK19 in gall bladder adenocarcinoma. Tumor cells are immunopositive for CK19 at 10× magnification.
- Pan CK-positive gall bladder adenocarcinoma at 10× magnification.
Her peripheral blood and bone marrow examination did not reveal any abnormal cell population. She was started on azacitidine, but on Day 16 of the 1st cycle, she developed tachypnea and respiratory distress. Her sputum culture was positive for multidrug resistant (MDR) Klebsiella. She ultimately expired a day later due to septic shock
Case 4: Synchronous malignancy of papillary renal cell carcinoma (RCC) and essential thrombocythemia (ET)
A 73-year-old male, a known smoker, was diagnosed with RCC based on imaging and scheduled for right nephrectomy. During the pre-anesthetic check-up, he was found to have a platelet count of 11 lakhs/cu mm and was referred to the hematology OPD. On further workup up, his bone marrow showed a normocellular picture with megakaryocytic hyperplasia and loose clustering of megakaryocytes, which was consistent with ET. An MPN reflex panel was positive for CAL-R. He was started on hydroxyurea and aspirin. Aspirin was stopped 1 week prior to nephrectomy, and on nephrectomy, he was diagnosed with a papillary RCC. A whole body PET-CT scan had shown he had stage I disease. He is alive and comes for regular follow-up 2 years post-surgery. The patient is still on hydroxyurea and maintains a platelet count in the normal range.
Case 5: Synchronous malignancy of non-small cell lung carcinoma (NSCLC) and diffuse large B-cell lymphoma (DLBCL)
A 71-year-old male had presented to the oncology OPD with complaints of cough with blood-streaked sputum on multiple occasions. On PET-CT scan, an FDG-avid left lung mass (4.8 × 2.5 cm) was seen besides an FDG-enhancing left tonsillar mass measuring 2.1 × 1.8 cm. The lung biopsy [Figure 4a] was suggestive of NSCLC, which on IHC showed strong patchy expression of p40 [Figure 4b]. The tonsillar biopsy was also taken and showed large, atypical cells [Figure 5a] with strong and diffuse expression of CD20 [Figure 5b] and BCL2 [Figure 5c] along with BCL6, MUM1, and C-MYC (>40%). The atypical lymphoid cells were negative for CD10, CD5, P63, and PanCK. A diagnosis of DLBCL (non-GCB type) was also made. So, a final diagnosis of squamous cell carcinoma of the left lung and synchronous DLBCL was made. The patient was initially managed with paclitaxel and carboplatin, after which he was referred to the hematology OPD, where R-CHOP21 was started. He has received six cycles of standard-dose R-CHOP and remains in metabolic remission.
- Non small cell lung carcinoma at 40× magnification (Hematoxylin and Eosin stain). The neoplastic cells are polygonal, have hyperchromatic nuclei and abundant eosinophilic cytoplasm.
- P40 expression in tumor cells ×40 magnification.
- Diffuse large B-cell lymphoma, Hematoxylin and Eosin Stain. The infiltrating lymphoid cells are medium to large in size.
- Immunohistochemitry for CD20 shows tumor cells are immunopositive.
- B-cell lymphoma 2 expression (B-cl2) expression in tumor cells at ×10 magnification.
DISCUSSION
A recent rising incidence of multiple primary malignancies has been observed, which may be attributed to the recent therapeutic and diagnostic improvements. Understanding the different malignant behaviors of solid tumors and hematological malignancies, in addition to the ability to differentiate between them, is crucial for selecting which lesion to biopsy and is also pivotal before treating such complicated conditions. Although it is difficult to diagnose synchronous or metachronous tumors, advanced diagnostic tools such as PET/CT can help suspect and diagnose multiple primary tumors. Each primary tumor should be evaluated individually, and the treatment plan should be tailored to the specific characteristics of each cancer. Among synchronous tumors, the more aggressive ones should be treated first. In case of metachronous tumors, if both tumors are present, the same principle should be applied.
Breast cancer is far more curable than in the past, but it requires a multimodality approach. Therapy-related MDNs are increasing as survival for breast cancer improves. The incidence of therapy-related myeloid neoplasms in breast cancer patients ranges from 0.6 to 1.8%.[4] Breast cancer patients treated with anthracyclines and alkylating agents have a higher risk of developing AML/MDS[4,5] while radiation alone has a modest risk. Great care must be taken to use the least leukemogenic treatment programmes that do not sacrifice efficacy. In case 2, AML occurred 2 years after urothelial cancer and was not associated with any chemotherapy or radiation exposure.
Synchronous MS and gall bladder adenocarcinoma have not been reported before. Isolated MS is a rare entity (2 cases per million).[6] The IHC panel of CD20, CD43, CD68, and MPO is useful for diagnosis.
Optimal treatment for MS is not established, but usually managed with the same regimen as AML, followed by transplant. For elderly and frail patients, hypomethylating agents may be used, but data are sparse. Radiation is an option for single-site disease.
ET is a Philadelphia chromosome negative myeloproliferative neoplasm (MPN) where thrombocytosis and megakaryocytic hyperplasia in the marrow are seen. Approximately 30% of RCC cases are associated with paraneoplastic syndromes, of which thrombocytosis occurs in approximately 20% of cases.[7] Here, however, we have described a case of synchronous RCC and thrombocytosis where the thrombocytosis component is neoplastic and driven by the CAL-R mutation. According to one study, patients with thrombocytosis had more advanced-stage RCC, poorer histopathological features, and rapid disease progression.[8] However, in the present case, the patient had thrombocytosis and stage I RCC.
According to one study, among synchronous tumors, the most common concomitant tumors are DLBCL and NSCLC.[9] Here we have reported one such case. However, according to this study, in 75% of these cases, DLBCL was treated with R-CHOP, and NSCLC appeared in the follow-up period.[7] In our case, NSCLC was diagnosed prior to DLBCL.
CONCLUSION
The diagnosis and management of dual hematological and non-hematological malignancies should be individualized with close follow-up, ancillary testing, and a multidisciplinary coordinated approach.
Author contribution
RA, AS, AK and AM: Involved in the management of clinical cases; DD and SH: Involved in diagnosis of the cases; BB and RA: Involved in preparation and review of the manuscript.
Ethical approval
Institutional Review Board approval is not required.
Declaration of patient consent
Patient's consent not required as patients identity is not disclosed or compromised.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
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