Case Studies in Pathology Compendium of Cases

Introduction -Case Studies in Pathology Compendium of Cases

In this report, there are separate analyses of two rather unique medical conditions. This one is of a 55-year-old teacher, Mr. A with a complaint of fatigue for ‘x’ years, weight loss and gastrointestinal symptoms that could point towards colorectal malignancy. The second case is the 35-year-old male amateur footballer with chronic fatigue, night sweats, leukocytosis and thus a haematological problem – positive for Mr. S. Both cases describe the patient’s clinical history, laboratory findings, diagnoses, and management.

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Case 1: Mr. A

Clinical History and Laboratory Data Analysis

A 55-year-old male teacher with complaints of fatigue leading to lethargy, weight loss, shortness of breath and alteration of bowel habits for six months. These symptoms’ causes are revealed when analysing his clinical history and laboratory data, which are also essential to determining his condition.

Minimal changes in weight loss: Mr A, now weighing 65 kg; has lost about 5 kg of his body weight and has a reduced appetite which when added to the chronic fatigue, points towards a chronic illness. This fact eliminates the cardiac or pulmonary origin of the disease: if a person has a cough, palpitations, or chest pain, the ailment stems from the heart or the lungs. Due to his past medical history of IBS which is controlled with diet and relatively recent alteration in bowel movement pattern characterised by constipation and diarrhoea, a GI problem cannot be ruled out.

The laboratory data indicate significant abnormalities:

• Haemoglobin: 9. 4 g/dL indicative of anaemia was also identified in the case of the patient.
• ESR: 87 mm/h (increased, pointing out a possibility of a chronic inflammatory process or cancer).
• Serum Iron: usually it is less than 7 µmol/L which more appropriately refers to Low.
• Serum Ferritin: The RfD for chromium is 8 µg/L (low).
• Serum Transferrin Saturation: There are transmutation values which are lower than 10% (low).

These findings suggest conditions particular to iron-deficiency anaemia and this is occasioned by chronic blood loss. The high ESR, which is higher than what has been observed in the previously admitted patients, also adds to inflammation or malignancy.

The colonoscopy findings include an annular tumour mass at the sigmoid colon level with two ulcers and a polyp in the close vicinity. There is marked enlargement of the tumour mass likely to be a colorectal carcinoma (CRC), a frequent source of chronic gastrointestinal blood loss with consequent iron deficiency anaemia. The presence of the ulcers and the polyp may hinder normal stool passing and may cause the observed changes in bowel movement patterns by bleeding at intervals.

Figure 1: Schematic illustration of the main mechanisms contributing to anemia

(Source: https://www.researchgate.net/)

Anaemia Development

Surgical excision of the carcinoma and postoperative blood transfusion results in improved patient survival with less bleeding in Mr. A who suffers from anaemia attributed to chronic blood loss from a CRC. This is evidenced by his clinical history, laboratory findings as well as colonoscopy of the patient.

Ida is by far the most frequent type of anaemia linked to chronic blood loss, which is mostly from the GI tract. In the case of the patient Mr A, he underwent a colonoscopy test and was noted to have an annular tumour mass in the sigmoid colon and this is a probable cause of chronic blood loss (Tiwary, Shah, Madke, & Kumar, 2021). Tumours of the GI tract may cause minor erosion of blood vessels, and thus cause haemorrhage which may be intermittent or continuous. Gradually, this results in the house loss of iron in the body, hence developing an illness known as adenoids or iron-deficiency anaemia.

Sticking to laboratory data, one can make this diagnosis. In regard to the blood test results, the haemoglobin level is 9 for the patient, Mr. A. 4 g/dL; this puts him well below the normal status and, therefore, a candidate for anaemia (Jajosky et al. 2021). His serum iron is 7 µmol/L, and serum ferritin is < 8 µg/L, which are very low figures meaning the patient has depleted iron stores. Serum transferrin saturation is less than 10%, and so increases support for iron deficiency. An ESR of 87 mm/h signifies a raised inflammatory activity and the presence of a surplus amount of globulins in the blood contributing to malignancies including CRC.

Also, the existence of ulcers and the observed polyp in the vicinity of the tumour mass can cause periodic GI bleeding, thus increasing iron deficiency and anaemia. While it is commendable that the subject, Mr A, learned how to deal with his IBS through his diet, it is clear that the worsening of bowel habits in cycles of constipation interspersed by diarrhoea is due to the worsening of the malignancy.

Significance of Colonoscopy Findings

The sigmoidoscopy results of polyps and ulcers of the sigmoid colon in Mr A are the signs of the worse condition in the colon and GI pathophysiology.

Polyps

Colorectal polyps are therefore issues whereby there is a formation of tissue on the inside lining of the colon and rectum. Although polyps are not malignant when developing into CRC, it is essential to know that they are precancerous. The adenoma-car crib neoplasia sequence relates to the developmental process of adenomatous polyps to carcinoma. This might imply that polyps compared and located close to Mr A’s tumour mass may have undergone or are undergoing dysplastic changes contributing to CRC (Riggioni et al. 2020). Eradicating the polyps is important, particularly if colonoscopy Surgery is to be undertaken since it may be the only time when the polyps are eliminated before they develop into cancer.

Ulcers

Thus, ulcers in the colon mean mucosal erosion, and its cause may include chronic inflammation, infection, or malignancy. Looking at colorectal carcinoma in particular, it should be noted that ulcers can be a manifestation of the tumour’s ability to penetrate the surrounding tissue and lead to local ischemia and bleeding (Billroth, 2022). Turbulence is significant as it accounts for the appearance of ulcers which accord with Mr. A’s symptoms of chronic blood loss leading to iron-deficiency anaemia. Sulphurated tumours mainly signify a more progressed disease, often ulcerated, as the suggests.

Clinical Implications

The existence of polyps at the same anatomical regions as ulcers and the mass tumour indicates the gravity of Mr A’s condition. The polyps throw light on the possibilities of an existing or coexisting precancerous state, and the ulcers brought about the visible mucosal injuries and bleeding which played a role in his anaemia. Such data require multidisciplinary oncological examination in order to evaluate the stage of the disease and the management required.

Management

Addressing the polyps and ulcers involves:

Surgical Resection: To cease bleeding, the surgeon has to also excise the whole tumour mass and the polyps, as well as the ulcerated areas to minimize the chances of cancer.

Histopathological Examination: Histological examination of the resected polyps and ulcers to know the degree of dysplasia or malignancy (Hassell et al. 2023).

Adjuvant Therapy: Chemotherapy or radiotherapy according to TNM staging and Histopathological examination.

Based on these results, the presence of colonic polyps close to Mr A’s tumour mass implies that these structures may have either undergone or are in the process of undergoing dysplastic alteration in the context of the development of CRC.

Figure 2: The inflammatory pathogenesis of colorectal cancer

(Source: https://www.nature.com/)

Management Strategies

Mr. A’s management plan for colorectal carcinoma (CRC) and associated complications should be comprehensive:

Surgical Intervention: Mr. A should be advised for colectomy to have the annular tumour mass in the sigmoid colon removed as well as any of the polyps and ulcers existing. This surgery is performed with the objective of removing the tumour for further unfavourable consequences based on the tumour’s stage and position.

Histopathological Examination: Histopathological examination of the resected tumour, polyps, and ulcers must be done after the surgery is complete. This will assist in grading the tumour, staging the cancer and assessing the margins and whether a tumour has spread to the lymph nodes or has metastasized.

Adjuvant Therapy: Histopathological findings in this case may suggest that, despite the corresponding alternate therapies, Mr. A may require the following treatments;

Chemotherapy: It was for the eradication of residual cancer cells so as to minimize the chances of recurrence with the help of agents such as fluorouracil, leucovorin and oxaliplatin (Lin et al. 2021).

Radiotherapy: This may be used for local invasion or as an advanced disease palliative measure.

Monitoring: Combined with other blood tests to monitor the haemoglobin and iron status of the patients.

Psychosocial Support:

Counselling: Care of the mind in terms of being able to handle the diagnosis and the treatment.

Support Groups: Engaging with other people who are going through similar cancer experiences for emotional and social interaction.

This has constructed a care plan that stresses interprofessional and aims at enhancing the overall touch to improve the prognosis of the health of Mr A.

Case 2: Mr. S

Analysis of Symptoms and Laboratory Results

a 35-year-old M with chronic fatigue, night sweats, left upper quadrant pain sometimes and splenomegaly. The patient had laboratory findings which deviated from the normal range and included a WBC count of 12, platelets count of 407, LDH 685 U/L, urate 0.51 mmol/L and white cell precursors in the blood film. These propositions indicate the existence of a haematologic disease that is wholly probably haematologic malignancy by genesis and most likely leukaemia.

Possible Explanations:

Chronic Myeloid Leukemia (CML)

Reasoning: There is an increased WBC count with a total count of 54 x 10^9/ L and the blood film reveals immature white cell precursors like metamyelocytes, myelocytes and promyelocytes which are pathognomic of a myeloproliferative disorder. CML is distinct by the growth of frequently myeloid cells in the bone marrow as well as their abnormal issue into the blood (Cyrta et al. 2022). The LDH level was high at 810 IU/L while urate was 634 µmol/L; this can be attributed to CML since the disease involves the increased rate of cellular turnover due to the rapid proliferation of cells and their death.

Splenomegaly: Splenomegaly is frequently experiential in patients with CML due to hypersplenism and extra-medullary hematopoiesis where the spleen stores the enlarged and abnormal cells of blood.

Ruling Out Other Causes: The cytogenetic analysis that stages confirm CML is the presence of the t(9;22) translocation or Philadelphia chromosome, which occurs in every patient with this disease. It increases the production of the BCR-ABL fusion protein, which causes the continuous growth of myeloid cells.

Other Myeloproliferative Neoplasms (MPNs)

Reasoning: Although not as likely considering the specificities of the case, other MPN could be polycythemia vera, essential thrombocythemia or primary myelofibrosis may involve splenomegaly and high RBC counts (Ajileye & Adeyemi, 2020). Besides the ultimate conditions usually accumulates dissimilar specificities and clinical appearances.

Ruling Out: The fact that the Philadelphia chromosome was present and specific blood film characteristics made the likelihood of CML much higher as compared with the other types of MPNs.

Figure 3: Mechanisms of BCR–ABL in the pathogenesis of chronic myelogenous leukaemia

(Source: https://www.nature.com)

Specific Diagnosis and Underlying Pathology

By noting the patient’s clinical examination and positive cytogenetic testing, Mr. S is diagnosed with Chronic Myeloid Leukemia (CML). The final diagnosis can only be arrived at when the PHP, caused by a t(9;22) translocation, is detected.

Underlying Pathology:

CML is a clonal MPD which is described by unbridled multiplication of myeloid cells. In this disease, as in other myeloproliferative disorders, CML has a molecular marker known as the Philadelphia chromosome which was detected as a consequence of reciprocal translocation between chromosomes 9 and 22 [t(9;22)]. This translocation forms the BCR-ABL hybrid gene which encodes for an oncogenic constitutively active tyrosine kinase (Oliveira, 2020). The BCR-ABL oncoprotein causes uncontrolled differentiation of myeloid progenitor cells in the bone marrow and prevents apoptosis resulting in peripheral blood myeloid immature cells.

Pathophysiology and Symptoms:

Fatigue: Due to the frequent replacement of myeloid cells and quick production of immature cells, the patient is turned into a hypermetabolic state, therefore, the patient experiences fatigue. Also, the attack of an increased number of pathological cells can overpower the production of healthy blood cells and source systemic properties.

Night Sweats: The presence of night sweats in patients with CML can be attributed to the overall metabolism and cytokine produced from the several transformations (Reddy et al. 2021).

Splenomegaly: It thus hypertrophies and causes discomfort to the body due to its function of alternately performing the responsibilities of bone marrow, through the process of extramedullary hematopoiesis, which helps accommodate the large production of these abnormally formed blood cells.

Abnormal Blood Counts:

Elevated WBC Count: These increase the production of myeloid cells causing leukocytosis.

LDH and Urate Levels: These are raised since there is increased turnover of leukemic cells hence increased cellular degradation resulting in high levels of the enzymes – LDH and higher levels of uric acid (urate).

Initial Treatment and Resistance:

Mr. S received his first line of treatment with Imatinib (Gleevec) which is a tyrosine kinase inhibitor (TKI) that works on the BCR-ABL fusion protein. CURED combines their approaches and Gleevec is effective in many patients who, of course, develop resistance.

Mechanisms of resistance include:

BCR-ABL Mutations: There are mutations within the Gleevec kinase domain that interfere with the binding of the drug resulting in ineffective therapy.

BCR-ABL Gene Amplification: This can be by increasing the levels of the BCR-ABL gene that overpowers the inhibitory effects of Gleevec (Amin & Tickoo, 2022).

Alternative Treatments

For resistance to Gleevec, second-generation and third-generation TKI’s that is dasatinib, nilotinib, and ponatinib are considered. It results from this that these inhibitors have various binding characteristics and can neutralize most of the Gleevec resistance mutations. TKIs have proven highly effective in the treatment of chronic myeloid leukaemia with indicated that patients who do not benefit from TKIs can opt for allogeneic stem cell transplantation akin to a cure.

Treatment and Prognosis

Treatment for Chronic Myeloid Leukemia (CML) and Gleevec Resistance

CML is mainly managed by TKIs; the first-line drug is Imatinib (Gleevec). Imatinib is a drug that targets tyrosine kinase associated with the Philadelphia chromosome translocation of BCR-ABL. Since Imatinib can interact with the ATP-binding site of BCR-ABL and inhibit its kinase activity the growth of leukemic cells is slowed down.

However, resistance to Imatinib can develop through several mechanisms:

1. BCR-ABL Mutations: Substitutions in the BCR-ABL kinase domain can switch the binding of Imatinib and the T315I mutation is one of the biggest offenders.
2. BCR-ABL Gene Amplification: Higher BCR-ABL levels favour the presence of the oncoprotein over Imatinib’s ability to neutralize it efficiently (Amin et al. 2021).
3. Drug Efflux: Imatinib can also be pumped out of the cells by efflux transporters such as P-Glycoprotein and therefore, this can lead to low intracellular concentrations hence, resistance.
4. Alternative Signaling Pathways: The growth and survival of leukemic cells can therefore be supported by pathways other than BCR-ABL.

When Imatinib resistance occurs, alternative treatments are considered:

1. Second-Generation TKIs:

Dasatinib (Sprycel): Active against most BCR-ABL clones except T315I.

Nilotinib (Tasigna): Inclusive of several Imatinib-resistant mutations.

Bosutinib (Bosulif): Potent against various BCR-ABL conformations and for patients with intolerance to other members of the TKIs class (Colvin, Chang, & Cornell, 2023).

2. Third-Generation TKIs:

Ponatinib (Iclusig): Described as designed to attack specifically the T315I and other resistant forms.

3. Allogeneic Stem Cell Transplantation: Provides a cure to patients who do not respond to TKIs. This is done through harvesting healthy marrow from a donor; however, this process is motivated with potential complications, for instance, graft-versus-host disease.
4. Investigational Therapies:

Asciminib: In addition, there is an Allosteric BCR-ABL inhibitor with better prospects, especially in the case of T315I mutation.

However, although most patients with CML developed resistance to Gleevec, the outlook for this disease is relatively good with the newer TKIs and constant evaluation (Ilgren, 2020). It is possible to say that Mr. S can have lasting remission and a good quality of life if he and his attending physician adjust the therapy and have a close follow-up.

Figure 4: Mechanisms of imatinib resistance in CML

(Source: https://www.researchgate.net/)

Conclusion

The case includes chronic myeloid leukaemia (CML) in Mr S and recurrent colorectal cancer in Mr. A both of which pose clinical concerns. Driven by enhanced diagnostic methods and individualistic therapies such as TKIs in CML or surgical novelties and oncological approaches in CRC, patients’ statuses consequently evolve. These diseases permit constant reviewing and adjusting of their management, which will improve the patient’s quality of life and outcome.

Reference list

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