Decreasing Histology Turnaround Time Through Stepwise Innovation and
Capacity Building in Rwanda
A staggering fact that has become apparent to all sectors (including funders) is
that, as of 2012, deaths resulting from cancer worldwide had exceeded those
resulting from HIV/AIDS, tuberculosis, and malaria combined. Current reports of cancer incidence,
prevalence, morbidity, and mortality demonstrate that the largest burden of this
disease is found in low- and middle-income countries (LMICs), particularly in
sub-Saharan Africa. In a 2011 WHO report, projections for global cancer incidence
and mortality between now and 2030 show increases of 65% (85% in Africa) and 71%,
respectively, with more than 70% of this total burden falling on LMICs. , In spite of this, only 5% of global oncology resources are spent
in LMICs. , A pathologic diagnosis is a critical requirement to treat any patient with cancer,
regardless of geography or economy. , Without an accurate
diagnosis, treatment plans that will optimize the chance for a good outcome cannot
be designed. Worse, if a patient is treated with chemotherapy or radiation therapy
for the wrong diagnosis, there is a risk of exposing the patient to toxicity without
a chance for cure. In the spectrum of cancer care, there are five components
relevant to patient care, involving specimen procurement, processes, report
delivery, and initiation of care . Although all of
these components are critical to the timely and effective treatment of patients with
cancer, we chose to focus on those under control of the treating physicians and
pathology laboratory. Specifically, we measured time from biopsy to creation of the
pathology report. Other factors can cause delay in diagnosis, including when a
patient decides to seek care and time from initial clinical evaluation to
performance of the biopsy. Once the clinician receives the results, they must still
be transmitted to the patient, and a treatment plan must be developed and treatment
initiated. In the best-case scenario, an optimized medical system can complete this
process in a few days, and therapy can begin in a timely fashion. However, in many
existing systems in LMICs, segments of this process can be greatly delayed for a
broad range of reasons. Importantly, the first segment relies heavily on patient education and community
engagement; however, the remaining steps fall to the medical system itself to
improve and optimize, which includes development of a sustainable workforce,
guaranteed supply chains for consumables, and modern systems for patient and
laboratory information processing. , In LMICs, diagnostic delays can have
exponential implications because patients often initially present with advanced
disease. Without optimized diagnostic and medical systems in place, patients will
start their treatments with more-advanced disease and poorer prognoses than at
initial presentation. Currently, there is limited turnaround time (TAT) data
available from LMICs; however, typically TATs are longer than what is considered
appropriate in high-income countries. As an integral part of the Butaro Cancer Center of Excellence (BCCOE), the pathology
laboratory was opened in July 2012 and subsequently underwent an iterative
development, progressively implementing key components of the process to enhance the
cancer diagnostics of BCCOE. Before the opening of this laboratory, TAT in this
setting could be measured in months because of inconsistent laboratory operations
and a paucity of in-country pathologists. The goal of this study was to determine the TATs for anatomic pathology specimens
during the implementation and progressive development of our pathology laboratory at
BCCOE in Rwanda. 

Setting BCCOE is located in rural, northern Rwanda near the Ugandan border, managed by
the Ministry of Health with the support of Partners In Health/Inshuti Mu Buzima,
and provides clinical and hospital services to a catchment area of 336,455
people, as well as
serving as a national referral center for cancer care. With the opening of this
facility, a pathology laboratory was put in place, but there was no pathologist
on site. From 2012 to 2017,
this site evolved to now include full-service automated histology and
immunohistochemistry (IHC) capabilities, an onsite pathologist, and static-image
and whole-slide imaging telepathology systems connecting the site to 15 expert
pathologists in the United States and Europe. Study Design This was a retrospective study comparing TATs across three different diagnostic
work streams that occurred during the pathology laboratory implementation at
BCCOE. TAT for each diagnostic method was defined as the number of days between
the date of the biopsy procedure and the date the finalized pathology report was
generated . This study relied on
data from 2013 through 2015, during the iterative development of diagnostic
processes including the initial use of remote diagnostics and static-image
telepathology and periodic onsite visiting pathologists. It is important to note that these work streams do not represent a specific
chronology or set duration of time. Instead, each work stream corresponds to a
specific mode by which one can obtain a diagnosis, and work-stream development
was iterative, not linear. Thus, the analyses are specific to each work stream
or diagnostic mode rather than a particular time period. The diagnostic modes
include: Diagnostic mode 1. Tissue blocks and slides were generated in Butaro and then physically
transported to Brigham and Women’s Hospital (BWH) in Boston,
Massachusetts, for evaluation and diagnosis. Diagnostic mode 2. Static images of slides prepared in Butaro by histotechnicians were uploaded
to case-sharing software/platform (iPath; https://www.ncbi.nlm.nih.gov/pubmed/16375782 ) and evaluated
and diagnosed remotely by pathologists at BWH. Diagnostic mode 3. Pathologists diagnosed patients on site at BCCOE through periodic visiting
pathologists from the United States and Kigali. Some samples were originally read through iPath, but because of a lack of
diagnostic certainty, they were shipped to BWH for an additional evaluation.
These patient cases were considered to be part of mode 1 and deleted from
the mode 2 data. Outliers were defined as any TAT longer than 1 year and any
mode 1 TAT shorter than 5 days; these were excluded from further analysis. As part of this iterative implementation approach, IHC, which is required for
certain final diagnoses, was implemented in Butaro in 2014 and was made
available throughout each diagnostic mode, occurring in either Boston or
Butaro. Data Collection and Analysis Data were compiled from BCCOE and BWH to create one data set of all patient cases
from January 1, 2013, to December 31, 2015. Samples from 2012 were excluded
because of inconsistent recordkeeping during the early operation of BCCOE. Only
samples from biopsies performed at BCCOE were included in analysis. Samples that
were received as fresh tissue, fixed tissue, or blocks/slides from other Rwandan
institutions were excluded because of the uncertainty of events and timeline
before arrival at BCCOE. Statistical analysis was conducted with Microsoft Excel and STATA software
(version 13; College Station, TX). Individual TAT was calculated for each
patient sample, followed by the median TAT and interquartile range (IQR) for
each year and diagnostic mode. A Kruskal-Wallis test was conducted to compare and assess statistical difference
among the TATs across all three modes. A nonparametric test for trend was
performed to test for a trend among the three diagnostic modes. Ethical Considerations This study was approved by the Rwandan National Ethics Committee, BWH
Institutional Review Board, and Inshuti Mu Buzima Research Committee. 

BCCOE is located in rural, northern Rwanda near the Ugandan border, managed by
the Ministry of Health with the support of Partners In Health/Inshuti Mu Buzima,
and provides clinical and hospital services to a catchment area of 336,455
people, as well as
serving as a national referral center for cancer care. With the opening of this
facility, a pathology laboratory was put in place, but there was no pathologist
on site. From 2012 to 2017,
this site evolved to now include full-service automated histology and
immunohistochemistry (IHC) capabilities, an onsite pathologist, and static-image
and whole-slide imaging telepathology systems connecting the site to 15 expert
pathologists in the United States and Europe. 

This was a retrospective study comparing TATs across three different diagnostic
work streams that occurred during the pathology laboratory implementation at
BCCOE. TAT for each diagnostic method was defined as the number of days between
the date of the biopsy procedure and the date the finalized pathology report was
generated . This study relied on
data from 2013 through 2015, during the iterative development of diagnostic
processes including the initial use of remote diagnostics and static-image
telepathology and periodic onsite visiting pathologists. It is important to note that these work streams do not represent a specific
chronology or set duration of time. Instead, each work stream corresponds to a
specific mode by which one can obtain a diagnosis, and work-stream development
was iterative, not linear. Thus, the analyses are specific to each work stream
or diagnostic mode rather than a particular time period. The diagnostic modes
include: Diagnostic mode 1. Tissue blocks and slides were generated in Butaro and then physically
transported to Brigham and Women’s Hospital (BWH) in Boston,
Massachusetts, for evaluation and diagnosis. Diagnostic mode 2. Static images of slides prepared in Butaro by histotechnicians were uploaded
to case-sharing software/platform (iPath; https://www.ncbi.nlm.nih.gov/pubmed/16375782 ) and evaluated
and diagnosed remotely by pathologists at BWH. Diagnostic mode 3. Pathologists diagnosed patients on site at BCCOE through periodic visiting
pathologists from the United States and Kigali. Some samples were originally read through iPath, but because of a lack of
diagnostic certainty, they were shipped to BWH for an additional evaluation.
These patient cases were considered to be part of mode 1 and deleted from
the mode 2 data. Outliers were defined as any TAT longer than 1 year and any
mode 1 TAT shorter than 5 days; these were excluded from further analysis. As part of this iterative implementation approach, IHC, which is required for
certain final diagnoses, was implemented in Butaro in 2014 and was made
available throughout each diagnostic mode, occurring in either Boston or
Butaro. 

Tissue blocks and slides were generated in Butaro and then physically
transported to Brigham and Women’s Hospital (BWH) in Boston,
Massachusetts, for evaluation and diagnosis. 

Static images of slides prepared in Butaro by histotechnicians were uploaded
to case-sharing software/platform (iPath; https://www.ncbi.nlm.nih.gov/pubmed/16375782 ) and evaluated
and diagnosed remotely by pathologists at BWH. 

Pathologists diagnosed patients on site at BCCOE through periodic visiting
pathologists from the United States and Kigali. Some samples were originally read through iPath, but because of a lack of
diagnostic certainty, they were shipped to BWH for an additional evaluation.
These patient cases were considered to be part of mode 1 and deleted from
the mode 2 data. Outliers were defined as any TAT longer than 1 year and any
mode 1 TAT shorter than 5 days; these were excluded from further analysis. As part of this iterative implementation approach, IHC, which is required for
certain final diagnoses, was implemented in Butaro in 2014 and was made
available throughout each diagnostic mode, occurring in either Boston or
Butaro. 

Data were compiled from BCCOE and BWH to create one data set of all patient cases
from January 1, 2013, to December 31, 2015. Samples from 2012 were excluded
because of inconsistent recordkeeping during the early operation of BCCOE. Only
samples from biopsies performed at BCCOE were included in analysis. Samples that
were received as fresh tissue, fixed tissue, or blocks/slides from other Rwandan
institutions were excluded because of the uncertainty of events and timeline
before arrival at BCCOE. Statistical analysis was conducted with Microsoft Excel and STATA software
(version 13; College Station, TX). Individual TAT was calculated for each
patient sample, followed by the median TAT and interquartile range (IQR) for
each year and diagnostic mode. A Kruskal-Wallis test was conducted to compare and assess statistical difference
among the TATs across all three modes. A nonparametric test for trend was
performed to test for a trend among the three diagnostic modes. 

This study was approved by the Rwandan National Ethics Committee, BWH
Institutional Review Board, and Inshuti Mu Buzima Research Committee. 

We originally identified 3,725 individual patient samples across the three phases of
study and removed 211 (57 duplicates, 139 with either a missing biopsy or diagnosis
date, and 15 outliers, all from mode 1); the final number of samples included in the
analysis was 3,514. During the given time period, diagnostic mode 1 accounted for
2,695 patient samples, diagnostic mode 2 for 279, and diagnostic mode 3 for 540
. Mode 1 had the highest total
median TAT at 30 days (IQR, 22 to 43 days). For mode 2, the median TAT was 14 days
(IQR, 7 to 27 days), and for mode 3, it was 5 days (IQR, 2 to 9 days; ). A Kruskal-Wallis test showed a statistically significant difference in median TATs
across the three diagnostic modes (χ 2 with ties = 1,378.78; P < .001). A nonparametric test for trend was significant
( P < .001), demonstrating a significant decreasing trend in
TAT across the three diagnostic modes . 

Ensuring accurate and timely pathology diagnoses is an essential component to cancer
care in LMICs and remains an implementation challenge. Our experience demonstrates
that developing pathology services is an iterative and ongoing process. Through
evolving stepwise implementation using the diagnostic modes noted here, pathology
diagnostic capacity on site in LMICs can sustainably increase, while simultaneously
decreasing TAT from obtaining of a biopsy to diagnosis. In 2012, trained histotechnicians initiated pathology services at BCCOE, such that
tissue blocks and hematoxylin and eosin–stained slides were produced in a
timely fashion. Diagnostic mode 1 was used in the absence of an onsite pathologist
as an interim step so as to have reliable pathology while waiting for the
availability of a trained pathologist on site. The primary delays that increased TAT
were moving the samples from Butaro to Boston. The delays in this process were
inconsistent, and the logistic challenges of this movement preceded the samples
being received in Boston, where subsequently they were processed the same as routine
BWH samples (data not shown). At the time, there were no neighboring countries with
reliable, time-efficient pathology that had the capacity to accept the number of
samples produced at BCCOE, and transport of material to either neighboring countries
or the United States by mail or special carrier was unreliable. Therefore, samples
were often carried to BWH in the United States by BCCOE travelers to assure their
safe arrival. It was also not clear that samples could be shipped more quickly to a
neighboring country than to the United States. Elimination of these logistic challenges through diagnostic modes 2 and 3 has had the
most impact on TAT. Investments in shipment demonstrated a more consistent means for
transport and reception of samples; samples were delivered via weekly air shipments
to Boston rather than carried by ad hoc travelers. Despite these improvements,
delays in country were spread across technical and professional areas but were more
consistent than those in diagnostic mode 1. Overall, we would recommend moving to
complete in-country processing as quickly as possible during implementation because
of the logistic challenges of moving samples from a location like Rwanda to a
developed country like the United States. Informal discussions among clinicians at BCCOE have emphasized the need for as short
a TAT as possible. Urgency of treatment initiation varies by disease, but all
patients with cancer should start treatment as soon as possible for both physical
and emotional reasons. Some circumstances, such as mediastinal lymphoma with
compromise of chest structures and vasculature, are near emergencies regarding
accurate diagnosis and treatment initiation. In general, a TAT of 5 days meets the
needs of most patients; however, reducing this to 3 days, a common standard in the
United States, would be ideal. In LMICs, many pathology laboratories are staffed solely with histotechnicians;
trained onsite pathologists may be absent or overburdened. It will also be years
before there are an adequate number of trained pathologists in many countries in
sub-Saharan Africa and similar sites. In an effort to fill this void, visiting
short-term pathologists from abroad staffed our laboratory periodically. This did
not replace the need for full-time pathologists but instead, taken together,
demonstrated a dramatic effect on the rate of diagnoses. However, this was not a
consistent approach, because pathologists were only on site intermittently. In
addition, part-time Rwandan pathologists were hired to diagnose patients on site in
Butaro. Although evaluation of patient cases was able to occur on site, this did not
provide enough capacity to provide timely and accurate diagnoses for all
patients. Static-image telepathology (diagnostic mode 2), however, allowed for remote diagnoses
to occur before pathologists were available full time on site. In the absence of a
pathologist, technical staff were trained and outfitted with a photography protocol
and system for collecting results using this static-imaging system. Implementation
of this telepathology triage system was brought online in a phased approach to both
train staff and optimize workflow from image upload to reception of results.
Static-image diagnoses were compiled and compared with those made based on standard
glass-slide histology, demonstrating a greater than 95% concordance rate. Although it is a more consistent
method and a means of bridging the human resource gap, static-image telepathology
was initiated at BCCOE only as an interim supplemental step. A full-time pathologist
was hired in 2016, and additional analysis of TAT will be needed to fully understand
the impact of this. The data presented here do not include a breakdown of diagnosis by disease, but a
majority of these patient cases were breast cancer. IHC is critical to many
diagnoses and is essential to subsequent treatment decisions for patients with
breast cancer. Determination of hormone receptor status of patients with breast
cancer directly affects treatment choice and was part of the first set of IHC tests
implemented on site at BCCOE. Before bringing IHC on site (now read via either
telepathology or onsite pathology), all patient cases requiring IHC had to be sent
to Boston. Incidence of breast cancer in LMICs is high, and additional analysis will
be needed to better understand the impact of IHC on TAT for these patients. IHC was
implemented at BCCOE in 2014; however, full analyses have not yet been performed to
understand its overall impact on TAT for this factor alone. In 2016, fully automated
histology and a whole-slide imaging system for enhanced telepathology were also
installed, and their impacts are being evaluated, as are cost implications. It is important to note that only developments in the preanalytic, analytic, and
postanalytic phases of the pathology process are examined here. It is also critical
for efficient and timely evaluation and scheduling of tissue acquisition to be
routine in these environments, which is often not the case in Rwanda or elsewhere,
and for initiation of treatment after the pathology report is received by the
clinician to be efficient as well. We believe the stepwise implementation of the pathology laboratory at BCCOE offers a
sustainable model for scaling up capacity where both human and laboratory resources
are constrained. Going forward, it will be critical to continue to measure TAT to
assure sustainability and to explore more ways to improve pathology processes. 

